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Sample records for human disease-associated haplotypes

  1. Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history.

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    James A Traherne

    2006-01-01

    Full Text Available The major histocompatibility complex (MHC is recognised as one of the most important genetic regions in relation to common human disease. Advancement in identification of MHC genes that confer susceptibility to disease requires greater knowledge of sequence variation across the complex. Highly duplicated and polymorphic regions of the human genome such as the MHC are, however, somewhat refractory to some whole-genome analysis methods. To address this issue, we are employing a bacterial artificial chromosome (BAC cloning strategy to sequence entire MHC haplotypes from consanguineous cell lines as part of the MHC Haplotype Project. Here we present 4.25 Mb of the human haplotype QBL (HLA-A26-B18-Cw5-DR3-DQ2 and compare it with the MHC reference haplotype and with a second haplotype, COX (HLA-A1-B8-Cw7-DR3-DQ2, that shares the same HLA-DRB1, -DQA1, and -DQB1 alleles. We have defined the complete gene, splice variant, and sequence variation contents of all three haplotypes, comprising over 259 annotated loci and over 20,000 single nucleotide polymorphisms (SNPs. Certain coding sequences vary significantly between different haplotypes, making them candidates for functional and disease-association studies. Analysis of the two DR3 haplotypes allowed delineation of the shared sequence between two HLA class II-related haplotypes differing in disease associations and the identification of at least one of the sites that mediated the original recombination event. The levels of variation across the MHC were similar to those seen for other HLA-disparate haplotypes, except for a 158-kb segment that contained the HLA-DRB1, -DQA1, and -DQB1 genes and showed very limited polymorphism compatible with identity-by-descent and relatively recent common ancestry (<3,400 generations. These results indicate that the differential disease associations of these two DR3 haplotypes are due to sequence variation outside this central 158-kb segment, and that shuffling of

  2. Kullback-Leibler divergence for detection of rare haplotype common disease association.

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    Lin, Shili

    2015-11-01

    Rare haplotypes may tag rare causal variants of common diseases; hence, detection of such rare haplotypes may also contribute to our understanding of complex disease etiology. Because rare haplotypes frequently result from common single-nucleotide polymorphisms (SNPs), focusing on rare haplotypes is much more economical compared with using rare single-nucleotide variants (SNVs) from sequencing, as SNPs are available and 'free' from already amassed genome-wide studies. Further, associated haplotypes may shed light on the underlying disease causal mechanism, a feat unmatched by SNV-based collapsing methods. In recent years, data mining approaches have been adapted to detect rare haplotype association. However, as they rely on an assumed underlying disease model and require the specification of a null haplotype, results can be erroneous if such assumptions are violated. In this paper, we present a haplotype association method based on Kullback-Leibler divergence (hapKL) for case-control samples. The idea is to compare haplotype frequencies for the cases versus the controls by computing symmetrical divergence measures. An important property of such measures is that both the frequencies and logarithms of the frequencies contribute in parallel, thus balancing the contributions from rare and common, and accommodating both deleterious and protective, haplotypes. A simulation study under various scenarios shows that hapKL has well-controlled type I error rates and good power compared with existing data mining methods. Application of hapKL to age-related macular degeneration (AMD) shows a strong association of the complement factor H (CFH) gene with AMD, identifying several individual rare haplotypes with strong signals.

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

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    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.

  4. 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-genome...... 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...... 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...

  5. In Vivo Characterization of Human APOA5 Haplotypes

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    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. Transgenic mice with -6A haplotype of the human angiotensinogen gene have increased blood pressure compared with -6G haplotype.

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    Jain, Sudhir; Tillinger, Andrej; Mopidevi, Brahmaraju; Pandey, Varunkumar G; Chauhan, Chetankumar K; Fiering, Steven N; Warming, Soren; Kumar, Ashok

    2010-12-24

    Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at -6, and the -6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with -6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with -6G. We have found that the hAGT gene has three additional SNPs (A/G at -1670, C/G at -1562, and T/G at -1561). Variants -1670A, -1562C, and -1561T almost always occur with -6A, and variants -1670G, -1562G, and -1561G almost always occur with -6G. Therefore, the hAGT gene may be subdivided into either -6A or -6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with -6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with -6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the -6A or -6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing -6A haplotype. Our studies also show that transgenic mice containing -6A haplotype have increased plasma AGT level and increased blood pressure as compared with -6G haplotype. Our studies explain the molecular mechanism involved in association of the -6A allele of the hAGT gene with hypertension.

  7. Linking disease associations with regulatory information in the human genome

    KAUST Repository

    Schaub, M. A.

    2012-09-01

    Genome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify "functional SNPs" that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.

  8. HIV-1 Vif adaptation to human APOBEC3H haplotypes.

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    Ooms, Marcel; Brayton, Bonnie; Letko, Michael; Maio, Susan M; Pilcher, Christopher D; Hecht, Frederick M; Barbour, Jason D; Simon, Viviana

    2013-10-16

    Several human APOBEC3 deaminases can inhibit HIV-1 replication in vitro. HIV-1 Vif counteracts this restriction by targeting APOBEC3 for proteasomal degradation. Human APOBEC3H (A3H) is highly polymorphic, with natural variants differing considerably in anti-HIV-1 activity in vitro. To examine HIV-1 adaptation to variation in A3H activity in a natural infection context, we determined the A3H haplotypes and Vif sequences from 76 recently infected HIV-1 patients. We detected A3H-specific Vif changes suggesting viral adaptation. The patient-derived Vif sequences were used to engineer viruses that specifically differed in their ability to counteract A3H. Replication of these Vif-variant viruses in primary T cells naturally expressing active or inactive A3H haplotypes showed that endogenously expressed A3H restricts HIV-1 replication. Proviral DNA from A3H-restricted viruses showed high levels of G-to-A mutations in an A3H-specific GA dinucleotide context. Taken together, our data validate A3H expressed at endogenous levels as a bona fide HIV-1 restriction factor.

  9. Complex high-resolution linkage disequilibrium and haplotype patterns of single-nucleotide polymorphisms in 2.5 Mb of sequence on human chromosome 21.

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    Olivier, M; Bustos, V I; Levy, M R; Smick, G A; Moreno, I; Bushard, J M; Almendras, A A; Sheppard, K; Zierten, D L; Aggarwal, A; Carlson, C S; Foster, B D; Vo, N; Kelly, L; Liu, X; Cox, D R

    2001-11-01

    One approach to identify potentially important segments of the human genome is to search for DNA regions with nonrandom patterns of human sequence variation. Previous studies have investigated these patterns primarily in and around candidate gene regions. Here, we determined patterns of DNA sequence variation in 2.5 Mb of finished sequence from five regions on human chromosome 21. By sequencing 13 individual chromosomes, we identified 1460 single-nucleotide polymorphisms (SNPs) and obtained unambiguous haplotypes for all chromosomes. For all five chromosomal regions, we observed segments with high linkage disequilibrium (LD), extending from 1.7 to>81 kb (average 21.7 kb), disrupted by segments of similar or larger size with no significant LD between SNPs. At least 25% of the contig sequences consisted of segments with high LD between SNPs. Each of these segments was characterized by a restricted number of observed haplotypes,with the major haplotype found in over 60% of all chromosomes. In contrast, the interspersed segments with low LD showed significantly more haplotype patterns. The position and extent of the segments of high LD with restricted haplotype variability did not coincide with the location of coding sequences. Our results indicate that LD and haplotype patterns need to be investigated with closely spaced SNPs throughout the human genome, independent of the location of coding sequences, to reliably identify regions with significant LD useful for disease association studies.

  10. Cardiac Disease Associated with Human Immunodeficiency Virus Infection.

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    Bloomfield, Gerald S; Leung, Claudia

    2017-02-01

    Over the last 2 decades human immunodeficiency virus (HIV) infection has become a chronic disease requiring long-term management. Aging, antiretroviral therapy, chronic inflammation, and several other factors contribute to the increased risk of cardiovascular disease in patients infected with HIV. In low-income and middle-income countries where antiretroviral therapy access is limited, cardiac disease is most commonly related to opportunistic infections and end-stage manifestations of HIV/acquired immunodeficiency syndrome, including HIV-associated cardiomyopathy, pericarditis, and pulmonary arterial hypertension. Cardiovascular screening, prevention, and risk factor management are important factors in the management of patients infected with HIV worldwide. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Interstitial lung disease associated with human papillomavirus vaccination

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    Yasushi Yamamoto

    2015-01-01

    Full Text Available Vaccinations against the human papillomavirus (HPV have been recommended for the prevention of cervical cancer. HPV-16/18 AS04-adjuvanted vaccines (Cervarix are said to have favourable safety profiles. Interstitial lung diseases (ILDs can occur following exposure to a drug or a biological agent. We report a case of ILD associated with a Cervarix vaccination. A woman in her 40's, with a history of conisation, received three inoculations of Cervarix. Three months later, she presented with a cough and shortness of breath. Findings from a computed tomography of the chest and a transbronchial lung biopsy were consistent with non-specific interstitial pneumonia. Workup eliminated all other causes of the ILD, except for the vaccination. Over the 11 months of the follow-up period, her symptoms resolved without steroid therapy. The onset and spontaneous resolution of the ILD showed a chronological association with the HPV vaccination. The semi-quantitative algorithm revealed that the likelihood of an adverse drug reaction to Cervarix was “Probable”. The outcome was relatively good, but more attention should be paid to a potential risk for HPV vaccinations to cause ILDs. Wherever possible, chest radiographic examinations should be performed in order not to overlook any ILDs.

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

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    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.

  13. Improved haplotype analysis of human myelin basic protein short tandem repeat loci.

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    Watanabe, G; Umetsu, K; Yuasa, I; Suzuki, T

    2000-06-01

    We report an improved haplotype analysis of the human myelin basic protein gene (MBP) short tandem repeat (STR) polymorphism. The polymorphic G-->A transition and 2 conventional STR polymorphisms, MBPA and MBPB, were simultaneously determined by an amplified product length polymorphism technique. After the MBPC fragments containing MBPA and MBPB were amplified, the linkage of these 2 STR loci was determined by a second amplification, using polymerase chain reaction (PCR) technique, of the isolated MBPC fragments. The present haplotype analysis dispensed with family studies for the haplotyping of MBPA and MBPB. Polymorphisms of the MBP loci studied in German and Japanese populations showed a high genomic variation. Haplotype analysis of the MBP loci showed distinct differences between the German and the Japanese populations. Consequently, haplotype analysis of the MBP loci promises to be useful in forensic identification and paternity testing.

  14. An Extensive Analysis of Y-Chromosomal Microsatellite Haplotypes in Globally Dispersed Human Populations

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    Kayser, Manfred; Krawczak, Michael; Excoffier, Laurent; Dieltjes, Patrick; Corach, Daniel; Pascali, Vincente; Gehrig, Christian; Bernini, Luigi F.; Jespersen, Jørgen; Bakker, Egbert; Roewer, Lutz; de Knijff, Peter

    2001-01-01

    The genetic variance at seven Y-chromosomal microsatellite loci (or short tandem repeats [STRs]) was studied among 986 male individuals from 20 globally dispersed human populations. A total of 598 different haplotypes were observed, of which 437 (73.1%) were each found in a single male only. Population-specific haplotype-diversity values were .86–.99. Analyses of haplotype diversity and population-specific haplotypes revealed marked population-structure differences between more-isolated indigenous populations (e.g., Central African Pygmies or Greenland Inuit) and more-admixed populations (e.g., Europeans or Surinamese). Furthermore, male individuals from isolated indigenous populations shared haplotypes mainly with male individuals from their own population. By analysis of molecular variance, we found that 76.8% of the total genetic variance present among these male individuals could be attributed to genetic differences between male individuals who were members of the same population. Haplotype sharing between populations, ΦST statistics, and phylogenetic analysis identified close genetic affinities among European populations and among New Guinean populations. Our data illustrate that Y-chromosomal STR haplotypes are an ideal tool for the study of the genetic affinities between groups of male subjects and for detection of population structure. PMID:11254455

  15. Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.

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    Andrea G Nackley

    Full Text Available Catechol-O-methyltransferase (COMT is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158met position, designated as low (LPS, average (APS, and high pain sensitive (HPS, are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs, accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224 is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488 are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.

  16. Brain expression genome-wide association study (eGWAS identifies human disease-associated variants.

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    Fanggeng Zou

    Full Text Available Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202 and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197. We conducted an expression genome-wide association study (eGWAS using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5-1.67 × 10(-82. Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5-1.70 × 10(-141. The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6. We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6 of significant cisSNPs with suggestive AD-risk association (p<10(-3 in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings

  17. Two independent apolipoprotein a5 Haplotypes influence human plasma triglyceride levels

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    Pennacchio, Len A.; Olivier, Michael; Hubacek, Jaroslav A.; Krauss, Ronald M.; Rubin, Edward M.; Cohen, Jonathan C.

    2002-09-16

    The recently identified apolipoprotein A5 gene (APOA5) has been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. We previously identified an APOA5 haplotype (designated APOA5*2) that is present in {approx}16 percent of Caucasians and is associated with increased plasma triglyceride concentrations. In this report we describe another APOA5 haplotype (APOA5*3) containing the rare allele of the single nucleotide polymorphism c.56C>G that changes serine to tryptophan at codon 19 and is independently associated with high plasma triglyceride levels in three different populations. In a sample of 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, the APOA5*3 haplotype was more than three-fold more common in the group with high plasma triglyceride levels. In a second independently ascertained sample of Caucasian men and women (n 1/4 419) who were studied while consuming their self-selected diets as well as after high-carbohydrate diets and high-fat diets, the APOA5*3 haplotype was associated with increased plasma triglyceride levels on all three dietary regimens. In a third population comprising 2660 randomly selected individuals, the APOA5*3 haplotype was found in 12 percent of Caucasians, 14 percent of African-Americans and 28 percent of Hispanics and was associated with increased plasma triglyceride levels in both men and women in each ethnic group. These findings establish that the APOA5 locus contributes significantly to inter-individual variation in plasma triglyceride levels in humans. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25 50 percent of African-Americans, Hispanics and Caucasians and support the contribution of common human variation to quantitative phenotypes in the general population.

  18. Transgenic Mice with −6A Haplotype of the Human Angiotensinogen Gene Have Increased Blood Pressure Compared with −6G Haplotype*

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    Jain, Sudhir; Tillinger, Andrej; Mopidevi, Brahmaraju; Pandey, Varunkumar G.; Chauhan, Chetankumar K.; Fiering, Steven N.; Warming, Soren; Kumar, Ashok

    2010-01-01

    Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at −6, and the −6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with −6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with −6G. We have found that the hAGT gene has three additional SNPs (A/G at −1670, C/G at −1562, and T/G at −1561). Variants −1670A, −1562C, and −1561T almost always occur with −6A, and variants −1670G, −1562G, and −1561G almost always occur with −6G. Therefore, the hAGT gene may be subdivided into either −6A or −6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with −6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with −6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the −6A or −6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing −6A haplotype. Our studies also show that transgenic mice containing −6A haplotype have increased plasma AGT level and increased blood pressure as compared with −6G haplotype. Our studies explain the molecular mechanism involved in association of the −6A allele of the hAGT gene with hypertension. PMID:20978123

  19. Nasopharyngeal Carcinoma (NPC Related Human Leukocyte Antigen (HLA Haplotype Sharing among Southern East Asian Population

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    Rika Yuliwulandari

    2017-02-01

    Full Text Available Abstract The human leukocyte antigens (HLAs play important roles in the immune systems to response to various pathogens and disease among individuals. The aim of this study was analyze the HLA allele and haplotype frequencies of Southern East Asian population that show high incidence of nasopharyngeal carcinoma (NPC to evaluate the shared HLA haplotype contribution to NPC susceptibility among the population and analyses the genetic affinities between the population. We collect information of HLA haplotype from our previous study, other published paper, and HLA database in 19 population during 2005 to 2015. Haplotype frequencies were estimated using the maximum likelihood method based on an expectation maximization algorithm with ARLEQUIN v.2.0 software. We also calculated the genetic distance among 19 Southern East Asians based on HLA allele frequency using modified Cavalli-Sforza (DA distance method. Then, a phylogenetic tree was constructed using DISPAN software and principal component analysis (PCA was performed using XLSTAT-PRO software. A33-B58-DR3 haplotype, tightly linked to NPC, was commonly observed in all populations, supporting the high incidence of NPC in the populations. In addition, A2-B46 haplotype also associated with NPC, was also commonly found in several population that may also have a role in the disease development. The conclusion is the HLA haplotype sharing has an important role than the HLA allele sharing. The A33-B58-DR3 haplotype and A2-B46-DR9 haplotype in this study could be related to NPC in the Southern East Asian populations. The observed haplotype needs to be tested in the real patients to confirm the assumption. Abstrak Human leukocyte antigens (HLAs berperan penting dalam sistem imun untuk merespons berbagai patogen dan penyakit di antara individu yang berbeda. Tujuan penelitian ini menganalisis frekuensi alel dan haplotipe HLA populasi Southern East Asia yang menunjukkan insidensi yang tinggi terhadap

  20. Y-chromosome haplotype distribution in Han Chinese populations and modern human origin in East Asians

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    We investigated the distribution of Y-chromosome haplotype using 19 Y-SNPs in Han Chinese populations from 22 provinces of China. Our data indicate distinctive patterns of Y chromosome between southern and northern Han Chinese populations. The southern populations are much more polymorphic than northern populations. The latter has only a subset of the southern haplotypes. This result confirms the genetic difference observed between southern and northern ethnic populations in East Asia. It supports the hypothesis that the first settlement of modern hu-mans of African origin occurred in the southern part of East Asia during the last Ice Age, and a northward migration led to the peopling of northern China.

  1. Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression

    NARCIS (Netherlands)

    Kumar, Vinod; Westra, Harm-Jan; Karjalainen, Juha; Zhernakova, Daria V.; Esko, Tonu; Hrdlickova, Barbara; Almeida, Rodrigo; Zhernakova, Alexandra; Reinmaa, Eva; Hofker, Marten H.; Fehrmann, Rudolf S. N.; Fu, Jingyuan; Withoff, Sebo; Metspalu, Andres; Franke, Lude; Wijmenga, Cisca; Vosa, Urmo

    2013-01-01

    Recently it has become clear that only a small percentage (7%) of disease-associated single nucleotide polymorphisms (SNPs) are located in protein-coding regions, while the remaining 93% are located in gene regulatory regions or in intergenic regions. Thus, the understanding of how genetic variation

  2. How to deal with Haplotype data: An Extension to the Conceptual Schema of the Human Genome

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    José Fabián Reyes Román

    2016-12-01

    Full Text Available The goal of this work is to describe the advantages of the application of Conceptual Modeling (CM in complex domains, such as genomics. Nowadays, the study and comprehension of the human genome is a major challenge due to its high level of complexity. The constant evolution in the genomic domain contributes to the generation of ever larger amounts of new data, which means that if we do not manage it correctly data quality could be compromised (i.e., problems related with heterogeneity and inconsistent data. In this paper, we propose the use of a Conceptual Schema of the Human Genome (CSHG, designed to understand and improve our ontological commitment to the domain and also extend (enrich this schema with the integration of a novel concept: Haplotypes. Our focus is on improving the understanding of the relationship between genotype and phenotype, since new findings show that this question is more complex than was originally thought. Here we present the first steps in our data management approach with haplotypes (variations, frequencies and populations and discuss the database evolution to support this data. Each new version in our conceptual schema (CS introduces changes to the underlying database structure that has essential and practical implications for better understanding and managing the relevant information. A solution based on conceptual models gives a clear definition of the domain with direct implications in the medical field (Precision Medicine, in which Genomic Information Systems (GeIS play a very important role.

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

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    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.

  4. A haplotype of human angiotensinogen gene containing -217A increases blood pressure in transgenic mice compared with -217G.

    Science.gov (United States)

    Jain, Sudhir; Vinukonda, Govindaiah; Fiering, Steven N; Kumar, Ashok

    2008-12-01

    The human angiotensinogen (hAGT) gene contains an A/G polymorphism at -217, and frequency of -217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb region of its promoter, and variant -217A almost always occurs with -532T, -793A, and -1074T, whereas variant -217G almost always occurs with -532C, -793G, and -1074G. Since allele -6A is the predominant allele in African-Americans, the AGT gene can be subdivided into two main haplotypes, -6A:-217A (AA) and -6A:-217G (AG). To understand the role of these haplotypes on hAGT gene expression and on blood pressure regulation in an in vivo situation, we have generated double transgenic mice containing human renin gene and either AA or AG haplotype of the hAGT gene using knock-in strategy at the hypoxanthine phosphoribosyltransferase locus. We show here that 1) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%; and 2) plasma AGT level is increased by approximately 40%, and plasma angiotensin II level is increased by approximately 50% in male double transgenic mice containing AA haplotype of the hAGT gene compared with the AG haplotype. In addition, systolic blood pressure is increased by 8 mmHg in transgenic mice containing the AA haplotype compared with the AG haplotype. This is the first report to show the effect of polymorphisms in the promoter of a human gene on its transcription in an in vivo situation that ultimately leads to an increase in blood pressure.

  5. 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.

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    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.

  6. Chloride and other anions inhibit dichloroacetate-induced inactivation of human liver GSTZ1 in a haplotype-dependent manner.

    Science.gov (United States)

    Zhong, Guo; Li, Wenjun; Gu, Yuan; Langaee, Taimour; Stacpoole, Peter W; James, Margaret O

    2014-05-25

    The in vivo elimination rate of dichloroacetate (DCA), an investigational drug; is determined by the rate of its biotransformation to glyoxylate, catalyzed by glutathione transferase ζ1 (GSTZ1). DCA is a mechanism-based inactivator of GSTZ1, thus elimination of DCA is slowed with repeated dosing. We observed that chloride, a physiologically important anion, attenuated DCA-induced GSTZ1 inactivation in human liver cytosol in a concentration and GSTZ1 haplotype-dependent way. In the absence of chloride, incubation with 0.5mM DCA resulted in inactivation of GSTZ1 with a half-life of 0.4h (samples with the KRT haplotype) to 0.5h (EGT haplotype). At the hepatic physiological chloride concentration, 38mM, samples with the EGT haplotype retained more activity (80%) following a 2-h incubation with 0.5mM DCA than those possessing the KRT haplotype (55%). The chloride concentration that protected 50% of the GSTZ1 activity following 2-h incubation with 0.5mM DCA (EC50) was 15.0±3.1mM (mean±S.D., n=3) for EGT samples and 36.2±2.2mM for KRT samples. Bromide, iodide and sulfite also protected GSTZ1 from inactivation by DCA, however fluoride, sulfate, carbonate, acetate, cyanide did not. Protection by bromide varied by GSTZ1 haplotype: EC50 was 1.3±0.3mM for the EGT haplotype and 5.0±0.60mM for the KRT haplotype. The EC50 values for iodide and sulfite in liver cytosol samples with EGT haplotype were respectively 0.14±0.06mM and 9.6±1.1mM (mean±S.D., n=3). Because the in vivo half-life of DCA is determined by the fraction of active GSTZ1 in the liver, identifying factors that regulate GSTZ1 activity is important in determining appropriate DCA dosing in humans.

  7. HUMAN MIGRATION, DIVERSITY AND DISEASE ASSOCIATION: A CONVERGENT ROLE OF ESTABLISHED AND EMERGING DNA MARKERS

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    Pohhraj eGuha

    2013-08-01

    Full Text Available With the gradual development of intelligence, human got curious to know his origin and evolutionary background. Historical statements and anthropological findings were his primary tool for solving the puzzles of his own origin, until came the golden era of molecular markers which took no time to prove it’s excellence in unveiling answers to the questions regarding the migration pattern of human across different geographical regions. As a bonus these markers proved very much beneficial in solving criminal offences and in understanding the etiology of many dreaded diseases and to design their prevention. In this review, we have aimed to throw light on some of the promising molecular markers which are very much in application now-a-days for not only understanding the evolutionary background and ancient migratory routes of humans but also in the field of forensics and human health.

  8. Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity.

    Science.gov (United States)

    Usher, Christina L; Handsaker, Robert E; Esko, Tõnu; Tuke, Marcus A; Weedon, Michael N; Hastie, Alex R; Cao, Han; Moon, Jennifer E; Kashin, Seva; Fuchsberger, Christian; Metspalu, Andres; Pato, Carlos N; Pato, Michele T; McCarthy, Mark I; Boehnke, Michael; Altshuler, David M; Frayling, Timothy M; Hirschhorn, Joel N; McCarroll, Steven A

    2015-08-01

    Hundreds of genes reside in structurally complex, poorly understood regions of the human genome. One such region contains the three amylase genes (AMY2B, AMY2A and AMY1) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity, although genome-wide association studies for obesity have found this locus unremarkable. Using whole-genome sequence analysis, droplet digital PCR and genome mapping, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling ∼3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI, yet found no association.

  9. The impact of metabolic disease associated with metabolic syndrome on human pregnancy.

    Science.gov (United States)

    Malek, Antoine

    2014-01-01

    Metabolic diseases induced by metabolic syndrome (MS) have been increased during the past two decades. During healthy pregnancy maternal organs and placenta are challenged to adapt to the increasingly physiological changes. In addition to the increasingly proatherogenic MS, pregnant woman develops a high cardiac output, hypercoagulability, increased inflammatory activity and insulin resistance with dyslipidemia. The MS describes a cluster of metabolic changes associated with an impact on the physiology of many organs. While the metabolic syndrome is directly responsible for the development of atherosclerotic cardiovascular disease, additional impact on human pregnancy like preterm delivery with low-birth-weight infants as well as the development of diseases such as diabetes, preeclampsia and hypertension. Recent evidence suggests that MS is originated in fetal life in association with maternal nutrition during pregnancy and fetal programming which apparently increases the susceptibility for MS in children and later life. This review will describe the MS in association with the origin of the emerging diseases during pregnancy such as diabetes, preeclampsia and others. The influence of perinatal environment and maternal diet and smoking on MS as well as the genetic biomarkers of MS will be described.

  10. Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets.

    Science.gov (United States)

    van Unen, Vincent; Li, Na; Molendijk, Ilse; Temurhan, Mine; Höllt, Thomas; van der Meulen-de Jong, Andrea E; Verspaget, Hein W; Mearin, M Luisa; Mulder, Chris J; van Bergen, Jeroen; Lelieveldt, Boudewijn P F; Koning, Frits

    2016-05-17

    Inflammatory intestinal diseases are characterized by abnormal immune responses and affect distinct locations of the gastrointestinal tract. Although the role of several immune subsets in driving intestinal pathology has been studied, a system-wide approach that simultaneously interrogates all major lineages on a single-cell basis is lacking. We used high-dimensional mass cytometry to generate a system-wide view of the human mucosal immune system in health and disease. We distinguished 142 immune subsets and through computational applications found distinct immune subsets in peripheral blood mononuclear cells and intestinal biopsies that distinguished patients from controls. In addition, mucosal lymphoid malignancies were readily detected as well as precursors from which these likely derived. These findings indicate that an integrated high-dimensional analysis of the entire immune system can identify immune subsets associated with the pathogenesis of complex intestinal disorders. This might have implications for diagnostic procedures, immune-monitoring, and treatment of intestinal diseases and mucosal malignancies.

  11. Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia.

    Science.gov (United States)

    Garrido, Patrícia; Ribeiro, Sandra; Fernandes, João; Vala, Helena; Rocha-Pereira, Petronila; Bronze-da-Rocha, Elsa; Belo, Luís; Costa, Elísio; Santos-Silva, Alice; Reis, Flávio

    2015-12-25

    This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.

  12. Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.

    Science.gov (United States)

    Lampa, Jon; Westman, Marie; Kadetoff, Diana; Agréus, Anna Nordenstedt; Le Maître, Erwan; Gillis-Haegerstrand, Caroline; Andersson, Magnus; Khademi, Mohsen; Corr, Maripat; Christianson, Christina A; Delaney, Ada; Yaksh, Tony L; Kosek, Eva; Svensson, Camilla I

    2012-07-31

    During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.

  13. Bone diseases associated with human immunodeficiency virus infection: pathogenesis, risk factors and clinical management.

    Science.gov (United States)

    Bongiovanni, Marco; Tincati, Camilla

    2006-06-01

    Bone disorders such as osteopenia and osteoporosis have been recently reported in patients infected with the human immunodeficiency virus (HIV), but their etiology remains still unknown. The prevalence estimates vary widely among the different studies and can be affected by concomitant factors such as the overlapping of other possible conditions inducing bone loss as lypodystrophy, advanced HIV-disease, advanced age, low body weight or concomitant use of other drugs. All the reports at the moment available in the literature showed a higher than expected prevalence of reduced bone mineral density (BMD) in HIV-infected subjects both naïve and receiving potent antiretroviral therapy compared to healthy controls. This controversial can suggest a double role played by both antiretroviral drugs and HIV itself due to immune activation and/or cytokines disregulation. An improved understanding of the pathogenesis of bone disorders can result in better preventative and therapeutic measures. However, the clinical relevance and the risk of fractures remains undefined in HIV-population. The clinical management of osteopenia and osteoporosis in HIV-infected subjects is still being evaluated. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake, use of corticosteroids, advanced age, low body weight), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in HIV-infected individuals who have risk factors for bone disease can be important strategies to prevent osteopenia and osteoporosis in this population. The administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be a reasonable and effective option to treat osteoporosis in these subjects.

  14. Orthologs of Human Disease Associated Genes and RNAi Analysis of Silencing Insulin Receptor Gene in Bombyx mori

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    Zan Zhang

    2014-10-01

    Full Text Available The silkworm, Bombyx mori L., is an important economic insect that has been domesticated for thousands of years to produce silk. It is our great interest to investigate the possibility of developing the B. mori as human disease model. We searched the orthologs of human disease associated genes in the B. mori by bi-directional best hits of BLAST and confirmed by searching the OrthoDB. In total, 5006 genes corresponding to 1612 kinds of human diseases had orthologs in the B. mori, among which, there are 25 genes associated with diabetes mellitus. Of these, we selected the insulin receptor gene of the B. mori (Bm-INSR to study its expression in different tissues and at different developmental stages and tissues. Quantitative PCR showed that Bm-INSR was highly expressed in the Malpighian tubules but expressed at low levels in the testis. It was highly expressed in the 3rd and 4th instar larvae, and adult. We knocked down Bm-INSR expression using RNA interference. The abundance of Bm-INSR transcripts were dramatically reduced to ~4% of the control level at 6 days after dsRNA injection and the RNAi-treated B. mori individuals showed apparent growth inhibition and malformation such as abnormal body color in black, which is the typical symptom of diabetic patients. Our results demonstrate that B. mori has potential use as an animal model for diabetic mellitus research.

  15. Combining haplotypers

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    Kääriäinen, Matti; Lappalainen, Sampsa; Mielikäinen, Taneli

    2007-01-01

    Statistically resolving the underlying haplotype pair for a genotype measurement is an important intermediate step in gene mapping studies, and has received much attention recently. Consequently, a variety of methods for this problem have been developed. Different methods employ different statistical models, and thus implicitly encode different assumptions about the nature of the underlying haplotype structure. Depending on the population sample in question, their relative performance can vary greatly, and it is unclear which method to choose for a particular sample. Instead of choosing a single method, we explore combining predictions returned by different methods in a principled way, and thereby circumvent the problem of method selection. We propose several techniques for combining haplotype reconstructions and analyze their computational properties. In an experimental study on real-world haplotype data we show that such techniques can provide more accurate and robust reconstructions, and are useful for out...

  16. Neanderthal origin of the haplotypes carrying the functional variant Val92Met in the MC1R in modern humans.

    Science.gov (United States)

    Ding, Qiliang; Hu, Ya; Xu, Shuhua; Wang, Chuan-Chao; Li, Hui; Zhang, Ruyue; Yan, Shi; Wang, Jiucun; Jin, Li

    2014-08-01

    Skin color is one of the most visible and important phenotypes of modern humans. Melanocyte-stimulating hormone and its receptor played an important role in regulating skin color. In this article, we present evidence of Neanderthal introgression encompassing the melanocyte-stimulating hormone receptor gene MC1R. The haplotypes from Neanderthal introgression diverged with the Altai Neanderthal 103.3 ka, which postdates the anatomically modern human-Neanderthal divergence. We further discovered that all of the putative Neanderthal introgressive haplotypes carry the Val92Met variant, a loss-of-function variant in MC1R that is associated with multiple dermatological traits including skin color and photoaging. Frequency of this Neanderthal introgression is low in Europeans (∼5%), moderate in continental East Asians (∼30%), and high in Taiwanese aborigines (60-70%). As the putative Neanderthal introgressive haplotypes carry a loss-of-function variant that could alter the function of MC1R and is associated with multiple traits related to skin color, we speculate that the Neanderthal introgression may have played an important role in the local adaptation of Eurasians to sunlight intensity.

  17. Y-chromosome haplotype distribution in Han Chinese populations and modern human origin in East Asians

    Institute of Scientific and Technical Information of China (English)

    KE; Yuehai

    2001-01-01

    using denaturing high performance liquid chromatography (DHPLC), Current Protocols in Human Genetics, Supplement, 1998, 19(7): 10.1-7.10.12.[17]Underhill, P. A., Jin, L., Zemans, R. et al., A pre-Columbian human Y chromosome-specific transition and its implications for human evolution, Proc. Natl. Acad. Sci., 1996, USA 93: 196-200.[18]Underhill, P. A., Jin, L., Lin, A. A. et al., Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography, Genome Research, 1997, 7: 996-1005.[19]Vollrath, D. S., Vollrath, D., Foote, S. et al.,The human Y chromosome: A 43-interval map based on naturally occurring deletions, Science,1992, 258: 52-59.[20]Underhill, P. A., Jin, L., Lin, A. A. et al., An African origin of human Y-chromosomes, Program and Abstract, 1997 An-nual Meeting of The American Society of Human Genetics, Am. J. Hum. Genet, 1997, 61(supplement): A18.[21]Kayser, M., Caglia, A., Corach, D. et al., Evaluation of Y-chromosomal STRs: a multicenter study, Int. J. Legal Med., 1997, 110: 125-133.[22]Su, B., Xiao, J. H., Underhill, P. et al., Y-chromosome evidence for a northward migration of modern humans into eastern Asia during the last ice age, Am. J. Hum. Genet., 1999, 6: 1718-1724.[23]Ballinger, S. W., Schurr, T. G., Torroni, A. et al., Southeast Asian mitochondrial DNA analysis reveals genetic continuity of ancient mongoloid migrations, Genetics, 1992, 130: 139-152.[24]Heyer, E., Puymirat, J., Dieltjes, P. et al., Estimating Y chromosome specific microsatellite mutation frequencies using deep rooting pedigrees, Human Molecular Genetics,1997, 6: 799-803.[25]Bianchi, N. O., Catanesi, C. I., Bailliet, G. et al., Characterization of ancestral and derived Y-chromosomal haplotypes of New World native populations, Am. J. Hum. Genet., 1998, 63: 1862-1871.[26]Turner, II C. G., Shifting continuity: modern human origin, in The Origin and Past of Modern Humans as Viewed From DNA (eds. Brenner

  18. [Human genomic project and human genomic haplotype map project: opportunitiy, challenge and strategy in stomatology].

    Science.gov (United States)

    Wu, Rui-qing; Zeng, Xin; Wang, Zhi

    2010-08-01

    The human genomic project and the international HapMap project were designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases, thus lead to molecular diagnosis and personnel therapy. The article briefly reviewed the creation, target and achievement of those two projects. Furthermore, the authors have given four suggestions in facing to the opportunities and challenges brought by the two projects, including cultivation improvement of elites, cross binding of multi-subjects, strengthening construction of research base and initiation of natural key scientific project.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Expression profiles of muscle disease-associated genes and their isoforms during differentiation of cultured human skeletal muscle cells

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    Abdul-Hussein Saba

    2012-12-01

    Full Text Available Abstract Background The formation of contractile myofibrils requires the stepwise onset of expression of muscle specific proteins. It is likely that elucidation of the expression patterns of muscle-specific sarcomeric proteins is important to understand muscle disorders originating from defects in contractile sarcomeric proteins. Methods We investigated the expression profile of a panel of sarcomeric components with a focus on proteins associated with a group of congenital disorders. The analyses were performed in cultured human skeletal muscle cells during myoblast proliferation and myotube development. Results Our culture technique resulted in the development of striated myotubes and the expression of adult isoforms of the sarcomeric proteins, such as fast TnI, fast TnT, adult fast and slow MyHC isoforms and predominantly skeletal muscle rather than cardiac actin. Many proteins involved in muscle diseases, such as beta tropomyosin, slow TnI, slow MyBPC and cardiac TnI were readily detected in the initial stages of muscle cell differentiation, suggesting the possibility of an early role for these proteins as constituent of the developing contractile apparatus during myofibrillogenesis. This suggests that in disease conditions the mechanisms of pathogenesis for each of the mutated sarcomeric proteins might be reflected by altered expression patterns, and disturbed assembly of cytoskeletal, myofibrillar structures and muscle development. Conclusions In conclusion, we here confirm that cell cultures of human skeletal muscle are an appropriate tool to study developmental stages of myofibrillogenesis. The expression of several disease-associated proteins indicates that they might be a useful model system for studying the pathogenesis of muscle diseases caused by defects in specific sarcomeric constituents.

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

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    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.

  2. Linkage disequilibrium blocks, haplotype structure, and htSNPs of human CYP7A1 gene

    Directory of Open Access Journals (Sweden)

    Wan Yu-Jui

    2006-05-01

    Full Text Available Abstract Background Cholesterol 7-alpha-hydroxylase (CYP7A1 is the rate limiting enzyme for converting cholesterol into bile acids. Genetic variations in the CYP7A1 gene have been associated with metabolic disorders of cholesterol and bile acids, including hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and gallstone disease. Current genetic studies are focused mainly on analysis of a single nucleotide polymorphism (SNP at A-278C in the promoter region of the CYP7A1 gene. Here we report a genetic approach for an extensive analysis on linkage disequilibrium (LD blocks and haplotype structures of the entire CYP7A1 gene and its surrounding sequences in Africans, Caucasians, Asians, Mexican-Americans, and African-Americans. Result The LD patterns and haplotype blocks of CYP7A1 gene were defined in Africans, Caucasians, and Asians using genotyping data downloaded from the HapMap database to select a set of haplotype-tagging SNPs (htSNP. A low cost, microarray-based platform on thin-film biosensor chips was then developed for high-throughput genotyping to study transferability of the HapMap htSNPs to Mexican-American and African-American populations. Comparative LD patterns and haplotype block structure was defined across all test populations. Conclusion A constant genetic structure in CYP7A1 gene and its surrounding sequences was found that may lead to a better design for association studies of genetic variations in CYP7A1 gene with cholesterol and bile acid metabolism.

  3. [Genetic ecological monitoring in human populations: heterozygosity, mtDNA haplotype variation, and genetic load].

    Science.gov (United States)

    Balanovskiĭ, O P; Koshel', S M; Zaporozhchenko, V V; Pshenichnov, A S; Frolova, S A; Kuznetsova, M A; Baranova, E E; Teuchezh, I E; Kuznetsova, A A; Romashkina, M V; Utevskaia, O M; Churnosov, M I; Villems, R; Balanovskaia, E V

    2011-11-01

    Yu. P. Altukhov suggested that heterozygosity is an indicator of the state of the gene pool. The idea and a linked concept of genetic ecological monitoring were applied to a new dataset on mtDNA variation in East European ethnic groups. Haplotype diversity (an analog of the average heterozygosity) was shown to gradually decrease northwards. Since a similar trend is known for population density, interlinked changes were assumed for a set of parameters, which were ordered to form a causative chain: latitude increases, land productivity decreases, population density decreases, effective population size decreases, isolation of subpopulations increases, genetic drift increases, and mtDNA haplotype diversity decreases. An increase in genetic drift increases the random inbreeding rate and, consequently, the genetic load. This was confirmed by a significant correlation observed between the incidence of autosomal recessive hereditary diseases and mtDNA haplotype diversity. Based on the findings, mtDNA was assumed to provide an informative genetic system for genetic ecological monitoring; e.g., analyzing the ecology-driven changes in the gene pool.

  4. Maori origins, Y-chromosome haplotypes and implications for human history in the Pacific.

    Science.gov (United States)

    Underhill, P A; Passarino, G; Lin, A A; Marzuki, S; Oefner, P J; Cavalli-Sforza, L L; Chambers, G K

    2001-04-01

    An assessment of 28 pertinent binary genetic markers on the non-recombining portion of the Y chromosome (NRY) in New Zealand Maori and other relevant populations has revealed a diverse genetic paternal heritage of extant Maori. A maximum parsimony phylogeny was constructed in which nine of the 25 possible binary haplotypes were observed. Although approximately 40% of the samples have haplotypes of unequivocal European origin, an equivalent number of samples have a single binary haplotype that is also observed in Indonesia and New Guinea, indicative of common indigenous Melanesian ancestry. The balance of the lineages has either typical East Asian signatures or alternative compositions consistent with their affinity to Melanesia or New Guinea. Molecular analysis of mtDNA variation confirms the presence of a single predominant characteristic Southeast Asian (9-bp deletion in the Region V) lineage. The Y-chromosome results support a pattern of complex interrelationships between Southeast Asia, Melanesia, and Polynesia, in contrast to mtDNA and linguistic data, which uphold a rapid and homogeneous Austronesian expansion. The Y-chromosome data highlight a distinctive gender-modulated pattern of differential gene flow in the history of Polynesia. Copyright 2001 Wiley-Liss, Inc.

  5. LincSNP 2.0: an updated database for linking disease-associated SNPs to human long non-coding RNAs and their TFBSs

    Science.gov (United States)

    Ning, Shangwei; Yue, Ming; Wang, Peng; Liu, Yue; Zhi, Hui; Zhang, Yan; Zhang, Jizhou; Gao, Yue; Guo, Maoni; Zhou, Dianshuang; Li, Xin; Li, Xia

    2017-01-01

    We describe LincSNP 2.0 (http://bioinfo.hrbmu.edu.cn/LincSNP), an updated database that is used specifically to store and annotate disease-associated single nucleotide polymorphisms (SNPs) in human long non-coding RNAs (lncRNAs) and their transcription factor binding sites (TFBSs). In LincSNP 2.0, we have updated the database with more data and several new features, including (i) expanding disease-associated SNPs in human lncRNAs; (ii) identifying disease-associated SNPs in lncRNA TFBSs; (iii) updating LD-SNPs from the 1000 Genomes Project; and (iv) collecting more experimentally supported SNP-lncRNA-disease associations. Furthermore, we developed three flexible online tools to retrieve and analyze the data. Linc-Mart is a convenient way for users to customize their own data. Linc-Browse is a tool for all data visualization. Linc-Score predicts the associations between lncRNA and disease. In addition, we provided users a newly designed, user-friendly interface to search and download all the data in LincSNP 2.0 and we also provided an interface to submit novel data into the database. LincSNP 2.0 is a continually updated database and will serve as an important resource for investigating the functions and mechanisms of lncRNAs in human diseases. PMID:27924020

  6. Human genetic affinities for Y-chromosome P49a,f/TaqI haplotypes show strong correspondence with linguistics

    OpenAIRE

    Poloni, Estella S; Semino, O.; Passarino, G.; Santachiara-Benerecetti, A S; Dupanloup, I.; Langaney, André; Excoffier, Laurent Georges Louis

    1997-01-01

    Numerous population samples from around the world have been tested for Y chromosome-specific p49a,f/TaqI restriction polymorphisms. Here we review the literature as well as unpublished data on Y-chromosome p49a,f/TaqI haplotypes and provide a new nomenclature unifying the notations used by different laboratories. We use this large data set to study worldwide genetic variability of human populations for this paternally transmitted chromosome segment. We observe, for the Y chromosome, an import...

  7. A haplotype of human angiotensinogen gene containing −217A increases blood pressure in transgenic mice compared with −217G

    Science.gov (United States)

    Jain, Sudhir; Vinukonda, Govindaiah; Fiering, Steven N.; Kumar, Ashok

    2008-01-01

    The human angiotensinogen (hAGT) gene contains an A/G polymorphism at −217, and frequency of −217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb region of its promoter, and variant −217A almost always occurs with −532T, −793A, and −1074T, whereas variant −217G almost always occurs with −532C, −793G, and −1074G. Since allele −6A is the predominant allele in African-Americans, the AGT gene can be subdivided into two main haplotypes, −6A:−217A (AA) and −6A:−217G (AG). To understand the role of these haplotypes on hAGT gene expression and on blood pressure regulation in an in vivo situation, we have generated double transgenic mice containing human renin gene and either AA or AG haplotype of the hAGT gene using knock-in strategy at the hypoxanthine phosphoribosyltransferase locus. We show here that 1) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%; and 2) plasma AGT level is increased by ∼40%, and plasma angiotensin II level is increased by ∼50% in male double transgenic mice containing AA haplotype of the hAGT gene compared with the AG haplotype. In addition, systolic blood pressure is increased by 8 mmHg in transgenic mice containing the AA haplotype compared with the AG haplotype. This is the first report to show the effect of polymorphisms in the promoter of a human gene on its transcription in an in vivo situation that ultimately leads to an increase in blood pressure. PMID:18945948

  8. Haplotype-based case-control study of the human AGTR1 gene and essential hypertension in Han Chinese subjects.

    Science.gov (United States)

    Nie, Sheng-jie; Wen-ru, Tang; Bi-feng, Chen; Jin, Li; Wen, Zhang; Sheng-jun, Luo; Wei-wei, Li; Hai-jing, Yu; Chun-jie, Xiao

    2010-02-01

    Essential hypertension is considered to be a multifactorial trait resulting from the combined influence of environmental and genetic determinants. The aim of the study is to assess the association between the human AGTR1 gene and essential hypertension (EH) using a haplotype-based case-control study in Han Chinese subjects. Seven tag SNPs and the A1166C polymorphism of the AGTR1 gene were genotyped in 510 hypertension subjects and 510 normotensive subjects using PCR-RFLP method. Single SNP analyses indicated that the rs12695895 was significantly associated with hypertension, adjusted for covariates. Compared with the other haplotypes, Hap4 (AGGACTT) which carry the susceptible rs12695895 A allele was found to significantly increase the risk of EH with odds ratios equal to 1.84 (p=0.0002). The present results indicate that rs12695895 might be a genetic marker for EH and Hap4 (AGGACTT) was associated with hypertension in Han Chinese population. (c) 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  9. Human C4 haplotypes with duplicated C4A or C4B.

    OpenAIRE

    Raum, D; Awdeh, Z; Anderson, J.; Strong, L; Granados, J.; Teran, L; Giblett, E; Yunis, E J; Alper, C A

    1984-01-01

    In the course of study of families for the sixth chromosome markers HLA-A, C, B, D/DR, BF, and C2, the two loci for C4, C4A, and C4B, and glyoxalase I, we encountered five examples of probable duplication of one or the other of the two loci for C4. In one of these, both parents and one sib expressed two different structural genes for C4B, one sib expressed one, and one sib expressed none, suggesting that two C4B alleles were carried on a single haplotype: HLA-A2, B7, DR3, BFS1, C2C, C4A2, C4B...

  10. Human leucocyte antigens class II allele and haplotype association with Type 1 Diabetes in Madeira Island (Portugal).

    Science.gov (United States)

    Spínola, H; Lemos, A; Couto, A R; Parreira, B; Soares, M; Dutra, I; Bruges-Armas, J; Brehm, A; Abreu, S

    2017-08-20

    This study confirms for Madeira Island (Portugal) population the Type 1 Diabetes (T1D) susceptible and protective Human leucocyte antigens (HLA) markers previously reported in other populations and adds some local specificities. Among the strongest T1D HLA associations, stands out, as susceptible, the alleles DRB1*04:05 (OR = 7.3), DQB1*03:02 (OR = 6.1) and DQA1*03:03 (OR = 4.5), as well as the haplotypes DRB1*04:05-DQA1*03:03-DQB1*03:02 (OR = 100.9) and DRB1*04:04-DQA1*03:01-DQB1*03:02 (OR = 22.1), and DQB1*06:02 (OR = 0.07) and DRB1*15:01-DQA1*01:02-DQB1*06:02 (OR = 0.04) as protective. HLA-DQA1 positive for Arginine at position 52 (Arg52) (OR = 15.2) and HLA-DQB1 negative for Aspartic acid at the position 57 (Asp57) (OR = 9.0) alleles appear to be important genetic markers for T1D susceptibility, with higher odds ratio values than any single allele and than most of the haplotypes. Genotypes generated by the association of markers Arg52 DQA1 positive and Asp57 DQB1 negative increase T1D susceptibility much more than one would expected by a simple additive effect of those markers separately (OR = 26.9). This study also confirms an increased risk for DRB1*04/DRB1*03 heterozygote genotypes (OR = 16.8) and also a DRB1*04-DQA1*03:01-DQB1*03:02 haplotype susceptibility dependent on the DRB1*04 allele (DRB1*04:01, OR = 7.9; DRB1*04:02, OR = 3.2; DRB1*04:04, OR = 22.1). © 2017 John Wiley & Sons Ltd.

  11. A path-based measurement for human miRNA functional similarities using miRNA-disease associations

    Science.gov (United States)

    Ding, Pingjian; Luo, Jiawei; Xiao, Qiu; Chen, Xiangtao

    2016-09-01

    Compared with the sequence and expression similarity, miRNA functional similarity is so important for biology researches and many applications such as miRNA clustering, miRNA function prediction, miRNA synergism identification and disease miRNA prioritization. However, the existing methods always utilized the predicted miRNA target which has high false positive and false negative to calculate the miRNA functional similarity. Meanwhile, it is difficult to achieve high reliability of miRNA functional similarity with miRNA-disease associations. Therefore, it is increasingly needed to improve the measurement of miRNA functional similarity. In this study, we develop a novel path-based calculation method of miRNA functional similarity based on miRNA-disease associations, called MFSP. Compared with other methods, our method obtains higher average functional similarity of intra-family and intra-cluster selected groups. Meanwhile, the lower average functional similarity of inter-family and inter-cluster miRNA pair is obtained. In addition, the smaller p-value is achieved, while applying Wilcoxon rank-sum test and Kruskal-Wallis test to different miRNA groups. The relationship between miRNA functional similarity and other information sources is exhibited. Furthermore, the constructed miRNA functional network based on MFSP is a scale-free and small-world network. Moreover, the higher AUC for miRNA-disease prediction indicates the ability of MFSP uncovering miRNA functional similarity.

  12. Protective human leucocyte antigen haplotype, HLA-DRB1*01-B*14, against chronic Chagas disease in Bolivia.

    Directory of Open Access Journals (Sweden)

    Florencia del Puerto

    Full Text Available BACKGROUND: Chagas disease, caused by the flagellate parasite Trypanosoma cruzi affects 8-10 million people in Latin America. The mechanisms that underlie the development of complications of chronic Chagas disease, characterized primarily by pathology of the heart and digestive system, are not currently understood. To identify possible host genetic factors that may influence the clinical course of Chagas disease, Human Leucocyte Antigen (HLA regional gene polymorphism was analyzed in patients presenting with differing clinical symptoms. METHODOLOGY: Two hundred and twenty nine chronic Chagas disease patients in Santa Cruz, Bolivia, were examined by serological tests, electrocardiogram (ECG, and Barium enema colon X-ray. 31.4% of the examinees showed ECG alterations, 15.7% megacolon and 58.1% showed neither of them. A further 62 seropositive megacolon patients who had undergone colonectomy due to acute abdomen were recruited. We analyzed their HLA genetic polymorphisms (HLA-A, HLA-B, MICA, MICB, DRB1 and TNF-alpha promoter region mainly through Sequence based and LABType SSO typing test using LUMINEX Technology. PRINCIPAL FINDINGS: The frequencies of HLA-DRB1*01 and HLA-B*14:02 were significantly lower in patients suffering from megacolon as well as in those with ECG alteration and/or megacolon compared with a group of patients with indeterminate symptoms. The DRB1*0102, B*1402 and MICA*011 alleles were in strong Linkage Disequilibrium (LD, and the HLA-DRB1*01-B*14-MICA*011 haplotype was associated with resistance against chronic Chagas disease. CONCLUSIONS: This is the first report of HLA haplotype association with resistance to chronic Chagas disease.

  13. Protective human leucocyte antigen haplotype, HLA-DRB1*01-B*14, against chronic Chagas disease in Bolivia.

    Directory of Open Access Journals (Sweden)

    Florencia del Puerto

    Full Text Available BACKGROUND: Chagas disease, caused by the flagellate parasite Trypanosoma cruzi affects 8-10 million people in Latin America. The mechanisms that underlie the development of complications of chronic Chagas disease, characterized primarily by pathology of the heart and digestive system, are not currently understood. To identify possible host genetic factors that may influence the clinical course of Chagas disease, Human Leucocyte Antigen (HLA regional gene polymorphism was analyzed in patients presenting with differing clinical symptoms. METHODOLOGY: Two hundred and twenty nine chronic Chagas disease patients in Santa Cruz, Bolivia, were examined by serological tests, electrocardiogram (ECG, and Barium enema colon X-ray. 31.4% of the examinees showed ECG alterations, 15.7% megacolon and 58.1% showed neither of them. A further 62 seropositive megacolon patients who had undergone colonectomy due to acute abdomen were recruited. We analyzed their HLA genetic polymorphisms (HLA-A, HLA-B, MICA, MICB, DRB1 and TNF-alpha promoter region mainly through Sequence based and LABType SSO typing test using LUMINEX Technology. PRINCIPAL FINDINGS: The frequencies of HLA-DRB1*01 and HLA-B*14:02 were significantly lower in patients suffering from megacolon as well as in those with ECG alteration and/or megacolon compared with a group of patients with indeterminate symptoms. The DRB1*0102, B*1402 and MICA*011 alleles were in strong Linkage Disequilibrium (LD, and the HLA-DRB1*01-B*14-MICA*011 haplotype was associated with resistance against chronic Chagas disease. CONCLUSIONS: This is the first report of HLA haplotype association with resistance to chronic Chagas disease.

  14. How well do HapMap haplotypes identify common haplotypes of genes? A comparison with haplotypes of 334 genes resequenced in the environmental genome project.

    Science.gov (United States)

    Taylor, Jack A; Xu, Zong-Li; Kaplan, Norman L; Morris, Richard W

    2006-01-01

    One of the goals of the International HapMap Project is the identification of common haplotypes in genes. However, HapMap uses an incomplete catalogue of single nucleotide polymorphisms (SNPs) and might miss some common haplotypes. We examined this issue using data from the Environmental Genome Project (EGP) which resequenced 335 genes in 90 people, and thus, has a nearly complete catalogue of gene SNPs. The EGP identified a total of 45,243 SNPs, of which 10,780 were common SNPs (minor allele frequency >or=0.1). Using EGP common SNP genotype data, we identified 1,459 haplotypes with frequency >or=0.05 and we use these as "benchmark" haplotypes. HapMap release 16 had genotype information for 1,573 of 10,780 (15%) EGP common SNPs. Using these SNPs, we identified common HapMap haplotypes (frequency >or=0.05) in each of the four HapMap ethnic groups. To compare common HapMap haplotypes to EGP benchmark haplotypes, we collapsed benchmark haplotypes to the set of 1,573 SNPs. Ninety-eight percent of the collapsed benchmark haplotypes could be found as common HapMap haplotypes in one or more of the four HapMap ethnic groups. However, collapsing benchmark haplotypes to the set of SNPs available in HapMap resulted in a loss of haplotype information: 545 of 1,459 (37%) benchmark haplotypes were uniquely identified, and only 25% of genes had all their benchmark haplotypes uniquely identified. We resampled the EGP data to examine the effect of increasing the number of HapMap SNPs to 5 million, and estimate that approximately 40% of common SNPs in genes will be sampled and that half of the genes will have sufficient SNPs to identify all common haplotypes. This inability to distinguish common haplotypes of genes may result in loss of power when examining haplotype-disease association.

  15. American Behcet's Disease Association

    Science.gov (United States)

    ... Behcet's Awareness Day Behcet's Disease Awareness Share your story and educate others about Behcet's: www.rareconnect.org/en/community/behcet-s-syndrome Upcoming Events American Behcet's Disease Association PO BOX 80576 Rochester, MI ...

  16. Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition

    Directory of Open Access Journals (Sweden)

    Ollier William

    2005-04-01

    Full Text Available Abstract Background The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs, at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs were identified for each map. Results Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. Conclusion For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results.

  17. Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition.

    Science.gov (United States)

    Zeggini, Eleftheria; Barton, Anne; Eyre, Stephen; Ward, Daniel; Ollier, William; Worthington, Jane; John, Sally

    2005-04-25

    The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results.

  18. 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.

  19. Convergent myotonic dystrophy (DM) haplotypes on 19q13.3: Potential inconsistencies in human disease gene localization

    Energy Technology Data Exchange (ETDEWEB)

    Tsilfidis, C. [Eye Research Institute of Canada, Toronto (Canada); Whiting, E.J. [Univ. of Ottawa (Canada); Korneluk, R.G. [Univ. of Ottawa (Canada)]|[Childrens Hospital of Eastern Ontario, Ottawa (Canada)

    1994-09-01

    Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease which has been shown to be caused by an unstable trinucleotide repeat located on chromosome 19q. We have conducted extensive haplotype analysis on 103 DM chromosome using thirteen 19q13.3 loci identifying 18 RFLPs, spanning a physical distance of 1.3 Mb containing the myotonic dystrophy gene. Three major haplotypes, H1, H2 and H3, comprising 45.6% of the DM chromosomes, were observed in our population. The later two haplotypes, observed exclusively on DM chromosomes of French Canadian origin, contain a 500 kb core region that is identical. The low frequency of this core on normal chromosomes (0.8%) is consistent with a mapping of the DM gene within this region. However, the DM mutation is found 160 kb distal to the point of divergence between these two haplotypes. In contrast, the 450 kb shared by haplotypes H1 and H2 contain the DM mutation. Further, analysis of the DM region using a polymorphic microsatellite GJ-VSSM2 located 15 kb telomeric to the DM gene revealed strong allelic association of allele V on DM chromosomes (present on 6% of normal and 88.2% of DM chromosomes). The fact that allele V was found on all DM chromosomes with the three major haplotypes is indicative of their common origin and includes the two French Canadian haplotypes which share a region proximal to the DM mutation. This analysis indicates that convergent haplotypes, in the absence of a more extensive linkage disequilibrium analysis, may lead to a spurious disease gene localization.

  20. Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

    DEFF Research Database (Denmark)

    Nolsøe, R L; Kelly, J A; Pociot, F;

    2005-01-01

    to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE...... variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE....

  1. Malaria haplotype frequency estimation.

    Science.gov (United States)

    Wigger, Leonore; Vogt, Julia E; Roth, Volker

    2013-09-20

    We present a Bayesian approach for estimating the relative frequencies of multi-single nucleotide polymorphism (SNP) haplotypes in populations of the malaria parasite Plasmodium falciparum by using microarray SNP data from human blood samples. Each sample comes from a malaria patient and contains one or several parasite clones that may genetically differ. Samples containing multiple parasite clones with different genetic markers pose a special challenge. The situation is comparable with a polyploid organism. The data from each blood sample indicates whether the parasites in the blood carry a mutant or a wildtype allele at various selected genomic positions. If both mutant and wildtype alleles are detected at a given position in a multiply infected sample, the data indicates the presence of both alleles, but the ratio is unknown. Thus, the data only partially reveals which specific combinations of genetic markers (i.e. haplotypes across the examined SNPs) occur in distinct parasite clones. In addition, SNP data may contain errors at non-negligible rates. We use a multinomial mixture model with partially missing observations to represent this data and a Markov chain Monte Carlo method to estimate the haplotype frequencies in a population. Our approach addresses both challenges, multiple infections and data errors.

  2. 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

  3. Mapping haplotype-haplotype interactions with adaptive LASSO.

    Science.gov (United States)

    Li, Ming; Romero, Roberto; Fu, Wenjiang J; Cui, Yuehua

    2010-08-27

    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. 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. 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 freely downloaded from http://www.stt.msu.edu/~cui/software.html.

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

    Science.gov (United States)

    Fernandez Vina, Marcelo A; 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

    2012-03-19

    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.

  5. Haplotyping and copy number estimation of the highly polymorphic human beta-defensin locus on 8p23 by 454 amplicon sequencing

    Directory of Open Access Journals (Sweden)

    Rosenstiel Philip

    2010-04-01

    Full Text Available Abstract Background The beta-defensin gene cluster (DEFB at chromosome 8p23.1 is one of the most copy number (CN variable regions of the human genome. Whereas individual DEFB CNs have been suggested as independent genetic risk factors for several diseases (e.g. psoriasis and Crohn's disease, the role of multisite sequence variations (MSV is less well understood and to date has only been reported for prostate cancer. Simultaneous assessment of MSVs and CNs can be achieved by PCR, cloning and Sanger sequencing, however, these methods are labour and cost intensive as well as prone to methodological bias introduced by bacterial cloning. Here, we demonstrate that amplicon sequencing of pooled individual PCR products by the 454 technology allows in-depth determination of MSV haplotypes and estimation of DEFB CNs in parallel. Results Six PCR products spread over ~87 kb of DEFB and harbouring 24 known MSVs were amplified from 11 DNA samples, pooled and sequenced on a Roche 454 GS FLX sequencer. From ~142,000 reads, ~120,000 haplotype calls (HC were inferred that identified 22 haplotypes ranging from 2 to 7 per amplicon. In addition to the 24 known MSVs, two additional sequence variations were detected. Minimal CNs were estimated from the ratio of HCs and compared to absolute CNs determined by alternative methods. Concordance in CNs was found for 7 samples, the CNs differed by one in 2 samples and the estimated minimal CN was half of the absolute in one sample. For 7 samples and 2 amplicons, the 454 haplotyping results were compared to those by cloning/Sanger sequencing. Intrinsic problems related to chimera formation during PCR and differences between haplotyping by 454 and cloning/Sanger sequencing are discussed. Conclusion Deep amplicon sequencing using the 454 technology yield thousands of HCs per amplicon for an affordable price and may represent an effective method for parallel haplotyping and CN estimation in small to medium-sized cohorts. The

  6. Haplotype-based banking of human pluripotent stem cells for transplantation: potential and limitations.

    Science.gov (United States)

    Zimmermann, Anna; Preynat-Seauve, Olivier; Tiercy, Jean-Marie; Krause, Karl-Heinz; Villard, Jean

    2012-09-01

    High expectations surround the area of stem cells therapeutics. However, the cells' source-adult or embryonic-and the cells' origin-patient-derived autologous or healthy donor genetically unrelated-remain subjects of debate. Autologous origins have the advantage of a theoretical absence of immune rejection by the recipient. However, this approach has several limitations with regard to the disease of the recipient and to potential problems with the generation, expansion, and manipulation of autologous induced pluripotent stem cells (iPS cells) preparation. An alternative to using autologous cells is the establishment of a bank of well-characterized adult cells that would be used to generate iPS cells and their derivatives. In the context of transplantation, such cells would come from genetically unrelated donors and the immune system of the recipient would reject the graft without immunosuppressive therapy. To minimize the risk of rejection, human leukocyte antigen (HLA) compatibility is certainly the best option, and the establishment of an HLA-organized bank would mean having a limited number of stem cells that would be sufficient for a large number of recipients. The concept of haplobanking with HLA homozygous cell lines would also limit the number of HLA mismatches, but such an approach will not necessarily be less immunogenic in terms of selection criteria, because of the limited number of HLA-compatible loci and the level of HLA typing resolution.

  7. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation.

    Science.gov (United States)

    Perron, Hervé; Lang, Alois

    2010-08-01

    Endogenous retroviruses represent about 8% of the human genome and belong to the superfamily of transposable and retrotransposable genetic elements. Altogether, these mobile genetic elements and their numerous inactivated "junk" sequences represent nearly one half of the human DNA. Nonetheless, a significant part of this "non-conventional" genome has retained potential activity. Epigenetic control is notably involved in silencing most of these genetic elements but certain environmental factors such as viruses are known to dysregulate their expression in susceptible cells. More particularly, embryonal cells with limited gene methylation are most susceptible to uncontrolled activation of these mobile genetic elements by, e.g., viral infections. In particular, certain viruses transactivate promoters from endogenous retroviral family type W (HERV-W). HERV-W RNA was first isolated in circulating viral particles (Multiple Sclerosis-associated RetroViral element, MSRV) that have been associated with the evolution and prognosis of multiple sclerosis. HERV-W elements encode a powerful immunopathogenic envelope protein (ENV) that activates a pro-inflammatory and autoimmune cascade through interaction with Toll-like receptor 4 on immune cells. This ENV protein has repeatedly been detected in MS brain lesions and may be involved in other diseases. Epigenetic factors controlling HERV-W ENV protein expression then reveal critical. This review addresses the gene-environment epigenetic interface of such HERV-W elements and its potential involvement in disease.

  8. Trypanosoma cruzi in Brazilian Amazonia: Lineages TCI and TCIIa in wild primates, Rhodnius spp. and in humans with Chagas disease associated with oral transmission.

    Science.gov (United States)

    Marcili, Arlei; Valente, Vera C; Valente, Sebastião A; Junqueira, Angela C V; da Silva, Flávia Maia; Pinto, Ana Yecê das Neves; Naiff, Roberto D; Campaner, Marta; Coura, José R; Camargo, Erney P; Miles, Michael A; Teixeira, Marta M G

    2009-04-01

    In this study, we provide phylogenetic and biogeographic evidence that the Trypanosoma cruzi lineages T. cruzi I (TCI) and T. cruzi IIa (TCIIa) circulate amongst non-human primates in Brazilian Amazonia, and are transmitted by Rhodnius species in overlapping arboreal transmission cycles, sporadically infecting humans. TCI presented higher prevalence rates, and no lineages other than TCI and TCIIa were found in this study in wild monkeys and Rhodnius from the Amazonian region. We characterised TCI and TCIIa from wild primates (16 TCI and five TCIIa), Rhodnius spp. (13 TCI and nine TCIIa), and humans with Chagas disease associated with oral transmission (14 TCI and five TCIIa) in Brazilian Amazonia. To our knowledge, TCIIa had not been associated with wild monkeys until now. Polymorphisms of ssrDNA, cytochrome b gene sequences and randomly amplified polymorphic DNA (RAPD) patterns clearly separated TCIIa from TCIIb-e and TCI lineages, and disclosed small intra-lineage polymorphisms amongst isolates from Amazonia. These data are important in understanding the complexity of the transmission cycles, genetic structure, and evolutionary history of T. cruzi populations circulating in Amazonia, and they contribute to both the unravelling of human infection routes and the pathological peculiarities of Chagas disease in this region.

  9. Incidence of cervical disease associated to HPV in human immunodeficiency infected women under highly active antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Mogtomo Martin

    2009-06-01

    Full Text Available Abstract Background Women infected with human immunodeficiency virus (HIV may be at higher risk of developing cervical cancer than non infected women. In a pilot study, we assessed the relationships among cervical cytology abnormalities associated to Human Papillomavirus (HPV, HIV infection and Highly Active Antiretroviral Therapy (HAART on the development of Squamous Intraepithelial lesions (SILs. Out of the 70 HIV infected women from Douala -Cameroon (Central Africa that we included in the study, half (35 were under HAART. After obtaining information related to their lifestyle and sexual behaviour, cervicovaginal samples for Pap smears and venous blood for CD4 count were collected and further divided into two groups based upon the presence or absence of cervical cytology abnormalities i.e. those with normal cervical cytology and those with low and high Squamous Intraepithelial lesions (LSIL, HSIL. Results Assessment was done according to current antiretroviral regimens available nationwide and CD4 count. It was revealed that 44.3% of HIV-infected women had normal cytology. The overall prevalence of LSIL and HSIL associated to HPV in the studied groups was 24.3% (17/70 and 31.4% (22/70 respectively. Among the 22 HSIL-positive women, 63.6% (14/22 were not on antiretroviral therapy, while 36.4% (8/22 were under HAART. HIV infected women under HAART with positive HSIL, showed a median CD4+ T cell count of 253.7 +/- 31.7 higher than those without therapy (164.7 +/- 26.1. The incidence of HSIL related to HPV infection within the study group independently of HAART initiation was high. Conclusion These results suggest the need for extension and expansion of the current study in order to evaluate the incidence of HPV infection and cervical cancer among HIV-infected and non HIV- infected women in Cameroon.

  10. Assessing the pathogenic potential of human Nephronophthisis disease-associated NPHP-4 missense mutations in C. elegans.

    Science.gov (United States)

    Masyukova, Svetlana V; Winkelbauer, Marlene E; Williams, Corey L; Pieczynski, Jay N; Yoder, Bradley K

    2011-08-01

    A spectrum of complex oligogenic disorders called the ciliopathies have been connected to dysfunction of cilia. Among the ciliopathies are Nephronophthisis (NPHP), characterized by cystic kidney disease and retinal degeneration, and Meckel-Gruber syndrome (MKS), a gestational lethal condition with skeletal abnormalities, cystic kidneys and CNS malformation. Mutations in multiple genes have been identified in NPHP and MKS patients, and an unexpected finding has been that mutations within the same gene can cause either disorder. Further, there is minimal genotype-phenotype correlation and despite recessive inheritance, numerous patients were identified as having a single heterozygous mutation. This has made it difficult to determine the significance of these mutations on disease pathogenesis and led to the hypothesis that clinical presentation in an individual will be determined by genetic interactions between mutations in multiple cilia-related genes. Here we utilize Caenorhabditis elegans and cilia-associated behavioral and morphologic assays to evaluate the pathogenic potential of eight previously reported human NPHP4 missense mutations. We assess the impact of these mutations on C. elegans NPHP-4 function, localization and evaluate potential interactions with mutations in MKS complex genes, mksr-2 and mksr-1. Six out of eight nphp-4 mutations analyzed alter ciliary function, and three of these modify the severity of the phenotypes caused by disruption of mksr-2 and mksr-1. Collectively, our studies demonstrate the utility of C. elegans as a tool to assess the pathogenicity of mutations in ciliopathy genes and provide insights into the complex genetic interactions contributing to the diversity of phenotypes associated with cilia disorders.

  11. β-Amyloid peptides display protective activity against the human Alzheimer's disease-associated herpes simplex virus-1.

    Science.gov (United States)

    Bourgade, Karine; Garneau, Hugo; Giroux, Geneviève; Le Page, Aurélie Y; Bocti, Christian; Dupuis, Gilles; Frost, Eric H; Fülöp, Tamàs

    2015-02-01

    Amyloid plaques, the hallmark of Alzheimer's disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.

  12. Frequency of alleles and haplotypes of the human leukocyte antigen system in Bauru, São Paulo, Brazil

    Directory of Open Access Journals (Sweden)

    Luana de Cassia Salvadori

    2014-04-01

    Full Text Available Background: HLA allele identification is used in bone marrow transplant programs as HLA compatibility between the donor and recipient may prevent graft rejection. Objective: This study aimed to estimate the frequency of alleles and haplotypes of the HLA system in the region of Bauru and compare these with the frequencies found in other regions of the country. Methods: HLA-A*, HLA-B*, and HLA-DRB1* allele frequencies and haplotypes were analyzed in a sample of 3542 volunteer donors at the National Registry of Voluntary Bone Marrow Donors (REDOME in Bauru. HLA low resolution typing was performed using reverse line blot with the Dynal Reli(tm SSO-HLA Typing Kit and automated Dynal AutoReli(tm48 device (Invitrogen, USA. Results: Twenty, 36, and 13 HLA-A*, HLA-B*, and HLA-DRB1* allele groups, respectively, were identified. The most common alleles for each locus were HLA-A*02, HLA-B*35, and HLA-DRB1*07. The most frequent haplotype was A*01-B*08-DRB1*03. Allele and haplotype frequencies were compared to other regions in Brazil and the similarities and differences among populations are shown. Conclusion: The knowledge of the immunogenic profile of a population contributes to the comprehension of the historical and anthropological aspects of different regions. Moreover, this helps to find suitable donors quickly, thereby shortening waiting lists for transplants and thus increasing survival rates among recipients.

  13. Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes

    Science.gov (United States)

    Weiss, Robert B.; Bolt, Daniel; von Niederhausern, Andrew; Fiore, Michael C.; Dunn, Diane M.; Piper, Megan E.; Matsunami, Nori; Smith, Stevens S.; Coon, Hilary; McMahon, William M.; Scholand, Mary B.; Singh, Nanda; Hoidal, John R.; Kim, Su-Young; Leppert, Mark F.; Cannon, Dale S.

    2009-01-01

    Introduction: Previous research revealed significant associations between haplotypes in the CHRNA5-A3-B4 subunit cluster and scores on the Fagerström Test for Nicotine Dependence among individuals reporting daily smoking by age 17. The present study used subsamples of participants from that study to investigate associations between the CHRNA5-A3-B4 haplotypes and an array of phenotypes not analyzed previously (i.e., withdrawal severity, ability to stop smoking, and specific scales on the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) that reflect loss of control, strong craving, and heavy smoking. Methods: Two cohorts of current or former smokers (N = 886) provided both self-report data and DNA samples. One sample (Wisconsin) comprised smokers making a quit smoking attempt, which permitted the assessment of withdrawal and relapse during the attempt. The other sample (Utah) comprised participants studied for risk factors for nicotine dependence and chronic obstructive pulmonary disease and included individuals originally recruited in the Lung Health Study. Results: The CHRNA5-A3-B4 haplotypes were significantly associated with the targeted WISDM-68 scales (Tolerance, Craving, Loss of Control) in both samples of participants but only among individuals who began smoking early in life. The haplotypes were significantly associated with relapse likelihood and withdrawal severity, but these associations showed no evidence of an interaction with age at daily smoking. Discussion: The CHRNA5-A3-B4 haplotypes are associated with a broad range of nicotine dependence phenotypes, but these associations are not consistently moderated by age at initial smoking. PMID:19436041

  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. Most parsimonious haplotype allele sharing determination

    Directory of Open Access Journals (Sweden)

    Xu Jiaofen

    2009-04-01

    Full Text Available Abstract Background The "common disease – common variant" hypothesis and genome-wide association studies have achieved numerous successes in the last three years, particularly in genetic mapping in human diseases. Nevertheless, the power of the association study methods are still low, in particular on quantitative traits, and the description of the full allelic spectrum is deemed still far from reach. Given increasing density of single nucleotide polymorphisms available and suggested by the block-like structure of the human genome, a popular and prosperous strategy is to use haplotypes to try to capture the correlation structure of SNPs in regions of little recombination. The key to the success of this strategy is thus the ability to unambiguously determine the haplotype allele sharing status among the members. The association studies based on haplotype sharing status would have significantly reduced degrees of freedom and be able to capture the combined effects of tightly linked causal variants. Results For pedigree genotype datasets of medium density of SNPs, we present two methods for haplotype allele sharing status determination among the pedigree members. Extensive simulation study showed that both methods performed nearly perfectly on breakpoint discovery, mutation haplotype allele discovery, and shared chromosomal region discovery. Conclusion For pedigree genotype datasets, the haplotype allele sharing status among the members can be deterministically, efficiently, and accurately determined, even for very small pedigrees. Given their excellent performance, the presented haplotype allele sharing status determination programs can be useful in many downstream applications including haplotype based association studies.

  16. Association of SNPs and haplotypes in GABA(A) receptor beta(2) gene with schizophrenia

    Institute of Scientific and Technical Information of China (English)

    WSLau; CFXuan; ZChan; CFFeng; GYHe; LCao; ZCLiu; HLuan; QMXue

    2005-01-01

    Disturbances in GABAergic system have been observed in schizophrenics.(1-3) In the present study, population association analysis was performed on 19 SNPs in the alpha(l), beta(2), gamma(2), epsilon and pi subunit genes of GABA(A) receptor. Five SNPs in GABRB2, namely B217G1584T, rs1816071, rs194072, rs252944 and rs187269,were found to be significantly associated, and their haplotypes in linkage disequilibrium, with schizophrenia. This represents the first report on any disease association of SNPs in the human GABA(A) receptor genes, and focuses attention on the GABAergic hypothesis of schizophrenia etiology.(3,4)

  17. Haplotype block structure is conserved across mammals.

    Directory of Open Access Journals (Sweden)

    Victor Guryev

    2006-07-01

    Full Text Available Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium in populations and have important applications in the design and interpretation of genetic experiments. Although evolutionary processes are known to drive the selection of individual polymorphisms, their effect on haplotype block structure dynamics has not been shown. Here, we present a high-resolution haplotype map for a 5-megabase genomic region in the rat and compare it with the orthologous human and mouse segments. Although the size and fine structure of haplotype blocks are species dependent, there is a significant interspecies overlap in structure and a tendency for blocks to encompass complete genes. Extending these findings to the complete human genome using haplotype map phase I data reveals that linkage disequilibrium values are significantly higher for equally spaced positions in genic regions, including promoters, as compared to intergenic regions, indicating that a selective mechanism exists to maintain combinations of alleles within potentially interacting coding and regulatory regions. Although this characteristic may complicate the identification of causal polymorphisms underlying phenotypic traits, conservation of haplotype structure may be employed for the identification and characterization of functionally important genomic regions.

  18. An overview of the haplotype problems and algorithms

    Institute of Scientific and Technical Information of China (English)

    ZHAO Yuzhong; XU Yun; ZHANG Qiangfeng; CHEN Guoliang

    2007-01-01

    A single nucleotide polymorphism (SNP),as the most common form of genetic variation,has been widely studied to help analyze the possible association between diseases and genomes.To gain more information,SNPs on a single chromosome are usually studied together,which constitute a haplotype.Gaining haplotypes from biological experiments is usually very costly and time-consuming,which causes people to develop efficient methods to determine haplotypes from the computational angle.Many problems and algorithms about haplotypes have been proposed to reduce the cost of studies of disease association.In general,four categories of problems are widely researched:the haplotype assembly problem,the haplotype inference problem,the haplotype block partition problem,and the haplotype tagging SNP selection problem.The former two problems have been well reviewed by many researchers,whereas the latter two have not been comprehensively surveyed to our knowledge.In this paper,we try to make a detailed introduction to the four problems,especially the latter two.

  19. Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid.

    Science.gov (United States)

    Alisson-Silva, Frederico; Kawanishi, Kunio; Varki, Ajit

    2016-10-01

    One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine-N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human

  20. Human leukocyte antigen class II (DRB1 and DQB1) alleles and haplotypes frequencies in patients with pemphigus vulgaris among the Serbian population.

    Science.gov (United States)

    Zivanovic, D; Bojic, S; Medenica, L; Andric, Z; Popadic, D

    2016-05-01

    The etiology of pemphigus vulgaris (PV) is multifactorial and includes genetic, environmental, hormonal, and immunological factors. Inheritance of certain Human class II leukocyte antigen (HLA) alleles is by far the best-established predisposing factor for the development of PV. Class II HLA alleles vary among racial/ethnic backgrounds. We have determined an association between HLA class II alleles and PV among the Serbian population. A total of 72 patients with confirmed diagnosis of PV were genotyped for HLA class II alleles. HLA frequencies were compared with unrelated healthy bone marrow donors. The statistical significance of differences between patients and controls was evaluated using Fisher's exact test. The DRB1*04 and DRB1*14 allelic groups were associated with PV (P adj = 4.45 × 10(-13) and 4.06 × 10(-19) respectively), while HLA-DRB1*11 was negatively associated with PV (P adj = 0.0067) suggesting a protective role. DRB1*04:02, DRB1*14:04, DQB1*03:02 and DQB1*05:03 alleles were shown to be strongly associated with PV (P adj = 1.63 × 10(-12), 5.20 × 10(-7), 1.28 × 10(-6), and 4.44 × 10(-5), respectively). The frequency of HLA DRB1*04-DQB1*03 and HLA DRB1*14-DQB1*05 haplotypes in PV patients was significantly higher than in controls (31.3% vs 8.8%, P adj =7.66 × 10(-8) and 30.6% vs 6.3%, P adj = 3.22 × 10(-10), respectively). At high-resolution level, statistical significance was observed in HLA-DRB1*04:02-DQB1*03:02 and HLA-DRB1*14:04-DQB1*05:03 haplotypes (P adj = 5.55 × 10(-12), and P adj = 3.91 × 10(-6), respectively). Our findings suggest that HLA-DRB1*04:02, DRB1*14:04, HLA-DQB1* 03:02 and DQB1*05:03 alleles and HLA-DRB1*04:02-DQB1*03:02 and HLA-DRB1*14:04-DQB1*05:03 haplotypes are genetic markers for susceptibility for PV, while DRB1*11 allelic group appears protective in Serbian population.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. The location of a disease-associated polymorphism and genomic structure of the human 52-kDa Ro/SSA locus (SSA1)

    Energy Technology Data Exchange (ETDEWEB)

    Tsugu, H.; Horowitz, R.; Gibson, N. [Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)] [and others

    1994-12-01

    Sera from approximately 30% of patients with systemic lupus erythematosus (SLE) contain high titers of autoantibodies that bind to the 52-kDa Ro/SSA protein. We previously detected polymorphisms in the 52-kDa Ro/SSA gene (SSA1) with restriction enzymes, one of which is strongly associated with the presence of SLE (P < 0.0005) in African Americans. A higher disease frequency and more severe forms of the disease are commonly noted among these female patients. To determine the location and nature of this polymorphism, we obtained two clones that span 8.5 kb of the 52-kDa Ro/SSA locus including its upstream regulatory region. Six exons were identified, and their nucleotide sequences plus adjacent noncoding regions were determined. No differences were found between these exons and the coding region of one of the reported cDNAs. The disease-associated polymorphic site suggested by a restriction enzyme map and confirmed by DNA amplification and nucleotide sequencing was present upstream of exon 1. This polymorphism may be a genetic marker for a disease-related variation in the coding region for the protein or in the upstream regulatory region of this gene. Although this RFLP is present in Japanese, it is not associated with lupus in this race. 41 refs., 4 figs., 2 tabs.

  3. Haplotypes versus genotypes on pedigrees

    Directory of Open Access Journals (Sweden)

    Kirkpatrick Bonnie B

    2011-04-01

    Full Text Available Abstract Background Genome sequencing will soon produce haplotype data for individuals. For pedigrees of related individuals, sequencing appears to be an attractive alternative to genotyping. However, methods for pedigree analysis with haplotype data have not yet been developed, and the computational complexity of such problems has been an open question. Furthermore, it is not clear in which scenarios haplotype data would provide better estimates than genotype data for quantities such as recombination rates. Results To answer these questions, a reduction is given from genotype problem instances to haplotype problem instances, and it is shown that solving the haplotype problem yields the solution to the genotype problem, up to constant factors or coefficients. The pedigree analysis problems we will consider are the likelihood, maximum probability haplotype, and minimum recombination haplotype problems. Conclusions Two algorithms are introduced: an exponential-time hidden Markov model (HMM for haplotype data where some individuals are untyped, and a linear-time algorithm for pedigrees having haplotype data for all individuals. Recombination estimates from the general haplotype HMM algorithm are compared to recombination estimates produced by a genotype HMM. Having haplotype data on all individuals produces better estimates. However, having several untyped individuals can drastically reduce the utility of haplotype data.

  4. Pure Parsimony Xor Haplotyping

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    Bonizzoni, Paola; Dondi, Riccardo; Pirola, Yuri; Rizzi, Romeo

    2010-01-01

    The haplotype resolution from xor-genotype data has been recently formulated as a new model for genetic studies. The xor-genotype data is a cheaply obtainable type of data distinguishing heterozygous from homozygous sites without identifying the homozygous alleles. In this paper we propose a formulation based on a well-known model used in haplotype inference: pure parsimony. We exhibit exact solutions of the problem by providing polynomial time algorithms for some restricted cases and a fixed-parameter algorithm for the general case. These results are based on some interesting combinatorial properties of a graph representation of the solutions. Furthermore, we show that the problem has a polynomial time k-approximation, where k is the maximum number of xor-genotypes containing a given SNP. Finally, we propose a heuristic and produce an experimental analysis showing that it scales to real-world large instances taken from the HapMap project.

  5. Pure parsimony xor haplotyping.

    Science.gov (United States)

    Bonizzoni, Paola; Della Vedova, Gianluca; Dondi, Riccardo; Pirola, Yuri; Rizzi, Romeo

    2010-01-01

    The haplotype resolution from xor-genotype data has been recently formulated as a new model for genetic studies. The xor-genotype data is a cheaply obtainable type of data distinguishing heterozygous from homozygous sites without identifying the homozygous alleles. In this paper, we propose a formulation based on a well-known model used in haplotype inference: pure parsimony. We exhibit exact solutions of the problem by providing polynomial time algorithms for some restricted cases and a fixed-parameter algorithm for the general case. These results are based on some interesting combinatorial properties of a graph representation of the solutions. Furthermore, we show that the problem has a polynomial time k-approximation, where k is the maximum number of xor-genotypes containing a given single nucleotide polymorphisms (SNP). Finally, we propose a heuristic and produce an experimental analysis showing that it scales to real-world large instances taken from the HapMap project.

  6. Does the pain-protective GTP cyclohydrolase haplotype significantly alter the pattern or severity of pain in humans with chronic pancreatitis?

    Directory of Open Access Journals (Sweden)

    Anderson Michelle A

    2008-11-01

    Full Text Available Abstract Background Pain is often a dominant clinical feature of chronic pancreatitis but the frequency and severity is highly variable between subjects. We hypothesized that genetic polymorphisms contribute to variations in clinical pain patterns. Since genetic variations in the GTP cyclohydrolase (GCH1 gene have been reported to protect some patients from pain, we investigated the effect of the "pain protective haplotype" in well characterized patients with chronic pancreatitis (CP or recurrent acute pancreatitis (RAP from the North American Pancreatitis Study 2 (NAPS2. Results Subjects in the NAPS2 study were asked to rank their pain in one of 5 categories reflecting different levels of pain frequency and severity. All subjects were genotyped at rs8007267 and rs3783641 to determine the frequency of the GCH1 pain-protective haplotype. In Caucasian subjects the frequency of the pain-protective GCH1 haplotype was no different in the control group (n = 236, CP patients (n = 265, RAP patients (N = 131, or in CP patients subclassified by pain category compared to previously reported haplotype frequencies in the general Caucasian population. Conclusion The GCH1 pain-protective haplotype does not have a significant effect on pain patterns or severity in RAP or CP. These results are important for helping to define the regulators of visceral pain, and to distinguish different mechanisms of pain.

  7. Haplotyping as perfect phylogeny: a direct approach.

    Science.gov (United States)

    Bafna, Vineet; Gusfield, Dan; Lancia, Giuseppe; Yooseph, Shibu

    2003-01-01

    A full haplotype map of the human genome will prove extremely valuable as it will be used in large-scale screens of populations to associate specific haplotypes with specific complex genetic-influenced diseases. A haplotype map project has been announced by NIH. The biological key to that project is the surprising fact that some human genomic DNA can be partitioned into long blocks where genetic recombination has been rare, leading to strikingly fewer distinct haplotypes in the population than previously expected (Helmuth, 2001; Daly et al., 2001; Stephens et al., 2001; Friss et al., 2001). In this paper we explore the algorithmic implications of the no-recombination in long blocks observation, for the problem of inferring haplotypes in populations. This assumption, together with the standard population-genetic assumption of infinite sites, motivates a model of haplotype evolution where the haplotypes in a population are assumed to evolve along a coalescent, which as a rooted tree is a perfect phylogeny. We consider the following algorithmic problem, called the perfect phylogeny haplotyping problem (PPH), which was introduced by Gusfield (2002) - given n genotypes of length m each, does there exist a set of at most 2n haplotypes such that each genotype is generated by a pair of haplotypes from this set, and such that this set can be derived on a perfect phylogeny? The approach taken by Gusfield (2002) to solve this problem reduces it to established, deep results and algorithms from matroid and graph theory. Although that reduction is quite simple and the resulting algorithm nearly optimal in speed, taken as a whole that approach is quite involved, and in particular, challenging to program. Moreover, anyone wishing to fully establish, by reading existing literature, the correctness of the entire algorithm would need to read several deep and difficult papers in graph and matroid theory. However, as stated by Gusfield (2002), many simplifications are possible and the

  8. Next-Generation Sequencing of the HLA locus: Methods and impacts on HLA typing, population genetics and disease association studies.

    Science.gov (United States)

    Carapito, Raphael; Radosavljevic, Mirjana; Bahram, Seiamak

    2016-11-01

    The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could be defined as a "super locus" (historically called "supergene") governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most gene-dense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  9. HLA class I and class II conserved extended haplotypes and their fragments or blocks in Mexicans: implications for the study of genetic diversity in admixed populations.

    Directory of Open Access Journals (Sweden)

    Joaquín Zúñiga

    Full Text Available Major histocompatibility complex (MHC genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C, and class II (HLA-DRB1, -DQB1 genes using high-resolution sequence based typing (SBT method and we structured the blocks and conserved extended haplotypes (CEHs in 234 non-related admixed Mexican individuals (468 haplotypes by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs and HLA-B that correlated with the frequency of most probable ancestral HLA-C/-B and -DRB1/-DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations.

  10. Haplotype-resolved genome sequencing of a Gujarati Indian individual.

    Science.gov (United States)

    Kitzman, Jacob O; Mackenzie, Alexandra P; Adey, Andrew; Hiatt, Joseph B; Patwardhan, Rupali P; Sudmant, Peter H; Ng, Sarah B; Alkan, Can; Qiu, Ruolan; Eichler, Evan E; Shendure, Jay

    2011-01-01

    Haplotype information is essential to the complete description and interpretation of genomes, genetic diversity and genetic ancestry. Although individual human genome sequencing is increasingly routine, nearly all such genomes are unresolved with respect to haplotype. Here we combine the throughput of massively parallel sequencing with the contiguity information provided by large-insert cloning to experimentally determine the haplotype-resolved genome of a South Asian individual. A single fosmid library was split into a modest number of pools, each providing ∼3% physical coverage of the diploid genome. Sequencing of each pool yielded reads overwhelmingly derived from only one homologous chromosome at any given location. These data were combined with whole-genome shotgun sequence to directly phase 94% of ascertained heterozygous single nucleotide polymorphisms (SNPs) into long haplotype blocks (N50 of 386 kilobases (kbp)). This method also facilitates the analysis of structural variation, for example, to anchor novel insertions to specific locations and haplotypes.

  11. Reconstruction of N-acetyltransferase 2 haplotypes using PHASE.

    Science.gov (United States)

    Golka, Klaus; Blaszkewicz, Meinolf; Samimi, Mirabutaleb; Bolt, Hermann M; Selinski, Silvia

    2008-04-01

    The genotyping of N-acetyltransferase 2 (NAT2) by PCR/RFLP methods yields in a considerable percentage ambiguous results. To resolve this methodical problem a statistical approach was applied. PHASE v2.1.1, a statistical program for haplotype reconstruction was used to estimate haplotype pairs from NAT2 genotyping data, obtained by the analysis of seven single nucleotide polymorphisms relevant for Caucasians. In 1,011 out of 2,921 (35%) subjects the haplotype pairs were clearcut by the PCR/RFLP data only. For the majority of the data the applied method resulted in a multiplicity (2-4) of possible haplotype pairs. Haplotype reconstruction using PHASE v2.1.1 cleared this ambiguity in all cases but one, where an alternative haplotype pair was considered with a probability of 0.029. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles *12A, *12B, *12C or *13 to the rapid or slow NAT2 genotype has been discussed controversially. A clear assignment is indispensable in surveys of human bladder cancer caused by aromatic amine exposures. In conclusion, PHASE v2.1.1 software allowed an unambiguous haplotype reconstruction in 2,920 of 2,921 cases (>99.9%).

  12. Variation in effects of non-Hodgkin lymphoma risk factors according to the human leukocyte antigen (HLA-DRB1*01:01 allele and ancestral haplotype 8.1.

    Directory of Open Access Journals (Sweden)

    Sophia S Wang

    Full Text Available Genetic variations in human leukocyte antigens (HLA are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH 8.1 (HLA-A*01-B*08-DR*03-TNF-308A. To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk.

  13. The human tyrosine aminotransferase gene: characterization of restriction fragment length polymorphisms and haplotype analysis in a family with tyrosinemia type II.

    Science.gov (United States)

    Westphal, E M; Natt, E; Grimm, T; Odievre, M; Scherer, G

    1988-07-01

    Deficiency in hepatic tyrosine aminotransferase (TAT) causes tyrosinemia type II, an autosomal recessively inherited disorder. Using a TAT cosmid clone, we have identified an MspI restriction fragment length polymorphism (RFLP) 5' to the TAT gene, with allele frequencies of 0.63 and 0.37. Analysis of the cloned maternal and paternal TAT alleles from a patient with tyrosinemia type II led to the identification of a HaeIII RFLP at the 3' end of the TAT gene, with allele frequencies of 0.94 and 0.06. The two RFLPs are 27 kb apart and in no allelic association. From haplotype frequencies, a polymorphism information content (PIC) value of 0.44 was obtained. The two RFLPs have allowed the unambiguous identification of the mutant TAT alleles in the patient's pedigree by haplotype analysis.

  14. The Effect of Haplotype-Block Definitions on Inference of Haplotype-Block Structure and htSNPs Selection

    Institute of Scientific and Technical Information of China (English)

    KeyueDing; KaixinZhou; JingZhang; JoanneKnight; XuegongZhang; YanShen

    2005-01-01

    It has been recently suggested that the human genome is organized as a series of haplotype blocks, and efforts to create a genome-wide haplotype map are already underway. Several computational algorithms have been proposed to partition the genome. However, little is known about their behaviors in relation to the haplotype-block partitioning and haplotypetagging SNPs selection. Here, we present a systematic comparison of three classes of haplotype-block partition definitions, a diversity-based method, a linkage-disequilibrium (LD)-based method, and a recombination-based method.The data used were derived from a coalescent simulation under both a uniform recombination model and one that assumes recombination hotspots. There were considerable differences in haplotype information loss in the measure of entropy when the partition methods were compared under different population-genetics scenarios. Under both recombination models, the results from the LD-based definition and the recombination-based definition were more similar to each other than were the results from the diversity-based definition. This work demonstrates that when undertaking haplotype-based association mapping, the choice of haplotype-block definition and SNP selection requires careful consideration.

  15. G16R single nucleotide polymorphism but not haplotypes of the ß2-adrenergic receptor gene alters cardiac output in humans

    DEFF Research Database (Denmark)

    Rokamp, Kim Z; Staalsø, Jonatan M; Gartmann, Martin

    2013-01-01

    studied. Five SNPs within ADRB2 (46G>A, 79C>G, 491C>T, 523C>A and 1053G>C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise......Variation in genes encoding the ß2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q¿ (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with ß2-mediated vasodilation, but the effect of ADRB2 haplotypes on Q¿ has not been...... V¿O2 (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0-0.9) l/min lower in Arg16 carriers (P=0.035). A similar effect size was observed for the Arg16 haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in Q¿ was 0...

  16. HaploForge: A Comprehensive Pedigree Drawing and Haplotype Visualisation Web Application.

    Science.gov (United States)

    Tekman, Mehmet; Medlar, Alan; Mozere, Monika; Kleta, Robert; Stanescu, Horia

    2017-08-14

    Haplotype reconstruction is an important tool for understanding the aetiology of human disease. Haplotyping infers the most likely phase of observed genotypes conditional on constraints imposed by the genotypes of other pedigree members. The results of haplotype reconstruction, when visualised appropriately, show which alleles are identical by descent despite the presence of untyped individuals. When used in concert with linkage analysis, haplotyping can help delineate a locus of interest and provide a succinct explanation for the transmission of the trait locus. Unfortunately, the design choices made by existing haplotype visualisation programs do not scale to large numbers of markers. Indeed, following haplotypes from generation to generation requires excessive scrolling back and forth. In addition, the most widely-used program for haplotype visualisation produces inconsistent recombination artefacts for the X chromosome. To resolve these issues, we developed HaploForge, a novel web application for haplotype visualisation and pedigree drawing. HaploForge takes advantage of HTML5 to be fast, portable and avoid the need for local installation. It can accurately visualise autosomal and X-linked haplotypes from both outbred and consanguineous pedigrees. Haplotypes are coloured based on identity by descent using a novel A* search algorithm and we provide a flexible viewing mode to aid visual inspection. HaploForge can currently process haplotype reconstruction output from Allegro, GeneHunter, Merlin and Simwalk. HaploForge is licensed under GPLv3 and is hosted and maintained via GitHub. Supplementary data is available from Bioinformatics online.

  17. Understanding Y haplotype matching probability.

    Science.gov (United States)

    Brenner, Charles H

    2014-01-01

    The Y haplotype population-genetic terrain is better explored from a fresh perspective rather than by analogy with the more familiar autosomal ideas. For haplotype matching probabilities, versus for autosomal matching probabilities, explicit attention to modelling - such as how evolution got us where we are - is much more important while consideration of population frequency is much less so. This paper explores, extends, and explains some of the concepts of "Fundamental problem of forensic mathematics - the evidential strength of a rare haplotype match". That earlier paper presented and validated a "kappa method" formula for the evidential strength when a suspect matches a previously unseen haplotype (such as a Y-haplotype) at the crime scene. Mathematical implications of the kappa method are intuitive and reasonable. Suspicions to the contrary raised in rest on elementary errors. Critical to deriving the kappa method or any sensible evidential calculation is understanding that thinking about haplotype population frequency is a red herring; the pivotal question is one of matching probability. But confusion between the two is unfortunately institutionalized in much of the forensic world. Examples make clear why (matching) probability is not (population) frequency and why uncertainty intervals on matching probabilities are merely confused thinking. Forensic matching calculations should be based on a model, on stipulated premises. The model inevitably only approximates reality, and any error in the results comes only from error in the model, the inexactness of the approximation. Sampling variation does not measure that inexactness and hence is not helpful in explaining evidence and is in fact an impediment. Alternative haplotype matching probability approaches that various authors have considered are reviewed. Some are based on no model and cannot be taken seriously. For the others, some evaluation of the models is discussed. Recent evidence supports the adequacy of

  18. HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies of 10 918 Koreans from bone marrow donor registry in Korea.

    Science.gov (United States)

    Park, H; Lee, Y-J; Song, E Y; Park, M H

    2016-10-01

    The human leucocyte antigen (HLA) system is the most polymorphic genetic system in humans, and HLA matching is crucial in organ transplantation, especially in hematopoietic stem cell transplantation. We investigated HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies at allelic level in 10 918 Koreans from bone marrow donor registry in Korea. Intermediate resolution HLA typing was performed using Luminex technology (Wakunaga, Japan), and additional allelic level typing was performed using PCR-single-strand conformation polymorphism method and/or sequence-based typing (Abbott Molecular, USA). Allele and haplotype frequencies were calculated by direct counting and maximum likelihood methods, respectively. A total of 39 HLA-A, 66 HLA-B and 47 HLA-DRB1 alleles were identified. High-frequency alleles found at a frequency of ≥5% were 6 HLA-A (A*02:01, *02:06, *11:01, *24:02, *31:01 and *33:03), 6 HLA-B (B*15:01, *35:01, *44:03, *51:01, 54:01 and *58:01) and 8 HLA-DRB1 (DRB1*01:01, *04:05, *04:06, *07:01, *08:03, *09:01, *13:02 and *15:01) alleles. At each locus, A*02, B*15 and DRB1*14 generic groups were most diverse at allelic level, consisting of 9, 12 and 11 different alleles, respectively. A total of 366, 197 and 21 different HLA-A-B-DRB1 haplotypes were estimated with frequencies of ≥0.05%, ≥0.1% and ≥0.5%, respectively. The five most common haplotypes with frequencies of ≥2.0% were A*33:03-B*44:03-DRB1*13:02 (4.97%), A*33:03-B*58:01-DRB1*13:02, A*33:03-B*44:03-DRB1*07:01, A*24:02-B*07:02-DRB1*01:01 and A*24:02-B*52:01-DRB1*15:02. Among 34 serologic HLA-A-B-DR haplotypes with frequencies of ≥0.5%, 17 haplotypes revealed allele-level diversity and majority of the allelic variation was arising from A2, A26, B61, B62, DR4 and DR14 specificities. Haplotype diversity obtained in this study is the most comprehensive data thus far reported in Koreans, and the information will be useful for unrelated stem cell transplantation as well as for disease

  19. Characterisation of TNF block haplotypes affecting the production of TNF and LTA.

    Science.gov (United States)

    Tan, J H; Temple, S E L; Kee, C; Waterer, G W; Tan, C R T; Gut, I; Price, P

    2011-02-01

    Polymorphisms in the central major histocompatibility complex (MHC) (particularly TNF and adjacent genes) associate with several immunopathological diseases and with susceptibility to pneumonia. The MHC is characterised by strong linkage disequilibrium (LD), so identification of loci affecting disease must be based on haplotypes. We have defined 31 tumour necrosis factor (TNF) block haplotypes (denoted FV1-31) in Caucasians, Asians and Australian Aboriginals. This study correlates the carriage of TNF block haplotypes with TNF and lymphotoxin alpha (LTA) protein production by peripheral blood mononuclear cells from 205 healthy Caucasian subjects, following in vitro stimulation with Streptococcus pneumoniae (S. pneumoniae; gram-positive bacteria), Escherichia coli (E. coli; gram-negative bacteria) or TNF over 4, 8 and 24 h. Fifteen haplotypes were present at >1%, accounting for 94.5% of the cohort. The haplotypes were grouped into five families based on common alleles. Following stimulation, cells from carriers of the FV10 haplotype (family 2) produced less LTA compared with non-FV10 carriers. Carriers of the FV18 haplotype (family 4) produced more LTA than other donors. Induction of TNF by S. pneumoniae following 24 h stimulation was also greater in donors with FV18. The FV18 haplotype associated with the 44.1 MHC ancestral haplotype (HLA-A2, -C5, -B44, -DRB1*0401 and -DQB1*0301) that has few disease associations. FV16 occurred in the 8.1 MHC haplotype (HLA-A2, B8, DR3) that is associated with multiple immunopathological diseases. FV16 did not affect TNF or LTA levels. The findings suggest that many genetic variations critical in vivo are not effectively modelled by short-term cultures.

  20. Diseases associated with leaky hemichannels

    Science.gov (United States)

    Retamal, Mauricio A.; Reyes, Edison P.; García, Isaac E.; Pinto, Bernardo; Martínez, Agustín D.; González, Carlos

    2015-01-01

    Hemichannels (HCs) and gap junction channels (GJCs) formed by protein subunits called connexins (Cxs) are major pathways for intercellular communication. While HCs connect the intracellular compartment with the extracellular milieu, GJCs allow the interchange of molecules between cytoplasm of two contacting cells. Under physiological conditions, HCs are mostly closed, but they can open under certain stimuli allowing the release of autocrine and paracrine molecules. Moreover, some pathological conditions, like ischemia or other inflammation conditions, significantly increase HCs activity. In addition, some mutations in Cx genes associated with human diseases, such as deafness or cataracts, lead to the formation of more active HCs or “leaky HCs.” In this article we will revise cellular and molecular mechanisms underlying the appearance of leaky HCs, and the consequences of their expression in different cellular systems and animal models, in seeking a common pattern or pathological mechanism of disease. PMID:26283912

  1. Diseases associated with leaky hemichannels.

    Directory of Open Access Journals (Sweden)

    Mauricio Antonio Retamal

    2015-07-01

    Full Text Available Hemichannels (HCs and gap junction channels (GJCs formed by protein subunits called connexins (Cxs are major pathways for intercellular communication. While HCs connect the intracellular compartment with the extracellular milieu, GJCs allow the interchange of molecules between cytoplasm of two contacting cells. Under physiological conditions, HCs are mostly closed, but they can open under certain stimuli allowing the release of autocrine and paracrine molecules. Moreover, some pathological conditions, like ischemia or other inflammation conditions, significantly increase HCs activity. In addition, some mutations in Cx genes associated with human diseases, such as deafness or cataracts, lead to the formation of more active HCs or leaky HCs. In this article we will revise cellular and molecular mechanisms underlying the appearance of leaky HCs, and the consequences of their expression in different cellular systems and animal models, in seeking a common pattern or pathological mechanism of disease.

  2. Cloud computing-based TagSNP selection algorithm for human genome data.

    Science.gov (United States)

    Hung, Che-Lun; Chen, Wen-Pei; Hua, Guan-Jie; Zheng, Huiru; Tsai, Suh-Jen Jane; Lin, Yaw-Ling

    2015-01-05

    Single nucleotide polymorphisms (SNPs) play a fundamental role in human genetic variation and are used in medical diagnostics, phylogeny construction, and drug design. They provide the highest-resolution genetic fingerprint for identifying disease associations and human features. Haplotypes are regions of linked genetic variants that are closely spaced on the genome and tend to be inherited together. Genetics research has revealed SNPs within certain haplotype blocks that introduce few distinct common haplotypes into most of the population. Haplotype block structures are used in association-based methods to map disease genes. In this paper, we propose an efficient algorithm for identifying haplotype blocks in the genome. In chromosomal haplotype data retrieved from the HapMap project website, the proposed algorithm identified longer haplotype blocks than an existing algorithm. To enhance its performance, we extended the proposed algorithm into a parallel algorithm that copies data in parallel via the Hadoop MapReduce framework. The proposed MapReduce-paralleled combinatorial algorithm performed well on real-world data obtained from the HapMap dataset; the improvement in computational efficiency was proportional to the number of processors used.

  3. Cloud Computing-Based TagSNP Selection Algorithm for Human Genome Data

    Science.gov (United States)

    Hung, Che-Lun; Chen, Wen-Pei; Hua, Guan-Jie; Zheng, Huiru; Tsai, Suh-Jen Jane; Lin, Yaw-Ling

    2015-01-01

    Single nucleotide polymorphisms (SNPs) play a fundamental role in human genetic variation and are used in medical diagnostics, phylogeny construction, and drug design. They provide the highest-resolution genetic fingerprint for identifying disease associations and human features. Haplotypes are regions of linked genetic variants that are closely spaced on the genome and tend to be inherited together. Genetics research has revealed SNPs within certain haplotype blocks that introduce few distinct common haplotypes into most of the population. Haplotype block structures are used in association-based methods to map disease genes. In this paper, we propose an efficient algorithm for identifying haplotype blocks in the genome. In chromosomal haplotype data retrieved from the HapMap project website, the proposed algorithm identified longer haplotype blocks than an existing algorithm. To enhance its performance, we extended the proposed algorithm into a parallel algorithm that copies data in parallel via the Hadoop MapReduce framework. The proposed MapReduce-paralleled combinatorial algorithm performed well on real-world data obtained from the HapMap dataset; the improvement in computational efficiency was proportional to the number of processors used. PMID:25569088

  4. Acute Respiratory Disease Associated with Mannheimia ...

    African Journals Online (AJOL)

    Acute Respiratory Disease Associated with Mannheimia Haemolytica ... to the Veterinary Teaching Hospital (VTH), University of Agriculture, Abeokuta, Nigeria. Mannheimia spp was isolated from the nasal swab and lymph node and lung ...

  5. Functionality and opposite roles of two interleukin 4 haplotypes in immune cells

    Science.gov (United States)

    Anovazzi, G; Medeiros, M C; Pigossi, S C; Finoti, L S; Souza Moreira, T M; Mayer, M P A; Zanelli, C F; Valentini, S R; Rossa-Junior, C; Scarel-Caminaga, R M

    2017-01-01

    Cytokines expression can be influenced by polymorphisms in their respective coding genes. We associated the CTI/TTD haplotype (Hap-1) and TCI/CCI haplotype (Hap-2) in the IL4 gene formed by the −590, +33 and variable number of tandem repeat polymorphisms with the severity of chronic periodontitis in humans. The functionality of these IL4 haplotypes in the response of immune cells to phorbol 12-myristate 13-acetate (PMA) with Ionomycin and IL-1β (as inflammatory stimuli) was evaluated. Gene expression (quantitative real-time PCR), profile of secreted cytokines (multiplex) and phenotypic polarization of T cells (flow cytometry) were the outcomes assessed. Green fluorescent protein reporter plasmid constructs containing specific IL4 haplotype were transiently transfected into JM cells to assess the influence of the individual haplotypes on promoter activity. In response to inflammatory stimuli the immune cells from Hap-1 haplotype had increased expression of anti-inflammatory IL4; conversely, the Hap-2 haplotype showed higher levels of pro-inflammatory cytokines. The haplotype CTI proved to be the most important for the regulation of IL4 promoter, regardless of the nature of the inflammatory stimulation; whereas the polymorphism in the promoter region had the least functional effect. In conclusion, IL4 haplotypes studied are functional and trigger opposite immune responses: anti-inflammatory (Hap-1) and pro-inflammatory (Hap-2). In addition, we identified the CTI haplotype as the main responsible for the regulation of IL4 transcriptional activity. PMID:28053321

  6. Definition of gene content for nine common group B haplotypes of the Caucasoid population: KIR haplotypes contain between seven and eleven KIR genes.

    Science.gov (United States)

    Uhrberg, Markus; Parham, Peter; Wernet, Peter

    2002-07-01

    The segregation of killer cell immunoglobulin-like receptor ( KIR) genes was determined for a panel of 21 Caucasoid families: 23 different KIR gene patterns were found and could be assigned to combinations of 16 different haplotypes. Four loci were held in common by all haplotypes: KIR2DL4, KIR3DL2, the putative pseudogene KIR3DL3 and KIR2DL2/KIR2DL3, the latter likely being alleles of one gene. Group A haplotypes, which have a unique combination of seven KIR genes, were found at 80% frequency in the family panel, the polygenic group B haplotypes at 65% frequency. KIR gene segregation was fully determined for the nine group B haplotypes, which occurred at highest frequencies in both the family panel and a panel of unrelated individuals. The group B haplotypes carried between seven and 11 KIR genes and encoded inhibitory KIR for one, two, or all three major HLA class I epitopes. Analysis of human leucocyte antigen (HLA) class I genotypes revealed that most, but not all, individuals possess an inhibitory KIR for a self HLA class I epitope. The number of stimulatory KIR genes in group B haplotypes varied considerably between one and five. The data show that group B haplotypes possess a broad spectrum of KIR gene patterns, which is largely complementary to the KIR gene set of group A haplotypes. The results suggest that rapid diversification of group B haplotypes is the result of pathogen-mediated selection for KIR genotypes that have more than the set of KIR genes provided by the group A haplotype.

  7. Common Membrane Trafficking Defects of Disease Associated Dynamin 2 Mutations

    OpenAIRE

    Liu, Ya-Wen; Lukiyanchuk, Vasyl; Schmid, Sandra L.

    2011-01-01

    Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, Centronuclear Myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cell...

  8. 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

    BACKGROUND AND OBJECTIVES: The 8.1 ancestral haplotype (AH) (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2) is a remarkably long and conserved haplotype in the human major histocompatibility complex. It has been associated with both beneficial and detrimental effects, consistent with antagonistic pleiotr...

  9. Complementarity of Binding Motifs is a General Property of HLA-A and HLA-B Molecules and Does Not Seem to Effect HLA Haplotype Composition

    OpenAIRE

    2013-01-01

    Different human leukocyte antigen (HLA) haplotypes (i.e., the specific combinations of HLA-A, -B, -DR alleles inherited together from one parent) are observed in different frequencies in human populations. Some haplotypes, like HLA-A1-B8, are very frequent, reaching up to 10% in the Caucasian population, while others are very rare. Numerous studies have identified associations between HLA haplotypes and diseases, and differences in haplotype frequencies can in part be explained by these assoc...

  10. Complement genetics, deficiencies, and disease associations.

    Science.gov (United States)

    Mayilyan, Karine R

    2012-07-01

    The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

  11. High-resolution haplotype block structure in the cattle genome

    Directory of Open Access Journals (Sweden)

    Choi Jungwoo

    2009-04-01

    Full Text Available Abstract Background The Bovine HapMap Consortium has generated assay panels to genotype ~30,000 single nucleotide polymorphisms (SNPs from 501 animals sampled from 19 worldwide taurine and indicine breeds, plus two outgroup species (Anoa and Water Buffalo. Within the larger set of SNPs we targeted 101 high density regions spanning up to 7.6 Mb with an average density of approximately one SNP per 4 kb, and characterized the linkage disequilibrium (LD and haplotype block structure within individual breeds and groups of breeds in relation to their geographic origin and use. Results From the 101 targeted high-density regions on bovine chromosomes 6, 14, and 25, between 57 and 95% of the SNPs were informative in the individual breeds. The regions of high LD extend up to ~100 kb and the size of haplotype blocks ranges between 30 bases and 75 kb (10.3 kb average. On the scale from 1–100 kb the extent of LD and haplotype block structure in cattle has high similarity to humans. The estimation of effective population sizes over the previous 10,000 generations conforms to two main events in cattle history: the initiation of cattle domestication (~12,000 years ago, and the intensification of population isolation and current population bottleneck that breeds have experienced worldwide within the last ~700 years. Haplotype block density correlation, block boundary discordances, and haplotype sharing analyses were consistent in revealing unexpected similarities between some beef and dairy breeds, making them non-differentiable. Clustering techniques permitted grouping of breeds into different clades given their similarities and dissimilarities in genetic structure. Conclusion This work presents the first high-resolution analysis of haplotype block structure in worldwide cattle samples. Several novel results were obtained. First, cattle and human share a high similarity in LD and haplotype block structure on the scale of 1–100 kb. Second, unexpected

  12. HaplotypeCN: copy number haplotype inference with Hidden Markov Model and localized haplotype clustering.

    Directory of Open Access Journals (Sweden)

    Yen-Jen Lin

    Full Text Available Copy number variation (CNV has been reported to be associated with disease and various cancers. Hence, identifying the accurate position and the type of CNV is currently a critical issue. There are many tools targeting on detecting CNV regions, constructing haplotype phases on CNV regions, or estimating the numerical copy numbers. However, none of them can do all of the three tasks at the same time. This paper presents a method based on Hidden Markov Model to detect parent specific copy number change on both chromosomes with signals from SNP arrays. A haplotype tree is constructed with dynamic branch merging to model the transition of the copy number status of the two alleles assessed at each SNP locus. The emission models are constructed for the genotypes formed with the two haplotypes. The proposed method can provide the segmentation points of the CNV regions as well as the haplotype phasing for the allelic status on each chromosome. The estimated copy numbers are provided as fractional numbers, which can accommodate the somatic mutation in cancer specimens that usually consist of heterogeneous cell populations. The algorithm is evaluated on simulated data and the previously published regions of CNV of the 270 HapMap individuals. The results were compared with five popular methods: PennCNV, genoCN, COKGEN, QuantiSNP and cnvHap. The application on oral cancer samples demonstrates how the proposed method can facilitate clinical association studies. The proposed algorithm exhibits comparable sensitivity of the CNV regions to the best algorithm in our genome-wide study and demonstrates the highest detection rate in SNP dense regions. In addition, we provide better haplotype phasing accuracy than similar approaches. The clinical association carried out with our fractional estimate of copy numbers in the cancer samples provides better detection power than that with integer copy number states.

  13. HaplotypeCN: Copy Number Haplotype Inference with Hidden Markov Model and Localized Haplotype Clustering

    Science.gov (United States)

    Lin, Yen-Jen; Chen, Yu-Tin; Hsu, Shu-Ni; Peng, Chien-Hua; Tang, Chuan-Yi; Yen, Tzu-Chen; Hsieh, Wen-Ping

    2014-01-01

    Copy number variation (CNV) has been reported to be associated with disease and various cancers. Hence, identifying the accurate position and the type of CNV is currently a critical issue. There are many tools targeting on detecting CNV regions, constructing haplotype phases on CNV regions, or estimating the numerical copy numbers. However, none of them can do all of the three tasks at the same time. This paper presents a method based on Hidden Markov Model to detect parent specific copy number change on both chromosomes with signals from SNP arrays. A haplotype tree is constructed with dynamic branch merging to model the transition of the copy number status of the two alleles assessed at each SNP locus. The emission models are constructed for the genotypes formed with the two haplotypes. The proposed method can provide the segmentation points of the CNV regions as well as the haplotype phasing for the allelic status on each chromosome. The estimated copy numbers are provided as fractional numbers, which can accommodate the somatic mutation in cancer specimens that usually consist of heterogeneous cell populations. The algorithm is evaluated on simulated data and the previously published regions of CNV of the 270 HapMap individuals. The results were compared with five popular methods: PennCNV, genoCN, COKGEN, QuantiSNP and cnvHap. The application on oral cancer samples demonstrates how the proposed method can facilitate clinical association studies. The proposed algorithm exhibits comparable sensitivity of the CNV regions to the best algorithm in our genome-wide study and demonstrates the highest detection rate in SNP dense regions. In addition, we provide better haplotype phasing accuracy than similar approaches. The clinical association carried out with our fractional estimate of copy numbers in the cancer samples provides better detection power than that with integer copy number states. PMID:24849202

  14. Transcriptional defect of an inherited NKX2-5 haplotype comprising a SNP, a nonsynonymous and a synonymous mutation, associated with human congenital heart disease.

    Directory of Open Access Journals (Sweden)

    Stella Marie Reamon-Buettner

    Full Text Available Germline mutations in cardiac-specific transcription factor genes have been associated with congenital heart disease (CHD and the homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. In pursuit of understanding causes of CHD, we analyzed n = 49 cardiac biopsies from 28 patients and identified by direct sequencing two nonsynonymous NKX2-5 alterations affecting alanine 119, namely c.356C>A (p.A119E and c.355G>T, (p.A119S, in patients with AVSD and HLHS, respectively. In functional assays, a significant reduction in transcriptional activities could be determined for the NKX2-5 variants. Importantly, in one family the mother, besides p.A119E, carried a synonymous mutant allele in the homeodomain (c.543G>A, p.Q181, and a synonymous dbSNP (c.63A>G, p.E21 in the transactivation domain of the protein, that were transmitted to the CHD daughter. The presence of these variants in-cis with the p.A119E mutation led to a further reduction in transcriptional activities. Such difference in activity may be in part related to reduced protein expression for the double variant c.356C>A and c.543G>A. We propose changes in mRNA stability and folding, due to a silent mutation and a dbSNP in the NKX2-5 coding region to contribute to the functional defect. Although the clinical significance of the NKX2-5 haplotype identified in the CHD patients remains to be ascertained, we provide evidence of an interaction of a dbSNP, with synonymous and nonsynonymous mutations to negatively impact NKX2-5 transcriptional activity.

  15. Disease-associated mutations that alter the RNA structural ensemble.

    Directory of Open Access Journals (Sweden)

    Matthew Halvorsen

    2010-08-01

    Full Text Available Genome-wide association studies (GWAS often identify disease-associated mutations in intergenic and non-coding regions of the genome. Given the high percentage of the human genome that is transcribed, we postulate that for some observed associations the disease phenotype is caused by a structural rearrangement in a regulatory region of the RNA transcript. To identify such mutations, we have performed a genome-wide analysis of all known disease-associated Single Nucleotide Polymorphisms (SNPs from the Human Gene Mutation Database (HGMD that map to the untranslated regions (UTRs of a gene. Rather than using minimum free energy approaches (e.g. mFold, we use a partition function calculation that takes into consideration the ensemble of possible RNA conformations for a given sequence. We identified in the human genome disease-associated SNPs that significantly alter the global conformation of the UTR to which they map. For six disease-states (Hyperferritinemia Cataract Syndrome, beta-Thalassemia, Cartilage-Hair Hypoplasia, Retinoblastoma, Chronic Obstructive Pulmonary Disease (COPD, and Hypertension, we identified multiple SNPs in UTRs that alter the mRNA structural ensemble of the associated genes. Using a Boltzmann sampling procedure for sub-optimal RNA structures, we are able to characterize and visualize the nature of the conformational changes induced by the disease-associated mutations in the structural ensemble. We observe in several cases (specifically the 5' UTRs of FTL and RB1 SNP-induced conformational changes analogous to those observed in bacterial regulatory Riboswitches when specific ligands bind. We propose that the UTR and SNP combinations we identify constitute a "RiboSNitch," that is a regulatory RNA in which a specific SNP has a structural consequence that results in a disease phenotype. Our SNPfold algorithm can help identify RiboSNitches by leveraging GWAS data and an analysis of the mRNA structural ensemble.

  16. Haplotype studies in Wilson disease

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.R.; Bull, P.C.; Roberts, E.A.; Cox, D.W.; Walshe, J.M. (Univ. of Toronto (Canada))

    1994-01-01

    In 51 families with Wilson disease, the authors have studied DNA haplotypes of dinucleotide repeat polymorphisms (CA repeats) in the 13q14.3 region, to examine these markers for association with the Wilson disease gene (WND). In addition to a marker (D13S133) described elsewhere, the authors have developed three new highly polymorphic markers (D13S314, D13S315, and D13S316) close to the WND locus. The authors have examined the distribution of marker alleles at the loci studied and have found that D13S314, D13S133, and D13S316 each show nonrandom distribution on chromosomes carrying the WND mutation. The authors have studied haplotypes of these three markers and have found that there are highly significant differences between WND and normal haplotypes in northern European families. These findings have important implications for mutation detection and molecular diagnosis in families with Wilson disease. 25 refs., 2 figs., 5 tabs.

  17. Disease-associated mutations prevent GPR56-collagen III interaction.

    Directory of Open Access Journals (Sweden)

    Rong Luo

    Full Text Available GPR56 is a member of the adhesion G protein-coupled receptor (GPCR family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP. Using the N-terminal fragment of GPR56 (GPR56(N as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N, the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown.

  18. Allele Polymorphism and Haplotype Diversity of HLA-A, -B and -DRB1 Loci in Sequence-Based Typing for Chinese Uyghur Ethnic Group

    Science.gov (United States)

    Shen, Chun-mei; Zhu, Bo-feng; Deng, Ya-jun; Ye, Shi-hui; Yan, Jiang-wei; Yang, Guang; Wang, Hong-dan; Qin, Hai-xia; Huang, Qi-zhao; Zhang, Jing-Jing

    2010-01-01

    /Significance The present findings could be useful to elucidate the genetic background of the population and to provide valuable data for HLA matching in clinical bone marrow transplantation, HLA-linked disease-association studies, population genetics, human identification and paternity tests in forensic sciences. PMID:21079793

  19. Inflammatory bowel disease associations with HLA Class II genes

    Energy Technology Data Exchange (ETDEWEB)

    Castro, R. [Cedars-Sinai Medical Center, Los Angeles, CA (United States); Yang, H.; Targan, S. [Roche Molecular Systems, Inc., Alameda, CA (United States)] [and others

    1994-09-01

    A PCR-SSOP assay has been used to analyze HLA-Class II DRB1 and DQB1 alleles in 378 Caucasians from a population in Southern California. The data has been analyzed separately for the Ashkenasi Jews and non-Jewish patients (n=286) and controls (n=92). Two common clinical forms of inflammatory bowel disease (IBD) have been studied: ulcerative colitis (UC) and Crohn`s disease (CD). In CD, we observed a susceptible effect with the rare DR1 allele - DRB*0103 [O.R.=4.56; 95% CI (0.96, 42.97); p=0.03]; a trend for an increase in DRB1*0103 was also observed in UC patients. A susceptible effect with DRB1*1502 [O.R.=5.20; 95% CI (1.10, 48.99); p=0.02] was observed in non-Jewish UC patients. This susceptible effect was restricted to UC ANCA-positive (antineutrophil cytoplasmic antibodies) patients. In addition, a significant association with DRB1*1101-DQB1*0301 [O.R.=9.46; 95% CI (1.30, 413.87); p=0.01] was seen with UC among non-Jewish patients: this haplotype was increased with CD among non-Jewish patients. Two protective haplotypes were detected among CD non-Jewish patients: DRB1*1301-DQB1*0603 [O.R.=0.34; 95% CI (0.09, 1.09); p=0.04], and DRB*0404-DQB1*0302 [O.R.=<0.08; 95% CI (0.0, 0.84); p=0.01]. When the same data were analyzed at the serology level, we observed a positive association in UC with DR2 [O.R.6.77; 95% CI (2.47, 22.95); p=2 x 10{sup -4}], and a positive association in CD with DR1 [O.R.=2.63; 95% CI (1.14, 6.62); p=0.01] consistent with previous reports. Thus, some IBD disease associations appear to be common to both UC and CD, while some are unique to one disease.

  20. SNP haplotype mapping in a small ALS family.

    Directory of Open Access Journals (Sweden)

    Katherine A Dick Krueger

    Full Text Available The identification of genes for monogenic disorders has proven to be highly effective for understanding disease mechanisms, pathways and gene function in humans. Nevertheless, while thousands of Mendelian disorders have not yet been mapped there has been a trend away from studying single-gene disorders. In part, this is due to the fact that many of the remaining single-gene families are not large enough to map the disease locus to a single site in the genome. New tools and approaches are needed to allow researchers to effectively tap into this genetic gold-mine. Towards this goal, we have used haploid cell lines to experimentally validate the use of high-density single nucleotide polymorphism (SNP arrays to define genome-wide haplotypes and candidate regions, using a small amyotrophic lateral sclerosis (ALS family as a prototype. Specifically, we used haploid-cell lines to determine if high-density SNP arrays accurately predict haplotypes across entire chromosomes and show that haplotype information significantly enhances the genetic information in small families. Panels of haploid-cell lines were generated and a 5 centimorgan (cM short tandem repeat polymorphism (STRP genome scan was performed. Experimentally derived haplotypes for entire chromosomes were used to directly identify regions of the genome identical-by-descent in 5 affected individuals. Comparisons between experimentally determined and in silico haplotypes predicted from SNP arrays demonstrate that SNP analysis of diploid DNA accurately predicted chromosomal haplotypes. These methods precisely identified 12 candidate intervals, which are shared by all 5 affected individuals. Our study illustrates how genetic information can be maximized using readily available tools as a first step in mapping single-gene disorders in small families.

  1. Whole-genome molecular haplotyping of single cells

    OpenAIRE

    Fan, H. Christina; Wang, Jianbin; Potanina, Anastasia; Quake, Stephen R

    2010-01-01

    Conventional experimental methods of studying the human genome are limited by the inability to independently study the combination of alleles, or haplotype, on each of the homologous copies of the chromosomes. We developed a microfluidic device capable of separating and amplifying homologous copies of each chromosome from a single human metaphase cell. Single-nucleotide polymorphism (SNP) array analysis of amplified DNA enabled us to achieve completely deterministic, whole-genome, personal ha...

  2. Haplotypes in the lipoprotein lipase gene influence fasting insulin and discovery of a new risk haplotype.

    Science.gov (United States)

    Goodarzi, Mark O; Taylor, Kent D; Guo, Xiuqing; Hokanson, John E; Haffner, Steven M; Cui, Jinrui; Chen, Yii-Der I; Wagenknecht, Lynne E; Bergman, Richard N; Rotter, Jerome I

    2007-01-01

    Prior studies of Mexican Americans described association of lipoprotein lipase (LPL) gene haplotypes with insulin sensitivity/resistance and atherosclerosis. The most common haplotype (haplotype 1) was protective, whereas the fourth most common haplotype (haplotype 4) conferred risk for insulin resistance and atherosclerosis. In this study of Hispanics in the Insulin Resistance Atherosclerosis Study Family Study, we sought to replicate LPL haplotype association with insulin sensitivity/resistance. LPL haplotypes based on 12 single nucleotide polymorphisms were analyzed for association with indexes of insulin sensitivity and other metabolic and adiposity measures. This study was conducted in the general community of San Antonio, Texas, and San Luis Valley, Colorado. Participants in this study were 978 members of 86 Hispanic families. LPL haplogenotype, metabolic phenotypes, and adiposity were measured in this study. The haplotype structure was identical with that observed in prior studies. Among 978 phenotyped subjects, haplotype 1 was associated with decreased fasting insulin (P = 0.01), and haplotype 4 was associated with increased fasting insulin (P = 0.02) and increased visceral fat mass (P = 0.002). Insulin sensitivity, derived from iv glucose tolerance testing, tended (P > 0.1) to be higher with haplotype 1 (S(I) = 1.72) and lower with haplotype 4 (S(I)=1.38). Haplotype 2 was associated with increases in fasting insulin, triglycerides (TGs), TG to high-density lipoprotein-cholesterol ratio, and apolipoprotein B (P = 0.01-0.04). This study independently replicates our prior results of LPL haplotypes 1 and 4 as associated with measures of insulin sensitivity and resistance, respectively. Haplotype 4 may confer insulin resistance by increasing visceral fat. Haplotype 2 was identified as a new risk haplotype, suggesting the complex nature of LPL's effect on features of the insulin resistance syndrome.

  3. Dengue fever virus and Japanese encephalitis virus synthetic peptides, with motifs to fit HLA class I haplotypes prevalent in human populations in endemic regions, can be used for application to skin Langerhans cells to prime antiviral CD8+ cytotoxic T cells (CTLs)--a novel approach to the protection of humans.

    Science.gov (United States)

    Becker, Y

    1994-09-01

    Flaviviruses were reported to induce CD8+ cytotoxic T cells in infected individuals, indicating that nonapeptides, proteolytic cleavage products of the viral precursor protein, enter the endoplasmic reticulum in infected cells and interact with HLA class I molecules. The assembled HLA class I molecules are transported to the plasma membrane and prime CD8+ T cells. Current knowledge of the interaction of viral peptides with HLA molecules is reviewed. Based on this review, an idea is presented to use synthetic flavivirus peptides with an amino acid motif to fit with the HLA class I peptide binding group of HLA haplotypes prevalent in a given population in an endemic area. These synthetic viral peptides may be introduced into the human skin using a lotion containing the peptides ("Peplotion") together with substances capable of enhancing the penetration of these peptides into the skin to reach Langerhans cells. The peptide-treated Langerhans cells, professional antigen-presenting cells, may bind the synthetic viral peptides by their HLA class I peptide-binding grooves. Antigens carrying Langerhans cells are able to migrate and induce the cellular immune response in the lymph nodes. This approach to the priming of antiviral CD8+ cytotoxic T cells may provide cellular immune protection from flavivirus infection without inducing the humoral immune response, which can lead to the shock syndrome in Dengue fever patients. To be able to develop anti-Dengue virus synthetic peptides for populations with different HLA class I haplotypes, it is necessary to develop computational studies to design HLA class I Dengue virus synthetic peptides with motifs to fit the HLA haplotypes of the population living in an endemic region for Dengue fever. Experiments to study Dengue virus and Japanese encephalitis peptides vaccines and their effectiveness in protection against Dengue fever and Japanese encephalitis are needed. The development of human antiviral vaccines for application of viral

  4. Conditional likelihood methods for haplotype-based association analysis using matched case-control data.

    Science.gov (United States)

    Chen, Jinbo; Rodriguez, Carmen

    2007-12-01

    Genetic epidemiologists routinely assess disease susceptibility in relation to haplotypes, that is, combinations of alleles on a single chromosome. We study statistical methods for inferring haplotype-related disease risk using single nucleotide polymorphism (SNP) genotype data from matched case-control studies, where controls are individually matched to cases on some selected factors. Assuming a logistic regression model for haplotype-disease association, we propose two conditional likelihood approaches that address the issue that haplotypes cannot be inferred with certainty from SNP genotype data (phase ambiguity). One approach is based on the likelihood of disease status conditioned on the total number of cases, genotypes, and other covariates within each matching stratum, and the other is based on the joint likelihood of disease status and genotypes conditioned only on the total number of cases and other covariates. The joint-likelihood approach is generally more efficient, particularly for assessing haplotype-environment interactions. Simulation studies demonstrated that the first approach was more robust to model assumptions on the diplotype distribution conditioned on environmental risk variables and matching factors in the control population. We applied the two methods to analyze a matched case-control study of prostate cancer.

  5. A haplotype of human angiotensinogen gene containing −217A increases blood pressure in transgenic mice compared with −217G

    OpenAIRE

    Jain, Sudhir; Vinukonda, Govindaiah; Fiering, Steven N; Kumar, Ashok

    2008-01-01

    The human angiotensinogen (hAGT) gene contains an A/G polymorphism at −217, and frequency of −217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb region of its promoter, and variant −217A almost always occurs with −532T, −793A, and −1074T, whereas variant −217G almost always occurs with −532C, −793G, and −1074G. Since allele −6A is the predominant allele in African-Americans, the AGT gene can be subdivided into two main h...

  6. Empirical vs Bayesian approach for estimating haplotypes from genotypes of unrelated individuals

    Directory of Open Access Journals (Sweden)

    Cheng Jacob

    2007-01-01

    Full Text Available Abstract Background The completion of the HapMap project has stimulated further development of haplotype-based methodologies for disease associations. A key aspect of such development is the statistical inference of individual diplotypes from unphased genotypes. Several methodologies for inferring haplotypes have been developed, but they have not been evaluated extensively to determine which method not only performs well, but also can be easily incorporated in downstream haplotype-based association analyses. In this paper, we attempt to do so. Our evaluation was carried out by comparing the two leading Bayesian methods, implemented in PHASE and HAPLOTYPER, and the two leading empirical methods, implemented in PL-EM and HPlus. We used these methods to analyze real data, namely the dense genotypes on X-chromosome of 30 European and 30 African trios provided by the International HapMap Project, and simulated genotype data. Our conclusions are based on these analyses. Results All programs performed very well on X-chromosome data, with an average similarity index of 0.99 and an average prediction rate of 0.99 for both European and African trios. On simulated data with approximation of coalescence, PHASE implementing the Bayesian method based on the coalescence approximation outperformed other programs on small sample sizes. When the sample size increased, other programs performed as well as PHASE. PL-EM and HPlus implementing empirical methods required much less running time than the programs implementing the Bayesian methods. They required only one hundredth or thousandth of the running time required by PHASE, particularly when analyzing large sample sizes and large umber of SNPs. Conclusion For large sample sizes (hundreds or more, which most association studies require, the two empirical methods might be used since they infer the haplotypes as accurately as any Bayesian methods and can be incorporated easily into downstream haplotype

  7. Effect of donor CTLA-4 alleles and haplotypes on graft-versus-host disease occurrence in Tunisian patients receiving a human leukocyte antigen-identical sibling hematopoietic stem cell transplant.

    Science.gov (United States)

    Sellami, Mohamed Hichem; Bani, Meriem; Torjemane, Lamia; Kaabi, Houda; Ladeb, Saloua; Ben Othmane, Tarek; Hmida, Slama

    2011-02-01

    The CTLA-4 genetic variation, such as single nucleotide polymorphisms (SNPs) may be critical and can affect the functional activity of cells that initiate the graft-versus-host disease (GVHD) effects. The aim of this study is to examine the effect of donor CTLA-4 alleles and haplotypes for the -318C>T and the 49A>G polymorphisms on the occurrence of GVHD in Tunisians recipients of HSCs. A total of 112 patients and their 112 respective sibling donors of HSCs were enrolled in this study. All patients had either grades 0-I or grades II-IV acute GVHD, or chronic GVHD. The SNPs genotyping assay was performed using sets of sequence specific primers (SSP-PCR). The single marker association analysis showed that the 49G allele, in a genetic recessive model, may be a potential risk factor only for the chronic GVHD (p = 0.032, odds ratio [OR] = 2.58, 95% confidence interval = 1.05-6.32). The haplotypes analyses showed that the CTLA-4 -318C49G nucleotide combination is significantly associated with the incidence of chronic GVHD (p = 0.043, χ² = 3.27). Donor CTLA-4 -318C49G haplotype may be a significant risk factor for developing chronic GVHD after allo-stem cell transplantation. We suppose that donor T cells expressing this haplotype in a homozygous state have higher proliferation than those expressing other haplotypes, especially after recognition of the recipient's minor histocompatibility antigens.

  8. Haplotype block structure is conserved across mammals

    NARCIS (Netherlands)

    Guryev, Victor; Smits, Bart M G; van de Belt, Jose; Verheul, Mark; Hubner, Norbert; Cuppen, Edwin

    2006-01-01

    Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium i

  9. 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...

  10. The Haplotyping Problem: An Overview of Computational Models and Solutions

    Institute of Scientific and Technical Information of China (English)

    Paola Bonizzoni; Gianluca Della Vedova; Riccardo Dondi; Jing Li

    2003-01-01

    The investigation of genetic differences among humans has given evidence that mutations in DNA sequences are responsible for some genetic diseases. The most common mutation is the one that involves only a single nucleotide of the DNA sequence, which is called a single nucleotide polymorphism (SNP). As a consequence, computing a complete map of all SNPs occurring in the human populations is one of the primary goals of recent studies in human genomics. The construction of such a map requires to determine the DNA sequences that from all chromosomes. In diploid organisms like humans, each chromosome consists of two sequences called haplotypes. Distinguishing the information contained in both haplotypes when analyzing chromosome sequences poses several new computational issues which collectively form a new emerging topic of Computational Biology known as Haplotyping.This paper is a comprehensive study of some new combinatorial approaches proposed in this research area and it mainly focuses on the formulations and algorithmic solutions of some basic biological problems. Three statistical approaches are briefly discussed at the end of the paper.

  11. Direct determination of MUC5B promoter haplotypes based on the method of single-strand conformation polymorphism and their statistical estimation.

    Science.gov (United States)

    Kamio, Koichiro; Matsushita, Ikumi; Tanaka, Goh; Ohashi, Jun; Hijikata, Minako; Nakata, Koh; Tokunaga, Katsushi; Azuma, Arata; Kudoh, Shoji; Keicho, Naoto

    2004-09-01

    Haplotype-based human genome research is important in identifying disease susceptibility genes efficiently. Although haplotype reconstruction by statistical methods is widely used, direct haplotype determination by molecular techniques has also been developed as a complementary method for statistical estimation. In this study, we demonstrate a molecular haplotyping method making use of single-strand conformation polymorphism (SSCP) gels. We identified 10 common SNPs and a dinucleotide insertion/deletion polymorphism within 2-kb region upstream of the transcription initiation site of MUC5B and determined haplotype structure, dividing the region into two DNA fragments. Real haplotypes were determined unambiguously by our SSCP-based analysis with fragments longer than 1 kb. Haplotypes reconstructed from diploid genotypes in the same region by the statistical methods including EM algorithm were also evaluated. Direct comparison between statistical estimation and direct determination of haplotypes revealed that major haplotypes containing multiple marker sites showing strong LD are estimated in great accuracy but that a variety of haplotypes reflecting weak LD are not reconstructed precisely enough. Our data can be helpful in implementing molecular haplotyping or statistical estimation, since usage of these methods may be determined depending on the haplotype structures.

  12. Complementarity of Binding Motifs is a General Property of HLA-A and HLA-B Molecules and Does Not Seem to Effect HLA Haplotype Composition.

    Science.gov (United States)

    Rao, Xiangyu; De Boer, Rob J; van Baarle, Debbie; Maiers, Martin; Kesmir, Can

    2013-01-01

    Different human leukocyte antigen (HLA) haplotypes (i.e., the specific combinations of HLA-A, -B, -DR alleles inherited together from one parent) are observed in different frequencies in human populations. Some haplotypes, like HLA-A1-B8, are very frequent, reaching up to 10% in the Caucasian population, while others are very rare. Numerous studies have identified associations between HLA haplotypes and diseases, and differences in haplotype frequencies can in part be explained by these associations: the stronger the association with a severe (autoimmune) disease, the lower the expected HLA haplotype frequency. The peptide repertoires of the HLA molecules composing a haplotype can also influence the frequency of a haplotype. For example, it would seem advantageous to have HLA molecules with non-overlapping binding specificities within a haplotype, as individuals expressing such an haplotype would present a diverse set of peptides from viruses and pathogenic bacteria on the cell surface. To test this hypothesis, we collect the proteome data from a set of common viruses, and estimate the total ligand repertoire of HLA class I haplotypes (HLA-A-B) using in silico predictions. We compare the size of these repertoires to the HLA haplotype frequencies reported in the National Marrow Donor Program (NMDP). We find that in most HLA-A and HLA-B pairs have fairly distinct binding motifs, and that the observed haplotypes do not contain HLA-A and -B molecules with more distinct binding motifs than random HLA-A and HLA-B pairs. In addition, the population frequency of a haplotype is not correlated to the distinctness of its HLA-A and HLA-B peptide binding motifs. These results suggest that there is a not a strong selection pressure on the haplotype level favoring haplotypes having HLA molecules with distinct binding motifs, which would result the largest possible presented peptide repertoires in the context of infectious diseases.

  13. Biomedical Information Extraction: Mining Disease Associated Genes from Literature

    Science.gov (United States)

    Huang, Zhong

    2014-01-01

    Disease associated gene discovery is a critical step to realize the future of personalized medicine. However empirical and clinical validation of disease associated genes are time consuming and expensive. In silico discovery of disease associated genes from literature is therefore becoming the first essential step for biomarker discovery to…

  14. Biomedical Information Extraction: Mining Disease Associated Genes from Literature

    Science.gov (United States)

    Huang, Zhong

    2014-01-01

    Disease associated gene discovery is a critical step to realize the future of personalized medicine. However empirical and clinical validation of disease associated genes are time consuming and expensive. In silico discovery of disease associated genes from literature is therefore becoming the first essential step for biomarker discovery to…

  15. Origin of celiac disease: How old are predisposing haplotypes?

    Institute of Scientific and Technical Information of China (English)

    Giovanni Gasbarrini; Olga Rickards; Cristina Martínez-Labarga; Elsa Pacciani; Filiberto Chilleri; Lucrezia Laterza; Giuseppe Marangi; Franco Scaldaferri; Antonio Gasbarrini

    2012-01-01

    We recently presented the case of a first century AD young woman,found in the archaeological site of Cosa,showing clinical signs of malnutrition,such as short height,osteoporosis,dental enamel hypoplasia and cribra orbitalia,indirect sign of anemia,all strongly suggestive for celiac disease (CD).However,whether these findings were actually associated to CD was not shown based on genetic parameters.To investigate her human leukocyte antigen (HLA) class Ⅱ polymorphism,we extracted DNA from a bone sample and a tooth and genotyped HLA using three HLA-tagging single nucleotide polymorphisms for DQ8,DQ2.2 and DQ2.5,specifically associated to CD.She displayed HLA DQ 2.5,the haplotype associated to the highest risk of CD.This is the first report showing the presence of a HLA haplotype compatible for CD in archaeological specimens.

  16. Complementarity of binding motifs is a general property of HLA-A and HLA-B molecules and does not seem to effect HLA haplotype composition

    Directory of Open Access Journals (Sweden)

    Xiangyu eRao

    2013-11-01

    Full Text Available Different HLA haplotypes (i.e., the specific combinations of HLA-A, -B, -DR alleles inherited together from one parent are observed in different frequencies in human populations. Some haplotypes, like HLA-A1-B8, are very frequent, reaching up to 10% in the Caucasian population, while others are very rare. Numerous studies have identified associations between HLA haplotypes and diseases, and differences in haplotype frequencies can in part be explained by these associations: the stronger the association with a severe (autoimmune disease, the lower the expected HLA haplotype frequency. The peptide repertoires of the HLA molecules composing a haplotype can also influence the frequency of a haplotype. For example, it would seem advantageous to have HLA molecules with non-overlapping binding specificities within a haplotype, as individuals expressing such an haplotype would present a diverse set of peptides from viruses and pathogenic bacteria on the cell surface. To test this hypothesis, we collect the proteome data from a set of common viruses, and estimate the total ligand repertoire of HLA class I haplotypes (HLA-A-B using in silico predictions. We compare the size of these repertoires to the HLA haplotype frequencies reported in the National Marrow Donor Program (NMDP. We find that in most HLA-A and HLA-B pairs have fairly distinct binding motifs, and that the observed haplotypes do not contain HLA-A and –B molecules with more distinct binding motifs than random HLA-A and HLA-B pairs. In addition, the population frequency of a haplotype is not correlated to the distinctness of its HLA-A and HLA-B peptide binding motifs. These results suggest that there is a not a strong selection pressure on the haplotype level favouring haplotypes having HLA molecules with distinct binding motifs, which would result the largest possible presented peptide repertoires in the context of infectious diseases.

  17. The association of XRCC1 haplotypes and chromosomal damage levels in peripheral blood lymphocyte among coke-oven workers

    Energy Technology Data Exchange (ETDEWEB)

    Shuguang Leng; Juan Cheng; Linyuan Zhang; Yong Niu; Yufei Dai; Zufei Pan; Bin Li; Fengsheng He; Yuxin Zheng [Chinese Center for Disease Control and Prevention, Beijing (China). National Institute of Occupational Health and Poison Control

    2005-05-15

    Theoretically, a haplotype has a higher level of heterozygosity than individual single nucleotide polymorphism (SNP) and the association study based on the haplotype may have an increased power for detecting disease associations compared with SNP-based analysis. In this study, we investigated the effects of four haplotype-tagging SNPs (htSNP) and the inferred haplotype pairs of the X-ray cross-complementing group 1 (XRCC1) gene on chromosome damage detected by the cytokinesis-block micronucleus assay. The study included 141 coke-oven workers with exposure to a high level of polycyclic aromatic hydrocarbons and 66 nonexposed controls. The frequencies of total MN and MNed cells were borderline associated with the Arg{sup 194}Trp polymorphism (P = 0.053 and P = 0.050, respectively) but not associated with the Arg{sup 280}His, Arg{sup 399}Gln and Gln{sup 632}Gln polymorphisms among coke-oven workers. Five haplotypes, including CGGG, TGGG, CAGG, CGAG, and CGGA, were inferred based on the four htSNPs of XRCC1 gene. The haplotype CGGG was associated with the decreased frequencies of total MN and MNed cells, and the haplotypes TGGG and CGAG were associated with the increased frequencies of total MN and MNed cells with adjustment for covariates among coke-oven workers. This study showed that the haplotypes derived from htSNPs in the XRCC1 gene were more likely than single SNPs to correlate with the polycyclic aromatic hydrocarbon-induced chromosome damage among coke-oven workers.

  18. LDAP: a web server for lncRNA-disease association prediction.

    Science.gov (United States)

    Lan, Wei; Li, Min; Zhao, Kaijie; Liu, Jin; Wu, Fang-Xiang; Pan, Yi; Wang, Jianxin

    2017-02-01

    Increasing evidences have demonstrated that long noncoding RNAs (lncRNAs) play important roles in many human diseases. Therefore, predicting novel lncRNA-disease associations would contribute to dissect the complex mechanisms of disease pathogenesis. Some computational methods have been developed to infer lncRNA-disease associations. However, most of these methods infer lncRNA-disease associations only based on single data resource. In this paper, we propose a new computational method to predict lncRNA-disease associations by integrating multiple biological data resources. Then, we implement this method as a web server for lncRNA-disease association prediction (LDAP). The input of the LDAP server is the lncRNA sequence. The LDAP predicts potential lncRNA-disease associations by using a bagging SVM classifier based on lncRNA similarity and disease similarity. The web server is available at http://bioinformatics.csu.edu.cn/ldap jxwang@mail.csu.edu.cn. Supplementary data are available at Bioinformatics online.

  19. Haplotype-phenotype relationships of paraoxonase-1.

    Science.gov (United States)

    Chen, Jia; Chan, Wendy; Wallenstein, Sylvan; Berkowitz, Gertrud; Wetmur, James G

    2005-03-01

    Paraoxonase 1 (PON1) is an enzyme with multiple activities, including detoxification of organophosphates. It is believed to be important in preventing neurotoxic damage and has also been implicated in atherosclerosis. The PON1 gene contains five common polymorphisms, three in the promoter (-909G > C, -162A > G, -108C > T) and two in the coding region (M55L, Q192R) with varying but incomplete linkage disequilibrium. Our previous study showed that functional polymorphisms in PON1 were strongly associated with enzymatic activity in both pregnant women [26-30 weeks of gestation] and neonates. However, there was substantial overlapping of enzyme activities between genotypes. In this study, we investigated whether haplotype (genotype + phase) information would strengthen the genotype-phenotype relationship for PON1. The study consisted of a multiethnic population of 402 mothers and 229 neonates. Haplotypes were imputed by two widely used programs, PHASE and tagSNPs, which yielded very similar results. There were seven haplotypes with a frequency of 5% or higher in at least one ethnic group of the study population. Haplotype composition varied substantially with respect to ethnicity. Haplotypes in Caucasians and African-Americans showed the largest difference, and Caribbean Hispanics seemed to be a mixture of Caucasian and African ancestry. Collectively, the genetic (genotype or haplotype) contribution to PON1 enzymatic activity (measured as phenylacetate hydrolysis) was greater in neonates compared with mothers. Specifically, 16.6% of PON1 variability was explained by genotypes in mothers compared with 30.9% in neonates. Haplotype information offered a slightly increased power in predicting PON1 activity; they explained 35.5% and 19.3% of PON1 variability in neonates and mothers, respectively.

  20. Founder mitochondrial haplotypes in Amerindian populations.

    Science.gov (United States)

    Bailliet, G; Rothhammer, F; Carnese, F R; Bravi, C M; Bianchi, N O

    1994-07-01

    It had been proposed that the colonization of the New World took place by three successive migrations from northeastern Asia. The first one gave rise to Amerindians (Paleo-Indians), the second and third ones to Nadene and Aleut-Eskimo, respectively. Variation in mtDNA has been used to infer the demographic structure of the Amerindian ancestors. The study of RFLP all along the mtDNA and the analysis of nucleotide substitutions in the D-loop region of the mitochondrial genome apparently indicate that most or all full-blooded Amerindians cluster in one of four different mitochondrial haplotypes that are considered to represent the founder maternal lineages of Paleo-Indians. We have studied the mtDNA diversity in 109 Amerindians belonging to 3 different tribes, and we have reanalyzed the published data on 482 individuals from 18 other tribes. Our study confirms the existence of four major Amerindian haplotypes. However, we also found evidence supporting the existence of several other potential founder haplotypes or haplotype subsets in addition to the four ancestral lineages reported. Confirmation of a relatively high number of founder haplotypes would indicate that early migration into America was not accompanied by a severe genetic bottleneck.

  1. Rare missense variants within a single gene form yin yang haplotypes.

    Science.gov (United States)

    Curtis, David

    2016-01-01

    Yin yang haplotype pairs differ at every SNP. They would not be accounted for by population models that incorporate sequential mutation, with or without recombination. Previous reports have claimed that there is a tendency for common SNPs to form yin yang haplotypes more often than would be expected by sequential mutation or by a random sample of all possible haplotypic arrangements of alleles. In the course of analysing next-generation sequencing data, instances of yin yang haplotypes being formed by very rare variants within a single gene were observed. As an example, this report describes a completely yin yang haplotype formed by eight rare missense variants in the ABCA13 gene. Of 1000 genome subjects, 21 have a copy of the alternate allele at all eight of these positions and a single subject is homozygous for all of them. None of the other 1070 subjects possesses any of the altetrnates. Thus, the eight alternate alleles are always found together and never occur separately. The existence of such yin yang haplotypes has important implications for statistical methods for analysing rare variants. Also, they may be of use for gaining a better understanding of the history of human populations.

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

    Science.gov (United States)

    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.

  3. Separation of Y-chromosomal haplotypes from male DNA mixtures via multiplex haplotype-specific extraction.

    Science.gov (United States)

    Rothe, Jessica; Nagy, Marion

    2015-11-01

    In forensic analysis, the interpretation of DNA mixtures is the subject of ongoing debate and requires expertise knowledge. Haplotype-specific extraction (HSE) is an alternative method that enables the separation of large chromosome fragments or haplotypes by using magnetic beads in conjunction with allele-specific probes. HSE thus allows physical separation of the components of a DNA mixture. Here, we present the first multiplex HSE separation of a Y-chromosomal haplotype consisting of six Yfiler short tandem repeat markers from a mixture of male DNA.

  4. Haplotypes, sub-haplotypes and geographical distribution in Omani patients with sickle cell disease

    Directory of Open Access Journals (Sweden)

    Suha Mustafa Hassan

    2015-05-01

    Full Text Available Despite the fact that patients homozygous for the sickle cell disease (SCD mutation have an identical genotype, the severity of the disease can be extremely variable. The hemoglobin (Hb S mutation has been described on five different haplotypes with different clinical expression. Identifying the genotypes, haplotypes and sub-haplotypes of the β gene cluster in Oman needs to be studied in more details to establish a correlation between the genotype/haplotype and phenotype diversity observed in SCD patients for prognostic purposes, accurate diagnosis and thus planning for the best tailored treatment. We have investigated 125 HbS homozygotes from different parts of Oman and determined their haplotypes and sub-haplotypes and correlated this to the hematological and clinical expression. We have found 11 haplotype combinations differently distributed in the country, with the Asian/Asian HbS haplotype being the most predominant. Sub-haplotypes was only found among patients with CAR/OmanI haplotype. As expected, the correlation between haplotypes, sub-haplotypes and disease severity was mainly associated with HbF expression. Our study on haplotype/phenotype correlation has shown which major haplotypes occur in the different regions of Oman. Furthermore, neither the haplotype or sub-haplotype nor the HbF alone appeared to be fully associable with the variable clinical phenotypes. External factors do occur and are associated with the expression of the disease.  尽管镰状细胞突变病(SCD)患者拥有相同的基因类型,但患者的病患程度却大相径庭。血红蛋白(Hb)S突变有五种不同的单体型,各种类型在临床表现上也不相同。为了识别在阿曼地区β基因簇的基因型、单体型,亚单体型,需要研究更多以SCD患者预后为目的,关于其观察到的基因型、单体型,表型多样性之间联系的更多细节,以便作出准确的诊断,为各

  5. 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.

  6. Haplotype reconstruction and estimation of haplotype frequencies from nuclear families with only one parent available.

    Science.gov (United States)

    Ding, Xiangdong; Zhang, Qin; Flury, Christine; Simianer, Henner

    2006-01-01

    Recent literature has suggested that haplotype inference through close relatives, especially from nuclear families can be an alternative strategy in determining the linkage phase. In this paper, haplotype reconstruction and estimation of haplotype frequencies via expectation maximization (EM) algorithm including nuclear families with only one parent available is proposed. Parent and his (her) child are treated as parent-child pair with one shared haplotype. This reduces the number of potential haplotype pairs for both parent and child separately, resulting in a higher accuracy of the estimation. In a series of simulations, the comparisons of PHASE, GENEHUNTER, EM-based approach for complete nuclear families and our approach are carried out. In all situations, EM-based approach for trio data is comparable but slightly worse error rate than PHASE, our approach is slightly better and much faster than PHASE for incomplete trios, the performance of GENEHUNTER is very bad in simple nuclear family settings and dramatically decreased with the number of markers being increased. On the other hand, the comparison result of different sampling designs demonstrates that sampling trios is the most efficient design to estimate haplotype frequencies in populations under same genotyping cost.

  7. 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.

  8. Identification of a 10/10 matched donor for patients with an uncommon haplotype is unlikely.

    Science.gov (United States)

    Olson, J A; Gibbens, Y; Tram, K; Kempenich, J; Novakovich, J; Buck, K; Dehn, J

    2017-02-01

    Despite over 6 million subjects contributing to the National Marrow Donor Program human leukocyte antigen (HLA) haplotype frequency reference data (HFD), haplotypes cannot be predicted from the HLA assignments of some patients searching for an unrelated donor (URD) in the Be The Match Registry®. We aimed to determine the incidence of these patient searches and whether haplotypes lacking from the HFD can be found among the low-resolution typed URD pool. New NMDP searches with uncommon patient haplotypes (UPH), defined as a lack of haplotype pairs in any single ethnic group in the HFD based upon HLA-A˜C˜B˜DRB1˜DQB1, were identified. Each search had up to 20 potential 10/10 or 8/8 URDs typed to determine the likelihood of an allele match. The incidence of patient searches without haplotype pairs in a single ethnic group in the HFD was 1.2% (N=144 out of 12,172) and a majority of these patients (117; 81%) had one uncommon haplotype previously uncharacterized in the HFD. Non-White patients had the highest incidence of UPH. Importantly, no patients with UPH had a 10/10 URD identified. The transplant rate among UPH patients was 15%, and a majority of these patients utilized cord blood units as their transplant stem cell source. Therefore, the HLA HFD that informs the HapLogic matching algorithm is thorough as UPH patient searches were infrequent. Since such patients are highly unlikely to have a fully 10/10 matched URD identified, this study supports the identification of alternative stem cell sources including cord blood or a mismatched URD early in the search process. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Understanding the contrasting spatial haplotype patterns of malaria-protective β-globin polymorphisms.

    Science.gov (United States)

    Hockham, Carinna; Piel, Frédéric B; Gupta, Sunetra; Penman, Bridget S

    2015-12-01

    The malaria-protective β-globin polymorphisms, sickle-cell (β(S)) and β(0)-thalassaemia, are canonical examples of human adaptation to infectious disease. Occurring on distinct genetic backgrounds, they vary markedly in their patterns of linked genetic variation at the population level, suggesting different evolutionary histories. β(S) is associated with five classical restriction fragment length polymorphism haplotypes that exhibit remarkable specificity in their geographical distributions; by contrast, β(0)-thalassaemia mutations are found on haplotypes whose distributions overlap considerably. Here, we explore why these two polymorphisms display contrasting spatial haplotypic distributions, despite having malaria as a common selective pressure. We present a meta-population genetic model, incorporating individual-based processes, which tracks the evolution of β-globin polymorphisms on different haplotypic backgrounds. Our simulations reveal that, depending on the rate of mutation, a large population size and/or high population growth rate are required for both the β(S)- and the β(0)-thalassaemia-like patterns. However, whilst the β(S)-like pattern is more likely when population subdivision is high, migration low and long-distance migration absent, the opposite is true for β(0)-thalassaemia. Including gene conversion has little effect on the overall probability of each pattern; however, when inter-haplotype fitness variation exists, gene conversion is more likely to have contributed to the diversity of haplotypes actually present in the population. Our findings highlight how the contrasting spatial haplotype patterns exhibited by β(S) and β(0)-thalassaemia may provide important indications as to the evolution of these adaptive alleles and the demographic history of the populations in which they have evolved.

  10. Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations.

    Science.gov (United States)

    Shi, Hongbo; Zhang, Guangde; Zhou, Meng; Cheng, Liang; Yang, Haixiu; Wang, Jing; Sun, Jie; Wang, Zhenzhen

    2016-01-01

    MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD.

  11. The effects of old and recent migration waves in the distribution of HBB*S globin gene haplotypes

    OpenAIRE

    Lindenau, Juliana D.; Sandrine C. Wagner; Simone M. Castro; Mara H. Hutz

    2016-01-01

    Abstract Sickle cell hemoglobin is the result of a mutation at the sixth amino acid position of the beta (β) globin chain. The HBB*S gene is in linkage disequilibrium with five main haplotypes in the β-globin-like gene cluster named according to their ethnic and geographic origins: Bantu (CAR), Benin (BEN), Senegal (SEN), Cameroon (CAM) and Arabian-Indian (ARAB). These haplotypes demonstrated that the sickle cell mutation arose independently at least five times in human history. The...

  12. Identification of HAVCR1 gene haplotypes associated with mRNA expression levels and susceptibility to autoimmune diseases.

    Science.gov (United States)

    García-Lozano, José Raúl; Abad, Cristina; Escalera, Ana; Torres, Belén; Fernández, Olga; García, Alicia; Sánchez-Román, Julio; Sabio, José-Mario; Ortego-Centeno, Norberto; Raya-Alvarez, Enrique; Núñez-Roldán, Antonio; Martín, Javier; González-Escribano, María Francisca

    2010-08-01

    Human HAVCR1 gene maps on 5q33.2, a region linked with susceptibility to allergic and autoimmune diseases. The aims of the present study were to define the haplotypes of HAVCR1 gene taking into account both HapMap Project SNP haplotypes and exon 4 variants, to investigate a possible relationship between these haplotypes and mRNA expression levels, and to assess whether HAVCR1 gene is involved in susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Genotyping of three ins/del variants in the exon 4 was performed by fragment length analysis. Five tag SNPs genotypes and mRNA levels were determined using TaqMan assays. We defined four major haplotypes in our population: the two major haplotypes (named haplotypes A and B) bear both the 5383_5397del variant and the two most common SNP sets found in the CEU population. Quantification analysis revealed that genotype B/B had the highest median of mRNA expression levels (vs. BX + XX, p < 0.0001). Additionally, frequency of the genotype BB was significantly higher in RA patients than in controls (12.3 vs. 5.9% in controls, p = 0.0046, p (c) = 0.014, OR = 2.23, 95% CI 1.23-4.10). Our results support a relationship between HAVCR1 haplotypes and mRNA expression levels, and suggest an association of this gene with autoimmune diseases.

  13. 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.

  14. The effects of old and recent migration waves in the distribution of HBB*S globin gene haplotypes

    Directory of Open Access Journals (Sweden)

    Juliana D. Lindenau

    Full Text Available Abstract Sickle cell hemoglobin is the result of a mutation at the sixth amino acid position of the beta (β globin chain. The HBB*S gene is in linkage disequilibrium with five main haplotypes in the β-globin-like gene cluster named according to their ethnic and geographic origins: Bantu (CAR, Benin (BEN, Senegal (SEN, Cameroon (CAM and Arabian-Indian (ARAB. These haplotypes demonstrated that the sickle cell mutation arose independently at least five times in human history. The distribution of βS haplotypes among Brazilian populations showed a predominance of the CAR haplotype. American populations were clustered in two groups defined by CAR or BEN haplotype frequencies. This scenario is compatible with historical records about the slave trade in the Americas. When all world populations where the sickle cell gene occurs were analyzed, three clusters were disclosed based on CAR, BEN or ARAB haplotype predominance. These patterns may change in the next decades due to recent migrations waves. Since these haplotypes show different clinical characteristics, these recent migrations events raise the necessity to develop optimized public health programs for sickle cell disease screening and management.

  15. The effects of old and recent migration waves in the distribution of HBB*S globin gene haplotypes.

    Science.gov (United States)

    Lindenau, Juliana D; Wagner, Sandrine C; Castro, Simone M de; Hutz, Mara H

    2016-01-01

    Sickle cell hemoglobin is the result of a mutation at the sixth amino acid position of the beta (β) globin chain. The HBB*S gene is in linkage disequilibrium with five main haplotypes in the β-globin-like gene cluster named according to their ethnic and geographic origins: Bantu (CAR), Benin (BEN), Senegal (SEN), Cameroon (CAM) and Arabian-Indian (ARAB). These haplotypes demonstrated that the sickle cell mutation arose independently at least five times in human history. The distribution of βS haplotypes among Brazilian populations showed a predominance of the CAR haplotype. American populations were clustered in two groups defined by CAR or BEN haplotype frequencies. This scenario is compatible with historical records about the slave trade in the Americas. When all world populations where the sickle cell gene occurs were analyzed, three clusters were disclosed based on CAR, BEN or ARAB haplotype predominance. These patterns may change in the next decades due to recent migrations waves. Since these haplotypes show different clinical characteristics, these recent migrations events raise the necessity to develop optimized public health programs for sickle cell disease screening and management.

  16. Polymorphic distribution of Y-chromosome haplotype and mitochondrial DNA in the Bouyei people in China

    Institute of Scientific and Technical Information of China (English)

    李永念; 左丽; 文波; 柯越海; 黄薇; 金力

    2004-01-01

    @@ In the evolution of humans, many kinds of mutations in the human genome have been accumulated, providing credible genetic evidence for the study of human origins and migrations. The "out-of-Africa" hypothesis of modern human evolution and the genetic origin of the Japanese has come about by studying mitochondrial DNA.l,2 Recently, researchers have recognized the power of Y-chromosome markers in resolving migratory patterns of modern humans as more and more Y-chromosome single nucleotide polymorphism markers have been found. The markers on the nonrecombinant part of the Y-chromosome allows for the reconstruction of intact haplotypes which are probably the best genetic tools to study human migrations. We can analyze the paternal history of some people in different areas by Y-chromosome haplotypes.

  17. Global Identification of Disease Associated Genes in Fragile X Cells

    Science.gov (United States)

    2016-08-01

    AWARD NUMBER: W81XWH-15-1-0204 TITLE: Global Identification of Disease-Associated Genes in Fragile X Cells PRINCIPAL INVESTIGATOR: Wenyi Feng...Global Identification of Disease-Associated Genes in Fragile X Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0204 GRANT1171 2389... genes in fragile X cells compared to normal cells. o What was accomplished under these goals? Below I list the experiments and conclusions for each goal

  18. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

    DEFF Research Database (Denmark)

    Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves;

    2010-01-01

    Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing ...

  19. The Wilson disease gene: Haplotypes and mutations

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.R.; Roberts, E.A.; Cox, D.W. [Hospital for Sick Children, Toronto (Canada); Walshe, J.M. [Middlesex Hospital, London (United Kingdom)

    1994-09-01

    Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

  20. A Method for Calling Copy Number Polymorphism Using Haplotypes

    Directory of Open Access Journals (Sweden)

    Gun Ho eJang

    2013-09-01

    Full Text Available Single nucleotide polymorphism (SNP and copy number variation (CNV are both widespread characteristic of the human genome, but are often called separately on common genotyping platforms. To capture integrated SNP and CNV information, methods have been developed for calling allelic specific copy numbers or so called copy number polymorphism (CNP, using limited inter-marker correlation. In this paper, we proposed a haplotype-based maximum likelihood method to call CNP, which takes advantage of the valuable multi-locus linkage disequilibrium (LD information in the population. We also developed a computationally efficient EM algorithm to estimate haplotype frequencies and optimize individual CNP calls simultaneously, even at presence of missing data. Through simulations, we demonstrated our model is more sensitive and accurate in detecting various CNV regions, compared with commonly-used CNV calling methods including PennCNV, another hidden Markov model using CNP, a scan statistic, segCNV, and cnvHap. Our method often performs better in the regions with higher LD, in longer CNV regions, and in common CNV than the opposite. We implemented our method on the genotypes of 90 HapMap CEU samples and 23 patients with acute lung injury (ALI. For each ALI patient the genotyping was performed twice. The CNPs from our method show good consistency and accuracy comparable to others.

  1. A linear-time algorithm for reconstructing zero-recombinant haplotype configuration on a pedigree

    Science.gov (United States)

    2012-01-01

    Background When studying genetic diseases in which genetic variations are passed on to offspring, the ability to distinguish between paternal and maternal alleles is essential. Determining haplotypes from genotype data is called haplotype inference. Most existing computational algorithms for haplotype inference have been designed to use genotype data collected from individuals in the form of a pedigree. A haplotype is regarded as a hereditary unit and therefore input pedigrees are preferred that are free of mutational events and have a minimum number of genetic recombinational events. These ideas motivated the zero-recombinant haplotype configuration (ZRHC) problem, which strictly follows the Mendelian law of inheritance, namely that one haplotype of each child is inherited from the father and the other haplotype is inherited from the mother, both without any mutation. So far no linear-time algorithm for ZRHC has been proposed for general pedigrees, even though the number of mating loops in a human pedigree is usually very small and can be regarded as constant. Results Given a pedigree with n individuals, m marker loci, and k mating loops, we proposed an algorithm that can provide a general solution to the zero-recombinant haplotype configuration problem in O(kmn + k2m) time. In addition, this algorithm can be modified to detect inconsistencies within the genotype data without loss of efficiency. The proposed algorithm was subject to 12000 experiments to verify its performance using different (n, m) combinations. The value of k was uniformly distributed between zero and six throughout all experiments. The experimental results show a great linearity in terms of execution time in relation to input size when both n and m are larger than 100. For those experiments where n or m are less than 100, the proposed algorithm runs very fast, in thousandth to hundredth of a second, on a personal desktop computer. Conclusions We have developed the first deterministic linear

  2. Fast and accurate haplotype frequency estimation for large haplotype vectors from pooled DNA data

    Directory of Open Access Journals (Sweden)

    Iliadis Alexandros

    2012-10-01

    Full Text Available Abstract Background Typically, the first phase of a genome wide association study (GWAS includes genotyping across hundreds of individuals and validation of the most significant SNPs. Allelotyping of pooled genomic DNA is a common approach to reduce the overall cost of the study. Knowledge of haplotype structure can provide additional information to single locus analyses. Several methods have been proposed for estimating haplotype frequencies in a population from pooled DNA data. Results We introduce a technique for haplotype frequency estimation in a population from pooled DNA samples focusing on datasets containing a small number of individuals per pool (2 or 3 individuals and a large number of markers. We compare our method with the publicly available state-of-the-art algorithms HIPPO and HAPLOPOOL on datasets of varying number of pools and marker sizes. We demonstrate that our algorithm provides improvements in terms of accuracy and computational time over competing methods for large number of markers while demonstrating comparable performance for smaller marker sizes. Our method is implemented in the "Tree-Based Deterministic Sampling Pool" (TDSPool package which is available for download at http://www.ee.columbia.edu/~anastas/tdspool. Conclusions Using a tree-based determinstic sampling technique we present an algorithm for haplotype frequency estimation from pooled data. Our method demonstrates superior performance in datasets with large number of markers and could be the method of choice for haplotype frequency estimation in such datasets.

  3. Large-scale prediction of microRNA-disease associations by combinatorial prioritization algorithm

    Science.gov (United States)

    Yu, Hua; Chen, Xiaojun; Lu, Lu

    2017-03-01

    Identification of the associations between microRNA molecules and human diseases from large-scale heterogeneous biological data is an important step for understanding the pathogenesis of diseases in microRNA level. However, experimental verification of microRNA-disease associations is expensive and time-consuming. To overcome the drawbacks of conventional experimental methods, we presented a combinatorial prioritization algorithm to predict the microRNA-disease associations. Importantly, our method can be used to predict microRNAs (diseases) associated with the diseases (microRNAs) without the known associated microRNAs (diseases). The predictive performance of our proposed approach was evaluated and verified by the internal cross-validations and external independent validations based on standard association datasets. The results demonstrate that our proposed method achieves the impressive performance for predicting the microRNA-disease association with the Area Under receiver operation characteristic Curve (AUC), 86.93%, which is indeed outperform the previous prediction methods. Particularly, we observed that the ensemble-based method by integrating the predictions of multiple algorithms can give more reliable and robust prediction than the single algorithm, with the AUC score improved to 92.26%. We applied our combinatorial prioritization algorithm to lung neoplasms and breast neoplasms, and revealed their top 30 microRNA candidates, which are in consistent with the published literatures and databases.

  4. Large-scale prediction of microRNA-disease associations by combinatorial prioritization algorithm

    Science.gov (United States)

    Yu, Hua; Chen, Xiaojun; Lu, Lu

    2017-01-01

    Identification of the associations between microRNA molecules and human diseases from large-scale heterogeneous biological data is an important step for understanding the pathogenesis of diseases in microRNA level. However, experimental verification of microRNA-disease associations is expensive and time-consuming. To overcome the drawbacks of conventional experimental methods, we presented a combinatorial prioritization algorithm to predict the microRNA-disease associations. Importantly, our method can be used to predict microRNAs (diseases) associated with the diseases (microRNAs) without the known associated microRNAs (diseases). The predictive performance of our proposed approach was evaluated and verified by the internal cross-validations and external independent validations based on standard association datasets. The results demonstrate that our proposed method achieves the impressive performance for predicting the microRNA-disease association with the Area Under receiver operation characteristic Curve (AUC), 86.93%, which is indeed outperform the previous prediction methods. Particularly, we observed that the ensemble-based method by integrating the predictions of multiple algorithms can give more reliable and robust prediction than the single algorithm, with the AUC score improved to 92.26%. We applied our combinatorial prioritization algorithm to lung neoplasms and breast neoplasms, and revealed their top 30 microRNA candidates, which are in consistent with the published literatures and databases. PMID:28317855

  5. A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis.

    Science.gov (United States)

    Benson, M; Mobini, R; Barrenäs, F; Halldén, C; Naluai, A T; Säll, T; Cardell, L O

    2009-09-01

    Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway. To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR. CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls. Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls. Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.

  6. Casein haplotypes and their association with milk production traits in Norwegian Red cattle.

    Science.gov (United States)

    Nilsen, Heidi; Olsen, Hanne Gro; Hayes, Ben; Sehested, Erling; Svendsen, Morten; Nome, Torfinn; Meuwissen, Theo; Lien, Sigbjørn

    2009-02-20

    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 beta-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.

  7. Establishment of a resource population of SLA haplotype-defined Korean native pigs.

    Science.gov (United States)

    Cho, Han-Ok; Ho, Chak-Sum; Lee, Yu-Joo; Cho, In-Cheol; Lee, Sung-Soo; Ko, Moon-Suck; Park, Chankyu; Smith, Douglas M; Jeon, Jin-Tae; Lee, Jun-Heon

    2010-05-01

    The highly polymorphic porcine major histocompatibility complex (MHC), or the swine leukocyte antigens (SLA), has been repeatedly associated with variations in swine immune response to pathogens and vaccines as well as with production traits. The SLA antigens are also important targets for immunological recognition of foreign tissue grafts. We recently established a resource population of Korean native pigs as models for human transplantation and xenotransplantation research. In this study, 115 animals derived from three generations of the Korean native pigs were genotyped for three SLA class I (SLA-2, SLA-3 and SLA-1) and three SLA class II loci (DRB1, DQB1, DQA) using PCR with sequence-specific primers (PCR-SSP) at the allele group resolution. A total of seven SLA haplotypes (Lr-5.34, Lr-7.23, Lr-31.13, Lr-56.23, Lr-56.30, Lr-59.1, Lr-65.34), comprising six unique class I and five unique class II haplotypes, were characterized in the founding animals. Class I haplotype Lr-65.0 and class II haplotype Lr-0.34 were novel; and together with Lr-56.0 these haplotypes appeared to be breed-specific. In the progeny population, Lr-7.23 and Lr-56.30 appeared to be the most prevalent haplotypes with frequencies of 34.7% and 31.6%, respectively; the overall homozygosity was 27.4%. This resource population of SLA-defined Korean native pigs will be useful as large animal models for various transplantation and xenotransplantation experiments, as well as for dissecting the roles of SLA proteins in swine disease resistance and production traits.

  8. 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.

  9. 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 (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

  10. 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

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

    Science.gov (United States)

    Haapalainen, Minna; Schott, Thomas; Thompson, Sarah M.; Smith, Grant R.; Nissinen, Anne I.; Pirhonen, Minna

    2017-01-01

    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. PMID:28158295

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Background 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. 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...

  13. HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

    Science.gov (United States)

    Cocco, Eleonora; Sardu, Claudia; Pieroni, Enrico; Valentini, Maria; Murru, Raffaele; Costa, Gianna; Tranquilli, Stefania; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Floris, Matteo; Contu, Paolo; Marrosu, Maria Giovanna

    2012-01-01

    Introduction Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS. Methods and Results A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10−3), *04:05-*03:01 (OR = 2.4, P = 4.4×10−6) and *03:01-*02:01 (OR = 2.1, P = 1.0×10−15) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10−11) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10−3) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05

  14. 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.

  15. Inference of population structure using dense haplotype data.

    Directory of Open Access Journals (Sweden)

    Daniel John Lawson

    2012-01-01

    Full Text Available The advent of genome-wide dense variation data provides an opportunity to investigate ancestry in unprecedented detail, but presents new statistical challenges. We propose a novel inference framework that aims to efficiently capture information on population structure provided by patterns of haplotype similarity. Each individual in a sample is considered in turn as a recipient, whose chromosomes are reconstructed using chunks of DNA donated by the other individuals. Results of this "chromosome painting" can be summarized as a "coancestry matrix," which directly reveals key information about ancestral relationships among individuals. If markers are viewed as independent, we show that this matrix almost completely captures the information used by both standard Principal Components Analysis (PCA and model-based approaches such as STRUCTURE in a unified manner. Furthermore, when markers are in linkage disequilibrium, the matrix combines information across successive markers to increase the ability to discern fine-scale population structure using PCA. In parallel, we have developed an efficient model-based approach to identify discrete populations using this matrix, which offers advantages over PCA in terms of interpretability and over existing clustering algorithms in terms of speed, number of separable populations, and sensitivity to subtle population structure. We analyse Human Genome Diversity Panel data for 938 individuals and 641,000 markers, and we identify 226 populations reflecting differences on continental, regional, local, and family scales. We present multiple lines of evidence that, while many methods capture similar information among strongly differentiated groups, more subtle population structure in human populations is consistently present at a much finer level than currently available geographic labels and is only captured by the haplotype-based approach. The software used for this article, ChromoPainter and fineSTRUCTURE, is

  16. Consideration of the haplotype diversity at nonallelic homologous recombination hotspots improves the precision of rearrangement breakpoint identification.

    Science.gov (United States)

    Hillmer, Morten; Summerer, Anna; Mautner, Victor-Felix; Högel, Josef; Cooper, David N; Kehrer-Sawatzki, Hildegard

    2017-09-01

    Precise characterization of nonallelic homologous recombination (NAHR) breakpoints is key to identifying those features that influence NAHR frequency. Until now, analysis of NAHR-mediated rearrangements has generally been performed by comparison of the breakpoint-spanning sequences with the human genome reference sequence. We show here that the haplotype diversity of NAHR hotspots may interfere with breakpoint-mapping. We studied the transmitting parents of individuals with germline type-1 NF1 deletions mediated by NAHR within the paralogous recombination site 1 (PRS1) or paralogous recombination site 2 (PRS2) hotspots. Several parental wild-type PRS1 and PRS2 haplotypes were identified that exhibited considerable sequence differences with respect to the reference sequence, which also affected the number of predicted PRDM9-binding sites. Sequence comparisons between the parental wild-type PRS1 or PRS2 haplotypes and the deletion breakpoint-spanning sequences from the patients (method #2) turned out to be an accurate means to assign NF1 deletion breakpoints and proved superior to crude reference sequence comparisons that neglect to consider haplotype diversity (method #1). The mean length of the deletion breakpoint regions assigned by method #2 was 269-bp in contrast to 502-bp by method #1. Our findings imply that paralog-specific haplotype diversity of NAHR hotspots (such as PRS2) and population-specific haplotype diversity must be taken into account in order to accurately ascertain NAHR-mediated rearrangement breakpoints. © 2017 Wiley Periodicals, Inc.

  17. Maximum likelihood model based on minor allele frequencies and weighted Max-SAT formulation for haplotype assembly.

    Science.gov (United States)

    Mousavi, Sayyed R; Khodadadi, Ilnaz; Falsafain, Hossein; Nadimi, Reza; Ghadiri, Nasser

    2014-06-07

    Human haplotypes include essential information about SNPs, which in turn provide valuable information for such studies as finding relationships between some diseases and their potential genetic causes, e.g., for Genome Wide Association Studies. Due to expensiveness of directly determining haplotypes and recent progress in high throughput sequencing, there has been an increasing motivation for haplotype assembly, which is the problem of finding a pair of haplotypes from a set of aligned fragments. Although the problem has been extensively studied and a number of algorithms have already been proposed for the problem, more accurate methods are still beneficial because of high importance of the haplotypes information. In this paper, first, we develop a probabilistic model, that incorporates the Minor Allele Frequency (MAF) of SNP sites, which is missed in the existing maximum likelihood models. Then, we show that the probabilistic model will reduce to the Minimum Error Correction (MEC) model when the information of MAF is omitted and some approximations are made. This result provides a novel theoretical support for the MEC, despite some criticisms against it in the recent literature. Next, under the same approximations, we simplify the model to an extension of the MEC in which the information of MAF is used. Finally, we extend the haplotype assembly algorithm HapSAT by developing a weighted Max-SAT formulation for the simplified model, which is evaluated empirically with positive results.

  18. ImmunemiR - a database of prioritized immune miRNA disease associations and its interactome.

    Science.gov (United States)

    Prabahar, Archana; Natarajan, Jeyakumar

    2017-01-17

    MicroRNAs are the key regulators of gene expression and their abnormal expression in the immune system may be associated with several human diseases such as inflammation, cancer and autoimmune diseases. Elucidation of microRNA (miRNA) disease association through the interactome will deepen the understanding of its disease mechanisms. In this present study, miRNAs specific to immune related diseases were retrieved from curated databases and literature based on MeSH classification of immune system diseases. In total 245 immune miRNAs associated with 92 OMIM disease categories were identified and they are prioritized to specific immune diseases using random walk ranking algorithm. These data were compiled as ImmunemiR, a database of prioritized immune miRNA disease associations. This database provides both text based annotation information and network visualization of its interactome network. To our knowledge, ImmunemiR is the first available database to provide a comprehensive repository of human immune disease associated miRNAs with network visualization options of its target genes, protein-protein interactions (PPI).

  19. Common SNP-Based Haplotype Analysis of the 4p16.3 Huntington Disease Gene Region

    Science.gov (United States)

    Lee, Jong-Min; Gillis, Tammy; Mysore, Jayalakshmi Srinidhi; Ramos, Eliana Marisa; Myers, Richard H.; Hayden, Michael R.; Morrison, Patrick J.; Nance, Martha; Ross, Christopher A.; Margolis, Russell L.; Squitieri, Ferdinando; Griguoli, Annamaria; Di Donato, Stefano; Gomez-Tortosa, Estrella; Ayuso, Carmen; Suchowersky, Oksana; Trent, Ronald J.; McCusker, Elizabeth; Novelletto, Andrea; Frontali, Marina; Jones, Randi; Ashizawa, Tetsuo; Frank, Samuel; Saint-Hilaire, Marie-Helene; Hersch, Steven M.; Rosas, Herminia D.; Lucente, Diane; Harrison, Madaline B.; Zanko, Andrea; Abramson, Ruth K.; Marder, Karen; Sequeiros, Jorge; MacDonald, Marcy E.; Gusella, James F.

    2012-01-01

    Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of “synthetic association” with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder. PMID:22387017

  20. Systematic localization of common disease-associated variation in regulatory DNA.

    Science.gov (United States)

    Maurano, Matthew T; Humbert, Richard; Rynes, Eric; Thurman, Robert E; Haugen, Eric; Wang, Hao; Reynolds, Alex P; Sandstrom, Richard; Qu, Hongzhu; Brody, Jennifer; Shafer, Anthony; Neri, Fidencio; Lee, Kristen; Kutyavin, Tanya; Stehling-Sun, Sandra; Johnson, Audra K; Canfield, Theresa K; Giste, Erika; Diegel, Morgan; Bates, Daniel; Hansen, R Scott; Neph, Shane; Sabo, Peter J; Heimfeld, Shelly; Raubitschek, Antony; Ziegler, Steven; Cotsapas, Chris; Sotoodehnia, Nona; Glass, Ian; Sunyaev, Shamil R; Kaul, Rajinder; Stamatoyannopoulos, John A

    2012-09-07

    Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn's disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.

  1. Infliximab in Crohn's disease-associated toxic megacolon

    NARCIS (Netherlands)

    Geenen, E.J.M. van; Sachar, D.B.

    2012-01-01

    Refractory medical treatment of Crohn disease-associated toxic megacolon usually requires surgery, which carries substantial morbidity and mortality. We report a case of a woman with steroid and antibiotic-refractory fulminant Crohn colitis and ileitis, complicated by a toxic megacolon, who was

  2. Infliximab in Crohn's disease-associated toxic megacolon

    NARCIS (Netherlands)

    Geenen, E.J.M. van; Sachar, D.B.

    2012-01-01

    Refractory medical treatment of Crohn disease-associated toxic megacolon usually requires surgery, which carries substantial morbidity and mortality. We report a case of a woman with steroid and antibiotic-refractory fulminant Crohn colitis and ileitis, complicated by a toxic megacolon, who was succ

  3. Cesarean section and disease associated with immune function

    DEFF Research Database (Denmark)

    Kristensen, Kim; Stokholm, Lonny Merete

    2016-01-01

    BACKGROUND: Earlier studies have shown that delivery by cesarean section (CS) is associated with an increased risk of disease associated with immune function in the offspring, but these studies have generally not discriminated between the effect of acute and elective CS. OBJECTIVE: We sought to f...

  4. National Tay-Sachs and Allied Diseases Association, Inc.

    Science.gov (United States)

    Exceptional Parent, 1977

    1977-01-01

    Reviewed are the history and organization, purpose and programs, and public services of the National Tay-Sachs and Allied Diseases Association, an organization geared toward eradicating Tay-Sachs disease (a hereditary disorder affecting primarily Jewish infants which generally leads to deterioration and death by the child's fifth year). (SBH)

  5. The National Tay Sachs and Allied Diseases Association.

    Science.gov (United States)

    Zeitlin, Paula

    1986-01-01

    The National Tay-Sachs and Allied Diseases Association is involved in education, research, and prevention of Tay-Sachs, an inherited metabolic disorder which destroys the central nervous system, and over 30 related disorders. The group features a parent peer group network and a support group for carrier couples. (CL)

  6. The National Tay Sachs and Allied Diseases Association.

    Science.gov (United States)

    Zeitlin, Paula

    1986-01-01

    The National Tay-Sachs and Allied Diseases Association is involved in education, research, and prevention of Tay-Sachs, an inherited metabolic disorder which destroys the central nervous system, and over 30 related disorders. The group features a parent peer group network and a support group for carrier couples. (CL)

  7. National Tay-Sachs and Allied Diseases Association, Inc.

    Science.gov (United States)

    Exceptional Parent, 1977

    1977-01-01

    Reviewed are the history and organization, purpose and programs, and public services of the National Tay-Sachs and Allied Diseases Association, an organization geared toward eradicating Tay-Sachs disease (a hereditary disorder affecting primarily Jewish infants which generally leads to deterioration and death by the child's fifth year). (SBH)

  8. Disease associated time consumption in early rheumatoid arthritis

    NARCIS (Netherlands)

    Kuper, IH; Prevoo, MLL; van Leeuwen, MA; van Riel, PLCM; Lolkema, WF; Postma, DS; van Rijswijk, MH

    2000-01-01

    Objective. To quantify the disease associated time consumption of normal activities of daily living and of treatment and monitoring activities in a cohort of patients with early rheumatoid arthritis (RA) with followup of at least 6 years. Comparison was made with a group of patients with asthma and

  9. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

    OpenAIRE

    1998-01-01

    Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. L...

  10. Haplotyping using a combination of polymerase chain reaction-single-strand conformational polymorphism analysis and haplotype-specific PCR amplification.

    Science.gov (United States)

    Zhou, Huitong; Li, Shaobin; Liu, Xiu; Wang, Jiqing; Luo, Yuzhu; Hickford, Jon G H

    2014-12-01

    A single nucleotide polymorphism (SNP) may have an impact on phenotype, but it may also be influenced by multiple SNPs within a gene; hence, the haplotype or phase of multiple SNPs needs to be known. Various methods for haplotyping SNPs have been proposed, but a simple and cost-effective method is currently unavailable. Here we describe a haplotyping approach using two simple techniques: polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) and haplotype-specific PCR. In this approach, individual regions of a gene are analyzed by PCR-SSCP to identify variation that defines sub-haplotypes, and then extended haplotypes are assembled from the sub-haplotypes either directly or with the additional use of haplotype-specific PCR amplification. We demonstrate the utility of this approach by haplotyping ovine FABP4 across two variable regions that contain seven SNPs and one indel. The simplicity of this approach makes it suitable for large-scale studies and/or diagnostic screening.

  11. A fast and accurate algorithm for diploid individual haplotype reconstruction.

    Science.gov (United States)

    Wu, Jingli; Liang, Binbin

    2013-08-01

    Haplotypes can provide significant information in many research fields, including molecular biology and medical therapy. However, haplotyping is much more difficult than genotyping by using only biological techniques. With the development of sequencing technologies, it becomes possible to obtain haplotypes by combining sequence fragments. The haplotype reconstruction problem of diploid individual has received considerable attention in recent years. It assembles the two haplotypes for a chromosome given the collection of fragments coming from the two haplotypes. Fragment errors significantly increase the difficulty of the problem, and which has been shown to be NP-hard. In this paper, a fast and accurate algorithm, named FAHR, is proposed for haplotyping a single diploid individual. Algorithm FAHR reconstructs the SNP sites of a pair of haplotypes one after another. The SNP fragments that cover some SNP site are partitioned into two groups according to the alleles of the corresponding SNP site, and the SNP values of the pair of haplotypes are ascertained by using the fragments in the group that contains more SNP fragments. The experimental comparisons were conducted among the FAHR, the Fast Hare and the DGS algorithms by using the haplotypes on chromosome 1 of 60 individuals in CEPH samples, which were released by the International HapMap Project. Experimental results under different parameter settings indicate that the reconstruction rate of the FAHR algorithm is higher than those of the Fast Hare and the DGS algorithms, and the running time of the FAHR algorithm is shorter than those of the Fast Hare and the DGS algorithms. Moreover, the FAHR algorithm has high efficiency even for the reconstruction of long haplotypes and is very practical for realistic applications.

  12. Functional Haplotypes in Interleukin 4 Gene Associated with Periodontitis

    Science.gov (United States)

    Mayer, Marcia Pinto Alves; Rossa, Carlos

    2017-01-01

    Chronic periodontitis (CP) is an infectious inflammatory disease that affects tooth-supporting structures and in which dental plaque bacteria, immune mechanisms and genetic predisposition play important roles. Interleukin 4 (IL-4) is a key anti-inflammatory cytokine with relevant action in imbalances in inflamed periodontal tissue. Individuals carrying the TCI/CCI genotype (S-haplotype) of the IL-4 gene are 5 times more susceptible to CP, whereas the CTI/TTD genotype (P-haplotype) confers protection against CP. Compared with the S-haplotype, subjects with the P-haplotype produce higher levels of the IL-4 protein after non-surgical periodontal therapy. The present in vitro study aimed to investigate the functionality of IL-4 haplotypes in immune cells to obtain insight into the influence of these genetic variations in regulating immune responses to CP-associated bacteria. Peripheral blood was collected from 6 subjects carrying each haplotype, and their immune cells were challenged with periodontopathogens to compare responses of the different haplotypes with regard to gene expression, protein secretion and the immunophenotype of T helper responses. We found higher IL-4 mRNA and protein levels in the P-haplotype, which also presented higher levels of anti-inflammatory cytokines. In contrast, cells from S-haplotype subjects responded with higher levels of pro-inflammatory cytokines. S-haplotype individuals exhibited significantly greater polarization toward the Th1 phenotype, whereas the P-haplotype was associated with an attenuated response to periodontopathogens, with suggestive skewing toward Th2/M2 phenotypes. In conclusion, IL-4 genetic variations associated with susceptibility to or protection against chronic periodontitis are directly associated with influencing the response of immune cells to periodontopathogens. PMID:28114408

  13. Molecular definition of red cell Rh haplotypes by tightly linked SphI RFLPs.

    Science.gov (United States)

    Huang, C H; Reid, M E; Chen, Y; Coghlan, G; Okubo, Y

    1996-01-01

    The Rh blood group system of human red cells contains five major antigens D, C/c, and E/e (the latter four designated "non-D") that are specified by eight gene complexes known as Rh haplotypes. In this paper, we report on the mapping of RH locus and identification of a set of SphI RFLPs that are tightly linked with the Rh structural genes. Using exon-specific probes, we have localized the SphI cleavage sites resulting in these DNA markers and derived a comprehensive map for the RH locus. It was found that the SphI fragments encompassing exons 4-7 of the Rh genes occur in four banding patterns or frameworks that correspond to the distribution and segregation of the common Rh haplotypes. This linkage disequilibrium allowed a genotype-phenotype correlation and direct determination of Rh zygosity related to the Rh-positive or Rh-negative status (D/D, D/d, and d/d). Studies on the occurrence of SphI RFLPs in a number of rare Rh variants indicated that Rh phenotypic diversity has taken place on different haplotype backgrounds and has arisen by diverse genetic mechanisms. The molecular definition of Rh haplotypes by SphI RFLP frameworks should provide a useful procedure for genetic counseling and prenatal assessment of Rh alloimmunization.

  14. Haplotype frequencies at the DRD2 locus in populations of the East European Plain

    Directory of Open Access Journals (Sweden)

    Mikulich Alexey I

    2009-09-01

    Full Text Available Abstract Background It was demonstrated previously that the three-locus RFLP haplotype, TaqI B-TaqI D-TaqI A (B-D-A, at the DRD2 locus constitutes a powerful genetic marker and probably reflects the most ancient dispersal of anatomically modern humans. Results We investigated TaqI B, BclI, MboI, TaqI D, and TaqI A RFLPs in 17 contemporary populations of the East European Plain and Siberia. Most of these populations belong to the Indo-European or Uralic language families. We identified three common haplotypes, which occurred in more than 90% of chromosomes investigated. The frequencies of the haplotypes differed according to linguistic and geographical affiliation. Conclusion Populations in the northwestern (Byelorussians from Mjadel', northern (Russians from Mezen' and Oshevensk, and eastern (Russians from Puchezh parts of the East European Plain had relatively high frequencies of haplotype B2-D2-A2, which may reflect admixture with Uralic-speaking populations that inhabited all of these regions in the Early Middle Ages.

  15. Major histocompatibility complex class II alleles and haplotypes associated with non-suppurative meningoencephalitis in greyhounds.

    Science.gov (United States)

    Shiel, R E; Kennedy, L J; Nolan, C M; Mooney, C T; Callanan, J J

    2014-09-01

    Non-suppurative meningoencephalitis is a breed-restricted canine neuroinflammatory disorder affecting young greyhounds in Ireland. A genetic risk factor is suspected because of the development of disease in multiple siblings and an inability to identify a causative infectious agent. The aim of this study was to examine potential associations between dog leucocyte antigen (DLA) class II haplotype and the presence of the disease. DLA three locus haplotypes were determined in 31 dogs with non-suppurative meningoencephalitis and in 115 healthy control dogs using sequence-based typing (SBT) methods. All dogs were unrelated at the parental level. Two haplotypes (DRB1*01802/DQA1*00101/DQB1*00802 and DRB1*01501/DQA1*00601/DQB1*02201) were significantly (P = 0.0099 and 0.037) associated with the presence of meningoencephalitis, with odds ratios (95% confidence interval) of 5.531 (1.168-26.19) and 3.736 (1.446-9.652), respectively. These results confirm that there is an association between DLA class II haplotype and greyhound meningoencephalitis, suggesting an immunogenetic risk factor for the development of the disease. Greyhound meningoencephalitis may be a suitable model for human neuroinflammatory diseases with an immunogenetic component. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. 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.

  17. Association between HLA-DQ genotypes and haplotypes vs Helicobacter pylori infection in an Indonesian population.

    Science.gov (United States)

    Zhao, Yang; Wang, Jingwen; Tanaka, Tsutomu; Hosono, Akihiro; Ando, Ryosuke; Soeripto, Soeripto; Ediati Triningsih, F X; Triono, Tegu; Sumoharjo, Suwignyo; Astuti, E Y Wenny; Gunawan, Stephanus; Tokudome, Shinkan

    2012-01-01

    Helicobacter pylori is an important gastrointestinal pathogen related to the development of not only atrophic gastritis and peptic ulcer, but also gastric cancer. Human leukocyte antigens (HLA) may play particular roles in host immune responses to bacterial antigens. This study aimed to investigate the association between HLA-DQA1 and DQB1 genotypes and haplotypes vs H. pylori infection in an Indonesian population. We selected 294 healthy participants in Mataram, Lombok Island, Indonesia. H. pylori infection was determined by urea breath test (UBT). We analyzed HLA-DQA1 and DQB1 genotypes by PCR-RFLP and constructed haplotypes of HLA-DQA1 and DQB1 genes. Multiple comparisons were conducted according to the Bonferroni method. The H. pylori infection rate was 11.2% in this Indonesian population. The DQB1*0401 genotype was noted to be associated with a high risk of H. pylori infection, compared with the DQB1*0301 genotype. None of the HLA-DQA1 or DQB1 haplotypes were related to the risk of H. pylori infection. The study suggests that HLADQB1 genes play important roles in H. pylori infection, but there was no statistically significant association between HLA-DQA1 or DQB1 haplotypes and H.pylori infection in our Lombok Indonesian population.

  18. MHC class I and class II phenotype, gene, and haplotype frequencies in Greeks using molecular typing data.

    Science.gov (United States)

    Papassavas, E C; Spyropoulou-Vlachou, M; Papassavas, A C; Schipper, R F; Doxiadis, I N; Stavropoulos-Giokas, C

    2000-06-01

    In the present study, DNA typing for HLA-A, C, B, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, and DPB1 was performed for 246 healthy, unrelated Greek volunteers of 20-59 years of age. Phenotype, genotype frequencies, Hardy-Weinberg equilibrium fit, and 3-locus haplotype frequencies for HLA-A, C, B, HLA-A, B, DRB1, HLA-DRB1, DQA1, DQB1, and HLA-DRB1, DQB1, DPB1 were calculated. Furthermore, linkage disequilibrium, deltas, relative deltas and p-values for significance of the deltas were defined. The population studied is in Hardy-Weinberg equilibrium, and many MHC haplotypes are in linkage disequilibrium. The most frequent specificities were HLA-A*02 (phenotype frequency = 44.3%) followed by HLA-A*24 (27.2%), HLA-B*51 (28.5%), HLA-B*18 (26.8%) and HLA-B*35 (26.4%) and HLA-Cw*04 (30.1%) and HLA-Cw*12 (26.8%). The most frequent MHC class II alleles were HLA-DRB1*1104 (34.1%), HLA-DQB1*0301 (54.5%) and HLA-DPB1*0401 with a phenotype frequency of 59.8%. The most prominent HLA-A, C, B haplotypes were HLA-A*24, Cw*04, B*35, and HLA-A*02, Cw*04, B*35, each of them observed in 21/246 individuals. The most frequent HLA-A, B, DRB1 haplotype was HLA-A*02, B*18, DRB1*1104 seen in 20/246 individuals, while the haplotype HLA-DRB1*1104, DQB1*0301, DPB1*0401 was found in 49/246 individuals. Finally, the haplotype DRB1*1104, DQA1*0501, DQB1*0301 was observed in 83/246 individuals. These results can be used for the estimation of the probability of finding a suitable haplotypically identical related or unrelated stem cell donor for patients of Greek ancestry. In addition, they can be used for HLA and disease association studies, genetic distance studies in the Balkan and Mediterranean area, paternity cases, and matching probability calculations for the optimal allocation of kidneys in Greece.

  19. A method for haplotype inference in general pedigrees without recombination

    Institute of Scientific and Technical Information of China (English)

    WANG ChunKao; WANG ZhiPeng; QIU XiaoTian; ZHANG Qin

    2007-01-01

    The abundance of single nucleotide polymorphisms (SNPs) makes the haplotype-based method instead of single-maker-oriented method the main approach to association studies on QTL mapping. The key problem in haploptype-based method is how to reconstruct haplotypes from genotype data. Directly assaying haplotypes in diploid individuals by experimental methods is too expensive, therefore the in silico haplotyping-determination methods are the major choice at the present. This paper presents a rapid and reliable algorithm for haplotype reconstruction for tightly linked SNPs in general pedigrees. It is based on six rules and consists of three steps. First, the parental origins of alleles in offspring are assigned conditional on genotypes in parent-offspring trios; second, the redundant haplotypes are eliminated based on the six rules; and finally, the most likely haplotype combinations are chosen via maximum likelihood method. Our method was verified and compared with PEDPHASE by simulated data with different pedigree sizes, numbers of loci, and proportions of missing genotypes. The result shows that our algorithm was superior to PEDPHASE in terms of computing time and accuracy of haplotype estimation. The computing time for 100 runs was 10-15 times less and the accuracy was 4%-10% higher than PEDPHASE. The result also indicates that our method was very robust and was hardly affected by pedigree size, number of loci, and proportion of missing genotypes.

  20. Restriction digestion method for haplotyping the potato psyllid, Bactericera cockerelli

    Science.gov (United States)

    A restriction digestion method has been developed for haplotyping the potato psyllid, Bactericera cockerelli Sulc., an economically important pest of solanaceous crops. This method differentiates the four known potato psyllid haplotypes by utilizing restriction enzyme digestion of a portion of the ...

  1. Mercury in Hair Is Inversely Related to Disease Associated Damage in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    William Crowe

    2015-12-01

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune inflammatory disease, and environmental factors are proposed to exacerbate existing symptoms. One such environmental factor is mercury. The aim of this study was to investigate the relationship between exposure to mercury (Hg and disease activity and disease associated damage in Total Hg concentrations in hair and urine were measured in 52 SLE patients. Dental amalgams were quantified. Disease activity was assessed using three indexes including the British Isles Lupus Assessment Group Index (BILAG. Disease associated damage was measured using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLICC/ACR Damage Index. Pearson’s correlation identified a significant negative correlation between hair Hg and BILAG (r = −0.323, p = 0.029 and SLICC/ACR (r = −0.377, p = 0.038. Multiple regression analysis identified hair Hg as a significant predictor of disease associated damage as determined by SLICC/ACR (β = −0.366, 95% confidence interval (CI: −1.769, −0.155 p = 0.019. Urinary Hg was not related to disease activity or damage. Fish consumption is the primary route of MeHg exposure in humans and the inverse association of hair Hg with disease activity observed here might be explained by the anti-inflammatory effects of n-3 long chain polyunsaturated fatty acids also found in fish.

  2. Mercury in Hair Is Inversely Related to Disease Associated Damage in Systemic Lupus Erythematosus.

    Science.gov (United States)

    Crowe, William; Doherty, Leanne; Watson, Gene; Armstrong, David; Ball, Elisabeth; Magee, Pamela; Allsopp, Philip; Bell, Aubrey; Strain, J J; McSorley, Emeir

    2015-12-23

    Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease, and environmental factors are proposed to exacerbate existing symptoms. One such environmental factor is mercury. The aim of this study was to investigate the relationship between exposure to mercury (Hg) and disease activity and disease associated damage in Total Hg concentrations in hair and urine were measured in 52 SLE patients. Dental amalgams were quantified. Disease activity was assessed using three indexes including the British Isles Lupus Assessment Group Index (BILAG). Disease associated damage was measured using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLICC/ACR Damage Index. Pearson's correlation identified a significant negative correlation between hair Hg and BILAG (r = -0.323, p = 0.029) and SLICC/ACR (r = -0.377, p = 0.038). Multiple regression analysis identified hair Hg as a significant predictor of disease associated damage as determined by SLICC/ACR (β = -0.366, 95% confidence interval (CI): -1.769, -0.155 p = 0.019). Urinary Hg was not related to disease activity or damage. Fish consumption is the primary route of MeHg exposure in humans and the inverse association of hair Hg with disease activity observed here might be explained by the anti-inflammatory effects of n-3 long chain polyunsaturated fatty acids also found in fish.

  3. Isolated Endobronchial Mycobacterium avium Disease Associated with Lobar Atelectasis in an Immunocompetent Young Adult: A Case Report and Literature Review.

    Science.gov (United States)

    Kim, Hye In; Kim, Ji Won; Kim, Jun Young; Kim, Young Nam; Kim, Jin Hae; Jeong, Byeong-Ho; Chung, Myung Jin; Koh, Won-Jung

    2015-10-01

    The prevalence of lung diseases caused by nontuberculous mycobacteria (NTM) is increasing worldwide. Unlike pulmonary tuberculosis, endobronchial NTM diseases are very rare with the majority of cases reported in patients with human immunodeficiency virus infection and acquired immune deficiency syndrome. We reported a rare case of endobronchial Mycobacterium avium disease associated with lobar atelectasis in a young immunocompetent patient and reviewed the relevant iterature.

  4. Haplotype map of sickle cell anemia in Tunisia.

    Science.gov (United States)

    Moumni, Imen; Ben Mustapha, Maha; Sassi, Sarra; Zorai, Amine; Ben Mansour, Ikbel; Douzi, Kais; Chouachi, Dorra; Mellouli, Fethi; Bejaoui, Mohamed; Abbes, Salem

    2014-01-01

    β-Globin haplotypes are important to establish the ethnic origin and predict the clinical development of sickle cell disease patients (SCD). To determine the chromosomal background of β (S) Tunisian sickle cell patients, in this first study in Tunisia, we have explored four polymorphic regions of β-globin cluster on chromosome 11. It is the 5' region of β-LCR-HS2 site, the intervening sequence II (IVSII) region of two fetal ((G)γ and (A)γ) genes and the 5' region of β-globin gene. The results reveal a high molecular diversity of a microsatellite configuration describing the sequences haplotypes. The linkage disequilibrium analysis showed various haplotype combinations giving 22 "extended haplotypes". These results confirm the utility of the β-globin haplotypes for population studies and contribute to knowledge of the Tunisian gene pool, as well as establishing the role of genetic markers in physiopathology of SCD.

  5. General Framework for Meta-Analysis of Haplotype Association Tests.

    Science.gov (United States)

    Wang, Shuai; Zhao, Jing Hua; An, Ping; Guo, Xiuqing; Jensen, Richard A; Marten, Jonathan; Huffman, Jennifer E; Meidtner, Karina; Boeing, Heiner; Campbell, Archie; Rice, Kenneth M; Scott, Robert A; Yao, Jie; Schulze, Matthias B; Wareham, Nicholas J; Borecki, Ingrid B; Province, Michael A; Rotter, Jerome I; Hayward, Caroline; Goodarzi, Mark O; Meigs, James B; Dupuis, Josée

    2016-04-01

    For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

  6. Inferring drug-disease associations based on known protein complexes.

    Science.gov (United States)

    Yu, Liang; Huang, Jianbin; Ma, Zhixin; Zhang, Jing; Zou, Yapeng; Gao, Lin

    2015-01-01

    Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html.

  7. The functional importance of disease-associated mutation

    Directory of Open Access Journals (Sweden)

    Klein Teri E

    2002-09-01

    Full Text Available Abstract Background For many years, scientists believed that point mutations in genes are the genetic switches for somatic and inherited diseases such as cystic fibrosis, phenylketonuria and cancer. Some of these mutations likely alter a protein's function in a manner that is deleterious, and they should occur in functionally important regions of the protein products of genes. Here we show that disease-associated mutations occur in regions of genes that are conserved, and can identify likely disease-causing mutations. Results To show this, we have determined conservation patterns for 6185 non-synonymous and heritable disease-associated mutations in 231 genes. We define a parameter, the conservation ratio, as the ratio of average negative entropy of analyzable positions with reported mutations to that of every analyzable position in the gene sequence. We found that 84.0% of the 231 genes have conservation ratios less than one. 139 genes had eleven or more analyzable mutations and 88.0% of those had conservation ratios less than one. Conclusions These results indicate that phylogenetic information is a powerful tool for the study of disease-associated mutations. Our alignments and analysis has been made available as part of the database at http://cancer.stanford.edu/mut-paper/. Within this dataset, each position is annotated with the analysis, so the most likely disease-causing mutations can be identified.

  8. Phasing for medical sequencing using rare variants and large haplotype reference panels

    Science.gov (United States)

    Sharp, Kevin; Kretzschmar, Warren; Delaneau, Olivier; Marchini, Jonathan

    2016-01-01

    Motivation: There is growing recognition that estimating haplotypes from high coverage sequencing of single samples in clinical settings is an important problem. At the same time very large datasets consisting of tens and hundreds of thousands of high-coverage sequenced samples will soon be available. We describe a method that takes advantage of these huge human genetic variation resources and rare variant sharing patterns to estimate haplotypes on single sequenced samples. Sharing rare variants between two individuals is more likely to arise from a recent common ancestor and, hence, also more likely to indicate similar shared haplotypes over a substantial flanking region of sequence. Results: Our method exploits this idea to select a small set of highly informative copying states within a Hidden Markov Model (HMM) phasing algorithm. Using rare variants in this way allows us to avoid iterative MCMC methods to infer haplotypes. Compared to other approaches that do not explicitly use rare variants we obtain significant gains in phasing accuracy, less variation over phasing runs and improvements in speed. For example, using a reference panel of 7420 haplotypes from the UK10K project, we are able to reduce switch error rates by up to 50% when phasing samples sequenced at high-coverage. In addition, a single step rephasing of the UK10K panel, using rare variant information, has a downstream impact on phasing performance. These results represent a proof of concept that rare variant sharing patterns can be utilized to phase large high-coverage sequencing studies such as the 100 000 Genomes Project dataset. Availability and implementation: A webserver that includes an implementation of this new method and allows phasing of high-coverage clinical samples is available at https://phasingserver.stats.ox.ac.uk/. Contact: marchini@stats.ox.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153703

  9. Understanding the contrasting spatial haplotype patterns of malaria-protective β-globin polymorphisms

    OpenAIRE

    Hockham, Carinna; Piel, Frédéric B; Gupta, Sunetra; Penman, Bridget S.

    2015-01-01

    The malaria-protective β-globin polymorphisms, sickle-cell (βS) and β0-thalassaemia, are canonical examples of human adaptation to infectious disease. Occurring on distinct genetic backgrounds, they vary markedly in their patterns of linked genetic variation at the population level, suggesting different evolutionary histories. βS is associated with five classical restriction fragment length polymorphism haplotypes that exhibit remarkable specificity in their geographical distributions; by con...

  10. DNA analysis of ancient dogs of the Americas: identifying possible founding haplotypes and reconstructing population histories.

    Science.gov (United States)

    Witt, Kelsey E; Judd, Kathleen; Kitchen, Andrew; Grier, Colin; Kohler, Timothy A; Ortman, Scott G; Kemp, Brian M; Malhi, Ripan S

    2015-02-01

    As dogs have traveled with humans to every continent, they can potentially serve as an excellent proxy when studying human migration history. Past genetic studies into the origins of Native American dogs have used portions of the hypervariable region (HVR) of mitochondrial DNA (mtDNA) to indicate that prior to European contact the dogs of Native Americans originated in Eurasia. In this study, we summarize past DNA studies of both humans and dogs to discuss their population histories in the Americas. We then sequenced a portion of the mtDNA HVR of 42 pre-Columbian dogs from three sites located in Illinois, coastal British Columbia, and Colorado, and identify four novel dog mtDNA haplotypes. Next, we analyzed a dataset comprised of all available ancient dog sequences from the Americas to infer the pre-Columbian population history of dogs in the Americas. Interestingly, we found low levels of genetic diversity for some populations consistent with the possibility of deliberate breeding practices. Furthermore, we identified multiple putative founding haplotypes in addition to dog haplotypes that closely resemble those of wolves, suggesting admixture with North American wolves or perhaps a second domestication of canids in the Americas. Notably, initial effective population size estimates suggest at least 1000 female dogs likely existed in the Americas at the time of the first known canid burial, and that population size increased gradually over time before stabilizing roughly 1200 years before present.

  11. 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.

  12. Accounting for haplotype phase uncertainty in linkage disequilibrium estimation.

    Science.gov (United States)

    Kulle, B; Frigessi, A; Edvardsen, H; Kristensen, V; Wojnowski, L

    2008-02-01

    The characterization of linkage disequilibrium (LD) is applied in a variety of studies including the identification of molecular determinants of the local recombination rate, the migration and population history of populations, and the role of positive selection in adaptation. LD suffers from the phase uncertainty of the haplotypes used in its calculation, which reflects limitations of the algorithms used for haplotype estimation. We introduce a LD calculation method, which deals with phase uncertainty by weighting all possible haplotype pairs according to their estimated probabilities as evaluated by PHASE. In contrast to the expectation-maximization (EM) algorithm as implemented in the HAPLOVIEW and GENETICS packages, our method considers haplotypes based on the entire genetic information available for the candidate region. We tested the method using simulated and real genotyping data. The results show that, for all practical purposes, the new method is advantageous in comparison with algorithms that calculate LD using only the most probable haplotype or bilocus haplotypes based on the EM algorithm. The new method deals especially well with low LD regions, which contribute strongly to phase uncertainty. Altogether, the method is an attractive alternative to standard LD calculation procedures, including those based on the EM algorithm. We implemented the method in the software suite R, together with an interface to the popular haplotype calculation package PHASE.

  13. Maximum-likelihood estimation of haplotype frequencies in nuclear families.

    Science.gov (United States)

    Becker, Tim; Knapp, Michael

    2004-07-01

    The importance of haplotype analysis in the context of association fine mapping of disease genes has grown steadily over the last years. Since experimental methods to determine haplotypes on a large scale are not available, phase has to be inferred statistically. For individual genotype data, several reconstruction techniques and many implementations of the expectation-maximization (EM) algorithm for haplotype frequency estimation exist. Recent research work has shown that incorporating available genotype information of related individuals largely increases the precision of haplotype frequency estimates. We, therefore, implemented a highly flexible program written in C, called FAMHAP, which calculates maximum likelihood estimates (MLEs) of haplotype frequencies from general nuclear families with an arbitrary number of children via the EM-algorithm for up to 20 SNPs. For more loci, we have implemented a locus-iterative mode of the EM-algorithm, which gives reliable approximations of the MLEs for up to 63 SNP loci, or less when multi-allelic markers are incorporated into the analysis. Missing genotypes can be handled as well. The program is able to distinguish cases (haplotypes transmitted to the first affected child of a family) from pseudo-controls (non-transmitted haplotypes with respect to the child). We tested the performance of FAMHAP and the accuracy of the obtained haplotype frequencies on a variety of simulated data sets. The implementation proved to work well when many markers were considered and no significant differences between the estimates obtained with the usual EM-algorithm and those obtained in its locus-iterative mode were observed. We conclude from the simulations that the accuracy of haplotype frequency estimation and reconstruction in nuclear families is very reliable in general and robust against missing genotypes.

  14. PBMDA: A novel and effective path-based computational model for miRNA-disease association prediction.

    Directory of Open Access Journals (Sweden)

    Zhu-Hong You

    2017-03-01

    Full Text Available In the recent few years, an increasing number of studies have shown that microRNAs (miRNAs play critical roles in many fundamental and important biological processes. As one of pathogenetic factors, the molecular mechanisms underlying human complex diseases still have not been completely understood from the perspective of miRNA. Predicting potential miRNA-disease associations makes important contributions to understanding the pathogenesis of diseases, developing new drugs, and formulating individualized diagnosis and treatment for diverse human complex diseases. Instead of only depending on expensive and time-consuming biological experiments, computational prediction models are effective by predicting potential miRNA-disease associations, prioritizing candidate miRNAs for the investigated diseases, and selecting those miRNAs with higher association probabilities for further experimental validation. In this study, Path-Based MiRNA-Disease Association (PBMDA prediction model was proposed by integrating known human miRNA-disease associations, miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity for miRNAs and diseases. This model constructed a heterogeneous graph consisting of three interlinked sub-graphs and further adopted depth-first search algorithm to infer potential miRNA-disease associations. As a result, PBMDA achieved reliable performance in the frameworks of both local and global LOOCV (AUCs of 0.8341 and 0.9169, respectively and 5-fold cross validation (average AUC of 0.9172. In the cases studies of three important human diseases, 88% (Esophageal Neoplasms, 88% (Kidney Neoplasms and 90% (Colon Neoplasms of top-50 predicted miRNAs have been manually confirmed by previous experimental reports from literatures. Through the comparison performance between PBMDA and other previous models in case studies, the reliable performance also demonstrates that PBMDA could serve as a powerful

  15. 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

    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.

  16. Granulomatous disease associated with pulmonary deposition of titanium.

    Science.gov (United States)

    Redline, S; Barna, B P; Tomashefski, J F; Abraham, J L

    1986-10-01

    A patient presented with granulomatous lung disease associated with the pulmonary deposition of various metallic particles. To evaluate the relation between the metallic dust and the granulomatous process, lymphocyte transformation tests to aluminium sulphate, titanium chloride, beryllium sulphate, and nickel sulphate were performed. A lymphocyte proliferative response to titanium chloride was observed on two separate occasions; no responses to the other metals were shown. These results are consistent with hypersensitivity to titanium, and suggest, in this individual, a possible aetiological role between the inhalation of titanium and a granulomatous disease process.

  17. Graves' disease associated with alopecia areata developing after Hashimoto's thyroiditis.

    Science.gov (United States)

    Aşık, Mehmet; Binnetoğlu, Emine; Şen, Hacer; Tekeli, Zeliha; Uysal, Fatma; Ukinç, Kubilay

    2013-01-01

    Graves' disease and Hashimoto's thyroiditis are the most common autoimmune thyroid diseases. Hypothyroidism can develop in patients with Graves' disease, either spontaneously or as a result of radioactive iodine therapy or surgery. However, it is rare for patients with Hashimoto's thyroiditis to subsequently develop Graves' disease. We report a case of alopecia areata associated with Graves' disease in a 41-year-old woman who had previously been diagnosed with Hashimoto's disease. Alopecia areata is an autoimmune disease associated with other autoimmune diseases such as thyroid disorders, anemia, and other skin disorders.

  18. Madelung's disease associated with polyneuropathy and symptomatic hypokalemia

    Directory of Open Access Journals (Sweden)

    Hoi-Fong Chan

    2013-05-01

    Full Text Available Madelung's disease (multiple symmetric lipomatosis is a rare disease characterized by abnormal diffuse lipomatosis in proximal upper limbs and neck. Previous reports have shown that this disease is associated with alcoholism, polyneuropathy, mitochondrial disease, and glucose intolerance. Here, we describe a 46-year-old man having Madelung's disease associated with polyneuropathy and symptomatic hypokalemia. He presented with insidious-onset weakness and numbness in lower limbs for 7 years and recent deterioration of symptoms. Proximal weakness improved with potassium supplement. Our observation may extend the phenotype of Madelung's disease to hypokalemic periodic paralysis.

  19. Preferred SLA class I/class II haplotype combinations in German Landrace pigs.

    Science.gov (United States)

    Gimsa, Ulrike; Ho, Chak-Sum; Hammer, Sabine E

    2017-01-01

    Major histocompatibility complex (MHC) molecules are responsible for the antigen presentation to T lymphocytes. High recombination rates in the MHC genes, as observed in humans, are believed to serve the evolutionary goal to achieve a high genetic diversity, allowing for a broad and efficient immune response. In a cohort of 155 pedigreed German Landrace pigs (65 founders and 90 piglets), we found that MHC genes occur in particular class I and class II haplotype combinations. This phenomenon has not been described before, probably because most of the earlier MHC studies in pigs were not pedigree-based. After comparing our data with published genotypes of different European pig breeds and Asian pigs, we hypothesise that the combination of particular but different haplotypes in different geographical regions may have developed under the evolutionary pressure of regionally endemic pathogens. This proposed mechanism ensures an efficient immune response despite low recombination rates.

  20. ICOS gene haplotypes correlate with IL10 secretion and multiple sclerosis evolution.

    Science.gov (United States)

    Castelli, Luca; Comi, Cristoforo; Chiocchetti, Annalisa; Nicola, Stefania; Mesturini, Riccardo; Giordano, Mara; D'Alfonso, Sandra; Cerutti, Elisa; Galimberti, Daniela; Fenoglio, Chiara; Tesser, Fabiana; Yagi, Junji; Rojo, José Maria; Perla, Franco; Leone, Maurizio; Scarpini, Elio; Monaco, Francesco; Dianzani, Umberto

    2007-05-01

    Human ICOS is a T cell costimulatory molecule supporting IL10 secretion. A pilot study investigating variations of the ICOS gene 3'UTR detected 8 polymorphisms forming three haplotypes (A, B, C). Haplotype-A and -C displayed the highest difference. Activated T cells from healthy AA homozygotes expressed significantly less ICOS and secreted more IL10 than AC heterozygotes, whereas AB heterozygotes displayed intermediate levels. Analysis of 441 multiple sclerosis patients and 793 controls showed that frequency of AA homozygosity was significantly lower in MS patients with relapsing-remitting onset (N=416) than in controls (OR=0.70). Moreover, AA patients with relapsing-remitting onset had lower relapse rate and multiple sclerosis severity score than non-AA patients.

  1. 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

    BACKGROUND AND OBJECTIVES: The 8.1 ancestral haplotype (AH) (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2) is a remarkably long and conserved haplotype in the human major histocompatibility complex. It has been associated with both beneficial and detrimental effects, consistent with antagonistic....... 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...

  2. Insights into HLA-G genetics provided by worldwide haplotype diversity

    Directory of Open Access Journals (Sweden)

    Erick C Castelli

    2014-10-01

    Full Text Available Human Leucocyte Antigen G (HLA-G belongs to the family of nonclassical HLA class I genes, located within the major histocompatibility complex (MHC. HLA-G has been the target of most recent research regarding the function of class I nonclassical genes. The main features that distinguish HLA-G from classical class I genes are: a limited protein variability; b alternative splicing generating several membrane bound and soluble isoforms; c short cytoplasmic tail; d modulation of immune response (immune tolerance; e restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments (promoter, coding and 3’untranslated regions. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding and 3’ untranslated regions are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.

  3. Power laws for heavy-tailed distributions: modeling allele and haplotype diversity for the national marrow donor program.

    Directory of Open Access Journals (Sweden)

    Noa Slater

    2015-04-01

    Full Text Available Measures of allele and haplotype diversity, which are fundamental properties in population genetics, often follow heavy tailed distributions. These measures are of particular interest in the field of hematopoietic stem cell transplant (HSCT. Donor/Recipient suitability for HSCT is determined by Human Leukocyte Antigen (HLA similarity. Match predictions rely upon a precise description of HLA diversity, yet classical estimates are inaccurate given the heavy-tailed nature of the distribution. This directly affects HSCT matching and diversity measures in broader fields such as species richness. We, therefore, have developed a power-law based estimator to measure allele and haplotype diversity that accommodates heavy tails using the concepts of regular variation and occupancy distributions. Application of our estimator to 6.59 million donors in the Be The Match Registry revealed that haplotypes follow a heavy tail distribution across all ethnicities: for example, 44.65% of the European American haplotypes are represented by only 1 individual. Indeed, our discovery rate of all U.S. European American haplotypes is estimated at 23.45% based upon sampling 3.97% of the population, leaving a large number of unobserved haplotypes. Population coverage, however, is much higher at 99.4% given that 90% of European Americans carry one of the 4.5% most frequent haplotypes. Alleles were found to be less diverse suggesting the current registry represents most alleles in the population. Thus, for HSCT registries, haplotype discovery will remain high with continued recruitment to a very deep level of sampling, but population coverage will not. Finally, we compared the convergence of our power-law versus classical diversity estimators such as Capture recapture, Chao, ACE and Jackknife methods. When fit to the haplotype data, our estimator displayed favorable properties in terms of convergence (with respect to sampling depth and accuracy (with respect to diversity

  4. Haplotype Map of Sickle Cell Anemia in Tunisia

    Directory of Open Access Journals (Sweden)

    Imen Moumni

    2014-01-01

    Full Text Available β-Globin haplotypes are important to establish the ethnic origin and predict the clinical development of sickle cell disease patients (SCD. To determine the chromosomal background of βS Tunisian sickle cell patients, in this first study in Tunisia, we have explored four polymorphic regions of β-globin cluster on chromosome 11. It is the 5′ region of β-LCR-HS2 site, the intervening sequence II (IVSII region of two fetal (γG and γA genes and the 5′ region of β-globin gene. The results reveal a high molecular diversity of a microsatellite configuration describing the sequences haplotypes. The linkage disequilibrium analysis showed various haplotype combinations giving 22 “extended haplotypes”. These results confirm the utility of the β-globin haplotypes for population studies and contribute to knowledge of the Tunisian gene pool, as well as establishing the role of genetic markers in physiopathology of SCD.

  5. Y-chromosome STR haplotypes in males from Greenland

    DEFF Research Database (Denmark)

    Hallenberg, Charlotte; Tomas Mas, Carmen; Simonsen, Bo;

    2009-01-01

    A total of 272 males from Greenland were typed for 11 Y-chromosome STRs DYS19, DYS385a/b, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 with the PowerPlex Y System (Promega). A total of 146 different haplotypes were observed and the haplotype diversity was 0.9887....

  6. Haplotype and missing data inference in nuclear families.

    Science.gov (United States)

    Lin, Shin; Chakravarti, Aravinda; Cutler, David J

    2004-08-01

    Determining linkage phase from population samples with statistical methods is accurate only within regions of high linkage disequilibrium (LD). Yet, affected individuals in a genetic mapping study, including those involving cases and controls, may share sequences identical-by-descent stretching on the order of 10s to 100s of kilobases, quite possibly over regions of low LD in the population. At the same time, inferring phase from nuclear families may be hampered by missing family members, missing genotypes, and the noninformativity of certain genotype patterns. In this study, we reformulate our previous haplotype reconstruction algorithm, and its associated computer program, to phase parents with information derived from population samples as well as from their offspring. In applications of our algorithm to 100-kb stretches, simulated in accordance to a Wright-Fisher model with typical levels of LD in humans, we find that phase reconstruction for 160 trios with 10% missing data is highly accurate (>90%) over the entire length. Furthermore, our algorithm can estimate allelic status for missing data at high accuracy (>95%). Finally, the input capacity of the program is vast, easily handling thousands of segregating sites in > or = 1000 chromosomes.

  7. Short communication: casein haplotype variability in sicilian dairy goat breeds.

    Science.gov (United States)

    Gigli, I; Maizon, D O; Riggio, V; Sardina, M T; Portolano, B

    2008-09-01

    In the Mediterranean region, goat milk production is an important economic activity. In the present study, 4 casein genes were genotyped in 5 Sicilian goat breeds to 1) identify casein haplotypes present in the Argentata dell'Etna, Girgentana, Messinese, Derivata di Siria, and Maltese goat breeds; and 2) describe the structure of the Sicilian goat breeds based on casein haplotypes and allele frequencies. In a sample of 540 dairy goats, 67 different haplotypes with frequency >or=0.01 and 27 with frequency >or=0.03 were observed. The most common CSN1S1-CSN2-CSN1S2-CSN3 haplotype for Derivata di Siria and Maltese was FCFB (0.17 and 0.22, respectively), whereas for Argentata dell'Etna, Girgentana and Messinese was ACAB (0.06, 0.23, and 0.10, respectively). According to the haplotype reconstruction, Argentata dell'Etna, Girgentana, and Messinese breeds presented the most favorable haplotype for cheese production, because the casein concentration in milk of these breeds might be greater than that in Derivata di Siria and Maltese breeds. Based on a cluster analysis, the breeds formed 2 main groups: Derivata di Siria, and Maltese in one group, and Argentata dell'Etna and Messinese in the other; the Girgentana breed was between these groups but closer to the latter.

  8. Haplotype allelic classes for detecting ongoing positive selection.

    Science.gov (United States)

    Hussin, Julie; Nadeau, Philippe; Lefebvre, Jean-François; Labuda, Damian

    2010-01-28

    Natural selection eliminates detrimental and favors advantageous phenotypes. This process leaves characteristic signatures in underlying genomic segments that can be recognized through deviations in allelic or haplotypic frequency spectra. To provide an identifiable signature of recent positive selection that can be detected by comparison with the background distribution, we introduced a new way of looking at genomic polymorphisms: haplotype allelic classes. The model combines segregating sites and haplotypic information in order to reveal useful data characteristics. We developed a summary statistic, Svd, to compare the distribution of the haplotypes carrying the selected allele with the distribution of the remaining ones. Coalescence simulations are used to study the distributions under standard population models assuming neutrality, demographic scenarios and selection models. To test, in practice, haplotype allelic class performance and the derived statistic in capturing deviation from neutrality due to positive selection, we analyzed haplotypic variation in detail in the locus of lactase persistence in the three HapMap Phase II populations. We showed that the Svd statistic is less sensitive than other tests to confounding factors such as demography or recombination. Our approach succeeds in identifying candidate loci, such as the lactase-persistence locus, as targets of strong positive selection and provides a new tool complementary to other tests to study natural selection in genomic data.

  9. Haplotype allelic classes for detecting ongoing positive selection

    Directory of Open Access Journals (Sweden)

    Lefebvre Jean-François

    2010-01-01

    Full Text Available Abstract Background Natural selection eliminates detrimental and favors advantageous phenotypes. This process leaves characteristic signatures in underlying genomic segments that can be recognized through deviations in allelic or haplotypic frequency spectra. To provide an identifiable signature of recent positive selection that can be detected by comparison with the background distribution, we introduced a new way of looking at genomic polymorphisms: haplotype allelic classes. Results The model combines segregating sites and haplotypic information in order to reveal useful data characteristics. We developed a summary statistic, Svd, to compare the distribution of the haplotypes carrying the selected allele with the distribution of the remaining ones. Coalescence simulations are used to study the distributions under standard population models assuming neutrality, demographic scenarios and selection models. To test, in practice, haplotype allelic class performance and the derived statistic in capturing deviation from neutrality due to positive selection, we analyzed haplotypic variation in detail in the locus of lactase persistence in the three HapMap Phase II populations. Conclusions We showed that the Svd statistic is less sensitive than other tests to confounding factors such as demography or recombination. Our approach succeeds in identifying candidate loci, such as the lactase-persistence locus, as targets of strong positive selection and provides a new tool complementary to other tests to study natural selection in genomic data.

  10. MHC Class II haplotypes of Colombian Amerindian tribes.

    Science.gov (United States)

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

    2013-07-01

    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.

  11. MHC Class II haplotypes of Colombian Amerindian tribes

    Directory of Open Access Journals (Sweden)

    Juan J. Yunis

    2013-01-01

    Full Text Available 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.

  12. Association testing by haplotype-sharing methods applicable to whole-genome analysis

    NARCIS (Netherlands)

    Nolte, Ilja M.; Vries, André R. de; Spijker, Geert T.; Jansen, Ritsert C.; Brinza, Dumitru; Zelikovsky, Alexander; Meerman, Gerard J. te

    2007-01-01

    We propose two new haplotype-sharing methods for identifying disease loci: the haplotype sharing statistic (HSS), which compares length of shared haplotypes between cases and controls, and the CROSS test, which tests whether a case and a control haplotype show less sharing than two random

  13. Glomerular Diseases Associated with Hepatitis C Virus Infection

    Directory of Open Access Journals (Sweden)

    Miller Sara

    2000-01-01

    Full Text Available Renal diseases associated with hepatitis C virus (HCV infection are a significant problem for clinicians and diagnostic pathologists. A wide variety of disorders, including a spectrum of immune-complex glomerulonephritides, has been reported in association with hepatitis and cirrhosis caused by HCV. For some of these diseases, including membranoproliferative glomerulonephritis type I and cryoglobulinemic glomerulonephritis, plausible links between HCV and the glomerular pathology have been proposed. In other cases, the role of the virus in the pathogenesis of the renal disease is less certain. This communication catalogues the renal manifestations of HCV infection, providing clinical and pathological descriptions of the most prevalent disorders. Where available, evidence implicating HCV in the causation of the disorders is also discussed.

  14. Immunoregulation by naturally occurring and disease-associated autoantibodies

    DEFF Research Database (Denmark)

    Nielsen, Claus H; Bendtzen, Klaus

    2012-01-01

    -receptors on antigen-presenting cells and thereby regulate T-cell activity. Knowledge of the influence of NAbs against cytokines on immune homeostasis is likely to have wide-ranging implications both in understanding pathogenesis and in treatment of many immunoinflammatory disorders, including a number of autoimmune......The role of naturally occurring autoantibodies (NAbs) in homeostasis and in disease manifestations is poorly understood. In the present chapter, we review how NAbs may interfere with the cytokine network and how NAbs, through formation of complement-activating immune complexes with soluble self......-antigens, may promote the uptake and presentation of self-molecules by antigen-presenting cells. Both naturally occurring and disease-associated autoantibodies against a variety of cytokines have been reported, including NAbs against interleukin (IL)-1α, IL-6, IL-8, IL-10, granulocyte-macrophage colony...

  15. A sequential Monte Carlo framework for haplotype inference in CNV/SNP genotype data.

    Science.gov (United States)

    Iliadis, Alexandros; Anastassiou, Dimitris; Wang, Xiaodong

    2014-01-01

    Copy number variations (CNVs) are abundant in the human genome. They have been associated with complex traits in genome-wide association studies (GWAS) and expected to continue playing an important role in identifying the etiology of disease phenotypes. As a result of current high throughput whole-genome single-nucleotide polymorphism (SNP) arrays, we currently have datasets that simultaneously have integer copy numbers in CNV regions as well as SNP genotypes. At the same time, haplotypes that have been shown to offer advantages over genotypes in identifying disease traits even though available for SNP genotypes are largely not available for CNV/SNP data due to insufficient computational tools. We introduce a new framework for inferring haplotypes in CNV/SNP data using a sequential Monte Carlo sampling scheme 'Tree-Based Deterministic Sampling CNV' (TDSCNV). We compare our method with polyHap(v2.0), the only currently available software able to perform inference in CNV/SNP genotypes, on datasets of varying number of markers. We have found that both algorithms show similar accuracy but TDSCNV is an order of magnitude faster while scaling linearly with the number of markers and number of individuals and thus could be the method of choice for haplotype inference in such datasets. Our method is implemented in the TDSCNV package which is available for download at http://www.ee.columbia.edu/~anastas/tdscnv.

  16. Mapping the genetic diversity of HLA haplotypes in the Japanese populations.

    Science.gov (United States)

    Saw, Woei-Yuh; Liu, Xuanyao; Khor, Chiea-Chuen; Takeuchi, Fumihiko; Katsuya, Tomohiro; Kimura, Ryosuke; Nabika, Toru; Ohkubo, Takayoshi; Tabara, Yasuharu; Yamamoto, Ken; Yokota, Mitsuhiro; Teo, Yik-Ying; Kato, Norihiro

    2015-12-09

    Japan has often been viewed as an Asian country that possesses a genetically homogenous community. The basis for partitioning the country into prefectures has largely been geographical, although cultural and linguistic differences still exist between some of the districts/prefectures, especially between Okinawa and the mainland prefectures. The Major Histocompatibility Complex (MHC) region has consistently emerged as the most polymorphic region in the human genome, harbouring numerous biologically important variants; nevertheless the presence of population-specific long haplotypes hinders the imputation of SNPs and classical HLA alleles. Here, we examined the extent of genetic variation at the MHC between eight Japanese populations sampled from Okinawa, and six other prefectures located in or close to the mainland of Japan, specifically focusing at the haplotypes observed within each population, and what the impact of any variation has on imputation. Our results indicated that Okinawa was genetically farther to the mainland Japanese than were Gujarati Indians from Tamil Indians, while the mainland Japanese from six prefectures were more homogeneous than between northern and southern Han Chinese. The distribution of haplotypes across Japan was similar, although imputation was most accurate for Okinawa and several mainland prefectures when population-specific panels were used as reference.

  17. Inductive matrix completion for predicting gene–disease associations

    Science.gov (United States)

    Natarajan, Nagarajan; Dhillon, Inderjit S.

    2014-01-01

    Motivation: Most existing methods for predicting causal disease genes rely on specific type of evidence, and are therefore limited in terms of applicability. More often than not, the type of evidence available for diseases varies—for example, we may know linked genes, keywords associated with the disease obtained by mining text, or co-occurrence of disease symptoms in patients. Similarly, the type of evidence available for genes varies—for example, specific microarray probes convey information only for certain sets of genes. In this article, we apply a novel matrix-completion method called Inductive Matrix Completion to the problem of predicting gene-disease associations; it combines multiple types of evidence (features) for diseases and genes to learn latent factors that explain the observed gene–disease associations. We construct features from different biological sources such as microarray expression data and disease-related textual data. A crucial advantage of the method is that it is inductive; it can be applied to diseases not seen at training time, unlike traditional matrix-completion approaches and network-based inference methods that are transductive. Results: Comparison with state-of-the-art methods on diseases from the Online Mendelian Inheritance in Man (OMIM) database shows that the proposed approach is substantially better—it has close to one-in-four chance of recovering a true association in the top 100 predictions, compared to the recently proposed Catapult method (second best) that has bigdata.ices.utexas.edu/project/gene-disease. Contact: naga86@cs.utexas.edu PMID:24932006

  18. Hereditary tyrosinemia type 1: Strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Demers, S.I.; Phaneuf, D.; Tanguay, R.M. (Centre de Recherche du CHUL, Quebec (Canada))

    1994-08-01

    Hereditary tyrosinemia type 1 (HT1), a severe inborn error of tyrosine catabolism, is caused by deficiency of the terminal enzyme, fumarylacetoacetate hydrolase (FAH). The highest reported frequency of HT1 is in the French Canadian population, especially in the Saguenay-Lac-St-Jean region. Using human FAH cDNA probes, the authors have identified 10 haplotypes with TaqI, KpnI, RsaI, BglII, and MspI RFLPs in 118 normal chromosomes from the French Canadian population. Interestingly, in 29 HT1 children, a prevalent haplotype, haplotype 6, was found to be strongly associated with the disease, at a frequency of 90% of alleles, as compared with [approximately] 18% in 35 control individuals. This increased to 96% in the 24 patients originating from Saguenay-Lac-St-Jean. These results suggest that one or only a few prevailing mutations are responsible for most of the HT1 cases in Saguenay-Lac-St-Jean. Since most patients were found to be homozygous for a specific haplotype in this population, FAH RFLPs have permitted simple carrier detection in nine different informative HT1 families, with a confidence level of 99.9%. Heterozygosity rate values obtained from 52 carriers indicated that [approximately] 88% of families at risk from Saguenay-Lac-St-Jean are fully or partially informative. Prenatal diagnosis was also achieved in an American family. Analysis of 24 HT1 patients from nine countries gave a frequency of [approximately] 52% for haplotype 6, suggesting a relatively high association, worldwide, of HT1 with this haplotype. 31 refs., 1 fig., 3 tabs.

  19. Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis.

    Science.gov (United States)

    Demers, S I; Phaneuf, D; Tanguay, R M

    1994-08-01

    Hereditary tyrosinemia type 1 (HT1), a severe inborn error of tyrosine catabolism, is caused by deficiency of the terminal enzyme, fumarylacetoacetate hydrolase (FAH). The highest reported frequency of HT1 is in the French Canadian population, especially in the Saguenay-Lac-St-Jean region. Using human FAH cDNA probes, we have identified 10 haplotypes with TaqI, KpnI, RsaI, BglII, and MspI RFLPs in 118 normal chromosomes from the French Canadian population. Interestingly, in 29 HT1 children, a prevalent haplotype, haplotype 6, was found to be strongly associated with the disease, at a frequency of 90% of alleles, as compared with approximately 18% in 35 control individuals. This increased to 96% in the 24 patients originating from Saguenay-Lac-St-Jean. These results suggest that one or only a few prevailing mutations are responsible for most of the HT1 cases in Saguenay-Lac-St-Jean. Since most patients were found to be homozygous for a specific haplotype in this population, FAH RFLPs have permitted simple carrier detection in nine different informative HT1 families, with a confidence level of 99.9%. Heterozygosity rate values obtained from 52 carriers indicated that approximately 88% of families at risk from Saguenay-Lac-St-Jean are fully or partially informative. Prenatal diagnosis was also achieved in an American family. Analysis of 24 HT1 patients from nine countries gave a frequency of approximately 52% for haplotype 6, suggesting a relatively high association, worldwide, of HT1 with this haplotype.

  20. A general approach for haplotype phasing across the full spectrum of relatedness.

    Directory of Open Access Journals (Sweden)

    Jared O'Connell

    2014-04-01

    Full Text Available Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.

  1. Genetic link between Asians and native Americans: evidence from HLA genes and haplotypes.

    Science.gov (United States)

    Tokunaga, K; Ohashi, J; Bannai, M; Juji, T

    2001-09-01

    We have been studying polymorphisms of HLA class I and II genes in East Asians including Buryat in Siberia, Mongolian, Han Chinese, Man Chinese, Korean Chinese, South Korean, and Taiwan indigenous populations in collaboration with many Asian scientists. Regional populations in Japan, Hondo-Japanese, Ryukyuan, and Ainu, were also studied. HLA-A, -B, and -DRB1 gene frequencies were subjected to the correspondence analysis and calculation of DA distances. The correspondence analysis demonstrated several major clusters of human populations in the world. "Mongoloid" populations were highly diversified, in which several clusters such as Northeast Asians, Southeast Asians, Oceanians, and Native Americans were observed. Interestingly, an indigenous population in North Japan, Ainu, was placed relatively close to Native Americans in the correspondence analysis. Distribution of particular HLA-A, -B, -DRB1 alleles and haplotypes was also analyzed in relation to migration and dispersal routes of ancestral populations. A number of alleles and haplotypes showed characteristic patterns of regional distribution. For example, B39-HR5-DQ7 (B*3901-DRB1*1406-DQB1*0301) was shared by Ainu and Native Americans. A24-Cw8-B48 was commonly observed in Taiwan indigenous populations, Maori in New Zealand, Orochon in Northeast China, Inuit, and Tlingit. These findings further support the genetic link between East Asians and Native Americans. We have proposed that various ancestral populations in East Asia, marked by different HLA haplotypes, had migrated and dispersed through multiple routes. Moreover, relatively small genetic distances and the sharing of several HLA haplotypes between Ainu and Native Americans suggest that these populations are descendants of some Upper Paleolithic populations of East Asia.

  2. Common 5' beta-globin RFLP haplotypes harbour a surprising level of ancestral sequence mosaicism.

    Science.gov (United States)

    Webster, Matthew T; Clegg, John B; Harding, Rosalind M

    2003-07-01

    Blocks of linkage disequilibrium (LD) in the human genome represent segments of ancestral chromosomes. To investigate the relationship between LD and genealogy, we analysed diversity associated with restriction fragment length polymorphism (RFLP) haplotypes of the 5' beta-globin gene complex. Genealogical analyses were based on sequence alleles that spanned a 12.2-kb interval, covering 3.1 kb around the psibeta gene and 6.2 kb of the delta-globin gene and its 5' flanking sequence known as the R/T region. Diversity was sampled from a Kenyan Luo population where recent malarial selection has contributed to substantial LD. A single common sequence allele spanning the 12.2-kb interval exclusively identified the ancestral chromosome bearing the "Bantu" beta(s) (sickle-cell) RFLP haplotype. Other common 5' RFLP haplotypes comprised interspersed segments from multiple ancestral chromosomes. Nucleotide diversity was similar between psibeta and R/T-delta-globin but was non-uniformly distributed within the R/T-delta-globin region. High diversity associated with the 5' R/T identified two ancestral lineages that probably date back more than 2 million years. Within this genealogy, variation has been introduced into the 3' R/T by gene conversion from other ancestral chromosomes. Diversity in delta-globin was found to lead through parts of the main genealogy but to coalesce in a more recent ancestor. The well-known recombination hotspot is clearly restricted to the region 3' of delta-globin. Our analyses show that, whereas one common haplotype in a block of high LD represents a long segment from a single ancestral chromosome, others are mosaics of short segments from multiple ancestors related in genealogies of unsuspected complexity.

  3. A haplotype at STAT2 Introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea.

    Science.gov (United States)

    Mendez, Fernando L; Watkins, Joseph C; Hammer, Michael F

    2012-08-10

    Signals of archaic admixture have been identified through comparisons of the draft Neanderthal and Denisova genomes with those of living humans. Studies of individual loci contributing to these genome-wide average signals are required for characterization of the introgression process and investigation of whether archaic variants conferred an adaptive advantage to the ancestors of contemporary human populations. However, no definitive case of adaptive introgression has yet been described. Here we provide a DNA sequence analysis of the innate immune gene STAT2 and show that a haplotype carried by many Eurasians (but not sub-Saharan Africans) has a sequence that closely matches that of the Neanderthal STAT2. This haplotype, referred to as N, was discovered through a resequencing survey of the entire coding region of STAT2 in a global sample of 90 individuals. Analyses of publicly available complete genome sequence data show that haplotype N shares a recent common ancestor with the Neanderthal sequence (~80 thousand years ago) and is found throughout Eurasia at an average frequency of ~5%. Interestingly, N is found in Melanesian populations at ~10-fold higher frequency (~54%) than in Eurasian populations. A neutrality test that controls for demography rejects the hypothesis that a variant of N rose to high frequency in Melanesia by genetic drift alone. Although we are not able to pinpoint the precise target of positive selection, we identify nonsynonymous mutations in ERBB3, ESYT1, and STAT2-all of which are part of the same 250 kb introgressive haplotype-as good candidates.

  4. Multiple major disease-associated clones of Legionella pneumophila have emerged recently and independently

    Science.gov (United States)

    David, Sophia; Rusniok, Christophe; Mentasti, Massimo; Gomez-Valero, Laura; Harris, Simon R.; Lechat, Pierre; Lees, John; Ginevra, Christophe; Glaser, Philippe; Ma, Laurence; Bouchier, Christiane; Underwood, Anthony; Jarraud, Sophie; Harrison, Timothy G.; Parkhill, Julian; Buchrieser, Carmen

    2016-01-01

    Legionella pneumophila is an environmental bacterium and the leading cause of Legionnaires’ disease. Just five sequence types (ST), from more than 2000 currently described, cause nearly half of disease cases in northwest Europe. Here, we report the sequence and analyses of 364 L. pneumophila genomes, including 337 from the five disease-associated STs and 27 representative of the species diversity. Phylogenetic analyses revealed that the five STs have independent origins within a highly diverse species. The number of de novo mutations is extremely low with maximum pairwise single-nucleotide polymorphisms (SNPs) ranging from 19 (ST47) to 127 (ST1), which suggests emergences within the last century. Isolates sampled geographically far apart differ by only a few SNPs, demonstrating rapid dissemination. These five STs have been recombining recently, leading to a shared pool of allelic variants potentially contributing to their increased disease propensity. The oldest clone, ST1, has spread globally; between 1940 and 2000, four new clones have emerged in Europe, which show long-distance, rapid dispersal. That a large proportion of clinical cases is caused by recently emerged and internationally dispersed clones, linked by convergent evolution, is surprising for an environmental bacterium traditionally considered to be an opportunistic pathogen. To simultaneously explain recent emergence, rapid spread and increased disease association, we hypothesize that these STs have adapted to new man-made environmental niches, which may be linked by human infection and transmission. PMID:27662900

  5. 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. i

  6. Geographic distribution of haplotype diversity at the bovine casein locus

    Directory of Open Access Journals (Sweden)

    Moazami-Goudarzi Katy

    2004-03-01

    Full Text Available Abstract The genetic diversity of the casein locus in cattle was studied on the basis of haplotype analysis. Consideration of recently described genetic variants of the casein genes which to date have not been the subject of diversity studies, allowed the identification of new haplotypes. Genotyping of 30 cattle breeds from four continents revealed a geographically associated distribution of haplotypes, mainly defined by frequencies of alleles at CSN1S1 and CSN3. The genetic diversity within taurine breeds in Europe was found to decrease significantly from the south to the north and from the east to the west. Such geographic patterns of cattle genetic variation at the casein locus may be a result of the domestication process of modern cattle as well as geographically differentiated natural or artificial selection. The comparison of African Bos taurus and Bos indicus breeds allowed the identification of several Bos indicus specific haplotypes (CSN1S1*C-CSN2*A2-CSN3*AI/CSN3*H that are not found in pure taurine breeds. The occurrence of such haplotypes in southern European breeds also suggests that an introgression of indicine genes into taurine breeds could have contributed to the distribution of the genetic variation observed.

  7. [Hemoglobin beta S haplotype in the Kebili region (southern Tunisia)].

    Science.gov (United States)

    Frikha, M; Fakhfakh, F; Mseddi, S; Gargouri, J; Ghali, L; Labiadh, Z; Harrabi, M; Souissi, T; Ayadi, H

    1998-04-01

    Sickle cell anemia is a monogenic hereditary disease characterized by a mutation in the beta globin gene. Five major haplotypes associated with the beta S mutation have been defined: Benin, Bantu, Senegalian, Camerounian, and Arabo-Indian. Previous studies in northern Tunisia showed that sickle cell anemia was of Benin origin in this region. Patients from the south of Tunisia, mainly from the Kebili region, were not previously concerned. In this study, we have determined the beta S haplotype and evaluated phenotypical expression of the disease in 14 patients from this latter region. The use of four restriction endonucleases having polymorphic sites in the beta globin gene showed that all patients had the Benin haplotype, confirming the Benin origin of sickle cell anemia in Tunisia. This haplotype is associated with an heterogeneous expression of fetal hemoglobin (HbF) with extremes varying from 2.4 to 16.3% and a mean expression rate of 8.16%, which is in accordance with literature data. In spite of the haplotype homogeneity in our patients, clinical heterogeneity was noted. A unique case of alpha-thalassemia could not explain this heterogeneity. In contrast, we found a certain correlation between fetal hemoglobin expression and clinical severity.

  8. Visualization of haplotype sharing patterns in pedigree samples.

    Science.gov (United States)

    Kim, Sulgi; Saad, Mohamad; Tsuang, Debby W; Wijsman, Ellen M

    2014-01-01

    A particular approach to the visualization of descent of founder DNA copies in a pedigree has been suggested, which helps to understand haplotype sharing patterns among subjects of interest. However, the approach does not provide the information in an ideal format to show haplotype sharing patterns. Therefore, we aimed to find an efficient way to visualize such sharing patterns and to demonstrate that our tool provides useful information for finding an informative subset of subjects for a sequence study. The visualization package, SharedHap, computes and visualizes a novel metric, the SharedHap proportion, which quantifies haplotype sharing among a set of subjects of interest. We applied SharedHap to simulated and real pedigree datasets to illustrate the approach. SharedHap successfully represents haplotype sharing patterns that contribute to linkage signals in both simulated and real datasets. Using the visualizations we were also able to find ideal sets of subjects for sequencing studies. Our novel metric that can be computed using the SharedHap package provides useful information about haplotype sharing patterns among subjects of interest. The visualization of the SharedHap proportion provides useful information in pedigree studies, allowing for a better selection of candidate subjects for use in further sequencing studies. © 2014 S. Karger AG, Basel.

  9. Associations of Haplotypes Upstream of IRS1 with Insulin Resistance, Type 2 Diabetes, Dyslipidemia, Preclinical Atherosclerosis, and Skeletal Muscle LOC646736 mRNA Levels

    Directory of Open Access Journals (Sweden)

    Selma M. Soyal

    2015-01-01

    Full Text Available The genomic region ~500 kb upstream of IRS1 has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible haplotypes, 6 haplotypes with frequencies >0.01 were observed. We identified one haplotype that was protective against insulin resistance (determined by HOMA-IR and fasting plasma insulin levels, type 2 diabetes, an adverse lipid profile, increased C-reactive protein, and asymptomatic atherosclerotic disease (assessed by intima media thickness of the common carotid arteries. BMI and total adipose tissue mass as well as visceral and subcutaneous adipose tissue mass did not differ between the reference and protective haplotypes. In 92 subjects, we observed an association of the protective haplotype with higher skeletal muscle mRNA levels of LOC646736, which is located in the same haplotype block as the informative SNPs and is mainly expressed in skeletal muscle, but only at very low levels in liver or adipose tissues. These data suggest a role for LOC646736 in human insulin resistance and warrant further studies on the functional effects of this locus.

  10. Criteria to define HLA haplotype loss in human solid tumors

    NARCIS (Netherlands)

    Ramal, LM; van der Zwan, AW; Collado, A; Lopez-Nevot, MA; Tilanus, M; Garrido, F

    2000-01-01

    Short tandem repeat (STR) markers are currently used to define loss of heterozygosity (LOH) of genes and chromosomes in tumors. Chromosome 6 and chromosome 15 STR markers are applied to define loss of HLA and related genes (e.g. TAP and beta(2)m) The number of STR identified in the HLA region is sti

  11. Association of an MHC class II haplotype with increased risk of polymyositis in Hungarian Vizsla dogs.

    Directory of Open Access Journals (Sweden)

    Jonathan Massey

    Full Text Available A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 "graded" controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032. When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011. Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis.

  12. Haplotyping a single triploid individual based on genetic algorithm.

    Science.gov (United States)

    Wu, Jingli; Chen, Xixi; Li, Xianchen

    2014-01-01

    The minimum error correction model is an important combinatorial model for haplotyping a single individual. In this article, triploid individual haplotype reconstruction problem is studied by using the model. A genetic algorithm based method GTIHR is presented for reconstructing the triploid individual haplotype. A novel coding method and an effectual hill-climbing operator are introduced for the GTIHR algorithm. This relatively short chromosome code can lead to a smaller solution space, which plays a positive role in speeding up the convergence process. The hill-climbing operator ensures algorithm GTIHR converge at a good solution quickly, and prevents premature convergence simultaneously. The experimental results prove that algorithm GTIHR can be implemented efficiently, and can get higher reconstruction rate than previous algorithms.

  13. JAK2 GGCC haplotype in MPL mutated myeloproliferative neoplasms.

    Science.gov (United States)

    Pietra, Daniela; Casetti, Ilaria; Da Vià, Matteo C; Elena, Chiara; Milanesi, Chiara; Rumi, Elisa

    2012-07-01

    JAK2 (V617F) is associated with a genetic predisposition to its acquisition,as it is preferentially found in subjects with a common constitutional JAK2 haplotype known as 46/1 or GGCC. A recent study suggests that a genetic predisposition to acquisition of MPL mutation may exist in sporadic patients, since an association was found with the JAK2 46/1 haplotype. We genotyped 509 patients with myeloproliferative neoplasms (MPN), 7% of which carrying a somatic mutation of MPL Exon 10. We found that the JAK2 GGCC haplotype was closely associated with JAK2 (V617F) (OR 1.84, P < 0.001) but not with MPL mutations (OR 0.98), suggesting a different genetic background for these molecular lesions.

  14. 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.

  15. Detecting disease-predisposing variants: The haplotype method

    Energy Technology Data Exchange (ETDEWEB)

    Valdes, A.M.; Thomson, G. [Univ. of California, Berkeley, CA (United States)

    1997-03-01

    For many HLA-associated diseases, multiple alleles - and, in some cases, multiple loci - have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some - compared with none - of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1 No. 52 (Arg predisposing) DQB1 No. 57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class H DRB1 data, the results were consistent with the shared-epitope hypothesis. 35 refs., 2 figs., 6 tabs.

  16. Molecular definition of red cell Rh haplotypes by tightly linked SphI RFLPs.

    OpenAIRE

    Huang, C. H.; Reid, M.E.; Chen, Y.; Coghlan, G.; Okubo, Y

    1996-01-01

    The Rh blood group system of human red cells contains five major antigens D, C/c, and E/e (the latter four designated "non-D") that are specified by eight gene complexes known as Rh haplotypes. In this paper, we report on the mapping of RH locus and identification of a set of SphI RFLPs that are tightly linked with the Rh structural genes. Using exon-specific probes, we have localized the SphI cleavage sites resulting in these DNA markers and derived a comprehensive map for the RH locus. It w...

  17. A reference panel of 64,976 haplotypes for genotype imputation.

    Science.gov (United States)

    McCarthy, Shane; Das, Sayantan; Kretzschmar, Warren; Delaneau, Olivier; Wood, Andrew R; Teumer, Alexander; Kang, Hyun Min; Fuchsberger, Christian; Danecek, Petr; Sharp, Kevin; Luo, Yang; Sidore, Carlo; Kwong, Alan; Timpson, Nicholas; Koskinen, Seppo; Vrieze, Scott; Scott, Laura J; Zhang, He; Mahajan, Anubha; Veldink, Jan; Peters, Ulrike; Pato, Carlos; van Duijn, Cornelia M; Gillies, Christopher E; Gandin, Ilaria; Mezzavilla, Massimo; Gilly, Arthur; Cocca, Massimiliano; Traglia, Michela; Angius, Andrea; Barrett, Jeffrey C; Boomsma, Dorrett; Branham, Kari; Breen, Gerome; Brummett, Chad M; Busonero, Fabio; Campbell, Harry; Chan, Andrew; Chen, Sai; Chew, Emily; Collins, Francis S; Corbin, Laura J; Smith, George Davey; Dedoussis, George; Dorr, Marcus; Farmaki, Aliki-Eleni; Ferrucci, Luigi; Forer, Lukas; Fraser, Ross M; Gabriel, Stacey; Levy, Shawn; Groop, Leif; Harrison, Tabitha; Hattersley, Andrew; Holmen, Oddgeir L; Hveem, Kristian; Kretzler, Matthias; Lee, James C; McGue, Matt; Meitinger, Thomas; Melzer, David; Min, Josine L; Mohlke, Karen L; Vincent, John B; Nauck, Matthias; Nickerson, Deborah; Palotie, Aarno; Pato, Michele; Pirastu, Nicola; McInnis, Melvin; Richards, J Brent; Sala, Cinzia; Salomaa, Veikko; Schlessinger, David; Schoenherr, Sebastian; Slagboom, P Eline; Small, Kerrin; Spector, Timothy; Stambolian, Dwight; Tuke, Marcus; Tuomilehto, Jaakko; Van den Berg, Leonard H; Van Rheenen, Wouter; Volker, Uwe; Wijmenga, Cisca; Toniolo, Daniela; Zeggini, Eleftheria; Gasparini, Paolo; Sampson, Matthew G; Wilson, James F; Frayling, Timothy; de Bakker, Paul I W; Swertz, Morris A; McCarroll, Steven; Kooperberg, Charles; Dekker, Annelot; Altshuler, David; Willer, Cristen; Iacono, William; Ripatti, Samuli; Soranzo, Nicole; Walter, Klaudia; Swaroop, Anand; Cucca, Francesco; Anderson, Carl A; Myers, Richard M; Boehnke, Michael; McCarthy, Mark I; Durbin, Richard

    2016-10-01

    We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

  18. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

    DEFF Research Database (Denmark)

    Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves;

    2010-01-01

    Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing...... narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1...... ratio = 0.02; P narcolepsy susceptibility....

  19. Y chromosome haplotype distribution of brown bears (Ursus arctos) in Northern Europe provides insight into population history and recovery.

    Science.gov (United States)

    Schregel, Julia; Eiken, Hans Geir; Grøndahl, Finn Audun; Hailer, Frank; Aspi, Jouni; Kojola, Ilpo; Tirronen, Konstantin; Danilov, Piotr; Rykov, Alexander; Poroshin, Eugene; Janke, Axel; Swenson, Jon E; Hagen, Snorre B

    2015-12-01

    High-resolution, male-inherited Y-chromosomal markers are a useful tool for population genetic analyses of wildlife species, but to date have only been applied in this context to relatively few species besides humans. Using nine Y-chromosomal STRs and three Y-chromosomal single nucleotide polymorphism markers (Y-SNPs), we studied whether male gene flow was important for the recent recovery of the brown bear (Ursus arctos) in Northern Europe, where the species declined dramatically in numbers and geographical distribution during the last centuries but is expanding now. We found 36 haplotypes in 443 male extant brown bears from Sweden, Norway, Finland and northwestern Russia. In 14 individuals from southern Norway from 1780 to 1920, we found two Y chromosome haplotypes present in the extant population as well as four Y chromosome haplotypes not present among the modern samples. Our results suggested major differences in genetic connectivity, diversity and structure between the eastern and the western populations in Northern Europe. In the west, our results indicated that the recovered population originated from only four male lineages, displaying pronounced spatial structuring suggestive of large-scale population size increase under limited male gene flow within the western subpopulation. In the east, we found a contrasting pattern, with high haplotype diversity and admixture. This first population genetic analysis of male brown bears shows conclusively that male gene flow was not the main force of population recovery.

  20. Evidence for HLA class II susceptible and protective haplotypes for osteomyelitis in pediatric patients with sickle cell anemia.

    Science.gov (United States)

    Al-Ola, K; Mahdi, N; Al-Subaie, A M; Ali, M E; Al-Absi, I K; Almawi, W Y

    2008-05-01

    We investigated the association of human leukocyte antigen (HLA) class II alleles and haplotypes with the pathogenesis of sickle cell anemia (SCA) osteomyelitis. SCA patients comprised 42 patients with osteomyelitis and 150 patients without osteomyelitis; HLA-DRB1* and HLA-DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming (SSP). DRB1*100101 (P value corrected for the number of different alleles tested, Pc=0.003) was positively associated with osteomyelitis. At the haplotype level, DRB1*100101-DQB1*050101 (Pc=0.001) was more prevalent among patients, while DRB1*030101-DQB1*0201 (Pc=0.020) and DRB1*040101-DQB1*0302 (Pc=0.039) were more prevalent among SCA controls, thereby conferring disease susceptibility or protection to these haplotypes, respectively. These results show that specific HLA haplotypes influence SCA osteomyelitis risk and that specific HLA types may serve as markers for identifying SCA patients at high risk for osteomyelitis.

  1. Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations

    Directory of Open Access Journals (Sweden)

    Jallow Muminatou

    2007-08-01

    Full Text Available Abstract Background The sickle (βs mutation in the beta-globin gene (HBB occurs on five "classical" βs haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the βs allele – a consequence of protection from severe malarial infection afforded by heterozygotes – has been associated with a high degree of extended haplotype similarity. The relationship between classical βs haplotypes and long-range haplotype similarity may have both anthropological and clinical implications, but to date has not been explored. Here we evaluate the haplotype similarity of classical βs haplotypes over 400 kb in population samples from Jamaica, The Gambia, and among the Yoruba of Nigeria (Hapmap YRI. Results The most common βs sub-haplotype among Jamaicans and the Yoruba was the Benin haplotype, while in The Gambia the Senegal haplotype was observed most commonly. Both subtypes exhibited a high degree of long-range haplotype similarity extending across approximately 400 kb in all three populations. This long-range similarity was significantly greater than that seen for other haplotypes sampled in these populations (P s mutation. Conclusion Two different classical βs haplotypes, sampled from different populations, exhibit comparable and extensive long-range haplotype similarity and strong LD. This LD extends across the adjacent recombination hotspot, and is discernable at distances in excess of 400 kb. Although the multi-centric geographic distribution of βs haplotypes indicates strong subdivision among early Holocene sub-Saharan populations, we find no evidence that selective pressures imposed by falciparum malaria varied in intensity or timing between these subpopulations. Our observations also suggest that cis-acting loci, which may influence outcomes in sickle cell disease, could lie considerable distances away from β-globin.

  2. Linkage Disequilibrium Decay and Haplotype Block Structure in the Pig

    NARCIS (Netherlands)

    Amaral, A.J.; Megens, H.J.W.C.; Crooijmans, R.P.M.A.; Heuven, H.C.M.; Groenen, M.A.M.

    2008-01-01

    Linkage disequilibrium (LD) may reveal much about domestication and breed history. Ail investigation was conducted, to analyze the extent of LD, haploblock partitioning, and haplotype diversity within haploblocks across several pig breeds from China and Europe and in European wild boar. In total, 37

  3. Rapid haplotype reconstruction in predigrees with dense marker maps

    NARCIS (Netherlands)

    Windig, J.J.; Meuwissen, T.H.E.

    2004-01-01

    Reconstruction of marker phases is not straightforward when parents are untyped. In these cases information from other relatives has to be used. In dense marker maps, however, the space of possible haplotype configurations tends to be too large for procedures such as Monte Carlo Markov chains (MCMC)

  4. 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.

  5. Accuracy of genomic selection using different methods to define haplotypes

    NARCIS (Netherlands)

    Calus, M.P.L.; Meuwissen, T.H.E.; Roos, de S.; Veerkamp, R.F.

    2008-01-01

    Genomic selection uses total breeding values for juvenile animals, predicted from a large number of estimated marker haplotype effects across the whole genome. In this study the accuracy of predicting breeding values is compared for four different models including a large number of markers, at diffe

  6. 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.

  7. 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 ...

  8. Quantitative trait loci and the relevance of phased haplotypes

    DEFF Research Database (Denmark)

    Gregersen, Vivi Raundahl

    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...

  9. 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

  10. A substantially lower frequency of uninformative matches between 23 versus 17 Y-STR haplotypes in north Western Europe.

    Science.gov (United States)

    Larmuseau, Maarten H D; Vanderheyden, Nancy; Van Geystelen, Anneleen; Decorte, Ronny

    2014-07-01

    The analysis of human short tandem repeats of the Y-chromosome (Y-STRs) provides a powerful tool in forensic cases for male sex identification, male lineage identification and identification of the geographical origin of male lineages. As the commonly used 12 and 17 Y-STR multiplexes do not discriminate between some unrelated males, additional Y-STRs were implemented in the PowerPlex(®) Y23 System to supplement the existing commercial Y-STR kits. Until today, the forensic value of a (near) 23 versus 17 Y-STR haplotype match between an unknown DNA donor and a certain biological sample in a database is not yet well studied. This will be of huge interest for cases where an autosomal DNA profile yields no match to a DNA database and the database is used for familial searching (male relative(s) of the offender) or for the estimation of the geographical origin of the offender. In order to value (near) 23 Y-STR haplotype matches in a local sample from Western Europe, we selected the region of Flanders (Belgium) due to the already present knowledge on its Y-chromosomal variants. Many Y-chromosomes of this region were previously genotyped with Y-SNPs at a high resolution of the most recently updated Y-chromosomal tree and the deep-rooted genealogy of each DNA donor was already established. By comparing (near) matches of 23 versus 17 Y-STR haplotypes between patrilineal-unrelated males, a substantial lower number of uninformative (near) 23 Y-STR haplotype matches has been observed compared to 17 Y-STR haplotypes. Furthermore, the use of SNP data was informative to discriminate >60% of unrelated males with an (near) identical 17 Y-STR match while SNP data was only necessary to discriminate about 10% of unrelated males with a 23 Y-STR haplotype that differed at only two Y-STRs. This shows the higher value of the Y23 haplotype within familial DNA searching and the estimation of the geographical origin of a DNA donor. Therefore, the use of the PowerPlex(®) Y23 System instead

  11. Screening for haplotypic variability within Oesophagostomum bifurcum (Nematoda) employing a single-strand conformation polymorphism approach.

    Science.gov (United States)

    de Gruijter, J M; Polderman, A M; Zhu, X Q; Gasser, R B

    2002-06-01

    Genetic markers in the mitochondrial genome have proven useful for population genetic studies because of their maternal inheritance and relatively high evolutionary rates. In this study, we exploited the high resolution capacity of PCR-coupled single-strand conformation polymorphism (SSCP) to screen for sequence variation in part of the cytochrome c oxidase subunit 1 gene (p cox 1) among individuals of the parasitic nematode, Oesophagostomum bifurcum from human or Mona monkey hosts from Africa. SSCP analysis revealed distinct profiles among some of the individuals, and subsequent sequence analysis of representative samples defined 10 different haplotypes. For comparative purposes, the p cox 1 sequences for representatives of four other species of Oesophagostomum from livestock were included. While there were high levels (11.5-13.7%) of sequence difference among the latter species, there was no fixed nucleotide difference between O. bifurcum individuals from humans and those from monkeys. The data support the proposal that O. bifurcum from the two primate hosts represents a single species and that the haplotypic variability in p cox 1 represents population variation. The results reinforce the usefulness of the SSCP-sequencing approach for studying genetic variation in nematode populations using mitochondrial markers.

  12. Functional Assessment of Disease-Associated Regulatory Variants In Vivo Using a Versatile Dual Colour Transgenesis Strategy in Zebrafish

    Science.gov (United States)

    Bhatia, Shipra; Gordon, Christopher T.; Foster, Robert G.; Melin, Lucie; Abadie, Véronique; Baujat, Geneviève; Vazquez, Marie-Paule; Amiel, Jeanne; Lyonnet, Stanislas; van Heyningen, Veronica; Kleinjan, Dirk A.

    2015-01-01

    Disruption of gene regulation by sequence variation in non-coding regions of the genome is now recognised as a significant cause of human disease and disease susceptibility. Sequence variants in cis-regulatory elements (CREs), the primary determinants of spatio-temporal gene regulation, can alter transcription factor binding sites. While technological advances have led to easy identification of disease-associated CRE variants, robust methods for discerning functional CRE variants from background variation are lacking. Here we describe an efficient dual-colour reporter transgenesis approach in zebrafish, simultaneously allowing detailed in vivo comparison of spatio-temporal differences in regulatory activity between putative CRE variants and assessment of altered transcription factor binding potential of the variant. We validate the method on known disease-associated elements regulating SHH, PAX6 and IRF6 and subsequently characterise novel, ultra-long-range SOX9 enhancers implicated in the craniofacial abnormality Pierre Robin Sequence. The method provides a highly cost-effective, fast and robust approach for simultaneously unravelling in a single assay whether, where and when in embryonic development a disease-associated CRE-variant is affecting its regulatory function. PMID:26030420

  13. 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.

  14. HLA-DRB1 and -DRB3 allele frequencies and haplotypic associations in Koreans.

    Science.gov (United States)

    Song, Eun Young; Park, Hyejin; Roh, Eun Youn; Park, Myoung Hee

    2004-03-01

    We have investigated the frequencies of human leukocyte antigen-DRB1 (HLA-DRB1) and -DRB3 alleles and DRB1-DRB3 haplotypic associations in 800 Koreans. DRB1 genotyping was done using polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) and PCR-single strand conformation polymorphism (SSCP) methods. DRB3 genotyping was done on 447 samples carrying DRB3-associated DRB1 alleles (DRB1*03, *11, *12, *13, and *14) using PCR-SSCP method. The allele frequencies of DRB3*0101, DRB3*0202, and DRB3*0301 were 0.073, 0.136, and 0.120, respectively, and we found one case of a probable new allele (DRB3*01new, 0.001). DRB1-DRB3 haplotypes with frequency (HF) > 0.005 exhibited strong associations between DRB3*0101 and DRB1*1201, *1301, and *1403; between DRB3*0301 and DRB1*1202 and *1302; between DRB3*0202 and DRB1*0301, *1101, *1401, *1405, and *1406 alleles. Most of the DRB1 alleles with frequency > 0.005 were exclusively associated with particular DRB3 alleles with relative linkage disequilibrium values of 1.0, except for DRB1*1201, *1202 and *1301; the rare presence (HF DRB3*0202 associations were observed for these DRB1 alleles. We also investigated and presented rare DRB1-DRB3 associations in additional 6000 Koreans. Comparison with other ethnic groups revealed that DRB1*0301 and *1301 related DRB1-DRB3 haplotypes vary among different populations, in that Koreans and other Asian populations show less diversity compared with Caucasoids or African Americans.

  15. Improved IBD detection using incomplete haplotype information

    Directory of Open Access Journals (Sweden)

    Pollak Martin R

    2010-06-01

    Full Text Available Abstract Background The availability of high density genetic maps and genotyping platforms has transformed human genetic studies. The use of these platforms has enabled population-based genome-wide association studies. However, in inheritance-based studies, current methods do not take full advantage of the information present in such genotyping analyses. Results In this paper we describe an improved method for identifying genetic regions shared identical-by-descent (IBD from recent common ancestors. This method improves existing methods by taking advantage of phase information even if it is less than fully accurate or missing. We present an analysis of how using phase information increases the accuracy of IBD detection compared to using only genotype information. Conclusions Our algorithm should have utility in a wide range of genetic studies that rely on identification of shared genetic material in large families or small populations.

  16. Absence of atypical haplotype and presence of Senegal haplotype sickle cell disease in African-descent population in the northern Brazil

    OpenAIRE

    Nascimento,Rafael E.; Castelo,Natália M.; Bueno,Adriana C.; Larissa Mescouto; Artemis S. N. Rodrigues

    2015-01-01

    Introduction: Sickle cell anemia (SCA) is the most severe form of sickle cell disease; it presents variants that are called haplotypes βS. There are five major haplotypes βS gene: Arab-Indian/Saudi, Senegal, Benin, Bantu, and Camaroon. Objective: Characterize the presence of haplotypes in patients with SCA in Amapá. Methods: 46 sample were studied, all samples were amplified and analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Resul...

  17. Moyamoya disease associated with an anterior inferior cerebellar artery arising from a persistent trigeminal artery

    Energy Technology Data Exchange (ETDEWEB)

    Uchino, A.; Sawada, A.; Takase, Y.; Kudo, S. [Department of Radiology, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501 (Japan); Koizumi, T. [Department of Neurosurgery, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501 (Japan)

    2002-07-01

    The authors present a case of moyamoya disease associated with a persistent trigeminal artery from which the anterior inferior cerebellar artery arose. We reviewed previously reported cases of moyamoya disease associated with persistent carotid-basilar arterial anastomosis and investigated the embryology of this rare arterial variation. (orig.)

  18. Beta-globin gene cluster haplotypes in sickle cell patients from southwest Iran.

    Science.gov (United States)

    Rahimi, Z; Karimi, M; Haghshenass, M; Merat, A

    2003-11-01

    Sickle cell anemia in Iran is accompanied by a high level of HbF and mild clinical presentation. Here we report haplotypes of the beta gene cluster found in 81 randomly selected sickle cell patients, including 47 sickle cell anemia (SS), 17 sickle cell trait (AS), and 17 sickle/thalassemia (S/thal) from southwest Iran. We found all five common typical haplotypes as well as five atypical haplotypes in our patients. Except for four patients with homozygous Benin haplotype, none of the other African typical haplotypes were found in a homozygous state. Arab-Indian was found to be the most prevalent haplotype in the study population. This haplotype accounted for 51.1% as the homozygous form in SS patients, where 69.1% of chromosomes in these patients had the Arab-Indian haplotype. Bantu A2 was the second most prevalent haplotype among all patients. The mean %HbF in SS patients was 27.83 and in the homozygous Arab-Indian haplotype it was still higher (30.40%), while in AS patients the %HbF was only 1.20. The high %Ggamma chain (71.81) in the Arab-Indian homozygous haplotype was concomitant with the presence of an Xmn I site in both chromosomes. The presence of the Arab-Indian haplotype as the predominant haplotype might be suggestive of a gene flow to/from Saudi Arabia or India. More haplotype investigations of a normal population can clarify the high incidence of Bantu A2 haplotype in our population.

  19. ASSOCIATION BETWEEN GAB2 HAPLOTYPE AND HIGHER GLUCOSE METABOLISM IN ALZHEIMER'S DISEASE-AFFECTED BRAIN REGIONS IN COGNITIVELY NORMAL APOEε4 CARRIERS

    Science.gov (United States)

    Liang, Winnie S.; Chen, Kewei; Lee, Wendy; Sidhar, Kunal; Corneveaux, Jason J.; Allen, April N.; Myers, Amanda; Villa, Stephen; Meechoovet, Bessie; Pruzin, Jeremy; Bandy, Daniel; Fleisher, Adam S.; Langbaum, Jessica B.S.; Huentelman, Matthew J.; Jensen, Kendall; Dunckley, Travis; Caselli, Richard J.; Kaib, Susan; Reiman, Eric M.

    2010-01-01

    In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative presymptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk. PMID:20888920

  20. Acute chest syndrome is associated with single nucleotide polymorphism-defined beta globin cluster haplotype in children with sickle cell anaemia.

    Science.gov (United States)

    Bean, Christopher J; Boulet, Sheree L; Yang, Genyan; Payne, Amanda B; Ghaji, Nafisa; Pyle, Meredith E; Hooper, W Craig; Bhatnagar, Pallav; Keefer, Jeffrey; Barron-Casella, Emily A; Casella, James F; Debaun, Michael R

    2013-10-01

    Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the β-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the β-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (β-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the β(S) -carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with β(S) -haplotypes. After controlling for covariates, an association was detected between haplotype and rate of hospitalization for acute chest syndrome (ACS) (incidence rate ratio 0·51, 95% confidence interval 0·29-0·89) but not incidence rate of vaso-occlusive pain or presence of silent cerebral infarct (SCI). Our results suggest that these SNP-defined β(S) -haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.

  1. Population differentiation and phylogeographic pattern of a relict species, Conandron ramondioides (Gesneriaceae), revealed from sequence polymorphism and haplotypes of the CYCLOIDEA gene

    Institute of Scientific and Technical Information of China (English)

    Li-Hong XIAO; Zhi LI; Rui WANG; yin-Zheng WANG

    2012-01-01

    Historical events are expected to affect population genetic differentiation and DNA molecular evolution,but the impact of these effects remains a matter of debate.Here,for Conandron ramondioides (Gesneriaceae),we analyzed the genetic structure and phylogeographical pattern of 248 individuals from 13 populations,distributed in mainland China and Taiwan Island,based on the nucleotide sequence and haplotype of the coding sequence of CYCLOIDEA1 (GCYC1).Among the populations,we found a high level of haplotype diversity (h =0.831) and a relatively low level of nucleotide diversity (Dij =0.004).Both the haplotype network and the neighbor-joining tree constructed from GCYC1 haplotypes suggest two major geographical groupings,one on the mainland and the other on Taiwan.Consistently,AMOVA analysis revealed high genetic differentiation between these groupings,with 84.65% variation partitioning the two regions,and the two groupings shared no haplotype.On the mainland,population genetic differentiation was correlated with more recent events,presumably Pleistocene glaciations and human activities since the Neolithic.In addition,C.ramondioides GCYC1 rapidly accumulated neutral mutations,consistent with this gene being silenced or down-regulated in actinomorphic lineages of the Lamiales,such as Conandron.

  2. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

    Science.gov (United States)

    Tiranti, V; Hoertnagel, K; Carrozzo, R; Galimberti, C; Munaro, M; Granatiero, M; Zelante, L; Gasparini, P; Marzella, R; Rocchi, M; Bayona-Bafaluy, M P; Enriquez, J A; Uziel, G; Bertini, E; Dionisi-Vici, C; Franco, B; Meitinger, T; Zeviani, M

    1998-12-01

    Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. Linkage analysis restricted the disease locus to the subtelomeric region of chromosome 9q, within the 7-cM interval between markers D9S1847 and D9S1826. Candidate genes within this region include SURF-1, the yeast homologue (SHY-1) of which encodes a mitochondrial protein necessary for the maintenance of COX activity and respiration. Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.

  3. Beta-globin gene cluster haplotypes in Venezuelan sickle cell patients from the State of Aragua

    OpenAIRE

    Nancy Moreno; Martínez, José A.; Zorella Blanco; Leidys Osorio; Patrick Hackshaw

    2002-01-01

    Seven polymorphic sites in the beta-globin gene cluster were analyzed on a sample of 96 chromosomes of Venezuelan sickle cell patients from the State of Aragua. The Benin haplotype was predominant with a frequency of 0.479, followed by the Bantu haplotype (0.406); a minority of cases with other haplotypes was also identified: atypical Bantu A2 (0.042), Senegal (0.031), atypical Bantu A7 (0.021) and Saudi Arabia/Indian (0.021) haplotypes; however, the Cameroon haplotype was not identified in t...

  4. Fetal Hemoglobin in Sickle Cell Anemia: Genetic Studies of the Arab-Indian Haplotype

    OpenAIRE

    Ngo, Duyen; Bae, Harold; Steinberg, Martin H.; Sebastiani, Paola; Solovieff, Nadia; Baldwin, Clinton T.; Melista, Efthymia; Safaya, Surinder; Farrar, Lindsay A.; Suliman, Ahmed M.; Albuali, Waleed H; Al Bagshi, Muneer H.; Akinsheye, Idowu; Gallagher, Patrick; Luo, Hong-yuan

    2013-01-01

    Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefor studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, ...

  5. Principles guiding embryo selection following genome-wide haplotyping of preimplantation embryos.

    Science.gov (United States)

    Dimitriadou, Eftychia; Melotte, Cindy; Debrock, Sophie; Esteki, Masoud Zamani; Dierickx, Kris; Voet, Thierry; Devriendt, Koen; de Ravel, Thomy; Legius, Eric; Peeraer, Karen; Meuleman, Christel; Vermeesch, Joris Robert

    2017-03-01

    How to select and prioritize embryos during PGD following genome-wide haplotyping? In addition to genetic disease-specific information, the embryo selected for transfer is based on ranking criteria including the existence of mitotic and/or meiotic aneuploidies, but not carriership of mutations causing recessive disorders. Embryo selection for monogenic diseases has been mainly performed using targeted disease-specific assays. Recently, these targeted approaches are being complemented by generic genome-wide genetic analysis methods such as karyomapping or haplarithmisis, which are based on genomic haplotype reconstruction of cell(s) biopsied from embryos. This provides not only information about the inheritance of Mendelian disease alleles but also about numerical and structural chromosome anomalies and haplotypes genome-wide. Reflections on how to use this information in the diagnostic laboratory are lacking. We present the results of the first 101 PGD cycles (373 embryos) using haplarithmisis, performed in the Centre for Human Genetics, UZ Leuven. The questions raised were addressed by a multidisciplinary team of clinical geneticist, fertility specialists and ethicists. Sixty-three couples enrolled in the genome-wide haplotyping-based PGD program. Families presented with either inherited genetic variants causing known disorders and/or chromosomal rearrangements that could lead to unbalanced translocations in the offspring. Embryos were selected based on the absence or presence of the disease allele, a trisomy or other chromosomal abnormality leading to known developmental disorders. In addition, morphologically normal Day 5 embryos were prioritized for transfer based on the presence of other chromosomal imbalances and/or carrier information. Some of the choices made and principles put forward are specific for cleavage-stage-based genetic testing. The proposed guidelines are subject to continuous update based on the accumulating knowledge from the implementation of

  6. Diseases associated with hidranitis suppurativa: part 2 of a series on hidradenitis.

    Science.gov (United States)

    Scheinfeld, Noah

    2013-06-15

    diseases is likely underreported. Pyoderma vegetans has been noted in 2 cases of HS and 4 cases of Inflammatory Bowel Disease (IBD) and is likely a clue to the linkage of the pathology of IBD and HS. Pityriasis rubra pilaris, in particular Type VI related to HIV, has a relationship more commonly with acne conglobata, but with HS also. Single case reports of diseases associated with HS include systemic lupus erythematosus, acromegaly, Down syndrome, Bazex-Dupre´-Christol, and prurtis ani, but these might be coincidences. Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA Syndrome) and Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis (PASH Syndrome) are pyodermic-arthritic syndromes that are associated with HS. Erythema nodosum and granulomatous lobular mastitis have been reported with HS but the significance of these reports is uncertain. Because of scarring, HS can result in lymphedema including scrotal elephantiasis and verrucous lymphedema. HS is sometimes accompanied by obesity, hypertension, and anemia and can be considered a disease in the spectrum of metabolic syndrome, a skin disease with systemic consequences. HS, like other types of chronic inflammation when long standing in the perianal and perineal areas, can result in squamous cell cancer. A variety of drugs can induce HS. These include lithium, sirolimus, cyclosporine, vemurafenib, and oral contraceptives. Inverse psoriasis or psoriasis vulgaris as a side effect of infliximab therapy may be associated with HS. These associations aside, most cases of HS occur in isolation without coincident morbidity.

  7. Polymorphic segmental duplications at 8p23.1 challenge the determination of individual defensin gene repertoires and the assembly of a contiguous human reference sequence

    Directory of Open Access Journals (Sweden)

    Loncarevic Ivan F

    2004-12-01

    multisite variations as well as haplotypes by sequencing based methods is the way for future studies of interindividual DEF locus variability and its disease association.

  8. HLA alleles and haplotypes among the Lakota Sioux: report of the ASHI minority workshops, part III.

    Science.gov (United States)

    Leffell, Mary S; Fallin, M Daniele; Hildebrand, William H; Cavett, Joshua W; Iglehart, Brian A; Zachary, Andrea A

    2004-01-01

    Human leukocyte antigen (HLA) class I and II alleles were defined for 302 Lakota Sioux American Indians as part of the American Society for Histocompatibility and Immunogenetics coordinated studies on minority populations. The study group was comprised of adult volunteers from the Cheyenne River and Ogala Sioux tribes residing, respectively, on the Cheyenne River and Pine Ridge Reservations in South Dakota. Of the participants, 263 (87%) claimed full American Indian ancestry through both maternal and paternal grandparents. The study group included 25 nuclear families that were informative for genotyping. HLA phenotypes from 202 adults with no other known first-degree relative included in the study were used for calculation of allele and haplotype frequencies by maximum likelihood estimation. HLA-A, -B, and -Cw alleles were found to be in Hardy Weinberg equilibrium. Deviation from equilibrium was observed for DRB1 alleles (p=0.01), but could be attributed to the sample size and the occurrence of some genotypes with low expected frequencies. Polymorphism among the Sioux was limited with four to seven alleles comprising >80% of those observed at each locus. Several alleles were found at high frequency (0.05-0.30) among the Sioux that are also prevalent in other Native Americans and Alaska Natives, including: A*2402, *3101, and *0206; B*3501,*3901, *5101, and *2705; Cw*0702, *0404, and *03041; DRB1*0407, *0404, *1402, and *16021; and DQB1*0301, *0302, and *0402. DRB1*0811, which has been only previously described in Navajo and Tlingit Indians, was found to occur at a frequency of 0.119 among the Sioux. Two new alleles were defined among the Sioux: Cw*0204 and DRB1*040703, which were found in two and four individuals, respectively. In the haplotype analyses, significant linkage disequilibrium (p<0.00001) was seen in all pairwise comparisons of loci and numerous two and three locus haplotypes were found to have strong, positive linkage disequilibrium values. The two most

  9. The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis.

    Directory of Open Access Journals (Sweden)

    F David Carmona

    Full Text Available 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 this

  10. HLA DRB1*130101-DQB1*060101 haplotype is associated with acute chest syndrome in sickle cell anemia patients.

    Science.gov (United States)

    Mahdi, N; Al-Subaie, A M; Al-Ola, K; Al-Irhayim, A Q; Ali, M E; Al-Irhayim, Z; Almawi, W Y

    2009-03-01

    We investigated the association of human leukocyte antigens (HLA) class II alleles and haplotypes with the pathogenesis of acute chest syndrome (ACS) in 186 sickle cell anemia (SCA) patients, of whom 58 had documented ACS (new pulmonary infiltrate, fever, and other associated clinical events) and 128 with a negative history of ACS, serving as controls. HLA DRB1* and -DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming. Of the DRB1* and DQB1* alleles analyzed, only DRB1*130101 (Pc haplotype was more prevalent among ACS patients (P = 0.018), thus conferring disease susceptibility. Specific HLA alleles and haplotypes may influence ACS risk in SCA patients, and specific HLA genotypes may be useful markers for identifying high-risk SCA ACS patients.

  11. The frequency of an IL-18-associated haplotype in Africans.

    Science.gov (United States)

    Thompson, Simon R; Humphries, Steve E; Thomas, Mark G; Ekong, Rosemary; Tarekegn, Ayele; Bekele, Endeshaw; Creemer, Olivia; Bradman, Neil; Veeramah, Krishna R

    2013-04-01

    Variation within the gene for the proinflammatory cytokine interleukin (IL)-18 has been associated with inter-individual differences in levels of free protein and disease risk. We investigated the frequency of function-associated IL18 gene haplotypes in an extensive sample (n=2357) of African populations from across the continent. A previously identified five tagging SNP (single-nucleotide polymorphism) haplotype (here designated hGTATA), known to be associated with lower levels of IL-18, was observed at a frequency of 27% in a British population of recent European ancestry, but was found at low frequency (African populations. Potentially protective variants may, as a consequence, be found at low frequency in African individuals and may confer a difference in disease risk.

  12. PRIMUS: improving pedigree reconstruction using mitochondrial and Y haplotypes.

    Science.gov (United States)

    Staples, Jeffrey; Ekunwe, Lynette; Lange, Ethan; Wilson, James G; Nickerson, Deborah A; Below, Jennifer E

    2016-02-15

    PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data. However, when genetic data for individuals within a pedigree are missing, often multiple pedigrees can be reconstructed that fit the data. We report a major expansion of PRIMUS that uses mitochondrial (mtDNA) and non-recombining Y chromosome (NRY) haplotypes to eliminate many pedigree structures that are inconsistent with the genetic data. We demonstrate that discordances in mtDNA and NRY haplotypes substantially reduce the number of potential pedigrees, and often lead to the identification of the correct pedigree. We have implemented PRIMUS updates in PERL and it is available at primus.gs.washington.edu. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. A common haplotype in the G-protein-coupled receptor gene GPR74 is associated with leanness and increased lipolysis

    DEFF Research Database (Denmark)

    Dahlman, Ingrid; Dicker, Andrea; Jiao, Hong

    2007-01-01

    0.36; P=.036) among those selected for obese or lean phenotypes. The ATAG haplotype was associated with increased adipocyte lipid mobilization (lipolysis) in vivo and in vitro. In human fat cells, GPR74 receptor stimulation and inhibition caused a significant and marked decrease and increase......, respectively, of lipolysis, which could be linked to catecholamine stimulation of adipocytes through beta -adrenergic receptors. These findings suggest that a common haplotype in the GPR74 gene protects against obesity, which, at least in part, is caused by a relief of inhibition of lipid mobilization from...... with protection against obesity in two samples selected for obese and lean phenotypes (odds ratio for obesity 0.48 and 0.62; nominal P=.0014 and .014; n=1,013 and 1,423, respectively). In a population-based sample, it was associated with lower waist (P=.02) among 3,937 men and with obesity protection (odds ratio...

  14. Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates.

    Directory of Open Access Journals (Sweden)

    Bo Yuan

    2015-12-01

    Full Text Available Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100 is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases-about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual's susceptibility to acquiring disease-associated alleles.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. 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.

  17. Global haplotype partitioning for maximal associated SNP pairs

    Directory of Open Access Journals (Sweden)

    Pezeshk Hamid

    2009-08-01

    Full Text Available Abstract Background Global partitioning based on pairwise associations of SNPs has not previously been used to define haplotype blocks within genomes. Here, we define an association index based on LD between SNP pairs. We use the Fisher's exact test to assess the statistical significance of the LD estimator. By this test, each SNP pair is characterized as associated, independent, or not-statistically-significant. We set limits on the maximum acceptable proportion of independent pairs within all blocks and search for the partitioning with maximal proportion of associated SNP pairs. Essentially, this model is reduced to a constrained optimization problem, the solution of which is obtained by iterating a dynamic programming algorithm. Results In comparison with other methods, our algorithm reports blocks of larger average size. Nevertheless, the haplotype diversity within the blocks is captured by a small number of tagSNPs. Resampling HapMap haplotypes under a block-based model of recombination showed that our algorithm is robust in reproducing the same partitioning for recombinant samples. Our algorithm performed better than previously reported models in a case-control association study aimed at mapping a single locus trait, based on simulation results that were evaluated by a block-based statistical test. Compared to methods of haplotype block partitioning, we performed best on detection of recombination hotspots. Conclusion Our proposed method divides chromosomes into the regions within which allelic associations of SNP pairs are maximized. This approach presents a native design for dimension reduction in genome-wide association studies. Our results show that the pairwise allelic association of SNPs can describe various features of genomic variation, in particular recombination hotspots.

  18. Investigation of extended Y chromosome STR haplotypes in Sardinia.

    Science.gov (United States)

    Lacerenza, D; Aneli, S; Di Gaetano, C; Critelli, R; Piazza, A; Matullo, G; Culigioni, C; Robledo, R; Robino, C; Calò, C

    2017-03-01

    Y-chromosomal variation of selected single nucleotide polymorphisms (SNPs) and 32 short tandem repeat (STR) loci was evaluated in Sardinia in three open population groups (Northern Sardinia, n=40; Central Sardinia, n=56; Southern Sardinia, n=91) and three isolates (Desulo, n=34; Benetutti, n=45, Carloforte, n=42). The tested Y-STRs consisted of Yfiler(®) Plus markers and the seven rapidly mutating (RM) loci not included in the YFiler(®) Plus kit (DYF399S1, DYF403S1ab, DYF404S1, DYS526ab, DYS547, DYS612, and DYS626). As expected, inclusion of additional Y-STR loci increased haplotype diversity (h), though complete differentiation of male lineages was impossible even by means of RM Y-STRs (h=0.99997). Analysis of molecular variance indicated that the three open populations were fairly homogeneous, whereas signs of genetic heterogeneity could be detected when the three isolates were also included in the analysis. Multidimensional scaling analysis showed that, even for extended haplotypes including RM Y-STR markers, Sardinians were clearly differentiated from populations of the Italian peninsula and Sicily. The only exception was represented by the Carloforte sample that, in accordance with its peculiar population history, clustered with Northern/Central Italian populations. The introduction of extended forensic Y-STR panels, including highly variable RM Y-STR markers, is expected to reduce the impact of population structure on haplotype frequency estimations. However, our results show that the availability of geographically detailed reference databases is still important for the assessment of the evidential value of a Y-haplotype match.

  19. beta(S)-Globin gene cluster haplotypes in the West Bank of Palestine.

    Science.gov (United States)

    Samarah, Fekri; Ayesh, Suhail; Athanasiou, Miranda; Christakis, John; Vavatsi, Norma

    2009-01-01

    Sickle cell disease is an inherited autosomal recessive disorder of the beta-globin chain. In Palestine it is accompanied by a low level of Hb F (mean 5.14%) and a severe clinical presentation. In this study, 59 Palestinian patients, homozygotes for Hb S were studied for their haplotype background. Eight polymorphic sites in the beta-globin gene cluster were examined. The Benin haplotype was predominant with a frequency of 88.1%, followed by a frequency of 5.1% for the Bantu haplotype. One chromosome was found to carry the Cameroon haplotype (0.85%). Three atypical haplotypes were also found (5.95%). Heterogeneity was observed in Hb F production, ranging between 1.5 and 17.0%, whereas the (G)gamma ratio was homogeneous among all haplotypes with a normal amount of about 41%. Our results are in agreement with previous reports of the Benin haplotype origin in the Mediterranean.

  20. Parsing the Interferon Transcriptional Network and Its Disease Associations.

    Science.gov (United States)

    Mostafavi, Sara; Yoshida, Hideyuki; Moodley, Devapregasan; LeBoité, Hugo; Rothamel, Katherine; Raj, Towfique; Ye, Chun Jimmie; Chevrier, Nicolas; Zhang, Shen-Ying; Feng, Ting; Lee, Mark; Casanova, Jean-Laurent; Clark, James D; Hegen, Martin; Telliez, Jean-Baptiste; Hacohen, Nir; De Jager, Philip L; Regev, Aviv; Mathis, Diane; Benoist, Christophe

    2016-01-28

    Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.

  1. 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.

  2. Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups

    Directory of Open Access Journals (Sweden)

    Wang Jun

    2009-03-01

    Full Text Available Abstract Background A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers. Methods We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk. Results We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the Fst value closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping. Conclusion The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations.

  3. Artificial selection on introduced Asian haplotypes shaped the genetic architecture in European commercial pigs.

    Science.gov (United States)

    Bosse, Mirte; Lopes, Marcos S; Madsen, Ole; Megens, Hendrik-Jan; Crooijmans, Richard P M A; Frantz, Laurent A F; Harlizius, Barbara; Bastiaansen, John W M; Groenen, Martien A M

    2015-12-22

    Early pig farmers in Europe imported Asian pigs to cross with their local breeds in order to improve traits of commercial interest. Current genomics techniques enabled genome-wide identification of these Asian introgressed haplotypes in modern European pig breeds. We propose that the Asian variants are still present because they affect phenotypes that were important for ancient traditional, as well as recent, commercial pig breeding. Genome-wide introgression levels were only weakly correlated with gene content and recombination frequency. However, regions with an excess or absence of Asian haplotypes (AS) contained genes that were previously identified as phenotypically important such as FASN, ME1, and KIT. Therefore, the Asian alleles are thought to have an effect on phenotypes that were historically under selection. We aimed to estimate the effect of AS in introgressed regions in Large White pigs on the traits of backfat (BF) and litter size. The majority of regions we tested that retained Asian deoxyribonucleic acid (DNA) showed significantly increased BF from the Asian alleles. Our results suggest that the introgression in Large White pigs has been strongly determined by the selective pressure acting upon the introgressed AS. We therefore conclude that human-driven hybridization and selection contributed to the genomic architecture of these commercial pigs.

  4. Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

    DEFF Research Database (Denmark)

    Kristiansen, O P; Karlsen, A E; Larsen, Z M;

    2004-01-01

    CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4(+) T cells. We previously found linkage between a CD4-1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we...... screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes...... promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP...

  5. Combining an Evolution-guided Clustering Algorithm and Haplotype-based LRT in Family Association Studies

    Directory of Open Access Journals (Sweden)

    Huang Su-Yun

    2011-05-01

    Full Text Available Abstract Background With the completion of the international HapMap project, many studies have been conducted to investigate the association between complex diseases and haplotype variants. Such haplotype-based association studies, however, often face two difficulties; one is the large number of haplotype configurations in the chromosome region under study, and the other is the ambiguity in haplotype phase when only genotype data are observed. The latter complexity may be handled based on an EM algorithm with family data incorporated, whereas the former can be more problematic, especially when haplotypes of rare frequencies are involved. Here based on family data we propose to cluster long haplotypes of linked SNPs in a biological sense, so that the number of haplotypes can be reduced and the power of statistical tests of association can be increased. Results In this paper we employ family genotype data and combine a clustering scheme with a likelihood ratio statistic to test the association between quantitative phenotypes and haplotype variants. Haplotypes are first grouped based on their evolutionary closeness to establish a set containing core haplotypes. Then, we construct for each family the transmission and non-transmission phase in terms of these core haplotypes, taking into account simultaneously the phase ambiguity as weights. The likelihood ratio test (LRT is next conducted with these weighted and clustered haplotypes to test for association with disease. This combination of evolution-guided haplotype clustering and weighted assignment in LRT is able, via its core-coding system, to incorporate into analysis both haplotype phase ambiguity and transmission uncertainty. Simulation studies show that this proposed procedure is more informative and powerful than three family-based association tests, FAMHAP, FBAT, and an LRT with a group consisting exclusively of rare haplotypes. Conclusions The proposed procedure takes into account the

  6. Disease-associated XMRV sequences are consistent with laboratory contamination

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    Garson Jeremy A

    2010-12-01

    Full Text Available Abstract Background Xenotropic murine leukaemia viruses (MLV-X are endogenous gammaretroviruses that infect cells from many species, including humans. Xenotropic murine leukaemia virus-related virus (XMRV is a retrovirus that has been the subject of intense debate since its detection in samples from humans with prostate cancer (PC and chronic fatigue syndrome (CFS. Controversy has arisen from the failure of some studies to detect XMRV in PC or CFS patients and from inconsistent detection of XMRV in healthy controls. Results Here we demonstrate that Taqman PCR primers previously described as XMRV-specific can amplify common murine endogenous viral sequences from mouse suggesting that mouse DNA can contaminate patient samples and confound specific XMRV detection. To consider the provenance of XMRV we sequenced XMRV from the cell line 22Rv1, which is infected with an MLV-X that is indistinguishable from patient derived XMRV. Bayesian phylogenies clearly show that XMRV sequences reportedly derived from unlinked patients form a monophyletic clade with interspersed 22Rv1 clones (posterior probability >0.99. The cell line-derived sequences are ancestral to the patient-derived sequences (posterior probability >0.99. Furthermore, pol sequences apparently amplified from PC patient material (VP29 and VP184 are recombinants of XMRV and Moloney MLV (MoMLV a virus with an envelope that lacks tropism for human cells. Considering the diversity of XMRV we show that the mean pairwise genetic distance among env and pol 22Rv1-derived sequences exceeds that of patient-associated sequences (Wilcoxon rank sum test: p = 0.005 and p pol and env, respectively. Thus XMRV sequences acquire diversity in a cell line but not in patient samples. These observations are difficult to reconcile with the hypothesis that published XMRV sequences are related by a process of infectious transmission. Conclusions We provide several independent lines of evidence that XMRV detected by

  7. Informatics-Based Discovery of Disease-Associated Immune Profiles

    Science.gov (United States)

    Delmas, Amber; Oikonomopoulos, Angelos; Lacey, Precious N.; Fallahi, Mohammad; Hommes, Daniel W.; Sundrud, Mark S.

    2016-01-01

    Advances in flow and mass cytometry are enabling ultra-high resolution immune profiling in mice and humans on an unprecedented scale. However, the resulting high-content datasets challenge traditional views of cytometry data, which are both limited in scope and biased by pre-existing hypotheses. Computational solutions are now emerging (e.g., Citrus, AutoGate, SPADE) that automate cell gating or enable visualization of relative subset abundance within healthy versus diseased mice or humans. Yet these tools require significant computational fluency and fail to show quantitative relationships between discrete immune phenotypes and continuous disease variables. Here we describe a simple informatics platform that uses hierarchical clustering and nearest neighbor algorithms to associate manually gated immune phenotypes with clinical or pre-clinical disease endpoints of interest in a rapid and unbiased manner. Using this approach, we identify discrete immune profiles that correspond with either weight loss or histologic colitis in a T cell transfer model of inflammatory bowel disease (IBD), and show distinct nodes of immune dysregulation in the IBDs, Crohn’s disease and ulcerative colitis. This streamlined informatics approach for cytometry data analysis leverages publicly available software, can be applied to manually or computationally gated cytometry data, is suitable for any clinical or pre-clinical setting, and embraces ultra-high content flow and mass cytometry as a discovery engine. PMID:27669154

  8. ParaHaplo 2.0: a program package for haplotype-estimation and haplotype-based whole-genome association study using parallel computing

    Directory of Open Access Journals (Sweden)

    Kamatani Naoyuki

    2010-06-01

    Full Text Available Abstract Background The use of haplotype-based association tests can improve the power of genome-wide association studies. Since the observed genotypes are unordered pairs of alleles, haplotype phase must be inferred. However, estimating haplotype phase is time consuming. When millions of single-nucleotide polymorphisms (SNPs are analyzed in genome-wide association study, faster methods for haplotype estimation are required. Methods We developed a program package for parallel computation of haplotype estimation. Our program package, ParaHaplo 2.0, is intended for use in workstation clusters using the Intel Message Passing Interface (MPI. We compared the performance of our algorithm to that of the regular permutation test on both Japanese in Tokyo, Japan and Han Chinese in Beijing, China of the HapMap dataset. Results Parallel version of ParaHaplo 2.0 can estimate haplotypes 100 times faster than a non-parallel version of the ParaHaplo. Conclusion ParaHaplo 2.0 is an invaluable tool for conducting haplotype-based genome-wide association studies (GWAS. The need for fast haplotype estimation using parallel computing will become increasingly important as the data sizes of such projects continue to increase. The executable binaries and program sources of ParaHaplo are available at the following address: http://en.sourceforge.jp/projects/parallelgwas/releases/

  9. Reverse immunogenetics: from HLA-disease associations to vaccine candidates.

    Science.gov (United States)

    Davenport, M P; Hill, A V

    1996-01-01

    Analysis of the human leukocyte antigens (HLA) in patients with either infectious or autoimmune diseases has led to the identification of several HLA alleles associated with either resistance or susceptibility to disease. Understanding the role of HLA molecules in the presentation of peptide antigens to T cells has led to the use of 'reverse immunogenetics': a novel approach to analysing the key antigenic peptides that are presented by the relevant HLA molecules. Recent advances in the analysis of naturally occurring peptides bound to HLA molecules has allowed the direct identification of antigenic peptides from living cells and has supported the development of vaccine candidates, such as the liver-stage antigen 1 in malaria.

  10. Regulation of disease-associated gene expression in the 3D genome.

    Science.gov (United States)

    Krijger, Peter Hugo Lodewijk; de Laat, Wouter

    2016-12-01

    Genetic variation associated with disease often appears in non-coding parts of the genome. Understanding the mechanisms by which this phenomenon leads to disease is necessary to translate results from genetic association studies to the clinic. Assigning function to this type of variation is notoriously difficult because the human genome harbours a complex regulatory landscape with a dizzying array of transcriptional regulatory sequences, such as enhancers that have unpredictable, promiscuous and context-dependent behaviour. In this Review, we discuss how technological advances have provided increasingly detailed information on genome folding; for example, genome folding forms loops that bring enhancers and target genes into close proximity. We also now know that enhancers function within topologically associated domains, which are structural and functional units of chromosomes. Studying disease-associated mutations and chromosomal rearrangements in the context of the 3D genome will enable the identification of dysregulated target genes and aid the progression from descriptive genetic association results to discovering molecular mechanisms underlying disease.

  11. Inhaled Pollutants: The Molecular Scene behind Respiratory and Systemic Diseases Associated with Ultrafine Particulate Matter

    Directory of Open Access Journals (Sweden)

    Hussein Traboulsi

    2017-01-01

    Full Text Available Air pollution of anthropogenic origin is largely from the combustion of biomass (e.g., wood, fossil fuels (e.g., cars and trucks, incinerators, landfills, agricultural activities and tobacco smoke. Air pollution is a complex mixture that varies in space and time, and contains hundreds of compounds including volatile organic compounds (e.g., benzene, metals, sulphur and nitrogen oxides, ozone and particulate matter (PM. PM0.1 (ultrafine particles (UFP, those particles with a diameter less than 100 nm (includes nanoparticles (NP are considered especially dangerous to human health and may contribute significantly to the development of numerous respiratory and cardiovascular diseases such as chronic obstructive pulmonary disease (COPD and atherosclerosis. Some of the pathogenic mechanisms through which PM0.1 may contribute to chronic disease is their ability to induce inflammation, oxidative stress and cell death by molecular mechanisms that include transcription factors such as nuclear factor κB (NF-κB and nuclear factor (erythroid-derived 2-like 2 (Nrf2. Epigenetic mechanisms including non-coding RNA (ncRNA may also contribute towards the development of chronic disease associated with exposure to PM0.1. This paper highlights emerging molecular concepts associated with inhalational exposure to PM0.1 and their ability to contribute to chronic respiratory and systemic disease.

  12. Inhaled Pollutants: The Molecular Scene behind Respiratory and Systemic Diseases Associated with Ultrafine Particulate Matter

    Science.gov (United States)

    Traboulsi, Hussein; Guerrina, Necola; Iu, Matthew; Maysinger, Dusica; Ariya, Parisa; Baglole, Carolyn J.

    2017-01-01

    Air pollution of anthropogenic origin is largely from the combustion of biomass (e.g., wood), fossil fuels (e.g., cars and trucks), incinerators, landfills, agricultural activities and tobacco smoke. Air pollution is a complex mixture that varies in space and time, and contains hundreds of compounds including volatile organic compounds (e.g., benzene), metals, sulphur and nitrogen oxides, ozone and particulate matter (PM). PM0.1 (ultrafine particles (UFP)), those particles with a diameter less than 100 nm (includes nanoparticles (NP)) are considered especially dangerous to human health and may contribute significantly to the development of numerous respiratory and cardiovascular diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Some of the pathogenic mechanisms through which PM0.1 may contribute to chronic disease is their ability to induce inflammation, oxidative stress and cell death by molecular mechanisms that include transcription factors such as nuclear factor κB (NF-κB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Epigenetic mechanisms including non-coding RNA (ncRNA) may also contribute towards the development of chronic disease associated with exposure to PM0.1. This paper highlights emerging molecular concepts associated with inhalational exposure to PM0.1 and their ability to contribute to chronic respiratory and systemic disease. PMID:28125025

  13. A network based method for analysis of lncRNA-disease associations and prediction of lncRNAs implicated in diseases.

    Science.gov (United States)

    Yang, Xiaofei; Gao, Lin; Guo, Xingli; Shi, Xinghua; Wu, Hao; Song, Fei; Wang, Bingbo

    2014-01-01

    Increasing evidence has indicated that long non-coding RNAs (lncRNAs) are implicated in and associated with many complex human diseases. Despite of the accumulation of lncRNA-disease associations, only a few studies had studied the roles of these associations in pathogenesis. In this paper, we investigated lncRNA-disease associations from a network view to understand the contribution of these lncRNAs to complex diseases. Specifically, we studied both the properties of the diseases in which the lncRNAs were implicated, and that of the lncRNAs associated with complex diseases. Regarding the fact that protein coding genes and lncRNAs are involved in human diseases, we constructed a coding-non-coding gene-disease bipartite network based on known associations between diseases and disease-causing genes. We then applied a propagation algorithm to uncover the hidden lncRNA-disease associations in this network. The algorithm was evaluated by leave-one-out cross validation on 103 diseases in which at least two genes were known to be involved, and achieved an AUC of 0.7881. Our algorithm successfully predicted 768 potential lncRNA-disease associations between 66 lncRNAs and 193 diseases. Furthermore, our results for Alzheimer's disease, pancreatic cancer, and gastric cancer were verified by other independent studies.

  14. Absence of atypical haplotype and presence of Senegal haplotype sickle cell disease in African-descent population in the northern Brazil

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    Rafael E. Nascimento

    2015-04-01

    Full Text Available Introduction: Sickle cell anemia (SCA is the most severe form of sickle cell disease; it presents variants that are called haplotypes βS. There are five major haplotypes βS gene: Arab-Indian/Saudi, Senegal, Benin, Bantu, and Camaroon. Objective: Characterize the presence of haplotypes in patients with SCA in Amapá. Methods: 46 sample were studied, all samples were amplified and analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP. Results: Bantu (61.2%, followed by Benin (26.5% and Senegal (12.2%. Conclusion: We identified three haplotypes characteristic of African ethnicity, with the presence of Senegal. In our study we found the presence of atypical haplotype, suggesting concentration and semi-isolation of the founding groups with little mixing.

  15. Two haplotype clusters of Echinococcus granulosus sensu stricto in northern Iraq (Kurdistan region) support the hypothesis of a parasite cradle in the Middle East.

    Science.gov (United States)

    Hassan, Zuber Ismael; Meerkhan, Azad Abdullah; Boufana, Belgees; Hama, Abdullah A; Ahmed, Bayram Dawod; Mero, Wijdan Mohammed Salih; Orsten, Serra; Interisano, Maria; Pozio, Edoardo; Casulli, Adriano

    2017-08-01

    Human cystic echinococcosis (CE) caused by Echinococcus granulosus s.s. is a major public health problem in Iraqi Kurdistan with a reported surgical incidence of 6.3 per 100,000 Arbil inhabitants. A total of 125 Echinococcus isolates retrieved from sheep, goats and cattle were used in this study. Our aim was to determine species/genotypes infecting livestock in Iraqi Kurdistan and examine intraspecific variation and population structure of Echinococcus granulosus s.s. in this region and relate it to that of other regions worldwide. Using nucleotide sequences of the mitochondrial cytochrome c oxidase subunit 1 (cox 1) we identified E. granulosus s.s. as the cause of hydatidosis in all examined animals. The haplotype network displayed a double-clustered topology with two main E. granulosus s.s. haplotypes, (KU05) and (KU33). The 'founder' haplotype (KU05) confirmed the presence of a common lineage of non-genetically differentiated populations as inferred by the low non-significant fixation index values. Overall diversity and neutrality indices indicated demographic expansion. We used E. granulosus s.s. nucleotide sequences from GenBank to draw haplotype networks for the Middle East (Iran, Jordan and Turkey), Europe (Albania, Greece, Italy, Romania and Spain), China, Mongolia, Russia, South America (Argentina, Brazil, Chile and Mexico) and Tunisia. Networks with two haplotype clusters like that reported here for Iraqi Kurdistan were seen for the Middle East, Europe, Mongolia, Russia and Tunisia using both 827bp and 1609bp cox1 nucleotide sequences, whereas a star-like network was observed for China and South America. We hypothesize that the double clustering seen at what is generally assumed to be the cradle of domestication may have emerged independently and dispersed from the Middle East to other regions and that haplotype (KU33) may be the main haplotype within a second cluster in the Middle East from where it has spread into Europe, Mongolia, Russia and North

  16. Microsatellite diversity and crossover regions within homozygous and heterozygous SLA haplotypes of different pig breeds.

    Science.gov (United States)

    Ando, Asako; Uenishi, Hirohide; Kawata, Hisako; Tanaka-Matsuda, Maiko; Shigenari, Atsuko; Flori, Laurence; Chardon, Patrick; Lunney, Joan K; Kulski, Jerzy K; Inoko, Hidetoshi

    2008-07-01

    Our aim was to investigate microsatellite (MS) diversity and find crossover regions at 42 polymorphic MS loci in the swine leukocyte antigen (SLA) genomic region of 72 pigs with different well-defined homozygous and heterozygous SLA haplotypes. We analyzed the genetic polymorphisms of 42 MS markers in 23 SLA homozygous-heterozygous, common pig breeds with 12 SLA serological haplotypes and 49 National Institutes of Health (NIH) and Clawn homozygous-heterozygous miniature pigs with nine SLA serological or genotyped haplotypes including four recombinant haplotypes. In comparing the same and different haplotypes, both haplospecific patterns and allelic variations were observed at the MS loci. Some of the shared haplotype blocks extended over 2 Mb suggesting the existence of strong linkage disequilibrium (LD) in the entire SLA region. Crossover regions were easily defined by the MS markers within the class I and/or III region in the NIH and Clawn recombinant haplotypes. The present haplotype comparison shows that our set of MS markers provides a fast and cost-efficient alternative, or complementary, method to the serological or sequence-based determination of the SLA alleles for the characterization of SLA haplotypes and/or the crossover regions between different haplotypes.

  17. 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.

  18. Zoonotic diseases associated with free-roaming cats.

    Science.gov (United States)

    Gerhold, R W; Jessup, D A

    2013-05-01

    Free-roaming cat populations have been identified as a significant public health threat and are a source for several zoonotic diseases including rabies, toxoplasmosis, cutaneous larval migrans because of various nematode parasites, plague, tularemia and murine typhus. Several of these diseases are reported to cause mortality in humans and can cause other important health issues including abortion, blindness, pruritic skin rashes and other various symptoms. A recent case of rabies in a young girl from California that likely was transmitted by a free-roaming cat underscores that free-roaming cats can be a source of zoonotic diseases. Increased attention has been placed on trap-neuter-release (TNR) programmes as a viable tool to manage cat populations. However, some studies have shown that TNR leads to increased immigration of unneutered cats into neutered populations as well as increased kitten survival in neutered groups. These compensatory mechanisms in neutered groups leading to increased kitten survival and immigration would confound rabies vaccination campaigns and produce naïve populations of cats that can serve as source of zoonotic disease agents owing to lack of immunity. This manuscript is a review of the various diseases of free-roaming cats and the public health implications associated with the cat populations.

  19. Intestinal invasion and disseminated disease associated with Penicillium chrysogenum

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    Herchline Thomas E

    2005-12-01

    Full Text Available Abstract Background Penicillium sp., other than P. marneffei, is an unusual cause of invasive disease. These organisms are often identified in immunosuppressed patients, either due to human immunodeficiency virus or from immunosuppressant medications post-transplantation. They are a rarely identified cause of infection in immunocompetent hosts. Case presentation A 51 year old African-American female presented with an acute abdomen and underwent an exploratory laparotomy which revealed an incarcerated peristomal hernia. Her postoperative course was complicated by severe sepsis syndrome with respiratory failure, hypotension, leukocytosis, and DIC. On postoperative day 9 she was found to have an anastamotic breakdown. Pathology from the second surgery showed transmural ischemic necrosis with angioinvasion of a fungal organism. Fungal blood cultures were positive for Penicillium chrysogenum and the patient completed a 6 week course of amphotericin B lipid complex, followed by an extended course oral intraconazole. She was discharged to a nursing home without evidence of recurrent infection. Discussion Penicillium chrysogenum is a rare cause of infection in immunocompetent patients. Diagnosis can be difficult, but Penicillium sp. grows rapidly on routine fungal cultures. Prognosis remains very poor, but aggressive treatment is essential, including surgical debridement and the removal of foci of infection along with the use of amphotericin B. The clinical utility of newer antifungal agents remains to be determined.

  20. Ribosome profiling reveals features of normal and disease-associated mitochondrial translation

    NARCIS (Netherlands)

    Rooijers, K.; Loayza-Puch, F.; Nijtmans, L.G.J.; Agami, R.

    2013-01-01

    Mitochondria are essential cellular organelles for generation of energy and their dysfunction may cause diabetes, Parkinson's disease and multi-systemic failure marked by failure to thrive, gastrointestinal problems, lactic acidosis and early lethality. Disease-associated mitochondrial mutations oft

  1. Ribosome profiling reveals features of normal and disease-associated mitochondrial translation

    NARCIS (Netherlands)

    Rooijers, K.; Loayza-Puch, F.; Nijtmans, L.G.J.; Agami, R.

    2013-01-01

    Mitochondria are essential cellular organelles for generation of energy and their dysfunction may cause diabetes, Parkinson's disease and multi-systemic failure marked by failure to thrive, gastrointestinal problems, lactic acidosis and early lethality. Disease-associated mitochondrial mutations oft

  2. Fine localization of the Nijmegen breakage syndrome gene to 8q21: Evidence for a common founder haplotype

    Energy Technology Data Exchange (ETDEWEB)

    Cerosaletti, K.M. [Univ. of Washington School of Medicine, Seattle, WA (United States); Lange, E.; Stringham, H.M. [Univ. of Michigan School of Public Health, Ann Arbor, MI (United States). Dept. of Biostatistics] [and others

    1998-07-01

    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, a birdlike face, growth retardation, immunodeficiency, lack of secondary sex characteristics in females, and increased incidence of lymphoid cancers. NBS cells display a phenotype similar to that of cells from ataxia-telangiectasia patients, including chromosomal instability, radiation sensitivity, and aberrant cell-cycle-checkpoint control following exposure to ionizing radiation. A recent study reported genetic linkage of NBs to human chromosome 8q21, with strong linkage disequilibrium detected at marker D8S1811 in eastern European NBS families. The authors collected a geographically diverse group of NBS families and tested them for linkage, using an expanded panel of markers at 8q21. In this article, the authors report linkage of NBS to 8q21 in 6/7 of these families, with a maximum LOD score of 3.58. Significant linkage disequilibrium was detected for 8/13 markers tested in the 8q21 region, including D8S1811. In order to further localize the gene for NBS, the authors generated a radiation-hybrid map of markers at 8q21 and constructed haplotypes based on this map. Examination of disease haplotypes segregating in 11 NBS pedigrees revealed recombination events that place the NBS gene between D8S1757 and D8S270. A common founder haplotype was present on 15/18 disease chromosomes from 9/11 NBS families. Inferred (ancestral) recombination events involving this common haplotype suggest that NBS can be localized further, to an interval flanked by markers D8S273 and D8S88.

  3. A novel prion disease associated with diarrhea and autonomic neuropathy.

    Science.gov (United States)

    Mead, Simon; Gandhi, Sonia; Beck, Jon; Caine, Diana; Gallujipali, Dillip; Carswell, Christopher; Hyare, Harpreet; Joiner, Susan; Ayling, Hilary; Lashley, Tammaryn; Linehan, Jacqueline M; Al-Doujaily, Huda; Sharps, Bernadette; Revesz, Tamas; Sandberg, Malin K; Reilly, Mary M; Koltzenburg, Martin; Forbes, Alastair; Rudge, Peter; Brandner, Sebastian; Warren, Jason D; Wadsworth, Jonathan D F; Wood, Nicholas W; Holton, Janice L; Collinge, John

    2013-11-14

    Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease. We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members. We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative. Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.).

  4. Transposable elements in disease-associated cryptic exons.

    Science.gov (United States)

    Vorechovsky, Igor

    2010-02-01

    Transposable elements (TEs) make up a half of the human genome, but the extent of their contribution to cryptic exon activation that results in genetic disease is unknown. Here, a comprehensive survey of 78 mutation-induced cryptic exons previously identified in 51 disease genes revealed the presence of TEs in 40 cases (51%). Most TE-containing exons were derived from short interspersed nuclear elements (SINEs), with Alus and mammalian interspersed repeats (MIRs) covering >18 and >16% of the exonized sequences, respectively. The majority of SINE-derived cryptic exons had splice sites at the same positions of the Alu/MIR consensus as existing SINE exons and their inclusion in the mRNA was facilitated by phylogenetically conserved changes that improved both traditional and auxiliary splicing signals, thus marking intronic TEs amenable for pathogenic exonization. The overrepresentation of MIRs among TE exons is likely to result from their high average exon inclusion levels, which reflect their strong splice sites, a lack of splicing silencers and a high density of enhancers, particularly (G)AA(G) motifs. These elements were markedly depleted in antisense Alu exons, had the most prominent position on the exon-intron gradient scale and are proposed to promote exon definition through enhanced tertiary RNA interactions involving unpaired (di)adenosines. The identification of common mechanisms by which the most dynamic parts of the genome contribute both to new exon creation and genetic disease will facilitate detection of intronic mutations and the development of computational tools that predict TE hot-spots of cryptic exon activation.

  5. Economic Burden of Disease-Associated Malnutrition at the State Level

    Science.gov (United States)

    Goates, Scott; Du, Kristy; Braunschweig, Carol A.; Arensberg, Mary Beth

    2016-01-01

    Background Disease-associated malnutrition has been identified as a prevalent condition, particularly for the elderly, which has often been overlooked in the U.S. healthcare system. The state-level burden of community-based disease-associated malnutrition is unknown and there have been limited efforts by state policy makers to identify, quantify, and address malnutrition. The objective of this study was to examine and quantify the state-level economic burden of disease-associated malnutrition. Methods Direct medical costs of disease-associated malnutrition were calculated for 8 diseases: Stroke, Chronic Obstructive Pulmonary Disease, Coronary Heart Failure, Breast Cancer, Dementia, Musculoskeletal Disorders, Depression, and Colorectal Cancer. National disease and malnutrition prevalence rates were estimated for subgroups defined by age, race, and sex using the National Health and Nutrition Examination Survey and the National Health Interview Survey. State prevalence of disease-associated malnutrition was estimated by combining national prevalence estimates with states’ demographic data from the U.S. Census. Direct medical cost for each state was estimated as the increased expenditures incurred as a result of malnutrition. Principal Findings Direct medical costs attributable to disease-associated malnutrition vary among states from an annual cost of $36 per capita in Utah to $65 per capita in Washington, D.C. Nationally the annual cost of disease-associated malnutrition is over $15.5 billion. The elderly bear a disproportionate share of this cost on both the state and national level. Conclusions Additional action is needed to reduce the economic impact of disease-associated malnutrition, particularly at the state level. Nutrition may be a cost-effective way to help address high health care costs. PMID:27655372

  6. Genetic diversity, haplotypes and allele groups of Duffy binding protein (PkDBPαII) of Plasmodium knowlesi clinical isolates from Peninsular Malaysia.

    Science.gov (United States)

    Fong, Mun-Yik; Lau, Yee-Ling; Chang, Phooi-Yee; Anthony, Claudia Nisha

    2014-04-03

    The monkey malaria parasite Plasmodium knowlesi is now recognized as the fifth species of Plasmodium that can cause human malaria. Like the region II of the Duffy binding protein of P. vivax (PvDBPII), the region II of the P. knowlesi Duffy binding protein (PkDBPαII) plays an essential role in the parasite's invasion into the host's erythrocyte. Numerous polymorphism studies have been carried out on PvDBPII, but none has been reported on PkDBPαII. In this study, the genetic diversity, haplotyes and allele groups of PkDBPαII of P. knowlesi clinical isolates from Peninsular Malaysia were investigated. Blood samples from 20 knowlesi malaria patients and 2 wild monkeys (Macaca fascicularis) were used. These samples were collected between 2010 and 2012. The PkDBPαII region of the isolates was amplified by PCR, cloned into Escherichia coli, and sequenced. The genetic diversity, natural selection and haplotypes of PkDBPαII were analysed using MEGA5 and DnaSP ver. 5.10.00 programmes. Fifty-three PkDBPαII sequences from human infections and 6 from monkeys were obtained. Comparison at the nucleotide level against P. knowlesi strain H as reference sequence showed 52 synonymous and 76 nonsynonymous mutations. Analysis on the rate of these mutations indicated that PkDBPαII was under purifying (negative) selection. At the amino acid level, 36 different PkDBPαII haplotypes were identified. Twelve of the 20 human and 1 monkey blood samples had mixed haplotype infections. These haplotypes were clustered into 2 distinct allele groups. The majority of the haplotypes clustered into the large dominant group. Our present study is the first to report the genetic diversity and natural selection of PkDBPαII. Hence, the haplotypes described in this report can be considered as novel. Although a high level of genetic diversity was observed, the PkDBPαII appeared to be under purifying selection. The distribution of the haplotypes was skewed, with one dominant major and one minor

  7. Pregnancy after azathioprine therapy for ulcerative colitis in a woman with autoimmune premature ovarian failure and Addison's disease: HLA haplotype characterization.

    Science.gov (United States)

    Ferraù, Francesco; Gangemi, Sebastiano; Vita, Giuseppe; Trimarchi, Francesco; Cannavò, Salvatore

    2011-06-01

    To present a case of fertility restored by azathioprine treatment in a woman with autoimmune premature ovarian failure, Addison's disease, and ulcerative colitis, and to study the genetic background of the three autoimmune diseases. Case report. Endocrinology and Immunology Units of an university hospital. A 30-year-old woman with autoimmune premature ovarian failure, Addison's disease, and ulcerative colitis. Azathioprine has been administered as immunosuppressive treatment. We performed analysis of human leukocyte antigens expression on lymphocytes and genomic haplotype of the patient. The human leukocyte antigen haplotype of the patient was consistent with the haplotypes predisposing for the three autoimmune diseases, as reported in the literature. The administration of azathioprine restored regular menses and allowed uneventful pregnancy. This is the first clinical evidence of association of immunosuppressive azathioprine treatment and restored ovarian function and fertility in a woman with autoimmune premature ovarian failure. In this patient, the haplotype was associated with susceptibility to autoimmune premature ovarian failure, Addison's disease, and ulcerative colitis. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  8. HDL-S1P: cardiovascular functions, disease-associated alterations, and therapeutic applications.

    Science.gov (United States)

    Levkau, Bodo

    2015-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid contained in High-density lipoproteins (HDL) and has drawn considerable attention in the lipoprotein field as numerous studies have demonstrated its contribution to several functions inherent to HDL. Some of them are partly and some entirely due to the S1P contained in HDL (HDL-S1P). Despite the presence of over 1000 different lipids in HDL, S1P stands out as it possesses its own cell surface receptors through which it exercises key physiological functions. Most of the S1P in human plasma is associated with HDL, and the amount of HDL-S1P influences the quality and quantity of HDL-dependent functions. The main binding partner of S1P in HDL is apolipoprotein M but others may also exist particularly under conditions of acute S1P elevations. HDL not only exercise functions through their S1P content but have also an impact on genuine S1P signaling by influencing S1P bioactivity and receptor presentation. HDL-S1P content is altered in human diseases such as atherosclerosis, coronary artery disease, myocardial infarction, renal insufficiency and diabetes mellitus. Low HDL-S1P has also been linked to impaired HDL functions associated with these disorders. Although the pathophysiological and molecular reasons for such disease-associated shifts in HDL-S1P are little understood, there have been successful approaches to circumvent their adverse implications by pharmacologically increasing HDL-S1P as means to improve HDL function. This mini-review will cover the current understanding of the contribution of HDL-S1P to physiological HDL function, its alteration in disease and ways for its restoration to correct HDL dysfunction.

  9. HDL-S1P: cardiovascular functions, disease-associated alterations, and therapeutic applications

    Science.gov (United States)

    Levkau, Bodo

    2015-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid contained in High-density lipoproteins (HDL) and has drawn considerable attention in the lipoprotein field as numerous studies have demonstrated its contribution to several functions inherent to HDL. Some of them are partly and some entirely due to the S1P contained in HDL (HDL-S1P). Despite the presence of over 1000 different lipids in HDL, S1P stands out as it possesses its own cell surface receptors through which it exercises key physiological functions. Most of the S1P in human plasma is associated with HDL, and the amount of HDL-S1P influences the quality and quantity of HDL-dependent functions. The main binding partner of S1P in HDL is apolipoprotein M but others may also exist particularly under conditions of acute S1P elevations. HDL not only exercise functions through their S1P content but have also an impact on genuine S1P signaling by influencing S1P bioactivity and receptor presentation. HDL-S1P content is altered in human diseases such as atherosclerosis, coronary artery disease, myocardial infarction, renal insufficiency and diabetes mellitus. Low HDL-S1P has also been linked to impaired HDL functions associated with these disorders. Although the pathophysiological and molecular reasons for such disease-associated shifts in HDL-S1P are little understood, there have been successful approaches to circumvent their adverse implications by pharmacologically increasing HDL-S1P as means to improve HDL function. This mini-review will cover the current understanding of the contribution of HDL-S1P to physiological HDL function, its alteration in disease and ways for its restoration to correct HDL dysfunction. PMID:26539121

  10. Globally dispersed Y chromosomal haplotypes in wild and domestic sheep.

    Science.gov (United States)

    Meadows, J R S; Hanotte, O; Drögemüller, C; Calvo, J; Godfrey, R; Coltman, D; Maddox, J F; Marzanov, N; Kantanen, J; Kijas, J W

    2006-10-01

    To date, investigations of genetic diversity and the origins of domestication in sheep have utilised autosomal microsatellites and variation in the mitochondrial genome. We present the first analysis of both domestic and wild sheep using genetic markers residing on the ovine Y chromosome. Analysis of a single nucleotide polymorphism (oY1) in the SRY promoter region revealed that allele A-oY1 was present in all wild bighorn sheep (Ovis canadensis), two subspecies of thinhorn sheep (Ovis dalli), European Mouflon (Ovis musimon) and the Barbary (Ammontragis lervia). A-oY1 also had the highest frequency (71.4%) within 458 domestic sheep drawn from 65 breeds sampled from Africa, Asia, Australia, the Caribbean, Europe, the Middle East and Central Asia. Sequence analysis of a second locus, microsatellite SRYM18, revealed a compound repeat array displaying fixed differences, which identified bighorn and thinhorn sheep as distinct from the European Mouflon and domestic animals. Combined genotypic data identified 11 male-specific haplotypes that represented at least two separate lineages. Investigation of the geographical distribution of each haplotype revealed that one (H6) was both very common and widespread in the global sample of domestic breeds. The remaining haplotypes each displayed more restricted and informative distributions. For example, H5 was likely founded following the domestication of European breeds and was used to trace the recent transportation of animals to both the Caribbean and Australia. A high rate of Y chromosomal dispersal appears to have taken place during the development of domestic sheep as only 12.9% of the total observed variation was partitioned between major geographical regions.

  11. Inducible nitric oxide synthase haplotype associated with migraine and aura.

    Science.gov (United States)

    de O S Mansur, Thiago; Gonçalves, Flavia M; Martins-Oliveira, Alisson; Speciali, Jose G; Dach, Fabiola; Lacchini, Riccardo; Tanus-Santos, Jose E

    2012-05-01

    Migraine is a complex neurological disorder with a clear neurogenic inflammatory component apparently including enhanced nitric oxide (NO) formation. Excessive NO amounts possibly contributing to migraine are derived from increased expression and activity of inducible NO synthase (iNOS). We tested the hypothesis that two functional, clinically relevant iNOS genetic polymorphisms (C(-1026)A-rs2779249 and G2087A-rs2297518) are associated with migraine with or without aura. We studied 142 healthy women without migraine (control group) and 200 women with migraine divided into two groups: 148 with migraine without aura (MWA) and 52 with aura (MA). Genotypes were determined by real-time polymerase chain reaction using the Taqman(®) allele discrimination assays. The PHASE 2.1 software was used to estimate the haplotypes. The A allele for the G2087A polymorphism was more commonly found in the MA group than in the MWA group (28 vs. 18%; P 0.05). The haplotype combining both A alleles for the two polymorphisms was more commonly found in the MA group than in the control group or in the MWA group (19 vs. 10 or 8%; P = 0.0245 or 0.0027, respectively). Our findings indicate that the G2087A and the C(-1026)A polymorphism in the iNOS gene affect the susceptibility to migraine with aura when their effects are combined within haplotypes, whereas the G2087A affects the susceptibility to aura in migraine patients. These finding may have therapeutic implications when examining the effects of selective iNOS inhibitors.

  12. Genome sequence, comparative analysis and haplotype structure of the domestic dog.

    Science.gov (United States)

    Lindblad-Toh, Kerstin; Wade, Claire M; Mikkelsen, Tarjei S; Karlsson, Elinor K; Jaffe, David B; Kamal, Michael; Clamp, Michele; Chang, Jean L; Kulbokas, Edward J; Zody, Michael C; Mauceli, Evan; Xie, Xiaohui; Breen, Matthew; Wayne, Robert K; Ostrander, Elaine A; Ponting, Chris P; Galibert, Francis; Smith, Douglas R; DeJong, Pieter J; Kirkness, Ewen; Alvarez, Pablo; Biagi, Tara; Brockman, William; Butler, Jonathan; Chin, Chee-Wye; Cook, April; Cuff, James; Daly, Mark J; DeCaprio, David; Gnerre, Sante; Grabherr, Manfred; Kellis, Manolis; Kleber, Michael; Bardeleben, Carolyne; Goodstadt, Leo; Heger, Andreas; Hitte, Christophe; Kim, Lisa; Koepfli, Klaus-Peter; Parker, Heidi G; Pollinger, John P; Searle, Stephen M J; Sutter, Nathan B; Thomas, Rachael; Webber, Caleb; Baldwin, Jennifer; Abebe, Adal; Abouelleil, Amr; Aftuck, Lynne; Ait-Zahra, Mostafa; Aldredge, Tyler; Allen, Nicole; An, Peter; Anderson, Scott; Antoine, Claudel; Arachchi, Harindra; Aslam, Ali; Ayotte, Laura; Bachantsang, Pasang; Barry, Andrew; Bayul, Tashi; Benamara, Mostafa; Berlin, Aaron; Bessette, Daniel; Blitshteyn, Berta; Bloom, Toby; Blye, Jason; Boguslavskiy, Leonid; Bonnet, Claude; Boukhgalter, Boris; Brown, Adam; Cahill, Patrick; Calixte, Nadia; Camarata, Jody; Cheshatsang, Yama; Chu, Jeffrey; Citroen, Mieke; Collymore, Alville; Cooke, Patrick; Dawoe, Tenzin; Daza, Riza; Decktor, Karin; DeGray, Stuart; Dhargay, Norbu; Dooley, Kimberly; Dooley, Kathleen; Dorje, Passang; Dorjee, Kunsang; Dorris, Lester; Duffey, Noah; Dupes, Alan; Egbiremolen, Osebhajajeme; Elong, Richard; Falk, Jill; Farina, Abderrahim; Faro, Susan; Ferguson, Diallo; Ferreira, Patricia; Fisher, Sheila; FitzGerald, Mike; Foley, Karen; Foley, Chelsea; Franke, Alicia; Friedrich, Dennis; Gage, Diane; Garber, Manuel; Gearin, Gary; Giannoukos, Georgia; Goode, Tina; Goyette, Audra; Graham, Joseph; Grandbois, Edward; Gyaltsen, Kunsang; Hafez, Nabil; Hagopian, Daniel; Hagos, Birhane; Hall, Jennifer; Healy, Claire; Hegarty, Ryan; Honan, Tracey; Horn, Andrea; Houde, Nathan; Hughes, Leanne; Hunnicutt, Leigh; Husby, M; Jester, Benjamin; Jones, Charlien; Kamat, Asha; Kanga, Ben; Kells, Cristyn; Khazanovich, Dmitry; Kieu, Alix Chinh; Kisner, Peter; Kumar, Mayank; Lance, Krista; Landers, Thomas; Lara, Marcia; Lee, William; Leger, Jean-Pierre; Lennon, Niall; Leuper, Lisa; LeVine, Sarah; Liu, Jinlei; Liu, Xiaohong; Lokyitsang, Yeshi; Lokyitsang, Tashi; Lui, Annie; Macdonald, Jan; Major, John; Marabella, Richard; Maru, Kebede; Matthews, Charles; McDonough, Susan; Mehta, Teena; Meldrim, James; Melnikov, Alexandre; Meneus, Louis; Mihalev, Atanas; Mihova, Tanya; Miller, Karen; Mittelman, Rachel; Mlenga, Valentine; Mulrain, Leonidas; Munson, Glen; Navidi, Adam; Naylor, Jerome; Nguyen, Tuyen; Nguyen, Nga; Nguyen, Cindy; Nguyen, Thu; Nicol, Robert; Norbu, Nyima; Norbu, Choe; Novod, Nathaniel; Nyima, Tenchoe; Olandt, Peter; O'Neill, Barry; O'Neill, Keith; Osman, Sahal; Oyono, Lucien; Patti, Christopher; Perrin, Danielle; Phunkhang, Pema; Pierre, Fritz; Priest, Margaret; Rachupka, Anthony; Raghuraman, Sujaa; Rameau, Rayale; Ray, Verneda; Raymond, Christina; Rege, Filip; Rise, Cecil; Rogers, Julie; Rogov, Peter; Sahalie, Julie; Settipalli, Sampath; Sharpe, Theodore; Shea, Terrance; Sheehan, Mechele; Sherpa, Ngawang; Shi, Jianying; Shih, Diana; Sloan, Jessie; Smith, Cherylyn; Sparrow, Todd; Stalker, John; Stange-Thomann, Nicole; Stavropoulos, Sharon; Stone, Catherine; Stone, Sabrina; Sykes, Sean; Tchuinga, Pierre; Tenzing, Pema; Tesfaye, Senait; Thoulutsang, Dawa; Thoulutsang, Yama; Topham, Kerri; Topping, Ira; Tsamla, Tsamla; Vassiliev, Helen; Venkataraman, Vijay; Vo, Andy; Wangchuk, Tsering; Wangdi, Tsering; Weiand, Michael; Wilkinson, Jane; Wilson, Adam; Yadav, Shailendra; Yang, Shuli; Yang, Xiaoping; Young, Geneva; Yu, Qing; Zainoun, Joanne; Zembek, Lisa; Zimmer, Andrew; Lander, Eric S

    2005-12-08

    Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.

  13. Haplotype-Phased Synthetic Long Reads from Short-Read Sequencing.

    Directory of Open Access Journals (Sweden)

    James A Stapleton

    Full Text Available Next-generation DNA sequencing has revolutionized the study of biology. However, the short read lengths of the dominant instruments complicate assembly of complex genomes and haplotype phasing of mixtures of similar sequences. Here we demonstrate a method to reconstruct the sequences of individual nucleic acid molecules up to 11.6 kilobases in length from short (150-bp reads. We show that our method can construct 99.97%-accurate synthetic reads from bacterial, plant, and animal genomic samples, full-length mRNA sequences from human cancer cell lines, and individual HIV env gene variants from a mixture. The preparation of multiple samples can be multiplexed into a single tube, further reducing effort and cost relative to competing approaches. Our approach generates sequencing libraries in three days from less than one microgram of DNA in a single-tube format without custom equipment or specialized expertise.

  14. Haplotype Map of Sickle Cell Anemia in Tunisia

    OpenAIRE

    Imen Moumni; Maha Ben Mustapha; Sarra Sassi; Amine Zorai; Ikbel Ben Mansour; Kais Douzi; Dorra Chouachi; Fethi Mellouli; Mohamed Bejaoui; Salem Abbes

    2014-01-01

    International audience; β-Globin haplotypes are important to establish the ethnic origin and predict the clinical development of sickle cell disease patients (SCD). To determine the chromosomal background of β (S) Tunisian sickle cell patients, in this first study in Tunisia, we have explored four polymorphic regions of β-globin cluster on chromosome 11. It is the 5' region of β-LCR-HS2 site, the intervening sequence II (IVSII) region of two fetal ((G)γ and (A)γ) genes and the 5' region of β-...

  15. The dopamine transporter haplotype and reward-related striatal responses in adult ADHD

    OpenAIRE

    Hoogman, M.; Onnink, M.; Coolen, R.; Aarts, E.; van Kan, C; Arias Vasquez, A.; Buitelaar, J; Franke, B

    2013-01-01

    Attention deficit/hyperactivity disorder (ADHD) is a highly heritable disorder and several genes increasing disease risk have been identified. The dopamine transporter gene, SLC6A3/DAT1, has been studied most extensively in ADHD research. Interestingly, a different haplotype of this gene (formed by genetic variants in the 3' untranslated region and intron 8) is associated with childhood ADHD (haplotype 10-6) and adult ADHD (haplotype 9-6). The expression of DAT1 is highest in striatal regions...

  16. Novel strategies to mine alcoholism-related haplotypes and genes by combining existing knowledge framework.

    Science.gov (United States)

    Zhang, RuiJie; Li, Xia; Jiang, YongShuai; Liu, GuiYou; Li, ChuanXing; Zhang, Fan; Xiao, Yun; Gong, BinSheng

    2009-02-01

    High-throughout single nucleotide polymorphism detection technology and the existing knowledge provide strong support for mining the disease-related haplotypes and genes. In this study, first, we apply four kinds of haplotype identification methods (Confidence Intervals, Four Gamete Tests, Solid Spine of LD and fusing method of haplotype block) into high-throughout SNP genotype data to identify blocks, then use cluster analysis to verify the effectiveness of the four methods, and select the alcoholism-related SNP haplotypes through risk analysis. Second, we establish a mapping from haplotypes to alcoholism-related genes. Third, we inquire NCBI SNP and gene databases to locate the blocks and identify the candidate genes. In the end, we make gene function annotation by KEGG, Biocarta, and GO database. We find 159 haplotype blocks, which relate to the alcoholism most possibly on chromosome 1 approximately 22, including 227 haplotypes, of which 102 SNP haplotypes may increase the risk of alcoholism. We get 121 alcoholism-related genes and verify their reliability by the functional annotation of biology. In a word, we not only can handle the SNP data easily, but also can locate the disease-related genes precisely by combining our novel strategies of mining alcoholism-related haplotypes and genes with existing knowledge framework.

  17. Haplotype-based association analysis of the MAPT locus in Late Onset Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morris John C

    2007-01-01

    Full Text Available Abstract Background Late onset Alzheimer's disease (LOAD is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a β-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c with AD. The current study is an attempt to replicate this association in an independently ascertained cohort. Results In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD. Conclusion In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD.

  18. Native and European haplotypes of Phragmites Australis (common reed) in the central Platte River, Nebraska

    Science.gov (United States)

    Larson, D.L.; Galatowitsch, S.M.; Larson, J.L.

    2011-01-01

    Phragmites australis (common reed) is known to have occurred along the Platte River historically, but recent rapid increases in both distribution and density have begun to impact habitat for migrating sandhill cranes and nesting piping plovers and least terns. Invasiveness in Phragmites has been associated with the incursion of a European genotype (haplotype M) in other areas; determining the genotype of Phragmites along the central Platte River has implications for proper management of the river system. In 2008 we sampled Phragmites patches along the central Platte River from Lexington to Chapman, NE, stratified by bridge segments, to determine the current distribution of haplotype E (native) and haplotype M genotypes. In addition, we did a retrospective analysis of historical Phragmites collections from the central Platte watershed (1902-2006) at the Bessey Herbarium. Fresh tissue from the 2008 survey and dried tissue from the herbarium specimens were classified as haplotype M or E using the restriction fragment length polymorphism procedure. The European haplotype was predominant in the 2008 samples: only 14 Phragmites shoots were identified as native haplotype E; 224 were non-native haplotype M. The retrospective analysis revealed primarily native haplotype individuals. Only collections made in Lancaster County, near Lincoln, NE, were haplotype M, and the earliest of these was collected in 1973. ?? 2011 Copyright by the Center for Great Plains Studies, University of Nebraska-Lincoln.

  19. Novel strategies to mine alcoholism-related haplotypes and genes by combining existing knowledge framework

    Institute of Scientific and Technical Information of China (English)

    ZHANG RuiJie; LI Xia; JIANG YongShuai; LIU GuiYou; LI ChuanXing; ZHANG Fan; XIAO Yun; GONG BinSheng

    2009-01-01

    High-throughout single nucleotide polymorphism detection technology and the existing knowledge provide strong support for mining the disease-related haplotypes and genes. In this study, first, we apply four kinds of haplotype identification methods (Confidence Intervals, Four Gamete Testa, Solid Spine of LD and fusing method of haplotype block) into high-throughout SNP genotype data to identify blocks, then use cluster analysis to verify the effectiveness of the four methods, and select the alcoholism-related SNP haplotypes through risk analysis. Second, we establish a mapping from haplotypes to alcoholism-related genes. Third, we inquire NCBI SNP and gene databases to locate the blocks and identify the candidate genes. In the end, we make gene function annotation by KEGG, Biocarta, and GO database. We find 159 haplotype blocks, which relate to the alcoholism most possibly on chromosome 1-22, including 227 haplotypes, of which 102 SNP haplotypes may increase the risk of alcoholism. We get 121 alcoholism-related genes and verify their reliability by the functional annotation of biology. In a word, we not only can handle the SNP data easily, but also can locate the disease-related genes precisely by combining our novel strategies of mining alcoholism-related haplotypes and genes with existing knowledge framework.

  20. Novel strategies to mine alcoholism-related haplotypes and genes by combining existing knowledge framework

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    High-throughout single nucleotide polymorphism detection technology and the existing knowledge provide strong support for mining the disease-related haplotypes and genes. In this study, first, we apply four kinds of haplotype identification methods (Confidence Intervals, Four Gamete Tests, Solid Spine of LD and fusing method of haplotype block) into high-throughout SNP genotype data to identify blocks, then use cluster analysis to verify the effectiveness of the four methods, and select the alco- holism-related SNP haplotypes through risk analysis. Second, we establish a mapping from haplotypes to alcoholism-related genes. Third, we inquire NCBI SNP and gene databases to locate the blocks and identify the candidate genes. In the end, we make gene function annotation by KEGG, Biocarta, and GO database. We find 159 haplotype blocks, which relate to the alcoholism most possibly on chromosome 1~22, including 227 haplotypes, of which 102 SNP haplotypes may increase the risk of alcoholism. We get 121 alcoholism-related genes and verify their reliability by the functional annotation of biology. In a word, we not only can handle the SNP data easily, but also can locate the disease-related genes pre- cisely by combining our novel strategies of mining alcoholism-related haplotypes and genes with ex- isting knowledge framework.

  1. 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...

  2. Mitochondrial haplotypes associated with biomarkers for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Perry G Ridge

    Full Text Available Various studies have suggested that the mitochondrial genome plays a role in late-onset Alzheimer's disease, although results are mixed. We used an endophenotype-based approach to further characterize mitochondrial genetic variation and its relationship to risk markers for Alzheimer's disease. We analyzed longitudinal data from non-demented, mild cognitive impairment, and late-onset Alzheimer's disease participants in the Alzheimer's Disease Neuroimaging Initiative with genetic, brain imaging, and behavioral data. We assessed the relationship of structural MRI and cognitive biomarkers with mitochondrial genome variation using TreeScanning, a haplotype-based approach that concentrates statistical power by analyzing evolutionarily meaningful groups (or clades of haplotypes together for association with a phenotype. Four clades were associated with three different endophenotypes: whole brain volume, percent change in temporal pole thickness, and left hippocampal atrophy over two years. This is the first study of its kind to identify mitochondrial variation associated with brain imaging endophenotypes of Alzheimer's disease. Our results provide additional evidence that the mitochondrial genome plays a role in risk for Alzheimer's disease.

  3. D-loop haplotype diversity in Brazilian horse breeds.

    Science.gov (United States)

    Ianella, Patrícia; Albuquerque, Maria do Socorro Maués; Paiva, Samuel Rezende; Egito, Andréa Alves do; Almeida, Leonardo Daniel; Sereno, Fabiana T P S; Carvalho, Luiz Felipe Ramos; Mariante, Arthur da Silva; McManus, Concepta Margaret

    2017-08-31

    The first horses were brought to Brazil by the colonizers after 1534. Over the centuries, these animals evolved and adapted to local environmental conditions usually unsuitable for exotic breeds, thereby originating locally adapted Brazilian breeds. The present work represents the first description of maternal genetic diversity in these horse breeds based on D-loop sequences. A D-Loop HSV-I fragment of 252 bp, from 141 horses belonging to ten Brazilian breeds / genetic groups (locally adapted and specialized breeds) were analysed. Thirty-five different haplotypes belonging to 18 haplogroups were identified with 33 polymorphic sites. Haplotype diversity (varying from 0.20 to 0.96) and nucleotide diversity (varying from 0.0039 to 0.0239) was lower for locally adapted than for specialized breeds, with the same pattern observed for FST values. Haplogroups identified in Brazilian breeds are in agreement with previous findings in South American samples. The low variability observed mainly in locally adapted breeds, indicates that, to ensure conservation of these breeds, careful reproductive management is needed. Additional genetic characterization studies are required to support accurate decision-making.

  4. 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.

  5. Prediction of MicroRNA-Disease Associations Based on Social Network Analysis Methods

    Directory of Open Access Journals (Sweden)

    Quan Zou

    2015-01-01

    Full Text Available MicroRNAs constitute an important class of noncoding, single-stranded, ~22 nucleotide long RNA molecules encoded by endogenous genes. They play an important role in regulating gene transcription and the regulation of normal development. MicroRNAs can be associated with disease; however, only a few microRNA-disease associations have been confirmed by traditional experimental approaches. We introduce two methods to predict microRNA-disease association. The first method, KATZ, focuses on integrating the social network analysis method with machine learning and is based on networks derived from known microRNA-disease associations, disease-disease associations, and microRNA-microRNA associations. The other method, CATAPULT, is a supervised machine learning method. We applied the two methods to 242 known microRNA-disease associations and evaluated their performance using leave-one-out cross-validation and 3-fold cross-validation. Experiments proved that our methods outperformed the state-of-the-art methods.

  6. 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

  7. Study of the optimum haplotype length to build genomic relationship matrices.

    Science.gov (United States)

    Ferdosi, Mohammad H; Henshall, John; Tier, Bruce

    2016-09-29

    As genomic data becomes more abundant, genomic prediction is more routinely used to estimate breeding values. In genomic prediction, the relationship matrix ([Formula: see text]), which is traditionally used in genetic evaluations is replaced by the genomic relationship matrix ([Formula: see text]). This paper considers alternative ways of building relationship matrices either using single markers or haplotypes of different lengths. We compared the prediction accuracies and log-likelihoods when using these alternative relationship matrices and the traditional [Formula: see text] matrix, for real and simulated data. For real data, we built relationship matrices using 50k genotype data for a population of Brahman cattle to analyze three traits: scrotal circumference (SC), age at puberty (AGECL) and weight at first corpus luteum (WTCL). Haplotypes were phased with hsphase and imputed with BEAGLE. The relationship matrices were built using three methods based on haplotypes of different lengths. The log-likelihood was considered to define the optimum haplotype lengths for each trait and each haplotype-based relationship matrix. Based on simulated data, we showed that the inverse of [Formula: see text] matrix and the inverse of the haplotype relationship matrices for methods using one-single nucleotide polymorphism (SNP) phased haplotypes provided coefficients of determination (R(2)) close to 1, although the estimated genetic variances differed across methods. Using real data and multiple SNPs in the haplotype segments to build the relationship matrices provided better results than the [Formula: see text] matrix based on one-SNP haplotypes. However, the optimal haplotype length to achieve the highest log-likelihood depended on the method used and the trait. The optimal haplotype length (7 to 8 SNPs) was similar for SC and AGECL. One of the haplotype-based methods achieved the largest increase in log-likelihood for SC, i.e. from -1330 when using [Formula: see text] to

  8. RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family

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    Elisangela P. S. Quedas

    2012-01-01

    Full Text Available Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.

  9. Genetic relationships among native americans based on beta-globin gene cluster haplotype frequencies

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    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.

  10. Mitochondrial DNA haplotyping revealed the presence of mixed up benign and neoplastic tissue sections from two individuals on the same prostatic biopsy slide.

    Science.gov (United States)

    Alonso, A; Alves, C; Suárez-Mier, M P; Albarrán, C; Pereira, L; Fernández de Simón, L; Martín, P; García, O; Gusmão, L; Sancho, M; Amorim, A

    2005-01-01

    DNA typing was requested to investigate a presumptive cancer diagnosis error by confirming whether benign and cancerous prostatic tissue in the same presurgical haematoxylin and eosin stained slide belonged to the same person. After independent histological re-examination of the slide by a pathologist, manual slide dissection was used to guarantee independent and high recovery DNA isolation from each tissue section, avoiding carryover and background contamination. Nuclear DNA quantification performed by real time polymerase chain reaction (PCR) revealed the absence of human DNA for short tandem repeat (STR) typing. Mitochondrial DNA was only obtained by performing PCR of very short fragments ( approximately 100 bp), indicating high DNA degradation. Different low frequency hypervariable region I haplotypes were obtained from each tissue section (normal tissue section haplotype: 16224C, 16234T, 16311C, 16356C; cancer tissue section haplotype: 16256T, 16270T, 16293G). Only the normal tissue section haplotype matched that obtained from the patient's blood sample, indicating that the cancer tissue section originated from an unknown patient. These results supported the hypothesis of sample mix up during block processing or slide preparation by a carryover mechanism. Mitochondrial genetic typing is recommended to exclude the possibility of carryover artefacts when low DNA content and high degradation compromise conventional STR typing.

  11. Analysis of FMR1 (CGG)(n) alleles and DXS548-FRAXAC1 haplotypes in three European circumpolar populations: traces of genetic relationship with Asia.

    Science.gov (United States)

    Larsen, L A; Vuust, J; Nystad, M; Evseeva, I; Van Ghelue, M; Tranebjaerg, L

    2001-09-01

    Fragile X syndrome, the most common form of inherited mental retardation, is caused by expansion of a (CGG)(n) repeat located in the FMR1 gene. The molecular factors involved in the mutation process from stable (CGG)(n) alleles towards unstable alleles are largely unknown, although family transmission studies and population studies have suggested that loss of AGG interruptions in the (CGG)(n) repeat is essential. We have analysed the AGG interspersion pattern of the FMR1 (CGG)(n) repeat and the haplotype distribution of closely located microsatellite markers DXS548 and FRAXAC1, in three circumarctic populations: Norwegians, Nenets and Saami. The data confirm the conservation, reported in all human populations studied so far, of an AGG interruption for each 9-10 CGG and support the stabilising effect of AGG interruptions. The data also indicate the existence of chromosomes of Asian origin in the Saami and Nenets population, thereby confirming a genetic relationship between Northern Europe and Asia. DXS548-FRAXAC1 haplotype frequencies were compared between 24 Norwegian fragile X males and 119 normal males. Significant linkage disequilibrium were found between the fragile X mutation and haplotype 6-4 and between normal (CGG)(n) alleles and haplotype 7-3.

  12. Association of ORAI1 haplotypes with the risk of HLA-B27 positive ankylosing spondylitis.

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    James Cheng-Chung Wei

    Full Text Available Ankylosing spondylitis (AS is a chronic inflammation of the sacroiliac joints, spine and peripheral joints. The aetiology of ankylosing spondylitis is still unclear. Previous studies have indicated that genetics factors such as human leukocyte antigen HLA-B27 associates to AS susceptibility. We carried out a case-control study to determine whether the genetic polymorphisms of ORAI1 gene, a major component of store-operated calcium channels that involved the regulation of immune system, is a susceptibility factor to AS in a Taiwanese population. We enrolled 361 AS patients fulfilled the modified New York criteria and 379 controls from community. Five tagging single nucleotides polymorphisms (tSNPs at ORAI1 were selected from the data of Han Chinese population in HapMap project. Clinical statuses of AS were assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI, and Bath Ankylosing Spondylitis Global Index (BAS-G. Our results indicated that subjects carrying the minor allele homozygote (CC of the promoter SNP rs12313273 or TT homozygote of the SNP rs7135617 had an increased risk of HLA-B27 positive AS. The minor allele C of 3'UTR SNP rs712853 exerted a protective effect to HLA-B27 positive AS. Furthermore, the rs12313273/rs7135617 pairwise allele analysis found that C-G (OR 1.69, 95% CI 1.27, 2.25; p = 0.0003 and T-T (OR 1.75, 95% CI 1.36, 2.27; p<0.0001 haplotypes had a significantly association with the risk of HLA-B27-positive AS in comparison with the T-G carriers. This is the first study that indicate haplotypes of ORAI1 (rs12313273 and rs7135617 are associated with the risk of HLA-B27 positive AS.

  13. Multisite haplotype on cattle chromosome 3 is associated with quantitative trait locus effects on lactation traits.

    Science.gov (United States)

    Cohen-Zinder, Miri; Donthu, Ravikiran; Larkin, Denis M; Kumar, Charu Gupta; Rodriguez-Zas, Sandra L; Andropolis, Kalista E; Oliveira, Rosane; Lewin, Harris A

    2011-11-07

    The goal of this study was to identify candidate genes and DNA polymorphisms for quantitative trait loci (QTL) affecting milk yield (MY), fat yield (FY), and protein yield (PY) previously mapped to bovine chromosome 3 (BTA3). To accomplish this, 373 half-siblings sired by three bulls previously shown to be segregating for lactation trait QTL, and 263 additional sires in the U.S. Dairy Bull DNA Repository (DBDR) were genotyped for 2,500 SNPs within a 16.3 Mbp QTL critical region on BTA3. Targeted resequencing of ∼1.8 Mbp within the QTL critical region of one of the QTL heterozygous sires identified additional polymorphisms useful for association studies. Twenty-three single nucleotide polymorphisms (SNPs) within a fine-mapped region were associated with effects on breeding values for MY, FY, or PY in DBDR sires, of which five SNPs were in strong linkage disequilibrium in the population. This multisite haplotype included SNPs located within exons or promoters of four tightly linked genes: RAP1A, ADORA3, OVGP1, and C3H1orf88. An SNP within RAP1A showed strong evidence of a recent selective sweep based on integrated haplotype score and was also associated with breeding value for PY. Because of its known function in alveolar lumen formation in the mammary gland, RAP1A is thus a strong candidate gene for QTL effects on lactation traits. Our results provide a detailed assessment of a QTL region that will be a useful guide for complex traits analysis in humans and other noninbred species.

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

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    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

  15. Glucose-6-phosphate dehydrogenase mutations and haplotypes in Mexican Mestizos.

    Science.gov (United States)

    Arámbula, E; Aguilar L, J C; Vaca, G

    2000-08-01

    In a screening for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in 1985 unrelated male subjects from the general population (Groups A and B) belonging to four states of the Pacific coast, 21 G-6-PD-deficient subjects were detected. Screening for mutations at the G-6-PD gene by PCR-restriction enzyme in these 21 G-6-PD-deficient subjects as well as in 14 G-6-PD-deficient patients with hemolytic anemia belonging to several states of Mexico showed two common G-6-PD variants: G-6-PD A-(202A/376G) (19 cases) and G-6-PD A-(376G/968C) (9 cases). In 7 individuals the mutations responsible for the enzyme deficiency remain to be determined. Furthermore, four silent polymorphic sites at the G-6-PD gene (PvuII, PstI, 1311, and NlaIII) were investigated in the 28 individuals with G-6-PD A- variants and in 137 G-6-PD normal subjects. As expected, only 10 different haplotypes were observed. To date, in our project aiming to determine the molecular basis of G-6-PD deficiency in Mexico, 60 unrelated G-6-PD-deficient Mexican males-25 in previous studies and 35 in the present work-have been studied. More than 75% of these individuals are from states of the Pacific coast (Sinaloa, Nayarit, Jalisco, Michoacán, Guerrero, Oaxaca, and Chiapas). The results show that although G-6-PD deficiency is heterogeneous at the DNA level in Mexico, only three polymorphic variants have been observed: G-6-PD A-(202A/376G) (36 cases), G-6-PD A-(376G/968C) (13 cases), and G-6-PD Seattle(844C) (2 cases). G-6-PD A- variants are relatively distributed homogeneously and both variants explain 82% of the overall prevalence of G-6-PD deficiency. The variant G-6-PD A-(202A/376G) represents 73% of the G-6-PD A- alleles. Our data also show that the variant G-6-PD A-(376G/968C)-which has been observed in Mexico in the context of two different haplotypes-is more common than previously supposed. The three polymorphic variants that we observed in Mexico are on the same haplotypes as found in subjects from

  16. COX-2 gene promoter haplotypes and prostate cancer risk.

    Science.gov (United States)

    Panguluri, Ramesh C K; Long, Layron O; Chen, Weidong; Wang, Songping; Coulibaly, Aoua; Ukoli, Flora; Jackson, Aaron; Weinrich, Sally; Ahaghotu, Chiledum; Isaacs, William; Kittles, Rick A

    2004-06-01

    Cyclooxygenase-2 (COX-2) is a key rate-limiting enzyme that converts arachidonic acid into pro-inflammatory prostaglandins. COX-2 expression is strongly correlated with increased tumor microvasculature density and plays an important role in inhibiting apoptosis, stimulating angiogenesis and promoting tumor cell metastasis and invasion. However, little is known about the role that sequence variation of the COX-2 gene contributes to prostate cancer. Thus, we searched for polymorphisms in the promoter region of the COX-2 gene using denaturing high-performance liquid chromatography. Four single nucleotide polymorphisms (SNPs), -1285A/G, -1265G/A, -899G/C and -297C/G, were detected and confirmed by direct sequencing. Three of the SNPs in the promoter region of COX-2 gene create at least three putative transcription factor binding sites and eliminate CCAAT/enhancer binding protein alpha (C/EBP alpha) and NF-kappa B binding sites. A case-control study of the four SNPs in African American (n = 288), Bini Nigerian (n = 264) and European American (n = 184) prostate cancer cases and age-matched controls revealed that SNP -297G was associated with a decreased risk for prostate cancer [odds ratio (OR) = 0.49; CI = 0.2-0.9; P = 0.01]. The effect on risk was observed in both African Americans (OR = 0.51; CI = 0.2-0.9; P = 0.01) and European Americans (OR = 0.33; CI = 0.1-0.9; P = 0.02). In addition, SNPs -1265A and -899C were associated with increased prostate cancer risk in African Americans (OR = 2.72; CI = 1.3-5.8; P = 0.007 and OR = 3.67; CI = 1.4-9.9; P = 0.007, respectively). Haplotype analyses revealed modest effects on susceptibility to prostate cancer across populations. Haplotype GGCC conferred increased risk in the African American and Nigerian populations. Conversely, haplotype AGGG exhibited a negative association with prostate cancer risk in African Americans (OR = 0.4; CI = 0.1-0.9; P = 0.02) and European Americans (OR = 0.2; CI = 0.1-0.9; P = 0.03). These data

  17. Haplotypes of NOS3 Gene Polymorphisms in Dilated Cardiomyopathy

    Science.gov (United States)

    Matsa, Lova Satyanarayana; Rangaraju, Advithi; Vengaldas, Viswamitra; Latifi, Mona; Jahromi, Hossein Mehraban; Ananthapur, Venkateshwari; Nallari, Pratibha

    2013-01-01

    Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO), a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3) gene viz., T-786C of the 5′ flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C) with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p = 0.01) was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34–3.27, p = 0.0011), with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p = 0.003). The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM

  18. Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy.

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    Lova Satyanarayana Matsa

    Full Text Available Dilated Cardiomyopathy (DCM is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO, a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3 gene viz., T-786C of the 5' flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p = 0.01 was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34-3.27, p = 0.0011, with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p = 0.003. The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM

  19. DiMeX: A Text Mining System for Mutation-Disease Association Extraction.

    Science.gov (United States)

    Mahmood, A S M Ashique; Wu, Tsung-Jung; Mazumder, Raja; Vijay-Shanker, K

    2016-01-01

    The number of published articles describing associations between mutations and diseases is increasing at a fast pace. There is a pressing need to gather such mutation-disease associations into public knowledge bases, but manual curation slows down the growth of such databases. We have addressed this problem by developing a text-mining system (DiMeX) to extract mutation to disease associations from publication abstracts. DiMeX consists of a series of natural language processing modules that preprocess input text and apply syntactic and semantic patterns to extract mutation-disease associations. DiMeX achieves high precision and recall with F-scores of 0.88, 0.91 and 0.89 when evaluated on three different datasets for mutation-disease associations. DiMeX includes a separate component that extracts mutation mentions in text and associates them with genes. This component has been also evaluated on different datasets and shown to achieve state-of-the-art performance. The results indicate that our system outperforms the existing mutation-disease association tools, addressing the low precision problems suffered by most approaches. DiMeX was applied on a large set of abstracts from Medline to extract mutation-disease associations, as well as other relevant information including patient/cohort size and population data. The results are stored in a database that can be queried and downloaded at http://biotm.cis.udel.edu/dimex/. We conclude that this high-throughput text-mining approach has the potential to significantly assist researchers and curators to enrich mutation databases.

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

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    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.

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

    Science.gov (United States)

    Calus, Mario P L; Meuwissen, Theo H E; Windig, Jack J; Knol, Egbert F; Schrooten, Chris; Vereijken, Addie L J; Veerkamp, Roel F

    2009-01-15

    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.

  2. Association between Gene Haplotypes and Growth Traits in Japanese Hinai-dori Crossbred Chickens

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    Hideaki Takahashi

    2014-03-01

    Full Text Available We previously identified quantitative trait loci (QTL for body weight and average daily gain in a common region between ADL0198 (chr 1: 171.7 Mb and ABR0287 (chr 1: 173.4 Mb on chicken chromosome 1 in an F2 resource population produced by crossing low- and high-growth lines of the Hinai-dori breed. Motilin receptor (MLNR is a candidate gene affecting growth traits in the region. In this study, we genotyped polymorphisms of the MLNR gene and investigated its association with growth traits in a Hinai-dori F2 intercross population. All the exons of the MLNR gene in the parental population were subjected to PCR amplification, nucleotide sequenced and haplotypes identified. To distinguish resultant diplotype individuals in the F2 population, a mismatch amplification mutation assay was performed. Three haplotypes (Haplotypes 1–3 were accordingly identified. Six genotypes produced by the combination of three haplotypes (Haplotype 1, 2, and 3 were examined in order to identify associations between MLNR haplotypes and growth traits. The data showed that Haplotype 1 was superior to Haplotype 2 and 3 in body weight at 10 and 14 weeks of age, average daily gain between 4 and 10 weeks, 10 and 14 weeks, and 0 and 14 weeks of age in female in F2 females. It was concluded that MLNR is a useful marker of growth traits and could be used to develop strategies for improving growth traits in the Hinai-dori breed.

  3. Clarifying haplotype ambiguity of NAT2 in multi-national cohorts.

    Science.gov (United States)

    Selinski, Silvia; Blaszkewicz, Meinolf; Agundez, Jose A G; Martinez, Carmen; Garcia-Martin, Elena; Hengstler, Jan G; Golka, Klaus

    2013-01-01

    N-Acetyltransferase 2 (NAT2) is the key enzyme in aromatic amine metabolism. NAT2 genotyping requires a subsequent determination of the haplotype pairs (formerly: alleles) to derive the acetylation status. The chromosomal phase of the single nucleotide polymorphisms (SNPs) is unclear for about 2/3 of the genotypes. We investigated NAT2 genotypes of 1,234 bladder cancer cases and 2,207 controls from Germany, Hungary, Pakistan and Venezuela plus 696 further German cancer cases. We reconstructed NAT2 haplotypes using PHASE v2.1.1. We analysed if the variability of the NAT2 haplotypes affected the haplotype reconstruction. Furthermore, we compared population haplotype frequencies in three Caucasian control cohorts (German, Hungarian, Spanish), in Pakistanis and Venezuelans and the impact on bladder cancer. We conclude that a common haplotype reconstruction is feasible, enhances precision and reliability. Hungarian controls showed the largest intra-ethnic variability whereas the Pakistanis showed a haplotype distribution typical for Caucasians. The main differences could be observed for the slow haplotypes *5B, *6A and *7B. The association of slow NAT2 genotypes with bladder cancer risk was most prominent in the Venezuelan study group.

  4. 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

    The lymphocytic choriomeningitis virus (LCMV)-specific Tc response in (C3 X D2) F1 hybrids (k X d) is markedly biased in favor of the H-2d haplotype. Adoptive transfer experiments established that this haplotype preference also applied to T cell function in vivo. Using different mouse strain...

  5. 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.

  6. 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...

  7. Haplotype sharing analysis with SNPs in candidate genes : The genetic analysis workshop 12 example

    NARCIS (Netherlands)

    Fischer, C; Beckmann, L; Majoram, P; Meerman, GT; Chang-Claude, J

    2003-01-01

    Haplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct

  8. Wolbachia infection differs among divergent mitochondrial haplotypes of Bactericera cockerelli (Hemiptera: Triozidae)

    Science.gov (United States)

    Four mitochondrial (cytrochrome oxidase I) haplotypes of the potato psyllid, Bactericera cockerelli (S'ulc) (Hemiptera: Triozidae), have been identified in North America: western, central, northwestern,and southwestern. A recent study found that females of the northwestern haplotype mated by males o...

  9. Haplotypes of beta S chromosomes among patients with sickle cell anemia from Georgia.

    Science.gov (United States)

    Hattori, Y; Kutlar, F; Kutlar, A; McKie, V C; Huisman, T H

    1986-01-01

    Fetal hemoglobin and G gamma levels have been correlated with the presence or absence of eight restriction sites within the beta globin gene cluster (haplotypes) for numerous sickle cell anemia patients from Georgia. The most common haplotypes were #19 (Benin) and #20 (CAR); all patients with haplotype combinations 19/19, 20/20, and 19/20 were severely affected with low Hb F and low G gamma levels. A modified #19 beta S chromosome with a -G gamma-G gamma- globin gene arrangement, instead of -G gamma-A gamma-, was present in SS and SC newborn babies with G gamma values above 80%. Haplotype #3 (Senegal) was present among 15% of the beta S chromosomes; the two adult patients with the 3/3 combination were mildly affected with high Hb F and G gamma values. The haplotype AT with the variant A gamma T chain was a rarity. A new haplotype was found in one 17-year-old SS patient and five of his Hb S heterozygous relatives. This haplotype is associated with an increased production of Hb F in heterozygous and homozygous Hb S individuals; this Hb F contained primarily A gamma chains. A comparison was made between the different haplotypes among SS patients and normal Black individuals, and a remarkable similarity was noted in the fetal hemoglobin data for subjects with these different chromosomes.

  10. Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma.

    Science.gov (United States)

    Tachdjian, Raffi; Mathias, Clinton; Al Khatib, Shadi; Bryce, Paul J; Kim, Hong S; Blaeser, Frank; O'Connor, Brian D; Rzymkiewicz, Danuta; Chen, Andrew; Holtzman, Michael J; Hershey, Gurjit K; Garn, Holger; Harb, Hani; Renz, Harald; Oettgen, Hans C; Chatila, Talal A

    2009-09-28

    Polymorphisms in the interleukin-4 receptor alpha chain (IL-4R alpha) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4R alpha has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target- and tissue-specific manner to mediate heightened expression of a subset of IL-4- and IL-13-responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4R alpha-dependent signaling.

  11. ADAM19 expression in human nephrogenesis and renal disease : Associations with clinical and structural deterioration

    NARCIS (Netherlands)

    Melenhorst, W. B. W. H.; van den Heuvel, M. C.; Timmer, A.; Huitema, S.; Bulthuis, M.; Timens, W.; van Goor, H.

    2006-01-01

    ADAM19, an enzyme from the ADAM (a disintegrin and metalloproteinase) family, is involved in various cell-cell and cell-matrix interactions. It can cleave epidermal growth factor (EGF)-like growth factors, such as heparin-binding (HB)-EGF and neuregulin (NRG), from the cell membrane. ADAM-mediated E

  12. A haplotype inference algorithm for trios based on deterministic sampling

    Directory of Open Access Journals (Sweden)

    Iliadis Alexandros

    2010-08-01

    Full Text Available Abstract Background In genome-wide association studies, thousands of individuals are genotyped in hundreds of thousands of single nucleotide polymorphisms (SNPs. Statistical power can be increased when haplotypes, rather than three-valued genotypes, are used in analysis, so the problem of haplotype phase inference (phasing is particularly relevant. Several phasing algorithms have been developed for data from unrelated individuals, based on different models, some of which have been extended to father-mother-child "trio" data. Results We introduce a technique for phasing trio datasets using a tree-based deterministic sampling scheme. We have compared our method with publicly available algorithms PHASE v2.1, BEAGLE v3.0.2 and 2SNP v1.7 on datasets of varying number of markers and trios. We have found that the computational complexity of PHASE makes it prohibitive for routine use; on the other hand 2SNP, though the fastest method for small datasets, was significantly inaccurate. We have shown that our method outperforms BEAGLE in terms of speed and accuracy for small to intermediate dataset sizes in terms of number of trios for all marker sizes examined. Our method is implemented in the "Tree-Based Deterministic Sampling" (TDS package, available for download at http://www.ee.columbia.edu/~anastas/tds Conclusions Using a Tree-Based Deterministic sampling technique, we present an intuitive and conceptually simple phasing algorithm for trio data. The trade off between speed and accuracy achieved by our algorithm makes it a strong candidate for routine use on trio datasets.

  13. Susceptibility of biallelic haplotype and genotype frequencies to genotyping error.

    Science.gov (United States)

    Moskvina, Valentina; Schmidt, Karl Michael

    2006-12-01

    With the availability of fast genotyping methods and genomic databases, the search for statistical association of single nucleotide polymorphisms with a complex trait has become an important methodology in medical genetics. However, even fairly rare errors occurring during the genotyping process can lead to spurious association results and decrease in statistical power. We develop a systematic approach to study how genotyping errors change the genotype distribution in a sample. The general M-marker case is reduced to that of a single-marker locus by recognizing the underlying tensor-product structure of the error matrix. Both method and general conclusions apply to the general error model; we give detailed results for allele-based errors of size depending both on the marker locus and the allele present. Multiple errors are treated in terms of the associated diffusion process on the space of genotype distributions. We find that certain genotype and haplotype distributions remain unchanged under genotyping errors, and that genotyping errors generally render the distribution more similar to the stable one. In case-control association studies, this will lead to loss of statistical power for nondifferential genotyping errors and increase in type I error for differential genotyping errors. Moreover, we show that allele-based genotyping errors do not disturb Hardy-Weinberg equilibrium in the genotype distribution. In this setting we also identify maximally affected distributions. As they correspond to situations with rare alleles and marker loci in high linkage disequilibrium, careful checking for genotyping errors is advisable when significant association based on such alleles/haplotypes is observed in association studies.

  14. Interleukin-10 haplotypes in Celiac Disease in the Spanish population

    Directory of Open Access Journals (Sweden)

    Fernández-Arquero Miguel

    2006-03-01

    Full Text Available Abstract Background Celiac disease (CD is a chronic disorder characterized by a pathological inflammatory response after exposure to gluten in genetically susceptible individuals. The HLA complex accounts for less than half of the genetic component of the disease, and additional genes must be implicated. Interleukin-10 (IL-10 is an important regulator of mucosal immunity, and several reports have described alterations of IL-10 levels in celiac patients. The IL-10 gene is located on chromosome 1, and its promoter carries several single nucleotide polymorphisms (SNPs and microsatellites which have been associated to production levels. Our aim was to study the role of those polymorphisms in susceptibility to CD in our population. Methods A case-control and a familial study were performed. Positions -1082, -819 and -592 of the IL-10 promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm. Results No significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02 status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either. Conclusion The IL-10 polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease.

  15. Beta-globin gene cluster haplotypes in Venezuelan sickle cell patients from the State of Aragua

    Directory of Open Access Journals (Sweden)

    Nancy Moreno

    2002-01-01

    Full Text Available Seven polymorphic sites in the beta-globin gene cluster were analyzed on a sample of 96 chromosomes of Venezuelan sickle cell patients from the State of Aragua. The Benin haplotype was predominant with a frequency of 0.479, followed by the Bantu haplotype (0.406; a minority of cases with other haplotypes was also identified: atypical Bantu A2 (0.042, Senegal (0.031, atypical Bantu A7 (0.021 and Saudi Arabia/Indian (0.021 haplotypes; however, the Cameroon haplotype was not identified in this study. Our results are in agreement with the historical records that establish Sudanese and Bantu origins for the African slaves brought into Venezuela.

  16. Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state

    Science.gov (United States)

    Morito, Daisuke; Nishikawa, Kouki; Hoseki, Jun; Kitamura, Akira; Kotani, Yuri; Kiso, Kazumi; Kinjo, Masataka; Fujiyoshi, Yoshinori; Nagata, Kazuhiro

    2014-03-01

    Moyamoya disease is an idiopathic human cerebrovascular disorder that is characterized by progressive stenosis and abnormal collateral vessels. We recently identified mysterin/RNF213 as its first susceptibility gene, which encodes a 591-kDa protein containing enzymatically active P-loop ATPase and ubiquitin ligase domains and is involved in proper vascular development in zebrafish. Here we demonstrate that mysterin further contains two tandem AAA+ ATPase modules and forms huge ring-shaped oligomeric complex. AAA+ ATPases are known to generally mediate various biophysical and mechanical processes with the characteristic ring-shaped structure. Fluorescence correlation spectroscopy and biochemical evaluation suggested that mysterin dynamically changes its oligomeric forms through ATP/ADP binding and hydrolysis cycles. Thus, the moyamoya disease-associated gene product is a unique protein that functions as ubiquitin ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell.

  17. 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

    2017-03-01

    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.

  18. β3 Integrin Haplotype Influences Gene Regulation and Plasma von Willebrand Factor Activity

    Science.gov (United States)

    Payne, Katie E; Bray, Paul F; Grant, Peter J; Carter, Angela M

    2008-01-01

    The Leu33Pro polymorphism of the gene encoding β3 integrin (ITGB3) is associated with acute coronary syndromes and influences platelet aggregation. Three common promoter polymorphisms have also been identified. The aims of this study were to (1) investigate the influence of the ITGB3 −400C/A, −425A/C and −468G/A promoter polymorphisms on reporter gene expression and nuclear protein binding and (2) determine genotype and haplotype associations with platelet αIIbβ3 receptor density. Promoter haplotypes were introduced into an ITGB3 promoter-pGL3 construct by site directed mutagenesis and luciferase reporter gene expression analysed in HEL and HMEC-1 cells. Binding of nuclear proteins was assessed by electrophoretic mobility shift assay. The association of ITGB3 haplotype with platelet αIIbβ3 receptor density was determined in 223 subjects. Species conserved motifs were identified in the ITGB3 promoter in the vicinity of the 3 polymorphisms. The GAA, GCC, AAC, AAA and ACC constructs induced ~50% increased luciferase expression relative to the GAC construct in both cell types. Haplotype analysis including Leu33Pro indicated 5 common haplotypes; no associations between ITGB3 haplotypes and receptor density were found. However, the GCC-Pro33 haplotype was associated with significantly higher vWF activity (128.6 [112.1–145.1]%) compared with all other haplotypes (107.1 [101.2–113.0]%, p=0.02). In conclusion, the GCC-Pro33 haplotype was associated with increased vWF activity but not with platelet αIIbβ3 receptor density, which may indicate ITGB3 haplotype influences endothelial function. PMID:18045606

  19. DRB1*03:01 haplotypes: differential contribution to multiple sclerosis risk and specific association with the presence of intrathecal IgM bands.

    Directory of Open Access Journals (Sweden)

    Emilio G de la Concha

    Full Text Available BACKGROUND: Multiple sclerosis (MS is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB in cerebrospinal fluid. METHODS: Genotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients/absence (M-, 81 patients of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M- were performed with the chi-square test or the Fisher exact test. RESULTS: Association of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH 18.2 the one causing the highest risk. Comparisons between M+, M- and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01. CONCLUSIONS: The diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB.

  20. Sequence Variants and Haplotype Analysis of Cat ERBB2 Gene: A Survey on Spontaneous Cat Mammary Neoplastic and Non-Neoplastic Lesions

    Science.gov (United States)

    Santos, Sara; Bastos, Estela; Baptista, Cláudia S.; Sá, Daniela; Caloustian, Christophe; Guedes-Pinto, Henrique; Gärtner, Fátima; Gut, Ivo G.; Chaves, Raquel

    2012-01-01

    The human ERBB2 proto-oncogene is widely considered a key gene involved in human breast cancer onset and progression. Among spontaneous tumors, mammary tumors are the most frequent cause of cancer death in cats and second most frequent in humans. In fact, naturally occurring tumors in domestic animals, more particularly cat mammary tumors, have been proposed as a good model for human breast cancer, but critical genetic and molecular information is still scarce. The aims of this study include the analysis of the cat ERBB2 gene partial sequences (between exon 17 and 20) in order to characterize a normal and a mammary lesion heterogeneous populations. Cat genomic DNA was extracted from normal frozen samples (n = 16) and from frozen and formalin-fixed paraffin-embedded mammary lesion samples (n = 41). We amplified and sequenced two cat ERBB2 DNA fragments comprising exons 17 to 20. It was possible to identify five sequence variants and six haplotypes in the total population. Two sequence variants and two haplotypes show to be specific for cat mammary tumor samples. Bioinformatics analysis predicts that four of the sequence variants can produce alternative transcripts or activate cryptic splicing sites. Also, a possible association was identified between clinicopathological traits and the variant haplotypes. As far as we know, this is the first attempt to examine ERBB2 genetic variations in cat mammary genome and its possible association with the onset and progression of cat mammary tumors. The demonstration of a possible association between primary tumor size (one of the two most important prognostic factors) and the number of masses with the cat ERBB2 variant haplotypes reveal the importance of the analysis of this gene in veterinary medicine. PMID:22489125

  1. HLA-A, B and DRB1 allele and haplotype frequencies in volunteer bone marrow donors from the north of Parana state

    OpenAIRE

    Marlene Silva Bardi; Luciana Ribeiro Jarduli; Adylson Justino Jorge; Rossana Batista Oliveira Godoy Camargo; Fernando Pagotto Carneiro; Jair Roberto Gelinski; Roseclei Assunção Feliciano Silva; Edson Lopes Lavado

    2012-01-01

    BACKGROUND: Knowledge of allele and haplotype frequencies of the human leukocyte antigen (HLA) system is important in the search for unrelated bone marrow donors. The Brazilian population is very heterogeneous and the HLA system is highly informative of populations because of the high level of polymorphisms. AIM: The aim of this study was to characterize the immunogenetic profile of ethnic groups (Caucasians, Afro-Brazilians and Asians) in the north of Parana State. METHODS: A study was carri...

  2. Haplotype identity between individuals who share a CFTR mutation allele ''identical by descent'' : Demonstration of the usefulness of the haplotype-sharing concept for gene mapping in real populations

    NARCIS (Netherlands)

    deVries, HG; vanderMeulen, MA; Rozen, R; Halley, DJJ; Scheffer, H; tenKate, LP; Buys, CHCM; teMeerman, GJ

    1996-01-01

    Cystic fibrosis (CF) patients with the A455E mutation, in both the French Canadian and the Dutch population, share a common haplotype over distances of up to 25 cM. French Canadian patients with the 621+1G-->T mutation share a common haplotype of more than 14 cM. In contrast, haplotypes containing t

  3. BRWLDA: bi-random walks for predicting lncRNA-disease associations.

    Science.gov (United States)

    Yu, Guoxian; Fu, Guangyuan; Lu, Chang; Ren, Yazhou; Wang, Jun

    2017-09-01

    Increasing efforts have been done to figure out the association between lncRNAs and complex diseases. Many computational models construct various lncRNA similarity networks, disease similarity networks, along with known lncRNA-disease associations to infer novel associations. However, most of them neglect the structural difference between lncRNAs network and diseases network, hierarchical relationships between diseases and pattern of newly discovered associations. In this study, we developed a model that performs Bi-Random Walks to predict novel LncRNA-Disease Associations (BRWLDA in short). This model utilizes multiple heterogeneous data to construct the lncRNA functional similarity network, and Disease Ontology to construct a disease network. It then constructs a directed bi-relational network based on these two networks and available lncRNAs-disease associations. Next, it applies bi-random walks on the network to predict potential associations. BRWLDA achieves reliable and better performance than other comparing methods not only on experiment verified associations, but also on the simulated experiments with masked associations. Case studies further demonstrate the feasibility of BRWLDA in identifying new lncRNA-disease associations.

  4. Ribosome profiling reveals features of normal and disease-associated mitochondrial translation

    NARCIS (Netherlands)

    K. Rooijers (Koos); F. Loayza-Puch (Fabricio); L.G.J. Nijtmans (Leo); R. Agami (Reuven)

    2013-01-01

    textabstractMitochondria are essential cellular organelles for generation of energy and their dysfunction may cause diabetes, Parkinson's disease and multi-systemic failure marked by failure to thrive, gastrointestinal problems, lactic acidosis and early lethality. Disease-associated mitochondrial m

  5. Systematic identification of trans eQTLs as putative drivers of known disease associations

    NARCIS (Netherlands)

    Westra, Harm-Jan; Peters, Marjolein J.; Esko, Tonu; Yaghootkar, Hanieh; Schurmann, Claudia; Kettunen, Johannes; Christiansen, Mark W.; Fairfax, Benjamin P.; Schramm, Katharina; Powell, Joseph E.; Zhernakova, Alexandra; Zhernakova, Daria V.; Veldink, Jan H.; Van den Berg, Leonard H.; Karjalainen, Juha; Withoff, Sebo; Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando; 't Hoen, Peter A. C.; Reinmaa, Eva; Fischer, Krista; Nelis, Mari; Milani, Lili; Melzer, David; Ferrucci, Luigi; Singleton, Andrew B.; Hernandez, Dena G.; Nalls, Michael A.; Homuth, Georg; Nauck, Matthias; Radke, Doerte; Voelker, Uwe; Perola, Markus; Salomaa, Veikko; Brody, Jennifer; Suchy-Dicey, Astrid; Gharib, Sina A.; Enquobahrie, Daniel A.; Lumley, Thomas; Montgomery, Grant W.; Makino, Seiko; Prokisch, Holger; Herder, Christian; Roden, Michael; Grallert, Harald; Meitinger, Thomas; Strauch, Konstantin; Li, Yang; Jansen, Ritsert C.; Visscher, Peter M.; Knight, Julian C.; Psaty, Bruce M.; Ripatti, Samuli; Teumer, Alexander; Frayling, Timothy M.; Metspalu, Andres; van Meurs, Joyce B. J.; Franke, Lude; Hoen, Peter A.C. ’t

    2013-01-01

    Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified

  6. Systematic identification of trans eQTLs as putative drivers of known disease associations

    NARCIS (Netherlands)

    H.J. Westra (Harm-Jan); M.J. Peters (Marjolein); T. Esko (Tõnu); H. Yaghootkar (Hanieh); C. Schurmann (Claudia); J. Kettunen (Johannes); M.W. Christiansen (Mark); B.P. Fairfax (Benjamin); K. Schramm (Katharina); J.E. Powell (Joseph); A. Zhernakova (Alexandra); J.H. Veldink (Jan); L.H. van den Berg (Leonard); J. Karjalainen (Juha); S. Withoff (Sebo); A.G. Uitterlinden (André); B. Hofman; F. Rivadeneira Ramirez (Fernando); P.A.C. 't Hoen (Peter); E. Reinmaa (Eva); K. Fischer (Kathelijn); M. Nelis (Mari); A.L. Milani (Alfredo); D. Melzer (David); L. Ferrucci (Luigi); A.B. Singleton (Andrew); D.G. Hernandez (Dena); M.A. Nalls (Michael); G. Homuth (Georg); M.A. Nauck (Matthias); D. Radke (Dörte); U. Vol̈ker (Uwe); M. Perola (Markus); V. Salomaa (Veikko); J. Brody (Jennifer); A. Suchy-Dicey (Astrid); S.A. Gharib (Sina); D. Enquobahrie; T. Lumley (Thomas); G.W. Montgomery; S. Makino (Seiko); H. Prokisch (Holger); C. Herder (Christian); M. Roden (Michael); H. Grallert (Harald); T. Meitinger (Thomas); K. Strauch (Konstantin); Y. Li (Yunmin); J.R.C. Jansen (Jos); P.M. Visscher (Peter M.); J.C. Knight (Julian); B.M. Psaty (Bruce); S. Ripatti (Samuli); A. Teumer (Alexander); T.M. Frayling (Timothy); A. Metspalu (Andres); J.B.J. van Meurs (Joyce); L. Franke (Lude)

    2013-01-01

    textabstractIdentifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We

  7. Systematic identification of trans eQTLs as putative drivers of known disease associations

    NARCIS (Netherlands)

    Westra, Harm-Jan; Peters, Marjolein J.; Esko, Tonu; Yaghootkar, Hanieh; Schurmann, Claudia; Kettunen, Johannes; Christiansen, Mark W.; Fairfax, Benjamin P.; Schramm, Katharina; Powell, Joseph E.; Zhernakova, Alexandra; Zhernakova, Daria V.; Veldink, Jan H.; Van den Berg, Leonard H.; Karjalainen, Juha; Withoff, Sebo; Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando; 't Hoen, Peter A. C.; Reinmaa, Eva; Fischer, Krista; Nelis, Mari; Milani, Lili; Melzer, David; Ferrucci, Luigi; Singleton, Andrew B.; Hernandez, Dena G.; Nalls, Michael A.; Homuth, Georg; Nauck, Matthias; Radke, Doerte; Voelker, Uwe; Perola, Markus; Salomaa, Veikko; Brody, Jennifer; Suchy-Dicey, Astrid; Gharib, Sina A.; Enquobahrie, Daniel A.; Lumley, Thomas; Montgomery, Grant W.; Makino, Seiko; Prokisch, Holger; Herder, Christian; Roden, Michael; Grallert, Harald; Meitinger, Thomas; Strauch, Konstantin; Li, Yang; Jansen, Ritsert C.; Visscher, Peter M.; Knight, Julian C.; Psaty, Bruce M.; Ripatti, Samuli; Teumer, Alexander; Frayling, Timothy M.; Metspalu, Andres; van Meurs, Joyce B. J.; Franke, Lude; Hoen, Peter A.C. ’t

    2013-01-01

    Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified a

  8. 75 FR 54496 - Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other...

    Science.gov (United States)

    2010-09-08

    ... AFFAIRS 38 CFR Part 3 RIN 2900-AN54 Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other Chronic B-Cell Leukemias, Parkinson's Disease and Ischemic Heart Disease... adjudication regulations concerning the presumptive service connection for certain diseases based upon the...

  9. Quantitated transcript haplotypes (QTH) of AGTR1, reduced abundance of mRNA haplotypes containing 1166C (rs5186:A>C), and relevance to metabolic syndrome traits.

    Science.gov (United States)

    Abdollahi, Mohammad R; Lewis, Rohan M; Gaunt, Tom R; Cumming, Debbie V E; Rodriguez, Santiago; Rose-Zerilli, Matthew; Collins, Andrew R; Syddall, Holly E; Howell, William M; Cooper, Cyrus; Godfrey, Keith M; Cameron, Iain T; Day, Ian N M

    2007-04-01

    The angiotensin II type 1 receptor (AGTR1) is the main target through which angiotensin II influences cardiovascular tone, cell growth, and fluid and electrolyte balance. AGTR1 polymorphism has been reported to associate with hypertension, myocardial infarction (MI), and metabolic traits. Here we describe a novel approach to quantitation of transcript haplotypes (QTH) of AGTR1. To determine relative allelic expression from haplotypes, within-individual-between-allele ratiometric analyses in placental cDNA were developed for the transcribed SNPs rs5182:C>T (encoding p.L191) and rs5186:A>C (3'-noncoding "A1166C"). Additionally, between-individual comparisons were made using TaqMan assays applied to both homozygous and heterozygous genotypes and haplotypes. In conjunction, linkage disequilibrium (LD) and genomic haplotype associations with metabolic syndrome were examined. There was no significant difference of mRNA level for alleles of rs5182:C>T, but allele and mRNA haplotypes carrying 1166C exhibited reduced abundance. The effect was much greater in CC homozygotes than in heterozygotes. The promoter region was confirmed to be in a separate haplotype block from the AGTR1 3' region containing rs5182:C>T and rs5186:A>C. Metabolic syndrome trait associations were strongest for the 3' block generally and for the C allele of rs5186:A>C specifically. All effects were much more prominent in homozygotes, possibly reflecting interallelic interaction through feedback loops of mRNA regulation. Differential abundance of AGTR1 mRNA haplotypes may mediate clinical phenotypic observations of the AGTR1 genotype. Copyright 2007 Wiley-Liss, Inc.

  10. Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations.

    Science.gov (United States)

    Teo, Yik-Ying; Sim, Xueling; Ong, Rick T H; Tan, Adrian K S; Chen, Jieming; Tantoso, Erwin; Small, Kerrin S; Ku, Chee-Seng; Lee, Edmund J D; Seielstad, Mark; Chia, Kee-Seng

    2009-11-01

    The Singapore Genome Variation Project (SGVP) provides a publicly available resource of 1.6 million single nucleotide polymorphisms (SNPs) genotyped in 268 individuals from the Chinese, Malay, and Indian population groups in Southeast Asia. This online database catalogs information and summaries on genotype and phased haplotype data, including allele frequencies, assessment of linkage disequilibrium (LD), and recombination rates in a format similar to the International HapMap Project. Here, we introduce this resource and describe the analysis of human genomic variation upon agglomerating data from the HapMap and the Human Genome Diversity Project, providing useful insights into the population structure of the three major population groups in Asia. In addition, this resource also surveyed across the genome for variation in regional patterns of LD between the HapMap and SGVP populations, and for signatures of positive natural selection using two well-established metrics: iHS and XP-EHH. The raw and processed genetic data, together with all population genetic summaries, are publicly available for download and browsing through a web browser modeled with the Generic Genome Browser.

  11. G6PD haplotypes spanning Xq28 from F8C to red/green color vision

    Energy Technology Data Exchange (ETDEWEB)

    Filosa, S.; Lania, G.; Martini, G. (Instituto Internazionale di Genetica e Biofisica, Naples (Italy)); Brancati, C.; Tagarelli, A. (Instituto per lo Studio delle Malattie Ereditarie e Carenziali, Cosenza (Italy)); Calabro, V. (Instituto per lo Studio delle Malattie Ereditarie e Carenziali, Cosenza (Italy) Hammersmith Hospital, London (United Kingdom)); Vulliamy, T.J.; Luzzatto, L. (Hammersmith Hospital, London (United Kingdom))

    1993-07-01

    The most telomeric region of the human X chromosome within band Xq28 consists of a gene-rich region of about 3 Mb which contains the genes for coagulation factor VIIIc, glucose-6-phosphate dehydrogenase (G6PD), and red/green color vision. The authors have studied five polymorphic sites from this region, in a sample of normal people from the Cosenza province of Southern Italy. These sites, which span a distance of some 350 kb, are in strong linkage disequilibrium. Of the 32 possible haplotypes only 10 were found, and 4 of these account for 80% of all X chromosomes analyzed. In addition, they found that all G6PD-deficient people with the G6PD Mediterranean mutation belong to only two haplotypes. One of these (Med 1) is found only within a small subregion of the area investigated, west of the Appennine mountain range. Most remarkably, all Med 1 G6PD-deficient individuals also had red/green color blindness. The more frequent haplotype (Med 2) is the same in Calabria and in Sardinia, where it accounts for about 90% of the G6PD Mediterranean mutations, despite the fact that gene flow between the populations of Sardinia and Southern Italy must have been limited. These data do not enable determination of whether the two types of G6PD Mediterranean have arisen through two separate identical mutational events or through a single mutational event followed by recombination. However, the data indicate relatively little recombination over an extended region of the X chromosome and they suggest that the G6PD Mediterranean mutation is recent by comparison to the other polymorphisms investigated. 44 refs., 4 figs., 5 tabs.

  12. Practical interpretation of CYP2D6 haplotypes: Comparison and integration of automated and expert calling.

    Science.gov (United States)

    Ruaño, Gualberto; Kocherla, Mohan; Graydon, James S; Holford, Theodore R; Makowski, Gregory S; Goethe, John W

    2016-05-01

    We describe a population genetic approach to compare samples interpreted with expert calling (EC) versus automated calling (AC) for CYP2D6 haplotyping. The analysis represents 4812 haplotype calls based on signal data generated by the Luminex xMap analyzers from 2406 patients referred to a high-complexity molecular diagnostics laboratory for CYP450 testing. DNA was extracted from buccal swabs. We compared the results of expert calls (EC) and automated calls (AC) with regard to haplotype number and frequency. The ratio of EC to AC was 1:3. Haplotype frequencies from EC and AC samples were convergent across haplotypes, and their distribution was not statistically different between the groups. Most duplications required EC, as only expansions with homozygous or hemizygous haplotypes could be automatedly called. High-complexity laboratories can offer equivalent interpretation to automated calling for non-expanded CYP2D6 loci, and superior interpretation for duplications. We have validated scientific expert calling specified by scoring rules as standard operating procedure integrated with an automated calling algorithm. The integration of EC with AC is a practical strategy for CYP2D6 clinical haplotyping.

  13. 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.

  14. Casein haplotypes and their association with milk production traits in the Finnish Ayrshire cattle.

    Science.gov (United States)

    Velmala, R; Vilkki, J; Elo, K; Mäki-Tanila, A

    1995-12-01

    Polymorphism of casein genes was studied in half-sib families of artificial insemination bulls of the Finnish Ayrshire dairy breed. Ten grandsires and 300 of their sons were genotyped for the following polymorphisms: alpha s1-casein (B, C), beta-casein (A1, A2), the microsatellite within the kappa-casein gene (ms5, ms4) and kappa-casein (A, B, E). Nine different combinations of these alleles, casein haplotypes, were found. Associations between casein haplotypes and milk production traits (milk and protein yield, fat and protein percentage and milking speed) were studied with ordinary least-squares analysis to find a direct effect of the haplotypes or an association within individual grandsire families using the granddaughter design. Estimated breeding values of sons were obtained from cow evaluation by animal model. No direct effect of the casein haplotypes on the traits was found. Within grandsire families, in one out of four families the chromosomal segment characterized by haplotype 3 (B-A2-ms4-A) was associated with an increase in milk yield (P < 0.01) and a decrease in fat percentage (P < 0.01) when contrasted with haplotype 8 (B-A1-ms4-E). The results provide evidence that in the Finnish Ayrshire breed at least one quantitative trait locus affecting the genetic variation in yields traits is segregating linked to either haplotype 3 (B-A2-ms4-A) or 8 (B-A1-ms4-E).

  15. Analysis of Swine Leukocyte Antigen Haplotypes in Yucatan Miniature Pigs Used as Biomedical Model Animal.

    Science.gov (United States)

    Choi, Nu-Ri; Seo, Dong-Won; Choi, Ki-Myung; Ko, Na-Young; Kim, Ji-Ho; Kim, Hyun-Il; Jung, Woo-Young; Lee, Jun-Heon

    2016-03-01

    The porcine major histocompatibility complex (MHC) is called swine leukocyte antigen (SLA), which controls immune responses and transplantation reactions. The SLA is mapped on pig chromosome 7 (SSC7) near the centromere. In this study, 3 class I (SLA-1, SLA-3, and SLA-2) and 3 class II (DRB1, DQB1, and DQA) genes were used for investigation of SLA haplotypes in Yucatan miniature pigs in Korea. This pig breed is a well-known model organism for biomedical research worldwide. The current study indicated that Korean Yucatan pig population had 3 Class I haplotypes (Lr-4.0, Lr-6.0, and Lr-25.0) and 3 class II haplotypes (Lr-0.5, Lr-0.7, and Lr-0.25). The combinations of SLA class I and II haplotype together, 2 homozygous (Lr-4.5/4.5 and Lr-6.7/6.7) and 3 heterozygous (Lr-4.5/6.7, Lr-4.5/25.25, and Lr-6.7/25.25) haplotypes were identified, including previously unidentified new heterozygous haplotypes (Lr-4.5/4.7). In addition, a new SLA allele typing method using Agilent 2100 bioanalyzer was developed that permitted more rapid identification of SLA haplotypes. These results will facilitate the breeding of SLA homozygous Yucatan pigs and will expedite the possible use of these pigs for the biomedical research, especially xenotransplantation research.

  16. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

    Science.gov (United States)

    Song, Chi; Chen, Gary K.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Ingles, Sue A.; Press, Michael F.; Deming, Sandra L.; Rodriguez-Gil, Jorge L.; Chanock, Stephen J.; Wan, Peggy; Sheng, Xin; Pooler, Loreall C.; Van Den Berg, David J.; Le Marchand, Loic; Kolonel, Laurence N.; Henderson, Brian E.; Haiman, Chris A.; Stram, Daniel O.

    2013-01-01

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density. PMID:23468962

  17. β-globin gene cluster haplotypes in ethnic minority populations of southwest China

    Science.gov (United States)

    Sun, Hao; Liu, Hongxian; Huang, Kai; Lin, Keqin; Huang, Xiaoqin; Chu, Jiayou; Ma, Shaohui; Yang, Zhaoqing

    2017-01-01

    The genetic diversity and relationships among ethnic minority populations of southwest China were investigated using seven polymorphic restriction enzyme sites in the β-globin gene cluster. The haplotypes of 1392 chromosomes from ten ethnic populations living in southwest China were determined. Linkage equilibrium and recombination hotspot were found between the 5′ sites and 3′ sites of the β-globin gene cluster. 5′ haplotypes 2 (+−−−), 6 (−++−+), 9 (−++++) and 3′ haplotype FW3 (−+) were the predominant haplotypes. Notably, haplotype 9 frequency was significantly high in the southwest populations, indicating their difference with other Chinese. The interpopulation differentiation of southwest Chinese minority populations is less than those in populations of northern China and other continents. Phylogenetic analysis shows that populations sharing same ethnic origin or language clustered to each other, indicating current β-globin cluster diversity in the Chinese populations reflects their ethnic origin and linguistic affiliations to a great extent. This study characterizes β-globin gene cluster haplotypes in southwest Chinese minorities for the first time, and reveals the genetic variability and affinity of these populations using β-globin cluster haplotype frequencies. The results suggest that ethnic origin plays an important role in shaping variations of the β-globin gene cluster in the southwestern ethnic populations of China. PMID:28205625

  18. Study on sickle cell disease haplotypes reveals the African origin of Amapá's population

    Directory of Open Access Journals (Sweden)

    Natália de Morais Castelo

    2014-04-01

    Full Text Available Introduction:Sickle cell disease (SCD is a hereditary, hematologic, multifactorial disease, with high prevalence worldwide; its cause is a mutation in the sixth codon of the beta globin gene (βs.Objective:To identify the haplotypes present in people with SCD in Amapá, and relate them to African descent.Methods:We analyzed, by molecular techniques, 46 blood samples from people with SCD in Macapá, the capital of Amapá, with the purpose of obtaining information about haplotype frequency distribution, which helps understand the ethnic background of Amapá's population.Results:Our study revealed that the most frequent haplotype is Bantu (61.2%, followed by Benin (26.6% and Senegal (12.2%. Results showed statistical differences from studies conducted in other regions. A high frequency of the Senegal haplotype stands out, in comparison with some Brazilian studies.Conclusion:Amapá's results exhibit unique characteristics when compared to haplotypes in other regions, with high frequency of Senegal and Benin haplotypes, absence of atypical, Cameroon and Saudi, confirming that Brazil shows ethnic background diversity, as well as different haplotype frequencies.

  19. Evaluation of logistic Bayesian LASSO for identifying association with rare haplotypes.

    Science.gov (United States)

    Biswas, Swati; Papachristou, Charalampos

    2014-01-01

    It has been hypothesized that rare variants may hold the key to unraveling the genetic transmission mechanism of many common complex traits. Currently, there is a dearth of statistical methods that are powerful enough to detect association with rare haplotypes. One of the recently proposed methods is logistic Bayesian LASSO for case-control data. By penalizing the regression coefficients through appropriate priors, logistic Bayesian LASSO weeds out the unassociated haplotypes, making it possible for the associated rare haplotypes to be detected with higher powers. We used the Genetic Analysis Workshop 18 simulated data to evaluate the behavior of logistic Bayesian LASSO in terms of its power and type I error under a complex disease model. We obtained knowledge of the simulation model, including the locations of the functional variants, and we chose to focus on two genomic regions in the MAP4 gene on chromosome 3. The sample size was 142 individuals and there were 200 replicates. Despite the small sample size, logistic Bayesian LASSO showed high power to detect two haplotypes containing functional variants in these regions while maintaining low type I errors. At the same time, a commonly used approach for haplotype association implemented in the software hapassoc failed to converge because of the presence of rare haplotypes. Thus, we conclude that logistic Bayesian LASSO can play an important role in the search for rare haplotypes.

  20. Predicting childhood effortful control from interactions between early parenting quality and children's dopamine transporter gene haplotypes.

    Science.gov (United States)

    Li, Yi; Sulik, Michael J; Eisenberg, Nancy; Spinrad, Tracy L; Lemery-Chalfant, Kathryn; Stover, Daryn A; Verrelli, Brian C

    2016-02-01

    Children's observed effortful control (EC) at 30, 42, and 54 months (n = 145) was predicted from the interaction between mothers' observed parenting with their 30-month-olds and three variants of the solute carrier family C6, member 3 (SLC6A3) dopamine transporter gene (single nucleotide polymorphisms in intron8 and intron13, and a 40 base pair variable number tandem repeat [VNTR] in the 3'-untranslated region [UTR]), as well as haplotypes of these variants. Significant moderating effects were found. Children without the intron8-A/intron13-G, intron8-A/3'-UTR VNTR-10, or intron13-G/3'-UTR VNTR-10 haplotypes (i.e., haplotypes associated with the reduced SLC6A3 gene expression and thus lower dopamine functioning) appeared to demonstrate altered levels of EC as a function of maternal parenting quality, whereas children with these haplotypes demonstrated a similar EC level regardless of the parenting quality. Children with these haplotypes demonstrated a trade-off, such that they showed higher EC, relative to their counterparts without these haplotypes, when exposed to less supportive maternal parenting. The findings revealed a diathesis-stress pattern and suggested that different SLC6A3 haplotypes, but not single variants, might represent different levels of young children's sensitivity/responsivity to early parenting.

  1. Association of USP26 haplotypes in men in Taiwan, China with severe spermatogenic defect

    Institute of Scientific and Technical Information of China (English)

    I-Wen Lee; Long-Ching Kuan; Chien-Hung Lin; Hsien-An Pan; Chao-Chin Hsu; Yung-Chieh Tsai; Pao-Lin Kuo; Yen-Ni Teng

    2008-01-01

    Aim: To complete comprehensive haplotype analysis of USP26 for both fertile and infertile men. Methods: Two hundred infertile men with severe oligospermia or non-obstructive azoospermia were subjected to sequence analysis for the entire coding sequences of the USP26 gene. Two hundred men with proven fertility were genotyped by primer extension methods. Allele/genotype frequencies, linkage disequilibrium (LD) characteristics and haplotypes of fertile men were compared with infertile men. Results: The allele frequencies of five single nucleotide polymor-phisms (370-371 insACA, 494T>C, 576G>A, ss6202791C>T, 1737G>A) were significantly higher in infertile patients than control subjects. The major haplotypes in infertile men were TACCGA (28% of the population), TGCCGA (15%), TACCAA (8%), TGCCAA (6%), TATCAA (5%) and CATCAA (5%). The major haplotypes for the control subjects were TACCGA (58% of the population), CACCGA (7%), CATCGA (6%) and TGCCGA (5%). Haplotypes TGCCGA, TATCAA, CATCAA, CATCGC, TACCAA and TGCCAA were over-transmitted in patients with spermato-genic defect, whereas haplotypes TACCGA, CACCGA, and CATCGA were under-transmitted in these patients.Conclusion: Some USP26 alleles and haplotypes are associated with spermatogenic defect in the Han nationality in Taiwan, China.

  2. Haplotype analysis in Huntington desease provides insights into mechanisms of CAG repeat expansion

    Energy Technology Data Exchange (ETDEWEB)

    Andrew, S.E.; Goldberg, Y.P.; Squitieri, F. [Univ. of British Columbia, Vancouver (Canada)] [and others

    1994-09-01

    Huntington disease (HD) is one of 7 disorders now known to be caused by expansion of a trinucleotide repeat. The HD mutation is a polymorphic trinucleotide (CAG) repeat in the 5{prime} region of a novel gene that expands beyond the normal range of 10-35 repeats in persons destined to develop the disease. Haplotype analysis of other dynamic mutation disorders such as myotonic dystrophy and Fragil X have suggested that a rare ancestral expansion event on a normal chromosome is followed by subsequent expansion events, resulting in a pool of chromosomes in the premutation range, which is inherently unstable and prone to further multiple expansion events leading to disease range chromosomes. Haplotype analysis of 67 HD and 84 control chromosomes using 5 polymorphic markers, both intragenic and 5{prime} to the disease mutation, demonstrate that multiple haplotypes underlie HD. However, 94% of the chromosomes can be grouped under two major haplotypes. These two haplotypes are also present in the normal population. A third major haplotype is seen on 38% of normal chromosomes but rarely on HD chromosomes (6%). CAG lengths on the normal chromosomes with the two haplotypes seen in the HD population are higher than those seen on the normal chromosomes with the haplotype rarely seen on HD chromosomes. Furthermore, in populations with a diminished frequency of HD, CAG length on normal chromosomes is significantly less than other populations with higher prevalence rates for HD. These data suggest that CAG length on normal chromosomes may be a significant factor contributing to repeat instability that eventually leads to chromosomes with CAG repeat lengths in the HD range. Haplotypes on the HD chromosomes are identical to those normal chromosomes which have CAG lengths in the high range of normal, suggesting that further expansions of this pool of chromosomes leads to chromosomes with CAG repeat sizes within the disease range, consistent with a multistep model.

  3. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype.

    Science.gov (United States)

    Ngo, Duyen; Bae, Harold; Steinberg, Martin H; Sebastiani, Paola; Solovieff, Nadia; Baldwin, Clinton T; Melista, Efthymia; Safaya, Surinder; Farrer, Lindsay A; Al-Suliman, Ahmed M; Albuali, Waleed H; Al Bagshi, Muneer H; Naserullah, Zaki; Akinsheye, Idowu; Gallagher, Patrick; Luo, Hong-yuan; Chui, David H K; Farrell, John J; Al-Ali, Amein K; Alsultan, Abdulrahman

    2013-06-01

    Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefore studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and employed targeted genotyping of polymorphic sites to explore cis- and trans- acting elements associated with high HbF expression. We also described sequences which appear to be unique to the AI haplotype for which future functional studies are needed to further define their role in HbF modulation. All cases, regardless of HbF concentration, were homozygous for AI haplotype-specific elements cis to HBB. SNPs in BCL11A and HBS1L-MYB that were associated with HbF in other populations explained only 8.8% of the variation in HbF. KLF1 polymorphisms associated previously with high HbF were not present in the 44 patients tested. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remains unexplained by the genetic loci that we studied. The dispersion of HbF levels among AI haplotype patients suggests that other genetic elements modulate the effects of the known cis- and trans-acting regulators. These regulatory elements, which remain to be discovered, might be specific in the Saudi and some other populations where HbF levels are especially high.

  4. 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.

  5. 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.

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

    Directory of Open Access Journals (Sweden)

    Sara Karami

    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.

  7. The Investigation of Haplotype Phasing Efficiency at the PAH Gene Region in Iranian Family Trios

    Directory of Open Access Journals (Sweden)

    Z Fazeli

    2009-12-01

    Full Text Available "nBackground: The haplotype phasing is more useful than genotyping markers independently at carrier detection and prena­tal diagnosis of diseases. The PAH gene region contains several markers used in detection of PKU disease. In the present study, the efficiency of BglII-EcoRI-VNTR haplotype phasing in Iranian family trios was investigated. Then, this informa­tion was compared with those obtained for unrelated individuals."nMethods: Blood samples were collected from 20 healthy family trios and 60 unrelated individuals. The genomic DNA was ex­tracted by use of salting-out procedure. The two markers BglII and EcoRI were genotyped by use of PCR-RFLP. The geno­type of VNTR marker was identified by use of PCR and electrophoresis. The genotyping data obtained from family trios was used to infer haplotype phase. We also compared this data with results obtained from a widely used method for hap­lotype frequency inference from unrelated individuals, the PHASE program."nResults: The haplotype phase of all members was only ascertained at eight family trios.  The comparison of this data with the results obtained by use of PHASE program showed that eight haplotypes [211, 221, 215, 216, 214, 121, 225 and 111] were in­formative haplotypes in Iranian population."nConclusion: Since diversity of BglII-EcoRI-VNTR haplotypes was high in Iranian population, haplotype phasing at family trios was difficult. The results of this study showed that the genotyping data obtained from family trios could not provide enough information for BglII-EcoRI-VNTR haplotype phasing at Iranian PKU families and the genotyping of other family mem­bers was necessary at most cases.

  8. 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.

  9. IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn's disease location

    Institute of Scientific and Technical Information of China (English)

    Rocio Sanchez; Emile Levy; Florin Costea; Daniel Sinnett

    2009-01-01

    AIM: To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-α and the interleukin (IL)-10 in childhood Crohn's disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes. METHODS: Ten variants in GR, TNF-α and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin. RESULTS: For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5'flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-α gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-α, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively. CONCLUSION: This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.

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

    Science.gov (United States)

    Dos Santos Silva, Wellington; de Nazaré Klautau-Guimarães, Maria; Grisolia, Cesar Koppe

    2010-07-01

    Five restriction site polymorphisms in the β-globin gene cluster (HincII-5' ε, HindIII-(G) γ, HindIII-(A) γ, 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 (- + - - +) and 6 (- + + - +) on the β(A) 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.

  11. Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients

    Institute of Scientific and Technical Information of China (English)

    Jessica; Mwinyi; Christa; Wenger; Jyrki; J; Eloranta; Gerd; A; Kullak-Ublick

    2010-01-01

    AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, whi...

  12. The role of antigens and HLA class I haplotypes in indigenous women in Tashkent with hysteromyoma

    Directory of Open Access Journals (Sweden)

    Landish Isanbaeva

    2011-05-01

    Full Text Available Immunogenetic analysis on HLA I class in 177 indigenous women with uterine myoma showed the positive association in the risk of uterine fibroids with antigens HLA-B8/B22 and haplotype A28/B22; antigens HLA-A28, Cw5 and haplotype B17-Sw5 played role of auxiliary markers. HLA-antigens A2, B35, Cw4 and haplotypes A2-B35, B5-Cw4 showed the negative association. Carrying immunogenetic studies may be useful to search for individual genes involved in the determination of the disease - uterine fibroids, especially among patients with hereditary anamnesis.

  13. γA gene repeats polymorphism for the analysis of haplotypes of abnormal hemoglobins

    Directory of Open Access Journals (Sweden)

    Nejat Akar

    2014-09-01

    Full Text Available Aim of this study was to analyze γ A gene repeat polymorphism for the analysis of haplotypes of hemoglobin (Hb variants such as Hb S, Hb D-Punjab, Hb O-Arab. Sickle cell cases had mainly Benin and Arab/Indian haplotype. We found three different haplotypes among Hb S, Hb O Arab and Hb D-Punjab cases. We named these three variants as Anatolian-1 and Anatolian-2 and Asian. Our data revealed that Hb O Arab may arise twice one from Asia and the other from Europe.

  14. HLA class II haplotypes distinctly associated with vaso-occlusion in children with sickle cell disease.

    Science.gov (United States)

    Mahdi, Najat; Al-Ola, Khadija; Al-Subaie, Abeer M; Ali, Muhallab E; Al-Irhayim, Zaid; Al-Irhayim, A Qader; Almawi, Wassim Y

    2008-04-01

    We investigated the association of HLA class II alleles and haplotypes with sickle cell anemia vaso-occlusive crisis (VOC). DRB1*100101 was positively associated, while DRB1*140101, DRB1*150101, and DQB1*060101 were negatively associated, with VOC. Both susceptible (DRB1*100101-DQB1*050101) and protective (DRB1*110101-DQB1*030101 and DRB1*150101-DQB1*060101) haplotypes were identified, indicating that HLA class II haplotypes influence VOC risk.

  15. Salt tolerance underlies the cryptic invasion of North American salt marshes by an introduced haplotype of the common reed Phragmites australis (Poaceae)

    Science.gov (United States)

    Vasquez, Edward A.; Glenn, Edward P.; Brown, J. Jed; Guntenspergen, Glenn R.; Nelson, Stephen G.

    2005-01-01

    A distinct, non-native haplotype of the common reed Phragmites australis has become invasive in Atlantic coastal Spartina marshes. We compared the salt tolerance and other growth characteristics of the invasive M haplotype with 2 native haplotypes (F and AC) in greenhouse experiments. The M haplotype retained 50% of its growth potential up to 0.4 M NaCl, whereas the F and AC haplotypes did not grow above 0.1 M NaCl. The M haplotype produced more shoots per gram of rhizome tissue and had higher relative growth rates than the native haplotypes on both freshwater and saline water treatments. The M haplotype also differed from the native haplotypes in shoot water content and the biometrics of shoots and rhizomes. The results offer an explanation for how the M haplotype is able to spread in coastal salt marshes and support the conclusion of DNA analyses that the M haplotype is a distinct ecotype of P. australis.

  16. Haplotype structure of the beta2-adrenergic receptor gene in 814 Danish Caucasian subjects and association with body mass index

    DEFF Research Database (Denmark)

    Jensen, Mette Kamp; Nielsen, Morten; Koefoed, Pernille

    2009-01-01

    with body mass index (BMI). The SNPs showed organization into 13 distinct haplotypes and 41 haplotype pairs. The study identified four common haplotypes: ACCCC (10.1 +/- 0.3 %), ACCCG (27.9 +/- 0.3 %), GCCAC (10.8 +/- 0.1 %) and GGCCG (41.0 +/- 0.2 %) (frequencies (SD), seen in 91 % of the population....... In the total population (mean age +/- SD: 50 +/- 16 years), BMI was not related to haplotype pairs, individual SNPs or allelic haplotypes. However, in subjects ... to individual SNPs. In subjects subjects (BMI

  17. Paraoxonase 1 (PON1 polymorphisms, haplotypes and activity in predicting cad risk in North-West Indian Punjabis.

    Directory of Open Access Journals (Sweden)

    Nidhi Gupta

    Full Text Available Human serum paraoxonase-1 (PON1 prevents oxidation of low density lipoprotein cholesterol (LDL-C and hydrolyzes the oxidized form, therefore preventing the development of atherosclerosis. The polymorphisms of PON1 gene are known to affect the PON1 activity and thereby coronary artery disease (CAD risk. As studies are lacking in North-West Indian Punjabi's, a distinct ethnic group with high incidence of CAD, we determined PON1 activity, genotypes and haplotypes in this population and correlated them with the risk of CAD.350 angiographically proven (≥ 70% stenosis CAD patients and 300 healthy controls were investigated. PON1 activity was determined towards paraoxon (Paraoxonase; PONase and phenylacetate (Arylesterase; AREase substrates. In addition, genotyping was carried out by using multiplex PCR, allele specific oligonucleotide -PCR and PCR-RFLP methods and haplotyping was determined by PHASE software. The serum PONase and AREase activities were significantly lower in CAD patients as compared to the controls. All studied polymorphisms except L55M had significant effect on PONase activity. However AREase activity was not affected by them. In a logistic regression model, after adjustment for the conventional risk factors for CAD, QR (OR: 2.73 (1.57-4.72 and RR (OR, 16.24 (6.41-41.14 genotypes of Q192R polymorphism and GG (OR: 2.07 (1.02-4.21 genotype of -162A/G polymorphism had significantly higher CAD risk. Haplotypes L-T-G-Q-C (OR: 3.25 (1.72-6.16 and L-T-G-R-G (OR: 2.82 (1.01-7.80 were also significantly associated with CAD.In conclusion this study shows that CAD patients had lower PONase and AREase activities as compared to the controls. The coding Q192R polymorphism, promoter -162A/G polymorphism and L-T-G-Q-C and L-T-G-R-G haplotypes are all independently associated with CAD.

  18. Excap: maximization of haplotypic diversity of linked markers.

    Directory of Open Access Journals (Sweden)

    André Kahles

    Full Text Available Genetic markers, defined as variable regions of DNA, can be utilized for distinguishing individuals or populations. As long as markers are independent, it is easy to combine the information they provide. For nonrecombinant sequences like mtDNA, choosing the right set of markers for forensic applications can be difficult and requires careful consideration. In particular, one wants to maximize the utility of the markers. Until now, this has mainly been done by hand. We propose an algorithm that finds the most informative subset of a set of markers. The algorithm uses a depth first search combined with a branch-and-bound approach. Since the worst case complexity is exponential, we also propose some data-reduction techniques and a heuristic. We implemented the algorithm and applied it to two forensic caseworks using mitochondrial DNA, which resulted in marker sets with significantly improved haplotypic diversity compared to previous suggestions. Additionally, we evaluated the quality of the estimation with an artificial dataset of mtDNA. The heuristic is shown to provide extensive speedup at little cost in accuracy.

  19. An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.

    Directory of Open Access Journals (Sweden)

    Yun Li

    2014-03-01

    Full Text Available Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia--progressive supranuclear palsy (PSP and frontotemporal dementia (FTD--revealed significant differentially methylated probes (DMPs in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology.

  20. Text mining facilitates database curation - extraction of mutation-disease associations from Bio-medical literature.

    Science.gov (United States)

    Ravikumar, Komandur Elayavilli; Wagholikar, Kavishwar B; Li, Dingcheng; Kocher, Jean-Pierre; Liu, Hongfang

    2015-06-06

    Advances in the next generation sequencing technology has accelerated the pace of individualized medicine (IM), which aims to incorporate genetic/genomic information into medicine. One immediate need in interpreting sequencing data is the assembly of information about genetic variants and their corresponding associations with other entities (e.g., diseases or medications). Even with dedicated effort to capture such information in biological databases, much of this information remains 'locked' in the unstructured text of biomedical publications. There is a substantial lag between the publication and the subsequent abstraction of such information into databases. Multiple text mining systems have been developed, but most of them focus on the sentence level association extraction with performance evaluation based on gold standard text annotations specifically prepared for text mining systems. We developed and evaluated a text mining system, MutD, which extracts protein mutation-disease associations from MEDLINE abstracts by incorporating discourse level analysis, using a benchmark data set extracted from curated database records. MutD achieves an F-measure of 64.3% for reconstructing protein mutation disease associations in curated database records. Discourse level analysis component of MutD contributed to a gain of more than 10% in F-measure when compared against the sentence level association extraction. Our error analysis indicates that 23 of the 64 precision errors are true associations that were not captured by database curators and 68 of the 113 recall errors are caused by the absence of associated disease entities in the abstract. After adjusting for the defects in the curated database, the revised F-measure of MutD in association detection reaches 81.5%. Our quantitative analysis reveals that MutD can effectively extract protein mutation disease associations when benchmarking based on curated database records. The analysis also demonstrates that incorporating

  1. Necrolytic acral erythema: a rare skin disease associated with hepatitis C virus infection*

    Science.gov (United States)

    Botelho, Luciane Francisca Fernandes; Enokihara, Milvia Maria Simões e Silva; Enokihara, Mauro Yoshiaki

    2016-01-01

    Necrolytic acral erythema is a rare skin disease associated with hepatitis C virus infection. We report a case of a 31-year-old woman with hepatitis C virus infection and decreased zinc serum level. Physical examination revealed scaly, lichenified plaques, well-demarcated with an erythematous peripheral rim located on the lower limbs. After blood transfusion and oral zinc supplementation the patient presented an improvement of lesions. PMID:27828642

  2. Crohn's Disease Associated with Sweet's Syndrome and Sjögren's Syndrome Treated with Infliximab

    Directory of Open Access Journals (Sweden)

    Erina N. Foster

    2005-01-01

    Full Text Available The association of Crohn's disease (CD and Sweet's syndrome is rare and the presence of Sjögren's syndrome in Crohn's disease is even rarer, with only three reports found in the literature. We describe two cases of Crohn's disease associated with Sweet's syndrome, one of which is the first case of CD and Sweet's concomitantly associated with Sjögren's syndrome. Both cases responded rapidly to Infliximab therapy with complete resolution of the skin lesions.

  3. Reducing the risk of Legionnaires' disease associated with cooling towers

    Energy Technology Data Exchange (ETDEWEB)

    Freije, M.R. [HC Information Resources Inc., Carlsbad, CA (United States)

    2008-08-15

    To reduce the health and legal risks associated with Legionnaires' disease, facility managers should take steps to minimize Legionella bacteria in plumbing systems, open industrial equipment, water features, cooling towers, and other aerosolizing water systems. The risk of Legionnaires' disease associated with cooling towers can be reduced by controlling Legionella bacteria in cooling water and preventing transmission of the bacteria from towers to people. This paper presents nine reasonable ways to accomplish these goals. (orig.)

  4. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

    OpenAIRE

    Zemojtel, T.; Koehler, S; Mackenroth, L; Jaeger, M.; Hecht, J.; Krawitz, P.; Graul-Neumann, L; Doelken, S.; Ehmke, N.; Spielmann, M.; Oien, N.C.; Schweiger, M R; Krueger, U; Frommer, G.; Fischer, B.

    2014-01-01

    Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method ...

  5. DNA sequence and haplotype variation in two candidate genes for dilated cardiomyopathy in the turkey Meleagris gallopavo.

    Science.gov (United States)

    Lin, Kuan-chin; Xu, Jun; Kamara, Davida; Geng, Tuoyu; Gyenai, Kwaku; Reed, Kent M; Smith, Edward J

    2007-05-01

    Determining variation in genes is fundamental to understanding their function in the disease state. Cardiac troponin T (cTnT) and phospholamban (PLN) genes have been implicated in dilated cardiomyopathy (DCM) in human and model species. To investigate the role of these 2 candidate genes in DCM in the turkey Meleagris gallopavo, understanding sequence variants and map position distribution is necessary. To this end, a total of 1854 and 1771 bp of cTnT and PLN gene sequences, respectively, were scanned for single nucleotide polymorphisms (SNPs) in a randomly bred population. A total of 15 SNPs was identified in the cTnT and PLN genomic sequences. Nine haplotypes, 5 in cTnT and 4 in PLN, were identified. Observed heterozygosities (0.02-0.39) in the turkey population were low for both genes. Within each gene, 1 SNP corresponding to a restriction enzyme site was identified and used to develop a PCR-restriction fragment length polymorphism (RFLP) genotyping assay. The PLN gene was genetically mapped to turkey chromosome 2, equivalent to Gallus gallus chromosome 3, and cTnT mapped to a turkey microchromosome. Although limited because of the relatively small sample size of 55 birds, the data from this SNP analysis of PLN and cTnT provide a foundation from which to evaluate the function of cTnT and PLN in the turkey. Information about the distribution of the SNPs and haplotypes will facilitate future association and linkage studies.

  6. Mitochondrial DNA haplotyping of Testudo graeca on both continental sides of the Straits of Gibraltar.

    Science.gov (United States)

    Alvarez, Y; Mateo, J A; Andreu, A C; Díaz-Paniagua, C; Diez, A; Bautista, J M

    2000-01-01

    Testudo graeca is an endangered species of tortoise that inhabits Mediterranean areas of Africa, Asia, and Europe. Western populations are found on both sides of the Straits of Gibraltar. The effects of geographical isolation on genetic divergence were assessed by the sequence analysis of two mitochondrial DNA regions of the 12S rRNA and cytochrome b genes. Four different haplotypes were identified. A single haplotype was shared by all Spanish and some east Moroccan specimens. Two haplotypes were unique to the west Moroccan T. graeca populations and allowed the clear discrimination between individual specimens found west of the Moulouya River. Phylogenetic analysis based on the estimation of nucleotide sequence distances of the haplotypes suggests an African origin for the Spanish populations and a subspecies status for the west Moroccan pool.

  7. Haplotypes on pig chromosome 3 distinguish metabolically healthy from unhealthy obese individuals

    DEFF Research Database (Denmark)

    Frederiksen, Simona Denise; Karlskov-Mortensen, Peter; Pant, Sameer D.

    2017-01-01

    association (GWA) to identify loci with effect on blood lipid levels. The most significantly associated single nucleotide polymorphisms (SNPs) were used for linkage disequilibrium (LD) and haplotype analyses. Three separate haploblocks which influence the ratio between high density lipoprotein cholesterol...

  8. Analysis of 24 Y-STR haplotype data in a Chinese Han population from Guangdong Province.

    Science.gov (United States)

    Wang, Ying; Liu, Chao; Zhang, Chu-chu; Li, Ran; Liu, Hong; Ou, Xue-ling; Li, Hai-xia; Sun, Hong-yu

    2016-05-01

    In this study, we investigated the genetic polymorphisms of 24 Y-chromosomal short tandem repeat (Y-STR) loci in 885 unrelated Chinese Han male individuals from Guangdong Province, using a domestic AGCU Y24 STR kit. A total of 878 different haplotypes were observed at the 24 Y-STR loci; among them, 871 haplotypes were unique and 7 haplotypes occurred twice. The overall haplotype diversity was 0.99998 and the discrimination capacity was 99.2%. The gene diversity values ranged from 0.4354 at DYS438 to 0.9606 at DYS385a/b. Population relationships between the Guangdong Han population and seven other published Chinese populations were evaluated by Rst values and visualized in a two multi-dimensional scaling plot. The results showed the 24 Y-STR loci are highly polymorphic in Guangdong Han population and of great value in forensic application.

  9. Atypical beta(s) haplotypes are generated by diverse genetic mechanisms.

    Science.gov (United States)

    Zago, M A; Silva, W A; Dalle, B; Gualandro, S; Hutz, M H; Lapoumeroulie, C; Tavella, M H; Araujo, A G; Krieger, J E; Elion, J; Krishnamoorthy, R

    2000-02-01

    The majority of the chromosomes with the beta(S) gene have one of the five common haplotypes, designated as Benin, Bantu, Senegal, Cameroon, and Arab-Indian haplotypes. However, in every large series of sickle cell patients, 5-10% of the chromosomes have less common haplotypes, usually referred to as "atypical" haplotypes. In order to explore the genetic mechanisms that could generate these atypical haplotypes, we extended our analysis to other rarely studied polymorphic markers of the beta(S)-gene cluster, in a total of 40 chromosomes with uncommon haplotypes from Brazil and Cameroon. The following polymorphisms were examined: seven restriction site polymorphisms of the epsilongammadeltabeta-cluster, the pre-(G)gamma framework sequence including the 6-bp deletion/insertion pattern, HS-2 LCR (AT)xR(AT)y and pre-beta (AT)xTy repeat motifs, the GC/TT polymorphism at -1105-1106 of (G)gamma-globin gene, the C/T polymorphism at -551 of the beta-globin gene, and the intragenic beta-globin gene framework. Among the Brazilian subjects, the most common atypical structure (7/16) was a Bantu 3'-subhaplotype associated with different 5'-sequences, while in two chromosomes a Benin 3'-subhaplotype was associated with two different 5'-subhaplotypes. A hybrid Benin/Bantu configuration was also observed. In three chromosomes, the atypical haplotype differed from the typical one by the change of a single restriction site. In 2/134 chromosomes identified as having a typical Bantu RFLP-haplotype, a discrepant LCR repeat sequence was observed, probably owing to a crossover 5' to the epsilon-gene. Among 80 beta(S) chromosomes from Cameroon, 22 were associated with an atypical haplotype. The most common structure was represented by a Benin haplotype (from the LCR to the beta-gene) with a non-Benin segment 3' to the beta-globin gene. In two cases a Bantu LCR was associated with a Benin haplotype and a non-Benin segment 3' to the beta-globin gene. In three other cases, a more complex

  10. Beta-thalassemia and beta[A] globin gene haplotypes in Mexican mestizos.

    Science.gov (United States)

    Villalobos-Arámbula, A R; Bustos, R; Casas-Castañeda, M; Gutiérrez, E; Perea, F J; Thein, S L; Ibarra, B

    1997-04-01

    B-globin haplotypes of 20 beta-thalassemia (beta-thal) and 87 beta(A) Mexican mestizo chromosomes were analyzed to ascertain the origin of the beta-thal alleles and the frequencies and distribution of the beta(A) haplotypes among northwestern Mexican mestizos. Sixteen beta-thal chromosomes carried six Mediterranean alleles [five codon 39 C-->T; two IVS1:1 G-->A; two IVS1:5 G-->A; three IVS1:110 G(A; one codon 11 (-T) and three (deltabeta)zero-thal]; the remaining four were linked to three rare alleles (two -28 A-->C and one each: -87 C-->T and initiation codon ATG-->GTG). Among the 87 beta(A) chromosomes, 17 different 5' haplotypes with frequencies for 1, 3, 2 and 5 of 39.0%, 17. 2%, 9.2% and 6.9%, respectively, were observed. The beta-haplotype analysis showed that 13 out of 16 Mediterranean chromosomes could easily be explained by gene migration; however, one codon 39 associated with haplotype 4 (----+ +-), one IVS1:1 with haplotype 1(+----++) and one IVS1:5 G-->A, may represent separate mutational events. Analysis of the rare alleles showed that the -28 A-->C mutation was associated with the commonest beta(A) haplotype in Mexican mestizos, Mediterraneans and the total world population; therefore an independent origin cannot be ruled out. The -87 C-->T and initiation codon ATG-->GTG were found with beta-haplotypes different from the reported ones, suggesting an indigenous origin.

  11. 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....

  12. An Efficient Trio-Based Mini-Haplotyping Method for Genetic Diagnosis of Phenylketonuria

    OpenAIRE

    Saeed Talebi; Mona Entezam; Neda Mohajer; Golnaz-Ensieh Kazemi-sefat; Masoumeh Razipour; Somayeh Ahmadloo; Aria Setoodeh; Mohammad Keramatipour

    2016-01-01

    Objective The phenylalanine hydroxylase (PAH) locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficient method for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explain how to resolve the dye shift challenge in multiplex short tandem repeat (STR) genotyping. Materials and Methods One...

  13. Fetal Haemoglobin and β-globin Gene Cluster Haplotypes among Sickle Cell Patients in Chhattisgarh

    OpenAIRE

    Bhagat, Sanjana; Patra, Pradeep Kumar; Thakur, Amar Singh

    2013-01-01

    Background: Foetal Haemoglobin (HbF) is the best-known genetic modulator of sickle cell anaemia, which varies dramatically in concentration in the blood of these patients. The patients with SCA display a remarkable variability in the disease severity. High HbF levels and the β-globin gene cluster haplotypes influence the clinical presentation of sickle cell disease. To identify the genetic modifiers which influence the disease severity, we conducted a β-globin haplotype analysis in the sickle...

  14. Interleukin-6 (IL-6) haplotypes and the response to therapy of chronic hepatitis C virus infection

    OpenAIRE

    2009-01-01

    Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-α-2a is successful in eradicating virus from only 30%–80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained vir...

  15. 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.

  16. The association between paired basic amino acid cleaving enzyme 4 gene haplotype and diastolic blood pressure

    Institute of Scientific and Technical Information of China (English)

    李建平; 王晓滨; 陈常忠; 徐新; 洪雪梅; 徐希平; 高炜; 霍勇

    2004-01-01

    Background In a previously identified locus linked to hypertension on chromosome 15q, we identified three blood pressure candidate genes: insulin-like growth factor 1 receptor gene (IGF1R), myocyte specific enhancer factor 2A gene (MEF2A), and paired basic amino acid cleaving enzyme 4 gene (PACE4). In this study, we tested their associations with hypertension using haplotype analysis.Methods A total of 288 unrelated individuals, including 163 high diastolic blood pressure (DBP) subjects and 125 normal DBP subjects were enrolled in this case-control study. Twenty single nucleotide polymorphisms (SNPs) in the three genes were genotyped using polymerase chain reaction followed by restriction enzyme digestion. Haplotype analysis was accomplished in the following stages: (1) pair-wise linkage disequilibrium test among SNPs on the same gene was performed to explore blocks in which recombination is very unlikely to happen; (2) Estimation-Maximization algorithm was applied to estimate haplotype frequencies in each block; (3) the chi-square test was used to examine the specific haplotype difference, and a permutation test was used to examine the overall haplotype profile difference between cases and controls in each block.Results An estimated haplotype "CCCCG" frequency in the haplotype block on the PACE4 gene was significantly higher in high DBP cases than in controls (P<0.01). The overall estimated haplotype profile in this block was also significantly different between the cases and the controls (P<0.001). This association indicates. Conclusions This study for the first time demonstrated that PACE4 gene may play an important role in the regulation of DBP. This association indicates that variations influencing DBP resides in or near this genomic region.

  17. Mining of haplotype-based expressed sequence tag single nucleotide polymorphisms in citrus

    OpenAIRE

    Chen, Chunxian; Gmitter Jr, Fred G

    2013-01-01

    Background Single nucleotide polymorphisms (SNPs), the most abundant variations in a genome, have been widely used in various studies. Detection and characterization of citrus haplotype-based expressed sequence tag (EST) SNPs will greatly facilitate further utilization of these gene-based resources. Results In this paper, haplotype-based SNPs were mined out of publicly available citrus expressed sequence tags (ESTs) from different citrus cultivars (genotypes) individually and collectively for...

  18. A reduced number of mtSNPs saturates mitochondrial DNA haplotype diversity of worldwide population groups.

    Science.gov (United States)

    Salas, Antonio; Amigo, Jorge

    2010-05-03

    The high levels of variation characterising the mitochondrial DNA (mtDNA) molecule are due ultimately to its high average mutation rate; moreover, mtDNA variation is deeply structured in different populations and ethnic groups. There is growing interest in selecting a reduced number of mtDNA single nucleotide polymorphisms (mtSNPs) that account for the maximum level of discrimination power in a given population. Applications of the selected mtSNP panel range from anthropologic and medical studies to forensic genetic casework. This study proposes a new simulation-based method that explores the ability of different mtSNP panels to yield the maximum levels of discrimination power. The method explores subsets of mtSNPs of different sizes randomly chosen from a preselected panel of mtSNPs based on frequency. More than 2,000 complete genomes representing three main continental human population groups (Africa, Europe, and Asia) and two admixed populations ("African-Americans" and "Hispanics") were collected from GenBank and the literature, and were used as training sets. Haplotype diversity was measured for each combination of mtSNP and compared with existing mtSNP panels available in the literature. The data indicates that only a reduced number of mtSNPs ranging from six to 22 are needed to account for 95% of the maximum haplotype diversity of a given population sample. However, only a small proportion of the best mtSNPs are shared between populations, indicating that there is not a perfect set of "universal" mtSNPs suitable for all population contexts. The discrimination power provided by these mtSNPs is much higher than the power of the mtSNP panels proposed in the literature to date. Some mtSNP combinations also yield high diversity values in admixed populations. The proposed computational approach for exploring combinations of mtSNPs that optimise the discrimination power of a given set of mtSNPs is more efficient than previous empirical approaches. In contrast to

  19. Allelic and haplotype frequencies of the p53 polymorphisms in brain tumor patients.

    Science.gov (United States)

    Biros, E; Kalina, I; Kohút, A; Bogyiová, E; Salagovic, J; Sulla, I

    2002-01-01

    The polymorphisms of the tumor suppressor gene p53 in exon 4 (p53 BstUI) and in intron 6 (p53 MspI) have been suggested to be associated with the genetically determined susceptibility in diverse types of human cancer. In our hospital-based case-control study, we examined the allele and genotype incidence of these polymorphisms as well as their haplotype combinations in 60 brain tumor patients (27 males and 33 females) and 183 controls without malignancies. The genotype characteristics were determined by the PCR-based RFLP method using DNA extracted from peripheral blood. In this study we show that the p53 BstUI and the p53 MspI polymorphisms are not associated with increased risk of brain tumors. Thus, we conclude that the p53 BstUI and the p53 MspI polymorphic sites within the tumor suppressor gene p53 do not represent genetic determinants of susceptibility to brain tumors.

  20. 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.

  1. Mitochondrial haplotypes reveal a strong genetic structure for three Indian sheep breeds.

    Science.gov (United States)

    Pardeshi, V C; Kadoo, N Y; Sainani, M N; Meadows, J R S; Kijas, J W; Gupta, V S

    2007-10-01

    This survey represents the first characterization of mitochondrial DNA diversity within three breeds of Indian sheep (two strains of the Deccani breed, as well as the Bannur and Garole breeds) from different geographic regions and with divergent phenotypic characteristics. A 1061-bp fragment of the mitochondrial genome spanning the control region, a portion of the 12S rRNA gene and the complete phenyl tRNA gene, was sequenced from 73 animals and compared with the corresponding published sequence from European and Asian breeds and the European Mouflon (Ovis musimon). Analysis of all 156 sequences revealed 73 haplotypes, 52 of which belonged to the Indian breeds. The three Indian breeds had no haplotypes in common, but one Indian haplotype was shared with European and other Asian breeds. The highest nucleotide and haplotype diversity was observed in the Bannur breed (0.00355 and 0.981 respectively), while the minimum was in the Sangamneri strain of the Deccani breed (0.00167 and 0.882 respectively). All 52 Indian haplotypes belonged to mitochondrial lineage A. Therefore, these Indian sheep are distinct from other Asian and European breeds studied so far. The relationships among the haplotypes showed strong breed structure and almost no introgression among these Indian breeds, consistent with Indian sheep husbandry, which discourages genetic exchange between breeds. These results have implications for the conservation of India's ovine biodiversity and suggest a common origin for the breeds investigated.

  2. Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

    Science.gov (United States)

    Vacic, Vladimir; Ozelius, Laurie J; Clark, Lorraine N; Bar-Shira, Anat; Gana-Weisz, Mali; Gurevich, Tanya; Gusev, Alexander; Kedmi, Merav; Kenny, Eimear E; Liu, Xinmin; Mejia-Santana, Helen; Mirelman, Anat; Raymond, Deborah; Saunders-Pullman, Rachel; Desnick, Robert J; Atzmon, Gil; Burns, Edward R; Ostrer, Harry; Hakonarson, Hakon; Bergman, Aviv; Barzilai, Nir; Darvasi, Ariel; Peter, Inga; Guha, Saurav; Lencz, Todd; Giladi, Nir; Marder, Karen; Pe'er, Itsik; Bressman, Susan B; Orr-Urtreger, Avi

    2014-09-01

    The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.

  3. 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

  4. Extended haplotypes in rheumatoid arthritis and preliminary evidence for an interaction with immunoglobulin genes.

    Science.gov (United States)

    Puttick, A; Briggs, D; Welsh, K; Jacoby, R; Williamson, E; Jones, V

    1986-06-01

    The incidence of extended haplotypes of the Major Histocompatibility Complex was compared between 20 probands with RA, their unaffected family members, and 42 controls. One haplotype only, HLA-Bw62 BfS C4A*3 C4B*3 DR4 GLO2, was significantly increased in the patient group, whereas HLA-B7 BfS C4A*3 C4B*1 DR2 GLO1, which was the most common haplotype in the control groups, was absent. The immunoglobulin allotype Glm(2) was significantly increased in frequency in the RA patients, and analysis showed that of the seven patients carrying Bw62-DR4, five were G1m(2) positive. Further, the increase in frequency of the phenotype Gm(1,2,17,21,3,5,23) was also significant and was carried by two of four probands with the extended haplotype HLA-Bw62 BfS C4A*3 C4B*3 DR4 GLO2 and by one proband also bearing this haplotype but with a null allele at the C4A locus. The striking association of G1m(2) and Bw62 with DR4 in our patients suggests that in interaction of immunoglobulin genes with DR4 is stronger when DR4 is associated with particular haplotypes rather than with DR4 in general.

  5. Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction.

    Science.gov (United States)

    Mannila, Maria Nastase; Eriksson, Per; Lundman, Pia; Samnegård, Ann; Boquist, Susanna; Ericsson, Carl-Göran; Tornvall, Per; Hamsten, Anders; Silveira, Angela

    2005-03-01

    Fibrinogen has consistently been recognized as an independent predictor of myocardial infarction (MI). Multiple mechanisms link fibrinogen to MI; therefore disentangling the factors underlying variation in plasma fibrinogen concentration is essential. Candidate regions in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes were screened for single nucleotide polymorphisms (SNPs). Several novel SNPs were detected in the FGG and FGA genes in addition to the previously known SNPs in the fibrinogen genes. Tight linkage disequilibrium extending over various physical distances was observed between most SNPs. Consequently, eight SNPs were chosen and determined in 377 postinfarction patients and 387 healthy individuals. None of the SNPs were associated with plasma fibrinogen concentration or MI. Haplotype analyses revealed a consistent pattern of haplotypes associated with variation in risk of MI. Of the four haplotypes inferred using the FGA -58G>A and FGG 1299 +79T>C SNPs, the most frequent haplotype, FGG-FGA*1 (prevalence 46.6%), was associated with increased risk of MI (OR 1.51; 95%CI 1.18, 1.93), whereas the least frequent haplotype, FGG-FGA*4 (11.8%), was associated with lower risk of MI (OR 0.79 95%CI 0.64, 0.98). In conclusion, fibrinogen haplotypes, but not SNPs in isolation, are associated with variation in risk of MI.

  6. Triad of Risk for Late Onset Alzheimer’s: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex

    Science.gov (United States)

    Wang, Yiwei; Brinton, Roberta D.

    2016-01-01

    Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function, e.g., Alzheimer’s, Parkinson’s, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer’s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer’s disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases.

  7. Minor differences in haplotype frequency estimates can produce very large differences in heterogeneity test statistics

    Directory of Open Access Journals (Sweden)

    Xu Ke

    2007-06-01

    Full Text Available Abstract Background Tests for association between a haplotype and disease are commonly performed using a likelihood ratio test for heterogeneity between case and control haplotype frequencies. Using data from a study of association between heroin dependence and the DRD2 gene, we obtained estimated haplotype frequencies and the associated likelihood ratio statistic using two different computer programs, MLOCUS and GENECOUNTING. We also carried out permutation testing to assess the empirical significance of the results obtained. Results Both programs yielded similar, though not identical, estimates for the haplotype frequencies. MLOCUS produced a p value of 1.8*10-15 and GENECOUNTING produced a p value of 5.4*10-4. Permutation testing produced a p value 2.8*10-4. Conclusion The fact that very large differences occur between the likelihood ratio statistics from the two programs may reflect the fact that the haplotype frequencies for the combined group are not constrained to be equal to the weighted averages of the frequencies for the cases and controls, as they would be if they were directly observed rather than being estimated. Minor differences in haplotype frequency estimates can result in very large differences in the likelihood ratio statistic and associated p value.

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

    Science.gov (United States)

    Gutiérrez-López, Nidia; Ovando-Medina, Isidro; Salvador-Figueroa, Miguel; Molina-Freaner, Francisco; Avendaño-Arrazate, Carlos H; Vázquez-Ovando, Alfredo

    2016-01-01

    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 (F ST = 0) and SAMOVA (F ST = 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.

  9. Correlation between haplotype of apolipoprotein B gene and natural longevity persons in Uygur Nationality

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    This paper investigated the correlation between polymorphisms and haplotypes in the apolipoprotein B (apoB) gene (SP-I/D, XbaI-RFLP, VNTR) and natural longevity persons among the Uygur people in Xin-jiang. For this purpose, 191 healthy Uygur individuals aged above 90 from Hetian area of Xinjiang were recruited, and another 53 persons aged 65—70 from the same nationality, the same region and with the same gender ratio, served as the control group. Genotyping was performed by PCR-SSP, PCR-RFLP and PCR-sequencing methods. Logistic regression analyses revealed that the frequencies of X+X+ genotype, M and L alleles and the genetypes composed of M and L were significantly higher in the longevity group than in the control group. In haplotype analyses, we found that, in the long-lived people, the frequency of haplotypes composed of the X+ and M alleles was significantly higher whereas the frequency of haplotypes composed of the X- and S alleles was significantly lower (both P<0.05) I than those of their controls. These results indicated that the S allele, SS genotype and X+-S, D-S, D-X+-S haplotypes were the possible adverse factors, whereas the M, L alleles, X+X+, MM, ML, LL genotypes and I-X+-M, X+-M haplotypes were the possibe protective factors for the naturally long-lived Uygur people in China.

  10. Correlation between haplotype of apolipoprotein B gene and natural longevity persons in Uygur Nationality

    Institute of Scientific and Technical Information of China (English)

    JIANG WenXi; QIU ChangChun; CHENG ZuHeng; ZHOU WenYu; GU MingLiang; XU Qun; FANG MingWu; NIU WenQuan

    2007-01-01

    This paper investigated the correlation between polymorphisms and haplotypes in the apolipoprotein B (apoB) gene (SP-I/D, XbaI-RFLP, VNTR) and natural longevity persons among the Uygur people in Xinjiang. For this purpose, 191 healthy Uygur individuals aged above 90 from Hetian area of Xinjiang were recruited, and another 53 persons aged 65-70 from the same nationality, the same region and with the same gender ratio, served as the control group. Genotyping was performed by PCR-SSP, PCR-RFLP and PCR-sequencing methods. Logistic regression analyses revealed that the frequencies of X+X+ genotype, M and L alleles and the genetypes composed of M and L were significantly higher in the longevity group than in the control group. In haplotype analyses, we found that, in the long-lived people, the frequency of haplotypes composed of the X+ and M alleles was significantly higher whereas the frequency of haplotypes composed of the X- and S alleles was significantly lower (both P<0.05) I than those of their controls. These results indicated that the S allele, SS genotype and X+-S, D-S, D-X+-S haplotypes were the possible adverse factors, whereas the M, L alleles, X+X+, MM, ML, LL genotypes and I-X+-M, X+-M haplotypes were the possibe protective factors for the naturally long-lived Uygur people in China.

  11. 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.

  12. Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci.

    Science.gov (United States)

    Cao, K; Moormann, A M; Lyke, K E; Masaberg, C; Sumba, O P; Doumbo, O K; Koech, D; Lancaster, A; Nelson, M; Meyer, D; Single, R; Hartzman, R J; Plowe, C V; Kazura, J; Mann, D L; Sztein, M B; Thomson, G; Fernández-Viña, M A

    2004-04-01

    The allelic and haplotypic diversity of the HLA-A, HLA-B, and HLA-C loci was investigated in 852 subjects from five sub-Saharan populations from Kenya (Nandi and Luo), Mali (Dogon), Uganda, and Zambia. Distributions of genotypes at all loci and in all populations fit Hardy-Weinberg equilibrium expectations. There was not a single allele predominant at any of the loci in these populations, with the exception of A*3002 [allele frequency (AF) = 0.233] in Zambians and Cw*1601 (AF = 0.283) in Malians. This distribution was consistent with balancing selection for all class I loci in all populations, which was evidenced by the homozygosity F statistic that was less than that expected under neutrality. Only in the A locus in Zambians and the C locus in Malians, the AF distribution was very close to neutrality expectations. There were six instances in which there were significant deviations of allele distributions from neutrality in the direction of balancing selection. All allelic lineages from each of the class I loci were found in all the African populations. Several alleles of these loci have intermediate frequencies (AF = 0.020-0.150) and seem to appear only in the African populations. Most of these alleles are widely distributed in the African continent and their origin may predate the separation of linguistic groups. In contrast to native American and other populations, the African populations do not seem to show extensive allelic diversification within lineages, with the exception of the groups of alleles A*02, A*30, B*57, and B*58. The alleles of human leukocyte antigen (HLA)-B are in strong linkage disequilibrium (LD) with alleles of the C locus, and the sets of B/C haplotypes are found in several populations. The associations between A alleles with C-blocks are weaker, and only a few A/B/C haplotypes (A*0201-B*4501-Cw*1601; A*2301-B*1503-Cw*0202; A*7401-B* 1503-Cw*0202; A*2902-B*4201-Cw*1701; A*3001-B*4201-Cw*1701; and A*3601-B*5301-Cw*0401) are found in multiple

  13. [Diagnosis and treatment of eye diseases associated with HIV infection and AIDS].

    Science.gov (United States)

    Geng, Shuang; Ye, Jun-Jie; Liu, Li-Qiu; Xu, Hai-Yan; Wang, Wei-Wei; Wang, Shu-Ran

    2009-12-01

    To investigate the manifestations and treatment principles of ocular diseases associated with human immunodeficiency virus infection (HIV) and acquired immunodeficiency syndrome (AIDS). It was a retrospective case series. One hundred and ten patients were recruited. Two hundred and twenty eyes underwent ophthalmologic examination that included vision acuity, anterior segment and fundus examinations with papillary dilation and fundus fluorescein angiography. CD(4)(+)T-lymphocyte was counted in peripheral blood of 110 patients. Intravitreal injection of ganciclovir 400 microg was performed in 4 eyes (2 patients) with cytomegalovirus (CMV) retinitis associated with AIDS. All statistical analyses were performed using SPSS 13.0 software. The association between the age, duration of HIV infection and HIV/AIDS related ocular manifestations was analyzed by Pearson Correlation Analysis. The association between the gender and HIV/AIDS related ocular manifestations was analyzed by Pearson Chi-Square test. For comparison of the CD(4)(+)T cells counts of the patients with normal fundus, HIV retinopathy, CMV retinitis, Kruskal-Wallis Test for Several Independent Samples was used. Baseline visual acuity: no light perception (NLP) 5 eyes; light perception (LP) to 0.04, 10 eyes; 0.05 to 0.2, 14 eyes; 0.3 to 0.7, 62 eyes and >/= 0.8, 129 eyes. Small grayish keratin precipitates or pigment keratin precipitates were present in 25 eyes, 22 eyes had positive aqueous flare, 4 eyes had posterior synechia of the iris, 28 eyes had cataract. HIV retinopathy was present in 34 eyes. Cotton-wool spots, retinal hemorrhages, and retinal microaneurysms were found in eyes with HIV retinopathy. CMV retinitis was present in 32 eyes. The fundus manifestations of CMV retinitis included retinal vasculitis; dense, full-thickness, yellow-white lesions along vascular distribution with irregular granules at the border, and hemorrhage on the retinal surface in 26 eyes. Late stage retinopathy was demonstrated

  14. Phylogeographic analyses of Phragmites australis in China: Native distribution and habitat preference of the haplotype that invaded North America

    Institute of Scientific and Technical Information of China (English)

    Jia-Xing AN; Qian WANG; Ji YANG; Jian-Quan LIU

    2012-01-01

    Phragmites australis is a cosmopolitan clonal species,but one haplotype from Eurasia has become highly invasive in North America.This article describes an investigation of the phylogeographic composition of 77 populations from China,based on the sequencing of two chloroplast non-coding DNA regions.A total of 11 haplotypes were detected,based on the sequence alignments of two chloroplast DNA fragments from 421 sampled individuals.Six of these haplotypes were completely new,and did not correspond to any of this species' 27 previously known haplotypes.The invasive haplotype M and haplotypes O and P were shown to occur frequently.Haplotype O is widely distributed across all regions and probably represents the primitive haplotype of this species.In contrast,P is mainly distributed in the humid eastern and northeastern regions of China,whereas M is more frequent in western and northwestern China— arid habitats with low precipitation.Between eastern and northeastern and western and northwestern regions,there was distinct genetic differentiation; the former region has a higher genetic diversity than the latter.The high occurrence of haplotype M in western China suggests that it prefers more arid habitats.These findings shed new light on the native distribution,adaptation,and habitat preference of haplotype M,which invaded North America.

  15. Effects of IL-10 haplotype and atomic bomb radiation exposure on gastric cancer risk.

    Science.gov (United States)

    Hayashi, Tomonori; Ito, Reiko; Cologne, John; Maki, Mayumi; Morishita, Yukari; Nagamura, Hiroko; Sasaki, Keiko; Hayashi, Ikue; Imai, Kazue; Yoshida, Kengo; Kajimura, Junko; Kyoizumi, Seishi; Kusunoki, Yoichiro; Ohishi, Waka; Fujiwara, Saeko; Akahoshi, Masazumi; Nakachi, Kei

    2013-07-01

    Gastric cancer (GC) is one of the cancers that reveal increased risk of mortality and incidence in atomic bomb survivors. The incidence of gastric cancer in the Life Span Study cohort of the Radiation Effects Research Foundation (RERF) increased with radiation dose (gender-averaged excess relative risk per Gy = 0.28) and remains high more than 65 years after exposure. To assess a possible role of gene-environment interaction, we examined the dose response for gastric cancer incidence based on immunosuppression-related IL-10 genotype, in a cohort study with 200 cancer cases (93 intestinal, 96 diffuse and 11 other types) among 4,690 atomic bomb survivors participating in an immunological substudy. Using a single haplotype block composed of four haplotype-tagging SNPs (comprising the major haplotype allele IL-10-ATTA and the minor haplotype allele IL-10-GGCG, which are categorized by IL-10 polymorphisms at -819A>G and -592T>G, +1177T>C and +1589A>G), multiplicative and additive models for joint effects of radiation and this IL-10 haplotyping were examined. The IL-10 minor haplotype allele(s) was a risk factor for intestinal type gastric cancer but not for diffuse type gastric cancer. Radiation was not associated with intestinal type gastric cancer. In diffuse type gastric cancer, the haplotype-specific excess relative risk (ERR) for radiation was statistically significant only in the major homozygote category of IL-10 (ERR = 0.46/Gy, P = 0.037), whereas estimated ERR for radiation with the minor IL-10 homozygotes was close to 0 and nonsignificant. Thus, the minor IL-10 haplotype might act to reduce the radiation related risk of diffuse-type gastric cancer. The results suggest that this IL-10 haplotyping might be involved in development of radiation-associated gastric cancer of the diffuse type, and that IL-10 haplotypes may explain individual differences in the radiation-related risk of gastric cancer. © 2013 by Radiation Research Society

  16. Fetal male lineage determination by analysis of Y-chromosome STR haplotype in maternal plasma.

    Science.gov (United States)

    Barra, Gustavo Barcelos; Santa Rita, Ticiane Henriques; Chianca, Camilla Figueiredo; Velasco, Lara Francielle Ribeiro; de Sousa, Claudia Ferreira; Nery, Lídia Freire Abdalla; Costa, Sandra Santana Soares

    2015-03-01

    The aim of this study is to determine the fetus Y-STR haplotype in maternal plasma during pregnancy and estimate, non-invasively, if the alleged father and fetus belong to the same male lineage. The study enrolled couples with singleton pregnancies and known paternity. All participants signed informed consent and the local ethics committee approved the study. Peripheral blood was collected in EDTA tubes (mother) and in FTA paper (father). Maternal plasma DNA was extracted by using NucliSens EasyMAG. Fetal gender was determined by qPCR targeting DYS-14 in maternal plasma and it was also confirmed after the delivery. From all included volunteers, the first consecutive 20 mothers bearing male fetuses and 10 mothers bearing female fetuses were selected for the Y-STR analysis. The median gestational age was 12 weeks (range 12-36). All DNA samples were subjected to PCR amplification by PowerPlex Y23, ampFLSTR Yfiler, and two in-house multiplexes, which together accounts for 27 different Y-STR. The PCR products were detected with 3500 Genetic Analyzer and they were analyzed using GeneMapper-IDX. Fetuses' haplotypes (Yfiler format) were compared to other 5328 Brazilian haplotypes available on Y-chromosome haplotypes reference database (YHRD). As a result, between 22 and 27 loci were successfully amplified from maternal plasma in all 20 cases of male fetuses. None of the women bearing female fetuses had a falsely amplified Y-STR haplotype. The haplotype detected in maternal plasma completely matched the alleged father haplotype in 16 out of the 20 cases. Four cases showed single mismatches and they did not configure exclusions; 1 case showed a mutation in the DYS 458 locus due to the loss of one repeat unit and 3 cases showed one DYS 385I/II locus dropout. All mismatches were confirmed after the delivery. Seventeen fetuses' haplotypes were not found in YHRD and one of them had a mutation, which corresponded to the paternity probability of 99.9812% and 95.7028%, respectively

  17. HLA DRB1*DQB1* haplotype in HTLV-I-associated familial infective dermatitis may predict development of HTLV-I-associated myelopathy/tropical spastic paraparesis

    Energy Technology Data Exchange (ETDEWEB)

    LaGrenade, L.; Miller, W.; Pate, E.; Rodgers-Johnson, P. [Univ. of the West Indies, Mona (Jamaica)] [and others

    1996-01-02

    A possible causal association between infective dermatitis and HTLV-I infection was reported in 1990 and confirmed in 1992. We now report familial infective dermatitis (ID) occurring in a 26-year-old mother and her 9-year-old son. The mother was first diagnosed with ID in 1969 at the age of 2 years in Dermatology Unit at the University Hospital of the West Indies (U.H.W.I.) in Jamacia. The elder of her 2 sons was diagnosed with ID at the age of 3 years, also at U.H.W.I. Both mother and son are HTLV-I-seropositive. A second, younger son, currently age 2 years, is also HTLV-I-seropositive, but without clinical evidence of ID. Major histocompatibility complex (MHC), class II, human leucocyte antigen (HLA) genotyping documented a shared class II haplotype, DRB1*DQB1* (1101-0301), in the mother and her 2 sons. This same haplotype has been described among Japanese patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and has been associated with a possible pathologically heightened immune response to HTLV-I infection. The presence of this haplotype in these familial ID cases with clinical signs of HAM/TSP may have contributed to their risk for development of HAM/TSP. The unaffected, HTLV-I-seropositive, younger son requires close clinical follow-up. 20 refs., 1 fig., 1 tab.

  18. Imprinting is also a mechanism for immediate or delayed hemizygous expression of several uniparental haplotypes selected from the genome of each sex.

    Science.gov (United States)

    Engel, E

    1997-05-02

    A peculiar and interesting aspect of monoallelic or hemizygous expression, resulting from genomic imprinting, should be a likeness or resemblance for some phenotypic traits between relatives inheriting identical active genes or domains. Although the word "likon," a neologism, is reminiscent of the above implication, it is here proposed for use in a broader sense, namely, to designate a haplotype or part of a haplotype of an imprinted domain. As learned from earlier studies of imprinting and uniparental disomies, haplotypes at loci of such domains may be expressed (E) or unexpressed (U) in somatic cells; they may also be transmitted to be expressed or not in the next generation by germ cells "acting" (A) or marked to be "resting" (R) for such loci. Thus the soma/germinal status of "likons" might for each genitor be abbreviated as EA, UA, ER, and UR. In an evolutionary sense the assumption is that the same monoallelically expressed loci and domains when carried by two or more relatives should be the source of identical transcripts contributing to a closely similar phenotype. If so, the overall phenotype would be distinct if arising from some 10 to 20 imprinted genes or domains potentially gaining expression from the germ cells of either one or the other sex in humans. The result may have evolutionary implications by narrowing the scope of random individual variation and by strengthening assortative and associative values (physical, behavioral, and instinctual) in one's own lineage and species.

  19. Disease-associated changes in the expression of ion channels, ion receptors, ion exchangers and Ca(2+)-handling proteins in heart hypertrophy.

    Science.gov (United States)

    Zwadlo, Carolin; Borlak, Jürgen

    2005-09-15

    The molecular pathology of cardiac hypertrophy is multifactorial with transcript regulation of ion channels, ion exchangers and Ca(2+)-handling proteins being speculative. We therefore investigated disease-associated changes in gene expression of various ion channels and their receptors as well as ion exchangers, cytoskeletal proteins and Ca(2+)-handling proteins in normotensive and spontaneously hypertensive (SHR) rats. We also compared experimental findings with results from hypertrophic human hearts, previously published (Borlak, J., and Thum, T., 2003. Hallmarks of ion channel gene expression in end-stage heart failure. FASEB J. 17, 1592-1608). We observed significant (P ion exchangers (Atp1A1, NCX-1, SERCA2a), ion channels (L-type Ca(2+)-channel, K(ir)3.4, Na(v)1.5) and RyR-2 in hypertrophic hearts, while gene expression was repressed in diseased human hearts. Further, the genes coding for calreticulin and calmodulin, PMCA 1 and 4 as well as alpha-skeletal actin were significantly (P diseased human and rat hearts. Our study enabled an identification of disease-associated candidate genes. Their regulation is likely to be the result of an imbalance between pressure load/stretch force and vascular tonus and the observed changes may provide a rational for the rhythm disturbances observed in patients with cardiac hypertrophy.

  20. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients.

    OpenAIRE

    Labie, D; Pagnier, J.; Lapoumeroulie, C; Rouabhi, F; Dunda-Belkhodja, O; Chardin, P; Beldjord, C; Wajcman, H; Fabry, M E; Nagel, R L

    1985-01-01

    We have studied 42 homozygous beta-thalassemia patients from Algeria and 34 sickle cell anemia patients from Senegal and Benin, determining the relationship between haplotypes, Hb F, and G gamma-globin/A gamma-globin ratios. Populations selected have a high frequency of haplotype homozygotes because of consanguinity (Algeria) and geographic homogeneity (West Africa). We find in beta-thalassemia patients, that haplotype IX in haplotypic homozygotes and heterozygotes, haplotype III in heterozyg...

  1. Effects of NKG2D haplotypes on the cell-surface expression of NKG2D protein on natural killer and CD8 T cells of peripheral blood among atomic-bomb survivors.

    Science.gov (United States)

    Imai, Kazue; Hayashi, Tomonori; Yamaoka, Mika; Kajimura, Junko; Yoshida, Kengo; Kusunoki, Yoichiro; Nakachi, Kei

    2012-06-01

    NKG2D is a primary activating receptor that triggers cell-mediated cytotoxicity in NK cells against tumor and virus-infected cells. We previously identified the NKG2D haplotypes in the natural killer gene complex region on chromosome 12p. Two major haplotype alleles, LNK1 and HNK1, were closely related to low and high natural cytotoxic activity phenotypes, respectively. Furthermore, the haplotype of HNK1/HNK1 has revealed a decreased risk of cancer compared with LNK1/LNK1. In the present study, using flow cytometry, we evaluated the functional effects of NKG2D haplotypes and five htSNPs in terms of the cell-surface expression of NKG2D protein on NK and CD8 T cells of peripheral blood among 732 atomic-bomb survivors. NKG2D expression on NK cells showed significant increases, in the order of LNK1/LNK1, LNK1/HNK1 and HNK1/HNK1 haplotypes (p for trend=0.003), or with major homozygous, heterozygous, and minor homozygous genotypes for individual htSNPs (p for trend=0.02-0.003). The same trend was observed for NKG2D expression on CD8 T cells. Our findings indicate that the NKG2D haplotypes are associated with the expression levels of NKG2D protein on NK and CD8 T cells, resulting in inter-individual variations in human cytotoxic response. Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  2. Tyrosinase-positive oculocutaneous albinism in Southern African blacks: P gene-associated haplotypes suggest a major mutation in the 5{prime} region of the gene

    Energy Technology Data Exchange (ETDEWEB)

    Ramsay, M.; Stevens, G.; Beukering, J. van [Univ. of the Witwatersrand, Johannesburg (South Africa)] [and others

    1994-09-01

    Tyrosinase-positive oculocutaneous albinism (ty-pos OCA) occurs with a prevalence of 1 in 3900 among Southern African (SA) blacks. The major contributors to morbidity and mortality are skin cancer and decreased visual acuity. Two distinct phenotypes occur, namely individuals with ephelides (darkly pigmented patches) and those without. There is complete concordance with regard to ephelus status among siblings. The disorder is linked to markers on chromosome 15q11.2-q12, and no obligatory cross-overs were observed with polymophic markers at the human homolog, P, of the mouse pink eyed dilute gene, p. Contrary to what has been shown for Caucasoid ty-pos OCA, this condition shows locus homogeneity among SA blacks. The P gene is an excellent candidate for ty-pos OCA and mutations in this gene will confirm its role in causing the common form of albinism in SA. Numerous P gene mutations have been described in other populations. In an attempt to detect mutations, the P gene cDNA was used to search for structural rearrangements or polymorphisms. Six polymorphisms (plR10/Scal, 912/Xbal, 912/HincII, 912/TaqI, 1412/TaqI [two systems] and 1412/HindIII) were detected with subclones of the P cDNA and haplotypes were determined in each family. None were clearly associated with an albinism-related rearrangement. However, strong linkage disequilibrium was observed with alleles at loci toward the 5{prime} region of the gene ({triangle}=0.65, 0.57 and 0.80 for the three polymorphisms detected with the 912 subclone), suggesting a major ty-pos OCA mutation in this region. Haplotype analysis provides evidence for a major mutation associated with the same haplotype in individuals with ephelides (8/12 OCA chromosomes) and those without ephelides (24:30). The presence of other ty-pos OCA associated haplotypes indicates several other less common mutations.

  3. The S haplotype-specific F-box protein gene, SFB, is defective in self-compatible haplotypes of Prunus avium and P. mume.

    Science.gov (United States)

    Ushijima, Koichiro; Yamane, Hisayo; Watari, Akiko; Kakehi, Eiko; Ikeda, Kazuo; Hauck, Nathanael R; Iezzoni, Amy F; Tao, Ryutaro

    2004-08-01

    Many Prunus species, including sweet cherry and Japanese apricot, of the Rosaceae, display an S-RNase-based gametophytic self-incompatibility (GSI). The specificity of this outcrossing mechanism is determined by a minimum of two genes that are located in a multigene complex, termed the S locus, which controls the pistil and pollen specificities. SFB, a gene located in the S locus region, encodes an F-box protein that has appropriate S haplotype-specific variation to be the pollen determinant in the self-incompatibility reaction. This study characterizes SFBs of two self-compatible (SC) haplotypes, S(4') and S(f), of Prunus. S(4') of sweet cherry is a pollen-part mutant (PPM) that was produced by X-ray irradiation, while S(f) of Japanese apricot is a naturally occurring SC haplotype that is considered to be a PPM. DNA sequence analysis revealed defects in both SFB(4') and SFB(f). A 4 bp deletion upstream from the HVa coding region of SFB(4') causes a frame-shift that produces transcripts of a defective SFB lacking the two hypervariable regions, HVa and HVb. Similarly, the presence of a 6.8 kbp insertion in the middle of the SFB(f) coding region leads to transcripts for a defective SFB lacking the C-terminal half that contains HVa and HVb. As all reported SFBs of functional S haplotypes encode intact SFB, the fact that the partial loss-of-function mutations in SFB are present in SC mutant haplotypes of Prunus provides additional evidence that SFB is the pollen S gene in GSI in Prunus.

  4. Powerful haplotype-based Hardy-Weinberg equilibrium tests for tightly linked loci.

    Directory of Open Access Journals (Sweden)

    Wei-Gao Mao

    Full Text Available Recently, there have been many case-control studies proposed to test for association between haplotypes and disease, wh