Science.gov

Sample records for addition haplotype analysis

  1. General Framework for Meta‐Analysis of Haplotype Association Tests

    PubMed Central

    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.

    2016-01-01

    ABSTRACT 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. PMID:27027517

  2. A deductive method of haplotype analysis in pedigrees.

    PubMed Central

    Wijsman, E M

    1987-01-01

    Derivation of haplotypes from pedigree data by means of likelihood techniques requires large computational resources and is thus highly limited in terms of the complexity of problems that can be analyzed. The present paper presents 20 rules of logic that are both necessary and sufficient for deriving haplotypes by means of nonstatistical techniques. As a result, automated haplotype analysis that uses these rules is fast and efficient, requiring computer memory that increases only linearly (rather than exponentially) with family size and the number of factors under analysis. Some error analysis is also possible. The rules are completely general with regard to any system of completely linked, discrete genetic markers that are autosomally inherited. There are no limitations on pedigree structure or the amount of missing data, although the existence of incomplete data usually reduces the fraction of haplotypes that can be completely determined. PMID:3115093

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

    PubMed

    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.

  4. Sequence-Level Analysis of the Major European Huntington Disease Haplotype.

    PubMed

    Lee, Jong-Min; Kim, Kyung-Hee; Shin, Aram; Chao, Michael J; Abu Elneel, Kawther; Gillis, Tammy; Mysore, Jayalakshmi Srinidhi; Kaye, Julia A; Zahed, Hengameh; Kratter, Ian H; Daub, Aaron C; Finkbeiner, Steven; Li, Hong; Roach, Jared C; Goodman, Nathan; Hood, Leroy; Myers, Richard H; MacDonald, Marcy E; Gusella, James F

    2015-09-01

    Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. Consequently, we performed whole-genome sequencing of HD and control subjects from four independent families in whom the major European HD haplotype segregates with the disease. Analysis of the full-sequence-based HTT haplotype indicated that these four families share a common ancestor sufficiently distant to have permitted the accumulation of family-specific variants. Confirmation of new CAG-expansion mutations on this haplotype suggests that unlike most founders of human disease, the common ancestor of HD-affected families with the major haplotype most likely did not have HD. Further, availability of the full sequence data validated the use of SNP imputation to predict the optimal variants for capturing heterozygosity in personalized allele-specific gene-silencing approaches. As few as ten SNPs are capable of revealing heterozygosity in more than 97% of European HD subjects. Extension of allele-specific silencing strategies to the few remaining homozygous individuals is likely to be achievable through additional known SNPs and discovery of private variants by complete sequencing of HTT. These data suggest that the current development of gene-based targeting for HD could be extended to personalized allele-specific approaches in essentially all HD individuals of European ancestry. PMID:26320893

  5. Incorporating Single-Locus Tests into Haplotype Cladistic Analysis in Case-Control Studies

    PubMed Central

    Liu, Jianfeng; Papasian, Chris; Deng, Hong-Wen

    2007-01-01

    In case-control studies, genetic associations for complex diseases may be probed either with single-locus tests or with haplotype-based tests. Although there are different views on the relative merits and preferences of the two test strategies, haplotype-based analyses are generally believed to be more powerful to detect genes with modest effects. However, a main drawback of haplotype-based association tests is the large number of distinct haplotypes, which increases the degrees of freedom for corresponding test statistics and thus reduces the statistical power. To decrease the degrees of freedom and enhance the efficiency and power of haplotype analysis, we propose an improved haplotype clustering method that is based on the haplotype cladistic analysis developed by Durrant et al. In our method, we attempt to combine the strengths of single-locus analysis and haplotype-based analysis into one single test framework. Novel in our method is that we develop a more informative haplotype similarity measurement by using p-values obtained from single-locus association tests to construct a measure of weight, which to some extent incorporates the information of disease outcomes. The weights are then used in computation of similarity measures to construct distance metrics between haplotype pairs in haplotype cladistic analysis. To assess our proposed new method, we performed simulation analyses to compare the relative performances of (1) conventional haplotype-based analysis using original haplotype, (2) single-locus allele-based analysis, (3) original haplotype cladistic analysis (CLADHC) by Durrant et al., and (4) our weighted haplotype cladistic analysis method, under different scenarios. Our weighted cladistic analysis method shows an increased statistical power and robustness, compared with the methods of haplotype cladistic analysis, single-locus test, and the traditional haplotype-based analyses. The real data analyses also show that our proposed method has practical

  6. Incorporating single-locus tests into haplotype cladistic analysis in case-control studies.

    PubMed

    Liu, Jianfeng; Papasian, Chris; Deng, Hong-Wen

    2007-03-23

    In case-control studies, genetic associations for complex diseases may be probed either with single-locus tests or with haplotype-based tests. Although there are different views on the relative merits and preferences of the two test strategies, haplotype-based analyses are generally believed to be more powerful to detect genes with modest effects. However, a main drawback of haplotype-based association tests is the large number of distinct haplotypes, which increases the degrees of freedom for corresponding test statistics and thus reduces the statistical power. To decrease the degrees of freedom and enhance the efficiency and power of haplotype analysis, we propose an improved haplotype clustering method that is based on the haplotype cladistic analysis developed by Durrant et al. In our method, we attempt to combine the strengths of single-locus analysis and haplotype-based analysis into one single test framework. Novel in our method is that we develop a more informative haplotype similarity measurement by using p-values obtained from single-locus association tests to construct a measure of weight, which to some extent incorporates the information of disease outcomes. The weights are then used in computation of similarity measures to construct distance metrics between haplotype pairs in haplotype cladistic analysis. To assess our proposed new method, we performed simulation analyses to compare the relative performances of (1) conventional haplotype-based analysis using original haplotype, (2) single-locus allele-based analysis, (3) original haplotype cladistic analysis (CLADHC) by Durrant et al., and (4) our weighted haplotype cladistic analysis method, under different scenarios. Our weighted cladistic analysis method shows an increased statistical power and robustness, compared with the methods of haplotype cladistic analysis, single-locus test, and the traditional haplotype-based analyses. The real data analyses also show that our proposed method has practical

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

    PubMed

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

    2015-05-01

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

  8. Linkage disequilibrium, haplotype analysis and Werner`s syndrome

    SciTech Connect

    Wijsman, E.M.; Goddard, K.A.B.; Martin, G.M.

    1994-09-01

    Werner`s syndrome (WS) is a rare, autosomal, recessive disorder of premature aging. Although the underlying defect is unknown, the gene for the disorder, WRN, has been mapped to the 8p11.1-21.1 region. We have assembled a sample of 30 Japanese and 24 non-Japanese (primary Caucasian) WS patients, as well as a control sample from each population. 25 of the Japanese patients and 10 of the Caucasian patients are from consanguineous marriages. We recently presented evidence from these families which places WRN in the 10.2 cM interval between D8S87 and D8S137. However, because WS is so rare and because many patients are from consanguineous marriages, fine localization of the gene by traditional meiotic mapping methods is unlikely to succeed. The existence of linkage disequilibrium is now recognized as a key piece of evidence in defining a small region (typically under 1-2 cM) containing a gene of interest. Thus an alternative approach for refining the location of WRN may be to identify linked markers which are in linkage disequilibrium with the disease. We recently suggested that WRN may be close to D8S339 and GSR in the above interval because of the presence of statistically significant evidence of linkage disequilibrium in the Japanese sample. In addition, there was evidence in both populations that a limited number of haplotypes was associated with the disease. Here we report an extension of this study to include a number of additional markers. We present additional evidence that there is linkage disequilibrium between many of these markers and WRN in both the Japanese and Caucasian samples. In addition, the additional markers do not markedly subdivide the disease haplotypes defined by D8S339 and GSR, while at the same time they introduce substantial numbers of new haplotypes into the control populations. These results suggest that the haplotypes associated with WS may be used to further define the limits of WRN.

  9. Genetic analysis of Iranian autosomal dominant polycystic kidney disease: new insight to haplotype analysis.

    PubMed

    Entezam, M; Khatami, M R; Saddadi, F; Ayati, M; Roozbeh, J; Saghafi, H; Keramatipour, M

    2016-01-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) caused by mutations in two PKD1 and PKD2 genes. Due to the complexity of the PKD1 gene, its direct mutation screening is an expensive and time-consuming procedure. Pedigree-based haplotype analysis is a useful indirect approach to identify the responsible gene in families with multiple affected individuals, before direct mutation analysis. Here, we applied this approach to investigate 15 appropriate unrelated ADPKD families, selected from 25 families, who referred for genetic counseling. Four polymorphic microsatellite markers were selected around each PKD1 and PKD2 loci. In addition, by investigating the genomic regions, two novel flanking tetranucleotide STR markers were identified. Haplotype analysis and calculating Lod score confirmed linkage to PKD1 in 9 families (60%) and to PKD2 in 2 families (13%). Linkage to both loci was excluded in one family (6.6%). In 2 families (13%) the Lod scores were inconclusive. Causative mutation was identified successfully by direct analysis in two families with confirmed linkage, one to PKD1 and another to PKD2 locus. The study showed that determining the causative locus prior to direct mutation analysis is an efficient strategy to reduce the resources required for genetic analysis of ADPKD families. This is more prominent in PKD2-linked families. Selection of suitable markers, and appropriate PCR multiplexing strategy, using fluorescent labeled primers and 3 primer system, will also add value to this approach. PMID:26950445

  10. Analysis of 22 Y chromosomal STR haplotypes and Y haplogroup distribution in Pathans of Pakistan.

    PubMed

    Lee, Eun Young; Shin, Kyoung-Jin; Rakha, Allah; Sim, Jeong Eun; Park, Myung Jin; Kim, Na Young; Yang, Woo Ick; Lee, Hwan Young

    2014-07-01

    We analyzed haplotypes for 22 Y chromosomal STRs (Y-STRs), including 17 Yfiler loci (DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DY438, DYS439, DYS448, DYS456, DYS458, DYS635 and Y-GATA-H4) and five additional STRs (DYS388, DYS446, DYS447, DYS449 and DYS464), and Y chromosomal haplogroup distribution in 270 unrelated individuals from the Pathans residing in the Federally Administered Tribal Areas and the North-West Frontier Province of Pakistan using in-house multiplex PCR systems. Each Y-STR showed diversities ranging from 0.2506 to 0.8538, and the discriminatory capacity (DC) was 73.7% with 199 observed haplotypes using 17 Yfiler loci. By the addition of 5 Y-STRs to the Yfiler system, the DC was increased to 85.2% while showing 230 observed haplotypes. Among the additional 5 Y-STRs, DYS446, DYS447 and DYS449 were major contributors to enhancing discrimination. In the analysis of molecular variance, the Pathans of this study showed significant differences from other Pathan populations as well as neighboring population sets. In Y-SNP analysis, a total of 12 Y chromosomal haplogroups were observed and the most frequent haplogroup was R1a1a with 49.3% frequency. To obtain insights on the origin of Pathans, the network analysis was performed for the haplogroups G and Q observed from the Pathans and the Jewish population groups including Ashkenazim and Sephardim, but little support for a Jewish origin could be found. In the present study, we report Y-STR population data in Pathans of Pakistan, and we emphasize the need for adding additional markers to the commonly used 17 Yfiler loci to achieve more improved discriminatory capacity in a population with low genetic diversity. PMID:24709582

  11. Linkage Disequilibrium Mapping via Cladistic Analysis of Single-Nucleotide Polymorphism Haplotypes

    PubMed Central

    Durrant, Caroline; Zondervan, Krina T.; Cardon, Lon R.; Hunt, Sarah; Deloukas, Panos; Morris, Andrew P.

    2004-01-01

    We present a novel approach to disease-gene mapping via cladistic analysis of single-nucleotide polymorphism (SNP) haplotypes obtained from large-scale, population-based association studies, applicable to whole-genome screens, candidate-gene studies, or fine-scale mapping. Clades of haplotypes are tested for association with disease, exploiting the expected similarity of chromosomes with recent shared ancestry in the region flanking the disease gene. The method is developed in a logistic-regression framework and can easily incorporate covariates such as environmental risk factors or additional unlinked loci to allow for population structure. To evaluate the power of this approach to detect disease-marker association, we have developed a simulation algorithm to generate high-density SNP data with short-range linkage disequilibrium based on empirical patterns of haplotype diversity. The results of the simulation study highlight substantial gains in power over single-locus tests for a wide range of disease models, despite overcorrection for multiple testing. PMID:15148658

  12. Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes.

    PubMed

    Durrant, Caroline; Zondervan, Krina T; Cardon, Lon R; Hunt, Sarah; Deloukas, Panos; Morris, Andrew P

    2004-07-01

    We present a novel approach to disease-gene mapping via cladistic analysis of single-nucleotide polymorphism (SNP) haplotypes obtained from large-scale, population-based association studies, applicable to whole-genome screens, candidate-gene studies, or fine-scale mapping. Clades of haplotypes are tested for association with disease, exploiting the expected similarity of chromosomes with recent shared ancestry in the region flanking the disease gene. The method is developed in a logistic-regression framework and can easily incorporate covariates such as environmental risk factors or additional unlinked loci to allow for population structure. To evaluate the power of this approach to detect disease-marker association, we have developed a simulation algorithm to generate high-density SNP data with short-range linkage disequilibrium based on empirical patterns of haplotype diversity. The results of the simulation study highlight substantial gains in power over single-locus tests for a wide range of disease models, despite overcorrection for multiple testing.

  13. Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease

    PubMed Central

    Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S.; Lee, Jong‐Min; Gögele, Martin; D'Elia, Yuri; Pichler, Irene; Sequeiros, Jorge; Pramstaller, Peter P.; Gusella, James F.; MacDonald, Marcy E.

    2015-01-01

    Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary choreic movements, cognitive impairment, and behavioral changes, caused by the expansion of an unstable CAG repeat in HTT. We characterized the genetic diversity of the HD mutation by performing an extensive haplotype analysis of ∼1Mb region flanking HTT in over 300 HD families of Portuguese origin. We observed that haplotype A, marked by HTT delta2642, was enriched in HD chromosomes and carried the two largest expansions reported in the Portuguese population. However, the most frequent HD haplotype B carried one of the largest (+12 CAGs) expansions, which resulted in an allele class change to full penetrance. Despite having a normal CAG distribution skewed to the higher end of the range, these two core haplotypes had similar expanded CAG repeat sizes compared to the other major core haplotypes (C and D) and there was no statistical difference in transmitted repeat instability across haplotypes. We observed a diversity of HTT region haplotypes in both normal and expanded chromosomes, representative of more than one ancestral chromosome underlying HD in Portugal, where multiple independent events on distinct chromosome 4 haplotypes have given rise to expansion into the pathogenic range. © 2015 Wiley Periodicals, Inc. PMID:25656686

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

    PubMed Central

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

    2012-01-01

    Most newborn screening (NBS) laboratories use second-tier molecular tests for cystic fibrosis (CF) using dried blood spots (DBS). The Centers for Disease Control and Prevention’s NBS Quality Assurance Program offers proficiency testing (PT) in DBS for CF transmembrane conductance regulator (CFTR) gene mutation detection. Extensive molecular characterization on 76 CF patients, family members or screen positive newborns was performed for quality assurance. The coding, regulatory regions and portions of all introns were sequenced and large insertions/deletions were characterized as well as two intronic di-nucleotide microsatellites. For CF patient samples, at least two mutations were identified/verified and four specimens contained three likely CF-associated mutations. Thirty-four sequence variations in 152 chromosomes were identified, five of which were not previously reported. Twenty-seven of these variants were used to predict haplotypes from the major haplotype block defined by HapMap data that spans the promoter through intron 19. Chromosomes containing the F508del (p.Phe508del), G542X (p.Gly542X) and N1303K (p.Asn1303Lys) mutations shared a common haplotype subgroup, consistent with a common ancient European founder. Understanding the haplotype background of CF-associated mutations in the U.S. population provides a framework for future phenotype/genotype studies and will assist in determining a likely cis/trans phase of the mutations without need for parent studies. PMID:22137130

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

    PubMed Central

    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

  16. Analysis of Swine Leukocyte Antigen Haplotypes in Yucatan Miniature Pigs Used as Biomedical Model Animal

    PubMed Central

    Choi, Nu-Ri; Seo, Dong-Won; Choi, Ki-Myung; Ko, Na-Young; Kim, Ji-Ho; Kim, Hyun-Il; Jung, Woo-Young; Lee, Jun-Heon

    2016-01-01

    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. PMID:26950861

  17. Analysis of Swine Leukocyte Antigen Haplotypes in Yucatan Miniature Pigs Used as Biomedical Model Animal.

    PubMed

    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. PMID:26950861

  18. Host Genetic Factors and Vaccine-Induced Immunity to HBV Infection: Haplotype Analysis

    PubMed Central

    Ryckman, Kelli K.; Fielding, Katherine; Hill, Adrian V.; Mendy, Maimuna; Rayco-Solon, Pura; Sirugo, Giorgio; van der Sande, Marianne A.; Waight, Pauline; Whittle, Hilton C.; Hall, Andrew J.; Williams, Scott M.; Hennig, Branwen J.

    2010-01-01

    Hepatitis B virus (HBV) infection remains a significant health burden world-wide, although vaccines help decrease this problem. We previously identified associations of single nucleotide polymorphisms in several candidate genes with vaccine-induced peak antibody level (anti-HBs), which is predictive of long-term vaccine efficacy and protection against infection and persistent carriage; here we report on a haplotype-based analysis. A total of 688 SNPs from 117 genes were examined for a two, three and four sliding window haplotype analysis in a Gambian cohort. Analysis was performed on 197 unrelated individuals, 454 individuals from 174 families, and the combined sample (N = 651). Global and individual haplotype association tests were carried out (adjusted for covariates), employing peak anti-HBs level as outcome. Five genes (CD44, CD58, CDC42, IL19 and IL1R1) had at least one significant haplotype in the unrelated or family analysis as well as the combined analysis. Previous single locus results were confirmed for CD44 (combined global p = 9.1×10−5 for rs353644-rs353630-rs7937602) and CD58 (combined global p = 0.008 for rs1414275-rs11588376-rs1016140). Haplotypes in CDC42, IL19 and IL1R1 also associated with peak anti-HBs level. We have identified strong haplotype effects on HBV vaccine-induced antibody level in five genes, three of which, CDC42, IL19 and IL1R1, did not show evidence of association in a single SNP analyses and corroborated the majority of these effects in two datasets. The haplotype analysis identified associations with HBV vaccine-induced immunity in several new genes. PMID:20806065

  19. Linkage disequilibrium and haplotype analysis among Polish families with spinal muscular atrophy

    SciTech Connect

    Brzustowicz, L.M.; Wang, C.H.; Matseoane, D.; Kleyn, P.W.; Vitale, E.; Das, K.; Penchaszadeh, G.K.; Gilliam, T.C.; Munsat, T.L.; Hausmanowa-Petrusewicz, I.

    1995-01-01

    Spinal muscular atrophy (SMA) is an inherited degenerative disorder of anterior horn cells that results in progressive muscle weakness and atrophy. The autosomal recessive forms of childhood-onset SMA have been mapped to chromosome 5q11.2-13.3, in a number of studies examining different populations. A total of 9 simple sequence repeat markers were genotyped against 32 Polish families with SMA. The markers span an {approximately}0.7 cM region defined by the SMA flanking markers D5S435 and MAP1B. Significant linkage disequilibrium (corrected P<0.5) was detected at four of these markers, with D/D{sub max} values of {le}.89. Extended haplotype analysis revealed a predominant haplotype associated with SMA. The apparently high mutation rate of some of the markers has resulted in a number of haplotypes that vary slightly from this predominant haplotype. The predominant haplotype and these closely related patterns represent 25% of the disease chromosomes and none of the nontransmitted parental chromosomes. This predominant haplotype is present both in patients with acute (type I) and in chronic (types II and III) forms of SMA and occurs twice in a homozygous state, both times in children with chronic SMA. 34 refs., 2 figs., 2 tabs.

  20. Addictions Biology: Haplotype-Based Analysis for 130 Candidate Genes on a Single Array

    PubMed Central

    Hodgkinson, Colin A.; Yuan, Qiaoping; Xu, Ke; Shen, Pei-Hong; Heinz, Elizabeth; Lobos, Elizabeth A.; Binder, Elizabeth B.; Cubells, Joe; Ehlers, Cindy L.; Gelernter, Joel; Mann, John; Riley, Brien; Roy, Alec; Tabakoff, Boris; Todd, Richard D.; Zhou, Zhifeng; Goldman, David

    2008-01-01

    Aims: To develop a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety. Methods: A total of 130 genes were haplotype tagged and genotyped in 7 case/control populations and 51 reference populations using Illumina GoldenGate SNP genotyping technology, determining haplotype coverage. We also constructed and determined the efficacy of a panel of 186 ancestry informative markers. Results: An average of 1465 loci were genotyped at an average completion rate of 91.3%, with an average call rate of 98.3% and replication rate of 99.7%. Completion and call rates were lowered by the performance of two datasets, highlighting the importance of the DNA quality in high throughput assays. A comparison of haplotypes captured by the Addictions Array tagging SNPs and commercially available whole-genome arrays from Illumina and Affymetrix shows comparable performance of the tag SNPs to the best whole-genome array in all populations for which data are available. Conclusions: Arrays of haplotype-tagged candidate genes, such as this addictions-focused array, represent a cost-effective approach to generate high-quality SNP genotyping data useful for the haplotype-based analysis of panels of genes such as these 130 genes of interest to alcohol and addictions researchers. The inclusion of the 186 ancestry informative markers allows for the detection and correction for admixture and further enhances the utility of the array. PMID:18477577

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

    PubMed

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

    2014-07-01

    The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models the probability distribution of the Y-STR haplotypes. Creating a consistent statistical model of the haplotypes enables us to perform a wide range of analyses. Previously, haplotype frequency estimation using the discrete Laplace method has been validated. In this paper we investigate how the discrete Laplace method can be used for cluster analysis to further validate the discrete Laplace method. A very important practical fact is that the calculations can be performed on a normal computer. We identified two sub-clusters of the Eastern and Western European Y-STR haplotypes similar to results of previous studies. We also compared pairwise distances (between geographically separated samples) with those obtained using the AMOVA method and found good agreement. Further analyses that are impossible with AMOVA were made using the discrete Laplace method: analysis of the homogeneity in two different ways and calculating marginal STR distributions. We found that the Y-STR haplotypes from e.g. Finland were relatively homogeneous as opposed to the relatively heterogeneous Y-STR haplotypes from e.g. Lublin, Eastern Poland and Berlin, Germany. We demonstrated that the observed distributions of alleles at each locus were similar to the expected ones. We also compared pairwise distances between geographically separated samples from Africa with those obtained using the AMOVA method and found good agreement.

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

    PubMed

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

    2015-07-01

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

  3. Haplotype Analysis of Hemochromatosis Gene Polymorphisms in Chronic Hepatitis C Virus Infection: A Case Control Study

    PubMed Central

    Gerayli, Sina; Pasdar, Alireza; Shakeri, Mohammad Taghi; Sepahi, Samaneh; Hoseini, Seyed Mousalreza; Ahadi, Mitra; Rostami, Sina; Meshkat, Zahra

    2016-01-01

    Background Chronic hepatitis C virus (HCV) infection is frequently associated with elevated serum iron markers. Polymorphisms in the hemochromatosis (HFE) genes are responsible for iron accumulation in most cases of hemochromatosis, and may play a role in HCV infection. Objectives We aimed to assess the prevalence of HFE gene polymorphisms in a group of Iranian HCV-infected patients, and to explore the association of these polymorphisms with HCV infection. Patients and Methods HFE gene polymorphisms were examined in a total of 69 HCV patients and 69 healthy controls using polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and diplotype analyses were performed using PHASE software. Results In a recessive analysis model of the His63Asp (H63D) locus (HH vs. HD + DD), the HH genotype was more common in patients compared to controls (adjusted P = 0.012; OR = 6.42 [95% CI: 1.51 - 27.33]). Also, in a recessive analysis model of the Cys282Tyr (C282Y) locus (CC vs. CY + YY), the CC genotype was more frequent in patients compared to controls (adjusted P = 0.03; OR = 5.06 [95% CI: 1.13 - 22.06]). In addition, there was a significant association between the HC haplotype and the HCDC diplotype and HCV infection. Conclusions Polymorphism in the hemochromatosis gene may confer some degree of risk for HCV infection, and individuals carrying the H and C alleles may be susceptible to this disease; however, a larger sample of HCV patients and healthy individuals may be necessary to further illustrate the role of these polymorphisms in HCV. PMID:27621921

  4. Genetic evidence for heterogeneity in the etiology of CBAVD: Haplotype analysis in families

    SciTech Connect

    Kerem, B.; Rave-Harel, N.; Goshen, R.

    1994-09-01

    Male infertility due to congenital aplasia of the vas deference (CBAVD) is present in almost all CF male patients. It is also found in 1-2% of infertile otherwise healthy males. Several studies have found that about 10% of males with CBAVD carry 2 CF mutations, 40% carry one mutation and 50% have no mutations. These results indicate that in some males CBAVD is caused by two mutated CF alleles. However, in cases of males with one or no identified CF mutations, the association between CBAVD and CF is unclear. We therefore performed, in addition to CF mutation analysis, an extended haplotype analysis in 7 families of CBAVD males (2 had 2 brothers with CBAVD). Our results show that in 6 of the families, the infertile males inherited different CF alleles than their fertile brothers. However, in 2 families, in which no CF mutations were as of yet identified, different results were found. In one family, 2 infertile brothers differed in their haplotypes: both inherited from their mother the same CF allele, while from their father they inherited different alleles. Furthermore, their fertile brother inherited the same CF alleles as one of his fertile brothers. In another family, 2 brothers, one with CBAVD and the other fertile, inherited the same 2 CFTR alleles. These results provide genetic evidence for heterogeneity in the etiology of CBAVD. In some families the CBAVD is caused by 2 CF mutations, in others it is caused by other mechanism(s): heterozygosity for a CF mutation influenced by different threshold levels, mutations in other gene(s), or interaction between the two.

  5. Haplotype Analysis of Hemochromatosis Gene Polymorphisms in Chronic Hepatitis C Virus Infection: A Case Control Study

    PubMed Central

    Gerayli, Sina; Pasdar, Alireza; Shakeri, Mohammad Taghi; Sepahi, Samaneh; Hoseini, Seyed Mousalreza; Ahadi, Mitra; Rostami, Sina; Meshkat, Zahra

    2016-01-01

    Background Chronic hepatitis C virus (HCV) infection is frequently associated with elevated serum iron markers. Polymorphisms in the hemochromatosis (HFE) genes are responsible for iron accumulation in most cases of hemochromatosis, and may play a role in HCV infection. Objectives We aimed to assess the prevalence of HFE gene polymorphisms in a group of Iranian HCV-infected patients, and to explore the association of these polymorphisms with HCV infection. Patients and Methods HFE gene polymorphisms were examined in a total of 69 HCV patients and 69 healthy controls using polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and diplotype analyses were performed using PHASE software. Results In a recessive analysis model of the His63Asp (H63D) locus (HH vs. HD + DD), the HH genotype was more common in patients compared to controls (adjusted P = 0.012; OR = 6.42 [95% CI: 1.51 - 27.33]). Also, in a recessive analysis model of the Cys282Tyr (C282Y) locus (CC vs. CY + YY), the CC genotype was more frequent in patients compared to controls (adjusted P = 0.03; OR = 5.06 [95% CI: 1.13 - 22.06]). In addition, there was a significant association between the HC haplotype and the HCDC diplotype and HCV infection. Conclusions Polymorphism in the hemochromatosis gene may confer some degree of risk for HCV infection, and individuals carrying the H and C alleles may be susceptible to this disease; however, a larger sample of HCV patients and healthy individuals may be necessary to further illustrate the role of these polymorphisms in HCV.

  6. Haplotype analysis finds linkage disequilibrium in the IL-12 gene in patients with HCV.

    PubMed

    Houldsworth, Annwyne; Metzner, Magdalena; Hodgkinson, Andrea; Shaw, Steve; Kaminski, Edward; Demaine, Andy G; Cramp, Matthew E

    2015-07-01

    HCV is a major cause of liver disease worldwide. IL-12 plays an essential role in the balance of T helper 1 (Th1) differentiation versus a T helper 2 (Th2) driven response from its naïve precursor. Linkage disequilibrium measures the degree to which alleles at two loci are associated and the non-random associations between alleles at two loci. Haplotypes of the three IL-12B loci studied were determined in the patient cases and the normal healthy control subjects. The frequency of the 12 possible IL-12B haplotypes on the 3 loci was determined in subjects heterozygous at only one of the loci within the studied haplotype. Haplotype frequencies were compared between the patient groups and controls (n = 49) to determine if any preferential combination of markers occurred using chi-squared and applying the Bonferroni correction. 45 HCV RNA negative patients; 88 HCV RNA positive patients; and 15 uninfected cases at high risk of HCV infection (EU) were studied. The haplotype "C" SNP of the 3'UTR with the "E" 4 bp deletion of the intron 4 region was in linkage disequilibrium (χ(2)  = 45.15, P < 0.001, 95% CL). The haplotype analysis of the insertion allele of the promoter with the deletion allele of the intron 4("E") IL-12B polymorphism showed linkage disequilibrium (χ(2)  = 5.64, P = 0.02). Linkage disequilibrium of polymorphisms is reported in the IL-12 gene in patients with HCV infection and contributes to the understanding of patient genotype and expected production of IL-12, responding to infection.

  7. Analysis of Polymorphisms and Haplotype Structure of the Human Thymidylate Synthase Genetic Region: A Tool for Pharmacogenetic Studies

    PubMed Central

    Ghosh, Soma; Hossain, M. Zulfiquer; Borges, Michael; Goggins, Michael G.; Ingersoll, Roxann G.; Eshleman, James R.; Klein, Alison P.; Kern, Scott E.

    2012-01-01

    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. PMID:22496803

  8. [Principal component analysis of Y-chromosome haplotype distribution in 18 ethnic groups in Yunnan Province].

    PubMed

    Dong, Yong-Li; Yang, Zhi-Li; Shi, Hong; Gao, Lu; Lu, Jing; Cheng, Bao-Wen; Li, Kai-Yuan; Zan, Rui-Guang; Xiao, Chun-Jie

    2004-10-01

    Based on the historical records, 18 of the 26 ethnic groups in Yunnan Province are the descendant populations of three ancient tribes, Bai-Yue, Bai-Pu and Di-Qiang, linguistically belonging to the Daic, Austro-Asiatic and Tibeto-Burman, respectively. In order to trace the origins of these native ethnic groups, a total of 13 East Asian specific Y-chromosome biallelic markers were used to study the genetic structure of 20 local populations covering all the 18 ethnic groups in Yunnan Province. Haplotypes were analysis by PCR-RFLP method. Our results showed that H11 and H12 were the predominant haplotypes in the descendant populations of Bai-Yue tribe. H5, H6 and H8 were the dominant haplotypes in Di-Qiang descendants, and the frequencies of H6, H8 and H11 were very high in the descendant populations of Bai-Pu. To investigate relationships among 20 populations, a three dimensional PC analysis were performed based on the distribution of the 13 haplotypes. All populations were divided into two clusters in the PC plot. The first cluster was mainly composed by the descendant populations of Bai-Yue, and the second one was mainly composed by the descendants of Di-Qiang tribe. This result indicated that Bai-Yue and Di-Qiang's paternal lineage had different origins, which was in agreement with the historical documents and linguistic classification.

  9. Haplotype and linkage disequilibrium analysis of the CRMP1 and EVC genes.

    PubMed

    Sivakumaran, Theru A; Lesperance, Marci M

    2004-11-01

    In this report, we present the haplotype and linkage disequilibrium (LD) pattern in the Collapsin Response Mediator Protein 1 (CRMP1) and Ellis-van Creveld syndrome (EVC) gene region. We genotyped eight different single nucleotide polymorphisms (SNPs) in the CRMP1 and EVC genes in 90 control individuals of diverse ethnicity. The minor allele frequencies ranged from 3.3-49.4%, with most having a frequency >25%. A total of 37 haplotypes were derived from these eight polymorphisms, with only one haplotype having a frequency >10%. Pairwise LD analysis showed a weak but significant LD between markers located about 243 kb apart in this region. The LD was significant between markers spaced about 208 kb apart in EVC, whereas no LD was found between a pair of markers located about 5 kb apart in CRMP1. However, in general, LD correlated with the distance between loci. The CRMP1 and EVC genes are located near WFS1, the Wolfram syndrome type 1 gene, in which mutations also cause low frequency sensorineural hearing loss (LFSNHL). The haplotypes obtained from these polymorphisms will be useful to track the segregation of phenotypes in families with Ellis-van Creveld syndrome, Weyers acrodental dysostosis, LFSNHL and Wolfram syndrome type 1.

  10. Analysis of recombinational hot spots associated with the p haplotype fo the mouse MHC

    SciTech Connect

    Heine, D.; Khambata, S.; Wydner, K.S.; Passmore, H.C.

    1994-09-01

    Most of the recombination events detected within the major histocompatibility complex (MHC) of the mouse fall into areas of limited physical size that have been designated recombinational hot spots. One of these hot spots, associated with the Ea gene, appears to be active only in the presence of the p haplotype of the MHC. To study the regulation of the Ea recombinational hot spot and its haplotype specificity, a high-resolution comparative map fo the MHC and adjacent regions was completed in four different backcrosses carrying the p haplotype. This mapping study utilized a total of 29 PCR-based molecular markers, including 7 newly developed markers spanning the region between Pim1 and D17Mit11 on Chromosome 17. The analysis of a total of 1093 backcross animals: (1) revealed that the presence of the p haplotype of the MHC is not sufficient to induce recombination at the Ea hot spot in a dominant manner, and (2) resulted in the definition of a new intra-MHC recombinational hot spot between the Tnfb and the H2-D genes.

  11. Haplotype analysis of ESR2 in Japanese patients with spermatogenic failure.

    PubMed

    Ogata, Tsutomu; Fukami, Maki; Yoshida, Rie; Nagata, Eiko; Fujisawa, Yasuko; Yoshida, Atsumi; Yoshimura, Yasunori

    2012-07-01

    The prevalence of spermatogenic failure (SF) has gradually increased during the past few decades at least in several countries. Although multiple factors would be involved in this phenomenon, one important factor would be excessive estrogen effects via estrogen receptors (ERs). Thus, we performed haplotype analysis of ESR2 encoding ERβ in 125 Japanese SF patients and 119 age-matched control males, using single nucleotide polymorphisms (SNPs) 1-9 that are widely distributed on the ~120-kb genomic sequence of ESR2. Consequently, a linkage disequilibrium (LD) block was detected in an ~60-kb region encompassing SNPs 2-7 in both groups, and four major estimated haplotypes were identified within the LD block. Furthermore, the most prevalent 'TGTAGA' haplotype was found to be significantly associated with SF, with the P-value obtained by the Cochran-Armitage trend test (0.0029) being lower than that obtained by a 100 000-times permutation test (0.0038) to cope with the problem of multiple comparisons. The results, in conjunction with our previous data indicating lack of a susceptibility factor on ESR1 encoding ERα, imply that the specific 'TGTAGA' haplotype of ESR2 raises the susceptibility to the development of SF.

  12. Refined localization of the branchiootorenal syndrome gene by linkage and haplotype analysis

    SciTech Connect

    Ni, L.; Johnson, K.; Smith, R.J.H.; Wagner, M.J.; Wells, D.E.; Kimberling, W.J.; Kumar, S.; Pembrey, M.E.; Grundfast, K.M.; Daiger, S.P.

    1994-06-01

    Branchiootorenal (BOR) syndrome is a common autosomal dominant form of hearing impairment previously mapped to 8q. This report refines the localization of the BOR syndrome gene by haplotype analysis to the interval flanked by markers D8S553 and D8S286. By multipoint linkage analysis, the disease locus most likely is flanked by markers D8S530 and D8S279. 31 refs., 4 figs., 2 tabs.

  13. Haplotype analysis of the polymorphic 40 Y-STR markers in Chinese populations.

    PubMed

    Ou, Xueling; Wang, Ying; Liu, Chao; Yang, Donggui; Zhang, Chuchu; Deng, Shujiao; Sun, Hongyu

    2015-11-01

    Forty Y-STR loci were analyzed in 1128 males from the following six Chinese ethnic populations: Han (n=300), Hui (n=244), Korean (n=100), Mongolian (n=100), Uighur (n=284) and Tibetan (n=100), utilizing two new generation multiplex Y-STR systems, AGCU Y24 STR and GFS Y24 STR genotyping kits, which allow for the genotyping of 24 loci from a single amplification reaction in each system. The lowest estimates of genetic diversity (below 0.5) correspond to markers DYS391 (0.441658) and DYS437 (0.496977), and the greatest diversity corresponds to markers DYS385a/b (0.969919) and DYS527a/b (0.94676). A considerable number of duplicate and off-ladder alleles were also revealed. Additionally, there were 1111 different haplotypes identified from the total 1128 samples, of which 1095 were unique. Notably, no shared haplotypes between populations were observed. The estimated overall haplotype diversity (HD) was 0.999085, and its discrimination capacity (DC) was 0.970745. An MDS plot based on the genetic distances between populations showed the genetic similarity of the southern Han population to the Northern populations of Hui, Korean, Mongolian and Uighur and a clear genetic departure of the Tibetan population from other populations. For the Y STR markers, population substructure correction was considered when calculating the rarity of the Y STR profile. However, because the haplotype based Fst values are extremely small within the present data (0.000153 with 40 Y-STRs), no substructure correction is required to estimate the rarity of a haplotype comprising 40 markers. In summary, the results of our study indicate that the 40 Y-STRs have a high level of polymorphism in Chinese ethnic groups and could therefore be a powerful tool for forensic applications and population genetic studies.

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

    PubMed

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

    2015-07-01

    We analyzed haplotypes for 24 Y chromosomal STRs (Y-STRs), including 17 Yfiler loci (DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DY438, DYS439, DYS448, DYS456, DYS458, DYS635 and Y-GATA-H4) and 7 additional STRs (DYS388, DYS444, DYS447, DYS449, DYS522 and DYS527a/b) in 1100 unrelated Chinese Han individuals from Henan Province using AGCU Y24 STR kit systems. The calculated average gene diversity (GD) values ranged from 0.4105 to 0.9647 for the DYS388 and DYS385a/b loci, respectively. The discriminatory capacity (DC) was 72.91% with 802 observed haplotypes using 17 Yfiler loci, by the addition of 7 Y-STRs to the Yfiler system, the DC was increased to 79.09% while showing 870 observed haplotypes. Among the additional 7 Y-STRs, DYS449, DYS527a/b, DYS444 and DYS522 were major contributors to enhancing discrimination. In the analysis of molecular variance, the Henan Han population clustered with Han origin populations and showed significant differences from other Non-Han populations. In the present study, we report 24 Y-STR population data in Henan Han population, and we emphasize the need for adding additional markers to the commonly used 17 Yfiler loci to achieve more improved discriminatory capacity in a population with low genetic diversity. PMID:25864156

  15. Major Soybean Maturity Gene Haplotypes Revealed by SNPViz Analysis of 72 Sequenced Soybean Genomes

    PubMed Central

    Langewisch, Tiffany; Zhang, Hongxin; Vincent, Ryan; Joshi, Trupti; Xu, Dong; Bilyeu, Kristin

    2014-01-01

    In this Genomics Era, vast amounts of next-generation sequencing data have become publicly available for multiple genomes across hundreds of species. Analyses of these large-scale datasets can become cumbersome, especially when comparing nucleotide polymorphisms across many samples within a dataset and among different datasets or organisms. To facilitate the exploration of allelic variation and diversity, we have developed and deployed an in-house computer software to categorize and visualize these haplotypes. The SNPViz software enables users to analyze region-specific haplotypes from single nucleotide polymorphism (SNP) datasets for different sequenced genomes. The examination of allelic variation and diversity of important soybean [Glycine max (L.) Merr.] flowering time and maturity genes may provide additional insight into flowering time regulation and enhance researchers' ability to target soybean breeding for particular environments. For this study, we utilized two available soybean genomic datasets for a total of 72 soybean genotypes encompassing cultivars, landraces, and the wild species Glycine soja. The major soybean maturity genes E1, E2, E3, and E4 along with the Dt1 gene for plant growth architecture were analyzed in an effort to determine the number of major haplotypes for each gene, to evaluate the consistency of the haplotypes with characterized variant alleles, and to identify evidence of artificial selection. The results indicated classification of a small number of predominant haplogroups for each gene and important insights into possible allelic diversity for each gene within the context of known causative mutations. The software has both a stand-alone and web-based version and can be used to analyze other genes, examine additional soybean datasets, and view similar genome sequence and SNP datasets from other species. PMID:24727730

  16. Haplotype and mutation analysis for newly suggested Y-STRs in Korean father-son pairs.

    PubMed

    Oh, Yu Na; Lee, Hwan Young; Lee, Eun Young; Kim, Eun Hye; Yang, Woo Ick; Shin, Kyoung-Jin

    2015-03-01

    In this study, 363 Korean father-son haplotype transfers in 351 families were analyzed using an in-house multiplex PCR system for 14 Y-STRs (DYS385a/b, DYF387S1, DYS391, DYS449, DYS460, DYS481, DYS518, DYS533, DYS549, DYS570, DYS576, DYS627 and DYS643), that included 11 loci newly added to the PowerPlex Y23 system or the Yfiler Plus system. The Y-STRs showed gene diversity values ranging from 0.2499 to 0.9612; the multicopy Y-STR loci DYS385 and DYF387S1 had high gene diversity of 0.9612 and 0.9457, respectively. In addition, DYF387S1, which has two copies, showed three alleles in seven individuals, and micro-variant alleles were observed in 14 individuals at four loci (DYS448, DYS518, DYS570 and DYS627). Among 351 haplotypes for the 11 newly added Y-STRs, 350 different haplotypes were observed, with an overall haplotype diversity of 0.9999 and discrimination capacity of 99.72%. In 363 haplotype transfers from 351 pedigrees, 29 single-step mutations were observed at 11 Y-STRs. Locus-specific mutation rate estimates varied from 0.0 to 1.93×10(-2), with an average estimated mutation rate of 6.66×10(-3). Two father-son pairs had mutations at two different loci in 11 Y-STRs. The number of pairs with mutations at multiple loci increased to five when the mutation event was investigated for haplotype transfer at 28 Y-STRs including 17 Yfiler loci and 11 Y-STRs examined in this study: four father-son pairs had mutations at two loci, and one pair had mutations at three loci. Overall, mutations were frequently observed at DYS449, DYS576 and DYS627 loci, which are known to be rapidly mutating Y-STRs. Mutation rate estimates at most loci were not significantly different from rates in other populations, but estimates for DYF387S1, DYS518 and DYS570 were considerably lower in the Korean population than in other populations. PMID:25459034

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

    PubMed

    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.

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

    PubMed

    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. PMID:25532803

  19. Haplotype Analysis and Linkage Disequilibrium at Five Loci in Eragrostis tef.

    PubMed

    Smith, Shavannor M; Yuan, Yinan; Doust, Andrew N; Bennetzen, Jeffrey L

    2012-03-01

    Eragrostis tef (Zucc.), a member of the Chloridoideae subfamily of grasses, is one of the most important food crops in Ethiopia. Lodging is the most important production problem in tef. The rht1 and sd1 dwarfing genes have been useful for improving lodging resistance in wheat and rice, respectively, in what has been known as the "Green Revolution." All homologs of rht1 and sd1 were cloned and sequenced from 31 tef accessions collected from across Ethiopia. The allotetraploid tef genome was found to carry two rht1 homologs. From sequence variation between these two putative homologs, an approximate ancestral divergence date of 6.4 million years ago was calculated for the two genomes within tef. Three sd1 homologs were identified in tef, with unknown orthologous/paralogous relationships. The genetic diversity in the 31 studied accessions was organized into a relatively small number of haplotypes (2-4) for four of these genes, whereas one rht1 homeologue exhibited 10 haplotypes. A low level of nucleotide diversity was observed at all loci. Linkage disequilibrium analysis demonstrated strong linkage disequilibrium, extending the length of the five genes investigated (2-4 kb), with no significant decline. There was no significant correlation between haplotypes of any of these genes and their recorded site of origin.

  20. Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism.

    PubMed

    Glaser, B; Furth, J; Stanley, C A; Baker, L; Thornton, P S; Landau, H; Permutt, M A

    1999-01-01

    Familial hyperinsulinism (HI; MIM# 256450) is an autosomal recessive disorder of pancreatic beta-cell function, characterized by inadequate suppression of insulin secretion despite severe recurrent fasting hypoglycemia. Subtotal pancreatectomy is frequently required to prevent permanent neurologic sequelae. The incidence of HI in the Caucasian population is estimated at 1:50,000, however an apparent increased incidence among Ashkenazi Jews and Saudi Arabian Arabs has been reported. A locus for HI was assigned by linkage analyses to human chromosome 11p15.1. The sulfonylurea receptor (MIM# 600509, SUR1) and the potassium channel, inwardly rectifying, subfamily J member 11 (MIM# 600937, KIR6.2) genes, 2 components of the beta-cell K(ATP) channel, are clustered in this chromosomal region, and mutations in these genes have been implicated in HI. We previously demonstrated that two mutations in the SUR1 gene are present on approximately 88% of HI-associated chromosomes in Ashkenazi Jewish patients. Haplotype analysis with microsatellite markers flanking the gene revealed that one mutation (delF1388), reported only in Ashkenazi probands, occurred on two related extended haplotypes. By contrast, the second, more common mutation (3992-9g-->a) was associated with nine different intergenic haplotypes and has been reported in non-Jewish HI patients as well. In this study, we evaluated disease-associated chromosomes from 41 Ashkenazi Jewish and 2 non-Jewish HI patients carrying the 3992-9g-->a mutation by assessing haplotypes defined by nine common single nucleotide polymorphisms (SNPs), six in the SUR1 gene, and three in the KIR6.2 gene. Our results indicate that all 54 chromosomes carrying the 3992-9g-->a mutation in the Jewish patients appear to have originated from one founder mutation, whereas the same mutation on chromosomes from non-Jewish patients originated independently. Furthermore, our findings have implications concerning the HI-associated chromosomes on which no

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

    PubMed Central

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

    1999-01-01

    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. PMID:10388827

  2. The identification of additional zebrafish DICP genes reveals haplotype variation and linkage to MHC class I genes.

    PubMed

    Rodriguez-Nunez, Ivan; Wcisel, Dustin J; Litman, Ronda T; Litman, Gary W; Yoder, Jeffrey A

    2016-04-01

    Bony fish encode multiple multi-gene families of membrane receptors that are comprised of immunoglobulin (Ig) domains and are predicted to function in innate immunity. One of these families, the diverse immunoglobulin (Ig) domain-containing protein (DICP) genes, maps to three chromosomal loci in zebrafish. Most DICPs possess one or two Ig ectodomains and include membrane-bound and secreted forms. Membrane-bound DICPs include putative inhibitory and activating receptors. Recombinant DICP Ig domains bind lipids with varying specificity, a characteristic shared with mammalian CD300 and TREM family members. Numerous DICP transcripts amplified from different lines of zebrafish did not match the zebrafish reference genome sequence suggesting polymorphic and haplotypic variation. The expression of DICPs in three different lines of zebrafish has been characterized employing PCR-based strategies. Certain DICPs exhibit restricted expression in adult tissues whereas others are expressed ubiquitously. Transcripts of a subset of DICPs can be detected during embryonic development suggesting roles in embryonic immunity or other developmental processes. Transcripts representing 11 previously uncharacterized DICP sequences were identified. The assignment of two of these sequences to an unplaced genomic scaffold resulted in the identification of an alternative DICP haplotype that is linked to a MHC class I Z lineage haplotype on zebrafish chromosome 3. The linkage of DICP and MHC class I genes also is observable in the genomes of the related grass carp (Ctenopharyngodon idellus) and common carp (Cyprinus carpio) suggesting that this is a shared character with the last common Cyprinidae ancestor.

  3. The identification of additional zebrafish DICP genes reveals haplotype variation and linkage to MHC class I genes.

    PubMed

    Rodriguez-Nunez, Ivan; Wcisel, Dustin J; Litman, Ronda T; Litman, Gary W; Yoder, Jeffrey A

    2016-04-01

    Bony fish encode multiple multi-gene families of membrane receptors that are comprised of immunoglobulin (Ig) domains and are predicted to function in innate immunity. One of these families, the diverse immunoglobulin (Ig) domain-containing protein (DICP) genes, maps to three chromosomal loci in zebrafish. Most DICPs possess one or two Ig ectodomains and include membrane-bound and secreted forms. Membrane-bound DICPs include putative inhibitory and activating receptors. Recombinant DICP Ig domains bind lipids with varying specificity, a characteristic shared with mammalian CD300 and TREM family members. Numerous DICP transcripts amplified from different lines of zebrafish did not match the zebrafish reference genome sequence suggesting polymorphic and haplotypic variation. The expression of DICPs in three different lines of zebrafish has been characterized employing PCR-based strategies. Certain DICPs exhibit restricted expression in adult tissues whereas others are expressed ubiquitously. Transcripts of a subset of DICPs can be detected during embryonic development suggesting roles in embryonic immunity or other developmental processes. Transcripts representing 11 previously uncharacterized DICP sequences were identified. The assignment of two of these sequences to an unplaced genomic scaffold resulted in the identification of an alternative DICP haplotype that is linked to a MHC class I Z lineage haplotype on zebrafish chromosome 3. The linkage of DICP and MHC class I genes also is observable in the genomes of the related grass carp (Ctenopharyngodon idellus) and common carp (Cyprinus carpio) suggesting that this is a shared character with the last common Cyprinidae ancestor. PMID:26801775

  4. Association between ABCB1 polymorphisms and haplotypes and Alzheimer's disease: a meta-analysis.

    PubMed

    Zhong, Xin; Liu, Ming-Yan; Sun, Xiao-Hong; Wei, Min-Jie

    2016-01-01

    Although several epidemiological studies have investigated the association between ATP-binding cassette subfamily B member 1 (ABCB1) gene polymorphisms and Alzheimer's disease (AD) susceptibility, controversial results exist. Here, we performed a meta-analysis to assess whether ABCB1 polymorphisms 3435C > T (rs1045642), 2677G > T/A (rs2032582), 1236C > T (rs1128503) and haplotypes were associated with AD risk. Nine independent publications were included and analyzed. Crude odds ratio (OR) and 95% confidence interval (CI) were applied to investigate the strength of the association. Sensitivity analysis was conducted to measure the robustness of our analysis. A funnel plot and trim and fill method were used to test and adjust for publication bias. The results showed a significant association between the 3435C > T single nucleotide polymorphism (SNP) and AD susceptibility (CT vs. CC: OR = 1.24, 95% CI = 1.06-1.45, P = 0.01; CT + TT vs. CC: OR = 1.21, 95% CI = 1.04-1.41, P = 0.01) in the total population, as well as in Caucasian subgroup. The 2677G > T/A SNP was related to a decreased AD risk in Caucasian subgroup (TT + TA + AA vs. GT + GA + GG: OR = 0.68, 95% CI = 0.47-0.98, P = 0.04). Moreover, the ABCB1 haplotype analysis showed that the 1236T/2677T/3435C haplotype was associated with a higher risk of AD (OR = 1.99, 95% CI = 1.24-3.18, P = 0.00). Our results suggest that the ABCB1 3435C > T SNP, the 2677G > T/A SNP and 1236T/2677T/3435C haplotype are significantly associated with AD susceptibility. PMID:27600024

  5. Association between ABCB1 polymorphisms and haplotypes and Alzheimer’s disease: a meta-analysis

    PubMed Central

    Zhong, Xin; Liu, Ming-Yan; Sun, Xiao-Hong; Wei, Min-Jie

    2016-01-01

    Although several epidemiological studies have investigated the association between ATP-binding cassette subfamily B member 1 (ABCB1) gene polymorphisms and Alzheimer’s disease (AD) susceptibility, controversial results exist. Here, we performed a meta-analysis to assess whether ABCB1 polymorphisms 3435C > T (rs1045642), 2677G > T/A (rs2032582), 1236C > T (rs1128503) and haplotypes were associated with AD risk. Nine independent publications were included and analyzed. Crude odds ratio (OR) and 95% confidence interval (CI) were applied to investigate the strength of the association. Sensitivity analysis was conducted to measure the robustness of our analysis. A funnel plot and trim and fill method were used to test and adjust for publication bias. The results showed a significant association between the 3435C > T single nucleotide polymorphism (SNP) and AD susceptibility (CT vs. CC: OR = 1.24, 95% CI = 1.06–1.45, P = 0.01; CT + TT vs. CC: OR = 1.21, 95% CI = 1.04–1.41, P = 0.01) in the total population, as well as in Caucasian subgroup. The 2677G > T/A SNP was related to a decreased AD risk in Caucasian subgroup (TT + TA + AA vs. GT + GA + GG: OR = 0.68, 95% CI = 0.47–0.98, P = 0.04). Moreover, the ABCB1 haplotype analysis showed that the 1236T/2677T/3435C haplotype was associated with a higher risk of AD (OR = 1.99, 95% CI = 1.24–3.18, P = 0.00). Our results suggest that the ABCB1 3435C > T SNP, the 2677G > T/A SNP and 1236T/2677T/3435C haplotype are significantly associated with AD susceptibility. PMID:27600024

  6. Genomic-assisted haplotype analysis and the development of high-throughput SNP markers for salinity tolerance in soybean

    PubMed Central

    Patil, Gunvant; Do, Tuyen; Vuong, Tri D.; Valliyodan, Babu; Lee, Jeong-Dong; Chaudhary, Juhi; Shannon, J. Grover; Nguyen, Henry T.

    2016-01-01

    Soil salinity is a limiting factor of crop yield. The soybean is sensitive to soil salinity, and a dominant gene, Glyma03g32900 is primarily responsible for salt-tolerance. The identification of high throughput and robust markers as well as the deployment of salt-tolerant cultivars are effective approaches to minimize yield loss under saline conditions. We utilized high quality (15x) whole-genome resequencing (WGRS) on 106 diverse soybean lines and identified three major structural variants and allelic variation in the promoter and genic regions of the GmCHX1 gene. The discovery of single nucleotide polymorphisms (SNPs) associated with structural variants facilitated the design of six KASPar assays. Additionally, haplotype analysis and pedigree tracking of 93 U.S. ancestral lines were performed using publically available WGRS datasets. Identified SNP markers were validated, and a strong correlation was observed between the genotype and salt treatment phenotype (leaf scorch, chlorophyll content and Na+ accumulation) using a panel of 104 soybean lines and, an interspecific bi-parental population (F8) from PI483463 x Hutcheson. These markers precisely identified salt-tolerant/sensitive genotypes (>91%), and different structural-variants (>98%). These SNP assays, supported by accurate phenotyping, haplotype analyses and pedigree tracking information, will accelerate marker-assisted selection programs to enhance the development of salt-tolerant soybean cultivars. PMID:26781337

  7. Fourteen short tandem repeat loci Y chromosome haplotypes: Genetic analysis in populations from northern Brazil.

    PubMed

    Palha, Teresinha; Ribeiro-Rodrigues, Elzemar; Ribeiro-dos-Santos, Andrea; Santos, Sidney

    2012-05-01

    Fourteen Y-STR loci (DYS458, DYS439, Y-GATA H4, DYS576, DYS447, DYS460, DYS456, YGATA A10, DYS437, DYS449, DYS570, DYS635 or Y-GATA C4, DYS448 and DYS438) were analysed in 873 males from eight northern Brazil populations: Belém (N=400), Santarém (N=69), Manaus (N=75), Macapá (N=65), Palmas (N=30), Rio Branco (N=32), Porto Velho (N=135) and Boa Vista (N=67). A total of 871 different haplotypes were identified, of which 869 were unique. The panel's estimated total haplotype diversity (HD) is 0.9988, and its discrimination capacity (DC) is 0.9980. The lowest estimates of genetic diversity correspond to markers Y-GATA H4 (0.550) and DYS460 (0.581), and the greatest (above 0.700) to markers DYS458, DYS576, DYS447, YS449, DYS570 and DYS635. The genetic parameters obtained were higher for the 14-Y-STR panel than that for the minimum haplotype set (HD=0.9969; DC=0.76) and the parameters were similar to those obtained with the panel of 17 YSTR of YHRD (HD=0.9987; DC=0. 9870). The analysis of molecular variance (AMOVA) indicated that most of the genetic variance is found within populations and a smaller, but significant part, is found among populations (R(ST)=0.027, p value=0.009). The data when compared with those from African, Amerindian and European populations have shown no significant genetic distance between northern Brazil populations and Europeans, but there is a significant genetic distance when compared to Africans and Amerindians. The discrimination capacity of the markers shows a high potential for forensic analysis.

  8. Haplotype analysis of BRCA1 intragenic markers in Iranian patients with familial breast and ovarian cancer

    PubMed Central

    Miresmaeili, Seyed Mohsen; Kordi Tamandani, Dor Mohammad; Kalantar, Seyed Mehdi; Moshtaghioun, Seyed Mohammad

    2016-01-01

    Background: Breast cancer is the most common malignancy in women. Breast Cancer Type 1 Susceptibility gene (BRCA1) is a tumor suppressor gene, involved in DNA damage repair and in 81% of the breast-ovarian cancer families were due to BRCA1. In some clinically investigated genes, the intragenic marker polymorphism is important and the screening of such mutations is faster by using short tandem repeat (STR) polymorphism. Individual polymorphism of STR is a good evidence for following inheritance of repeat polymorphism. Objective: The aim of this study was to evaluate three intragenic BRCA1 marker polymorphisms in families, which have two or more patients with breast/ovarian cancer in comparison to healthy women. Materials and Methods: A total of 107 breast and/or ovarian cancer patients and 93 unrelated healthy women with no clinical phenotype of any malignancy or familial cancer history constitute the study groups. Haplotyping analysis, at 3 intragenic BRCA1 microsatellite markers (D17S855, D17S1322 and D17S1323), were performed for all subject and control groups using labeled primers. Results: After fragment analysis, significance differences were observed as follows: two alleles of D17S855; allele 146 (p=0.02) and 150 (p=0.006), and two alleles of D17S1322, allele 121 (p=0.015) and 142 (p=0.043). These differences were compared with control group. There was significance difference in 8 di/tri allelic haplotypes in present experimental subjects. Some haplotypes were observed to have approximately twice the relation risk for breast cancer. Conclusion: According to recent results, assessment of presence or absence of mentioned alleles in BRCA1 microsatellite can be used for prognosis in individuals, suspected of having or not having the breast cancer. PMID:27351029

  9. KIR and HLA haplotype analysis in a family lacking the KIR 2DL1-2DP1 genes

    PubMed Central

    Vojvodić, S; Ademović-Sazdanić, D

    2015-01-01

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

  10. Strong linkage disequilibrium and haplotype analysis in Japanese pedigrees with Machado-Joseph disease

    SciTech Connect

    Endo, Kotaro; Tanaka, Hajime; Saito, Masaaki

    1996-09-20

    To identify the markers tightly linked to Machado-Joseph disease (MJD) and to investigate whether a limited number of ancestral chromosomes are shared by Japanese MJD pedigrees, a detailed linkage analysis employing D14S55, D14S48, D14S67, D14S291, D14S280, AFM343vf1, D14S81, D14S265, D14S62, and D14S65 was performed. The results of multipoint linkage analysis as well as detection of critical recombination events indicate that the gene for MJD is localized in a 4-cM region between D14S280-D14S81. We found strong linkage disequilibria at AFM343vf1 and D14S81, and association of a few common haplotypes with MJD. These results indicate that there is an obvious founder effect in Japanese MJD and suggest the possibility of the existence of predisposing haplotypes which are prone to expansions of CAG repeats. 47 refs., 3 figs., 2 tabs.

  11. The analysis of BDNF gene polymorphism haplotypes and impulsivity in methamphetamine abusers.

    PubMed

    Su, Hang; Tao, Jingyan; Zhang, Jie; Xie, Ying; Han, Bin; Lu, Yuling; Sun, Haiwei; Wei, Youdan; Wang, Yue; Zhang, Yu; Zou, Shengzhen; Wu, Wenxiu; Zhang, Jiajia; Xu, Ke; Zhang, Xiangyang; He, Jincai

    2015-05-01

    An increasing number of evidence showed that genetic factors might contribute to drug abuse vulnerability. Data from genetic scans in humans suggest that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be associated with substance abuse or dependence. To test the hypothesis that the BDNF gene polymorphism is involved in methamphetamine abuse, we compared three single nucleotide polymorphisms (SNPs, rs16917204, rs16917234, and rs2030324) of the BDNF gene in 200 methamphetamine abusers and 219 healthy individuals. We also considered the association of these polymorphisms with impulsivity in methamphetamine abusers using Barratt Impulsivity Scale-11(BIS-11) Chinese version. Individual SNP analysis showed no significant differences in genotype and allele distributions between the methamphetamine abusers and controls. Haplotype analysis of rs16917204-rs16917234-rs2030324 revealed that a major C-C-T haplotype was significantly associated a lower odds of methamphetamine abuse, even after Bonferroni correction. Within the methamphetamine-abuse group, subjects carrying the T allele of rs2030324 genotype had significantly higher motor impulsivity scores of BIS compared to those with the C/C genotype. Our findings suggest that the BDNF gene polymorphism may contribute to the impulsivity in methamphetamine abusers.

  12. Genealogical analysis of cystic fibrosis families and chromosome 7q RFLP haplotypes in the Hutterite Brethren.

    PubMed Central

    Fujiwara, T M; Morgan, K; Schwartz, R H; Doherty, R A; Miller, S R; Klinger, K; Stanislovitis, P; Stuart, N; Watkins, P C

    1989-01-01

    In the 100-year period 1880-1980 the Hutterite population increased from about 442 to 23,000 individuals in North America. There are three endogamous subdivisions in this Caucasian genetic isolate. A total of 11 cystic fibrosis (CF) families from Canada and the United States were investigated, including at least two families from each of the three subdivisions, the Dariusleut, Lehrerleut, and Schmiedeleut. A study of RFLPs for the loci D7S8, D7S23, MET, and D7S18 (also called D7S16) in the region of the CF gene in 10 families shows considerable genetic variability. There were three different extended CF gene-region haplotypes on CF chromosomes (CF haplotypes), and there were 13 different extended CF gene-region haplotypes on normal chromosomes (normal haplotypes). The three CF haplotypes have different D7S23 and MET haplotypes. Parents who have the same CF haplotype are, on the average, more closely related than parents who have different haplotypes, but only within the same subdivision. A marriage node graph of 11 families illustrates the complexity of Hutterite genealogies. The frequency distribution of CF haplotypes in the Hutterite sample differs notably from those of larger agglomerates of family data from collaborative studies, with respect to D7S8, MET haplotypes, and D7S23 haplotypes. We propose that there were at least three CF carriers among the founders of the Hutterite population and that copies of a particular CF haplotype in current individuals are identical by descent. The alternative that one or more genetically distinguishable CF haplotypes resulted from recombination since the founding of the population is considered to be less likely. PMID:2563632

  13. Hereditary Sensory Neuropathy Type I: Haplotype Analysis Shows Founders in Southern England and Europe

    PubMed Central

    Nicholson, G. A.; Dawkins, J. L.; Blair, I. P.; Auer-Grumbach, M.; Brahmbhatt, S. B.; Hulme, D. J.

    2001-01-01

    Hereditary sensory neuropathy type I (HSN1) is the most common dominantly inherited degenerative disorder of sensory neurons. The gene mutation was mapped to chromosome 9 in a large Australian family, descended from an ancestor from southern England who was a convict. Dawkins et al. recently reported gene mutations in the SPTLC1 gene, in this and other families. The first description of hereditary sensory neuropathy, by Hicks, was in a family from London and Exeter. To determine if the families in the present study that have SPTLC1 mutations are related to English families with HSN1 and, possibly, to the family studied by Hicks, we performed haplotype analysis of four Australian families of English extraction, four English families, and one Austrian family. Three Australian families of English extraction and three English families (two of whom have been described elsewhere) had the 399T→G SPTLC1 mutation, the same chromosome 9 haplotype, and the same phenotype. The Australian and English families may therefore have a common founder who, on the basis of historical information, has been determined to have lived in southern England prior to 1800. The sensorimotor neuropathy phenotype caused by the 399T→G SPTLC1 mutation is the same as that reported by Campbell and Hoffman and, possibly, the same as that originally described by Hicks. PMID:11479835

  14. Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe.

    PubMed

    Nicholson, G A; Dawkins, J L; Blair, I P; Auer-Grumbach, M; Brahmbhatt, S B; Hulme, D J

    2001-09-01

    Hereditary sensory neuropathy type I (HSN1) is the most common dominantly inherited degenerative disorder of sensory neurons. The gene mutation was mapped to chromosome 9 in a large Australian family, descended from an ancestor from southern England who was a convict. Dawkins et al. recently reported gene mutations in the SPTLC1 gene, in this and other families. The first description of hereditary sensory neuropathy, by Hicks, was in a family from London and Exeter. To determine if the families in the present study that have SPTLC1 mutations are related to English families with HSN1 and, possibly, to the family studied by Hicks, we performed haplotype analysis of four Australian families of English extraction, four English families, and one Austrian family. Three Australian families of English extraction and three English families (two of whom have been described elsewhere) had the 399T-->G SPTLC1 mutation, the same chromosome 9 haplotype, and the same phenotype. The Australian and English families may therefore have a common founder who, on the basis of historical information, has been determined to have lived in southern England prior to 1800. The sensorimotor neuropathy phenotype caused by the 399T-->G SPTLC1 mutation is the same as that reported by Campbell and Hoffman and, possibly, the same as that originally described by Hicks. PMID:11479835

  15. Beta-globin haplotype analysis suggests that a major source of Malagasy ancestry is derived from Bantu-speaking Negroids.

    PubMed Central

    Hewitt, R.; Krause, A.; Goldman, A.; Campbell, G.; Jenkins, T.

    1996-01-01

    The origins of the inhabitants of Madagascar have not been fully resolved. Anthropological studies and preliminary genetic data point to two main sources of ancestry of the Malagasy, namely, Indonesian and African, with additional contributions from India and Arabia. The sickle-cell (beta s) mutation is found in populations of African and Indian origin. The frequency of the beta s-globin gene, derived from 1,425 Malagasy individuals, varies from 0 in some highland populations to .25 in some coastal populations. The beta s mutation is thought to have arisen at least five times, on the basis of the presence of five distinct beta s-associated haplotypes, each found in a separate geographic area. Twenty-five of the 35 Malagasy beta s haplotypes were of the typical "Bantu" type, 1 "Senegal" haplotype was found, and 2 rare or atypical haplotypes were observed; the remaining 7 haplotypes were consistent with the Bantu haplotype. The Bantu beta s mutation is thought to have been introduced into Madagascar by Bantu-speaking immigrants (colonists or slaves) from central or east Africa. The Senegal beta s mutation may have been introduced to the island via Portuguese naval explorers. This study provides the first definitive biological evidence that a major component of Malagasy ancestry is derived from African populations, in particular, Bantu-speaking Negroids. beta A haplotypes are also consistent with the claim for a significant African contribution to Malagasy ancestry but are also suggestive of Asian/Oceanic and Caucasoid admixture within the Malagasy population. PMID:8651308

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

    PubMed

    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

    2005-12-01

    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.

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

    PubMed Central

    Jomoui, Wittaya; Fucharoen, Goonnapa; Sanchaisuriya, Kanokwan; Nguyen, Van Hoa; Fucharoen, Supan

    2015-01-01

    Background Hemoglobin Constant Spring (Hb CS) is an abnormal Hb caused by a mutation at the termination codon of α2-globin gene found commonly among Southeast Asian and Chinese people. Association of Hb CS with α°-thalassemia leads to a thalassemia intermedia syndrome commonly encountered in the region. We report chromosome background and addressed genetic origins of Hb CS observed in a large cohort of Hb CS among Southeast Asian populations. Materials and Methods A study was done on 102 Vietnamese (aged 15–49 year-old) and 40 Laotian (aged 18–39 year-old) subjects with Hb CS and results compared with 120 Hb CS genes in Thailand. Hematological parameters were recorded and Hb analysis was performed using capillary electrophoresis. Hb CS mutation and thalassemia genotypes were defined by DNA analysis. Six DNA polymorphisms within α-globin gene cluster including 5’Xba I, Bgl I, Inter-zeta HVR, AccI, RsaI and αPstI 3’, were determined using PCR-RFLP assay. Results Nine different genotypes of Hb CS were observed. In contrast to the Thai Hb CS alleles which are mostly linked to haplotype (+—S + + -), most of the Vietnamese and the Laotian Hb CS genes were associated with haplotype (+—M + + -), both of which are different from that of the European Hb CS. Conclusions Hb CS is commonly found in combination with other thalassemias among Southeast Asian populations. Accurate genotyping of the cases requires both hematologic and DNA analyses. At least two independent origins are associated with the Hb CS gene which could indirectly explain the high prevalence of this Hb variant in the region. PMID:26683994

  18. Analysis of 17 Y-STR loci haplotype and Y-chromosome haplogroup distribution in five Chinese ethnic groups.

    PubMed

    Wang, Ying; Liu, Chao; Zhang, Chu-chu; Li, Ran; Li, Yue; Ou, Xue-ling; Sun, Hong-yu

    2015-10-01

    To investigate genetic diversity in Chinese populations, 706 unrelated male individuals from five ethnic groups (Han, Korean, Hui, Mongolian, and Tibetan, respectively) were analyzed with 17 Y-chromosomal STRs. The haplotype diversity was 0.99985 in the combined data. A total of 675 distinct haplotypes were observed, of which 649 were unique. Y-chromosome haplogroups in the five groups were also predicted with Y-STR haplotypes. Genetic distance between the five studied ethnic groups and other published groups was analyzed by analysis of molecular variance and visualized in a multidimensional scaling plot. In conclusion, the 17 Y-STR loci are highly polymorphic markers in the five groups and hence are very useful in forensic application, population genetics, and human evolution studies.

  19. A Cladistic Analysis of Phenotype Associations with Haplotypes Inferred from Restriction Endonuclease Mapping. II. the Analysis of Natural Populations

    PubMed Central

    Templeton, A. R.; Sing, C. F.; Kessling, A.; Humphries, S.

    1988-01-01

    Genes that code for products involved in the physiology of a phenotype are logical candidates for explaining interindividual variation in that phenotype. We present a methodology for discovering associations between genetic variation at such candidate loci (assayed through restriction endonuclease mapping) with phenotypic variation at the population level. We confine our analyses to DNA regions in which recombination is very rare. In this case, the genetic variation at the candiate locus can be organized into a cladogram that represents the evolutionary relationships between the observed haplotypes. Any mutation causing a significant phenotypic effect should be imbedded within the same historical structure defined by the cladogram. We showed, in the first paper of this series, how to use the cladogram to define a nested analysis of variance (NANOVA) that was very efficient at detecting and localizing phenotypically important mutations. However, the NANOVA of haplotype effects could only be applied to populations of homozygous genotypes. In this paper, we apply the quantitative genetic concept of average excess to evaluate the phenotypic effect of a haplotype or group of haplotypes stratified and contrasted according to the nested design defined by the cladogram. We also show how a permutational procedure can be used to make statistical inferences about the nested average excess values in populations containing heterozygous as well as homozygous genotypes. We provide two worked examples that investigate associations between genetic variation at or near the Alcohol dehydrogenase (Adh) locus and Adh activity in Drosophila melanogaster, and associations between genetic variation at or near some apolipoprotein loci and various lipid phenotypes in a human population. PMID:3147219

  20. Massively parallel haplotyping on microscopic beads for the high-throughput phase analysis of single molecules.

    PubMed

    Boulanger, Jérôme; Muresan, Leila; Tiemann-Boege, Irene

    2012-01-01

    In spite of the many advances in haplotyping methods, it is still very difficult to characterize rare haplotypes in tissues and different environmental samples or to accurately assess the haplotype diversity in large mixtures. This would require a haplotyping method capable of analyzing the phase of single molecules with an unprecedented throughput. Here we describe such a haplotyping method capable of analyzing in parallel hundreds of thousands single molecules in one experiment. In this method, multiple PCR reactions amplify different polymorphic regions of a single DNA molecule on a magnetic bead compartmentalized in an emulsion drop. The allelic states of the amplified polymorphisms are identified with fluorescently labeled probes that are then decoded from images taken of the arrayed beads by a microscope. This method can evaluate the phase of up to 3 polymorphisms separated by up to 5 kilobases in hundreds of thousands single molecules. We tested the sensitivity of the method by measuring the number of mutant haplotypes synthesized by four different commercially available enzymes: Phusion, Platinum Taq, Titanium Taq, and Phire. The digital nature of the method makes it highly sensitive to detecting haplotype ratios of less than 1:10,000. We also accurately quantified chimera formation during the exponential phase of PCR by different DNA polymerases. PMID:22558329

  1. Linkage disequilibrium mapping via cladistic analysis of phase-unknown genotypes and inferred haplotypes in the Genetic Analysis Workshop 14 simulated data.

    PubMed

    Durrant, Caroline; Morris, Andrew P

    2005-01-01

    We recently described a method for linkage disequilibrium (LD) mapping, using cladistic analysis of phased single-nucleotide polymorphism (SNP) haplotypes in a logistic regression framework. However, haplotypes are often not available and cannot be deduced with certainty from the unphased genotypes. One possible two-stage approach is to infer the phase of multilocus genotype data and analyze the resulting haplotypes as if known. Here, haplotypes are inferred using the expectation-maximization (EM) algorithm and the best-guess phase assignment for each individual analyzed. However, inferring haplotypes from phase-unknown data is prone to error and this should be taken into account in the subsequent analysis. An alternative approach is to analyze the phase-unknown multilocus genotypes themselves. Here we present a generalization of the method for phase-known haplotype data to the case of unphased SNP genotypes. Our approach is designed for high-density SNP data, so we opted to analyze the simulated dataset. The marker spacing in the initial screen was too large for our method to be effective, so we used the answers provided to request further data in regions around the disease loci and in null regions. Power to detect the disease loci, accuracy in localizing the true site of the locus, and false-positive error rates are reported for the inferred-haplotype and unphased genotype methods. For this data, analyzing inferred haplotypes outperforms analysis of genotypes. As expected, our results suggest that when there is little or no LD between a disease locus and the flanking region, there will be no chance of detecting it unless the disease variant itself is genotyped.

  2. Linkage disequilibrium mapping via cladistic analysis of phase-unknown genotypes and inferred haplotypes in the Genetic Analysis Workshop 14 simulated data

    PubMed Central

    Durrant, Caroline; Morris, Andrew P

    2005-01-01

    We recently described a method for linkage disequilibrium (LD) mapping, using cladistic analysis of phased single-nucleotide polymorphism (SNP) haplotypes in a logistic regression framework. However, haplotypes are often not available and cannot be deduced with certainty from the unphased genotypes. One possible two-stage approach is to infer the phase of multilocus genotype data and analyze the resulting haplotypes as if known. Here, haplotypes are inferred using the expectation-maximization (EM) algorithm and the best-guess phase assignment for each individual analyzed. However, inferring haplotypes from phase-unknown data is prone to error and this should be taken into account in the subsequent analysis. An alternative approach is to analyze the phase-unknown multilocus genotypes themselves. Here we present a generalization of the method for phase-known haplotype data to the case of unphased SNP genotypes. Our approach is designed for high-density SNP data, so we opted to analyze the simulated dataset. The marker spacing in the initial screen was too large for our method to be effective, so we used the answers provided to request further data in regions around the disease loci and in null regions. Power to detect the disease loci, accuracy in localizing the true site of the locus, and false-positive error rates are reported for the inferred-haplotype and unphased genotype methods. For this data, analyzing inferred haplotypes outperforms analysis of genotypes. As expected, our results suggest that when there is little or no LD between a disease locus and the flanking region, there will be no chance of detecting it unless the disease variant itself is genotyped. PMID:16451556

  3. Haplotype Analysis of GSK-3β Gene Polymorphisms in Bipolar Disorder Lithium Responders and Nonresponders

    PubMed Central

    Iwahashi, Kazuhiko; Nishizawa, Daisuke; Narita, Shin; Numajiri, Maki; Murayama, Ohoshi; Yoshihara, Eiji; Onozawa, Yuuya; Nagahori, Kenta; Fukamauchi, Fumihiko; Ikeda, Kazutaka; Ishigooka, Jun

    2014-01-01

    Abstract The GSK-3β gene, GSK3B, codes for an enzyme that is a target for the action of mood stabilizers, lithium and possibly valproic acid. In this study, the relationship between haplotypes consisting of single nucleotide polymorphisms (SNPs) of GSK3B −50T/C and −1727A/T and the effect of lithium was studied among Japanese bipolar disorder lithium nonresponders and responders. The distributions of the GSK3B haplotypes (−50T/C and −1727A/T) showed a trend for significant difference between the lithium nonresponders and responders (global P=0.07074). Haplotype 1 (T-A) was associated with a higher lithium response (haplotype-specific P=0.03477), whereas haplotype 2 (C-A) was associated with a lower lithium response (haplotype-specific P=0.03443). The pairwise D′ and r2 values between the 2 SNPs in this study were 1.0 and 0.097, respectively. The 2 SNPs showed weak linkage disequilibrium with each other. PMID:24992082

  4. Clinical study and haplotype analysis in two brothers with Partington syndrome.

    PubMed

    Frints, Suzanna G M; Borghgraef, Martine; Froyen, Guy; Marynen, Peter; Fryns, Jean-Pierre

    2002-11-01

    Partington et al. [1988] described a three-generation family (MRXS1, MIM *309510, PRTS) with a syndromic form of X-linked mental retardation (XLMR). The clinical features in 10 affected males included mild to moderate MR, dystonic movements of the hands, and dysarthria. After refinement, the PRTS locus was mapped to marker DXS989 (with maximum LOD score of 3.1) with flanking markers DXS365 and DXS28. Since then, no other patients with a similar phenotype have been described. We present a detailed description of the neurological symptoms and the disease history of two brothers with the clinical features of PRTS. Psychomotor development was delayed in both, and neurological features included mild to moderate mental retardation, dysarthria, facial muscle weakness, severe dysdiadochokinesis, slow dystonic movements, and mild spasticity of the hands, without ataxia or spasticity of the legs. The symptoms were nonprogressive and extrapyramidal, and without cerebellar involvement. In general, behavior of the two brothers was friendly and quiet, although the elder brother had periods of depressed mood and outbursts of anger. Karyotypes and subsequent investigation of the subtelomeres as well as DNA analysis of the FMR1 gene, the androgen receptor gene, and the DM locus did not reveal a genetic abnormality. Haplotype analysis showed that the affected brothers share the PRTS region at Xp22.1. Mutation screening of the PDH-E1alpha gene did not reveal a pathogenic mutation.

  5. Linkage disequlibrium in the DTNBP1 (dysbindin) gene region and on chromosome 1p36 among psychotic patients from a genetic isolate in Israel: findings from identity by descent haplotype sharing analysis.

    PubMed

    Kohn, Yoav; Danilovich, Eduardo; Filon, Dvorah; Oppenheim, Ariella; Karni, Osnat; Kanyas, Kyra; Turetsky, Neil; Korner, Mira; Lerer, Bernard

    2004-07-01

    Several genes have been reported recently to be associated with schizophrenia and bipolar disorder. Because of the complexity of the inheritance of these disorders, there is an urgent need to replicate these findings and to search for additional candidate genes. The study of genetic isolates is a powerful technique that may overcome some of the obstacles caused by genetic heterogeneity and ambiguity of phenotype definition. Identity by descent (IBD) haplotype sharing analysis in these populations may be used to detect mutations within shared haplotypes in smaller samples of affected individuals. In this study, we used IBD haplotype sharing analysis to replicate positive linkage and association findings in psychotic disorders, and to identify other regions of interest. Fifty-two patients with major psychiatric disorders from a genetically isolated village in Israel were studied. By studying eight Y chromosome markers, we were able to confirm the oral tradition of members of this isolate regarding a common paternal origin. Three hundred fifty nine microsatellite markers on 9 candidate chromosomes were genotyped, and haplotypes were reconstructed using information from family members. Two highly significant (P < 0.0001) peaks of haplotype sharing were found. One was for psychotic patients with any diagnosis at the location of dysbindin, a gene previously associated with schizophrenia. The other peak was for patients with schizophrenia on chromosome 1p36. Thus, this study both replicates an earlier finding and points to a novel region of interest, which might be unique to this population.

  6. Fine genetic mapping using haplotype analysis and the missing data problem.

    PubMed

    Chiano, M N; Clayton, D G

    1998-01-01

    The genetic basis of many human diseases, especially those with substantial genetic determinants, has been identified. Notable amongst others are cystic fibrosis, Huntington's disease and some forms of cancer. However, the detection of genetic factors with more modest effects such as in bipolar disorders and a majority of the cancers, has been more complicated. Standard linkage analysis procedures may not only have little power to detect such genes but they do, at best, only narrow the location of the disease susceptibility gene to a rather large region. Association studies are therefore necessary to further unveil the aetiological relevance of these factors to disease. However, the number of tests required if such procedures were used in extended genome-wide screens, is prohibitive and as such association studies have seen limited application, except in the investigation of candidate genes. In this paper, we discuss a logistic regression approach as a generalization of this procedure so that it can accommodate clusters of linked markers or candidate genes. Furthermore, we introduce an expectation maximization (E-M) algorithm with which to estimate haplotype frequencies for multiple locus systems with incomplete information on phase.

  7. Comparative analysis of S haplotypes with very similar SLG alleles in Brassica rapa and Brassica oleracea.

    PubMed

    Kusaba, M; Nishio, T

    1999-01-01

    Self-incompatibility in Brassica is controlled by a single multi-allelic locus (the S locus) which harbors at least two highly polymorphic genes, SLG and SRK. SRK is a putative transmembrane receptor kinase and its amino acid sequence of the extracellular domain of SRK (the S domain) exhibits high homology to that of SLG. The amino acid sequences of the SLGs of S8 and S46 haplotypes of B. rapa are very similar and those of S23 and S29 haplotypes of B. oleracea were also found to be almost identical. In both cases, SLG and the S domain of SRK of the same haplotype were less similar. This seems to contradict the idea that SLG and SRK of the same haplotype have the same self-recognition specificity. In the transmembrane-kinase domain, the SRK alleles of the S8 and S46 haplotypes had almost identical nucleotide sequences in spite of their lower homology in the S domain. Such a cluster of nucleotide substitutions is probably due to recombination or related events, although recombination in the S locus is thought to be suppressed. Based on our observations, the recognition mechanism and the evolution of self-incompatibility in Brassica are discussed.

  8. Founder mitochondrial haplotypes in Amerindian populations.

    PubMed Central

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

    1994-01-01

    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. PMID:7517626

  9. Haplotype analysis of DNA microsatellites tightly linked to the locus of Usher syndrome type I on chromosome 11q

    SciTech Connect

    Korostishevsky, M.; Kalinsky, H.; Seroussi, E.

    1994-09-01

    Usher syndrome type I (USHI), an autosomal recessive disorder associated with congenital sensorineural deafness and progressive visual loss, is closely linked to the D11S533 locus. The availability of 7 other polymorphic markers within few centimorgans spanning the disease locus allowed us to identify a unique and single haplotype among all carriers of USHI gene in the Samaritan kindred. Occurrence of recombination in this small chromosomal interval is rare, hindering the detection of the mitotic recombination events needed for analysis by traditional linkage methods. Attempts to order the eight loci by linkage disequilibrium models proved to be problematic. However, our haplotype analysis implied that recombinations which had arisen in past generations may be utilized in fine mapping of the USHI gene and in resolving the conflicting linkage maps previously obtained for this region. We have developed a simple algorithm for predicting the order of the microsatellites on the basis of haplotype resemblance. The following chromosomal map in which the USHI gene is closest to D11S533 (location score of 31.0 by multipoint analysis) is suggested: D11S916, GARP, D11S527, D11S533, OMP, D11S906, D11S911, D11S937. Physical mapping efforts are currently directed to verify and to detail the map of this chromosomal region.

  10. Consanguinity Protecting Effect Against Breast Cancer among Tunisian Women: Analysis of BRCA1 Haplotypes.

    PubMed

    Medimegh, Imen; Troudi, Wafa; Omrane, Ines; Ayari, Hajer; Uhrhummer, Nancy; Majoul, Hamdi; Benayed, Farhat; Mezlini, Amel; Bignon, Yves-Jean; Sibille, Catherine; Elgaaied, Amel Benammar

    2015-01-01

    The purpose of this study is to assess the effect of consanguinity on breast cancer incidence in Tunisia. We conducted a case-control study to evaluate the involvement of heterozygote and homozygote haplotypes of BRCA1 gene SNPs according to consanguinity among 40 cases of familial breast cancer, 46 cases with sporadic breast cancer and 34 healthy controls. We showed significant difference in consanguinity rate between breast cancer patients versus healthy controls P = 0.001. Distribution of homozygous BRCA1 haplotypes among healthy women versus breast cancer patients was significantly different; p=0.02. Parental consanguinity seems to protect against breast cancer in the Tunisian population. PMID:25987085

  11. Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse

    PubMed Central

    Wiltshire, Tim; Pletcher, Mathew T.; Batalov, Serge; Barnes, S. Whitney; Tarantino, Lisa M.; Cooke, Michael P.; Wu, Hua; Smylie, Kevin; Santrosyan, Andrey; Copeland, Neal G.; Jenkins, Nancy A.; Kalush, Francis; Mural, Richard J.; Glynne, Richard J.; Kay, Steve A.; Adams, Mark D.; Fletcher, Colin F.

    2003-01-01

    The nature and organization of polymorphisms, or differences, between genomes of individuals are of great interest, because these variations can be associated with or even underlie phenotypic traits, including disease susceptibility. To gain insight into the genetic and evolutionary factors influencing such biological variation, we have examined the arrangement (haplotype) of single-nucleotide polymorphisms across the genomes of eight inbred strains of mice. These analyses define blocks of high or low diversity, often extending across tens of megabases that are delineated by abrupt transitions. These observations provide a striking contrast to the haplotype structure of the human genome. PMID:12612341

  12. Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus

    PubMed Central

    Wilson, Gareth A.; Rakyan, Vardhman K.; Teschendorff, Andrew E.; Akan, Pelin; Stupka, Elia; Down, Thomas A.; Prokopenko, Inga; Morison, Ian M.; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M.; Hattersley, Andrew T.; McCarthy, Mark I.; Beck, Stephan; Hitman, Graham A.

    2010-01-01

    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. PMID:21124985

  13. Disclosing the Genetic Structure of Brazil through Analysis of Male Lineages with Highly Discriminating Haplotypes

    PubMed Central

    Palha, Teresinha; Gusmão, Leonor; Ribeiro-Rodrigues, Elzemar; Guerreiro, João Farias; Ribeiro-dos-Santos, Ândrea; Santos, Sidney

    2012-01-01

    In a large variety of genetic studies, probabilistic inferences are made based on information available in population databases. The accuracy of the estimates based on population samples are highly dependent on the number of chromosomes being analyzed as well as the correct representation of the reference population. For frequency calculations the size of a database is especially critical for haploid markers, and for countries with complex admixture histories it is important to assess possible substructure effects that can influence the coverage of the database. Aiming to establish a representative Brazilian population database for haplotypes based on 23 Y chromosome STRs, more than 2,500 Y chromosomes belonging to Brazilian, European and African populations were analyzed. No matter the differences in the colonization history of the five geopolitical regions that currently exist in Brazil, for the Y chromosome haplotypes of the 23 studied Y-STRs, a lack of genetic heterogeneity was found, together with a predominance of European male lineages in all regions of the country. Therefore, if we do not consider the diverse Native American or Afro-descendent isolates, which are spread through the country, a single Y chromosome haplotype frequency database will adequately represent the urban populations in Brazil. In comparison to the most commonly studied group of 17 Y-STRs, the 23 markers included in this work allowed a high discrimination capacity between haplotypes from non-related individuals within a population and also increased the capacity to discriminate between paternal relatives. Nevertheless, the expected haplotype mutation rate is still not enough to distinguish the Y chromosome profiles of paternally related individuals. Indeed, even for rapidly mutating Y-STRs, a very large number of markers will be necessary to differentiate male lineages from paternal relatives. PMID:22808085

  14. Molecular and immunogenetic analysis of major histocompatibility haplotypes in Northern Bobwhite enable direct identification of corresponding haplotypes in an endangered subspecies, the Masked Bobwhite

    USGS Publications Warehouse

    Drake, B.M.; Goto, R.M.; Miller, M.M.; Gee, G.F.; Briles, W.E.

    1999-01-01

    The major histocompatibility complex (MHC) is a group of genetic loci coding for haplotypes that have been associated with fitness traits in mammals and birds. Such associations suggest that MHC diversity may be an indicator of overall genetic fitness of endangered or threatened species. The MHC haplotypes of a captive population of 12 families of northern bobwhites (Colinus virginianus) were identified using a combination of immunogenetic and molecular techniques. Alloantisera were produced within families of northern bobwhites and were then tested for differential agglutination of erythrocytes of all members of each family. The pattern of reactions determined from testing these alloantisera identified a single genetic system of alloantigens in the northern bobwhites, resulting in the assignment of a tentative genotype to each individual within the quail families. Restriction fragment patterns of the DNA of each bird were determined using the chicken MHC B-G cDNA probe bg11. The concordance between the restriction fragment patterns and the alloantisera reactions showed that the alloantisera had identified the MHC of the northern bobwhite and supported the tentative genotype assignments, identifying at least 12 northern bobwhite MHC haplotypes.

  15. Genetic analysis of 17 Y-chromosomal STRs haplotypes of Chinese Tibetan ethnic minority group.

    PubMed

    Yi, Zhou; Jun, Wang; XingBo, Song; XiaoJun, Lu; Liu, Ding; BinWu, Ying

    2010-03-01

    We have co-amplified and analyzed 17 Y-chromosomal STRs loci (DYS19, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS438, DYS439, DYS437, DYS448, DYS456, DYS458, DYS635, YGATA-H4 and DYS385a/b) in 132 healthy unrelated autochthonous male individuals of Chinese Tibetan ethnic group residing in Lassa area of China. The gene diversity values for the Y-STRs loci ranged from a minimum 0.206 for DYS391 locus to a maximum of 0.912 for DYS385a/b locus in the populations. A total of 123 haplotypes were identified, among which 115 were unique and 8 occurred more than once. The overall haplotype diversity for 17 Y-STRs loci was 0.998. Research results will be valuable for forensic use in the regions and for Chinese population genetic study. PMID:20116321

  16. Detecting local haplotype sharing and haplotype association

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype...

  17. Haplotype inference constrained by plausible haplotype data.

    PubMed

    Fellows, Michael R; Hartman, Tzvika; Hermelin, Danny; Landau, Gad M; Rosamond, Frances; Rozenberg, Liat

    2011-01-01

    The haplotype inference problem (HIP) asks to find a set of haplotypes which resolve a given set of genotypes. This problem is important in practical fields such as the investigation of diseases or other types of genetic mutations. In order to find the haplotypes which are as close as possible to the real set of haplotypes that comprise the genotypes, two models have been suggested which are by now well-studied: The perfect phylogeny model and the pure parsimony model. All known algorithms up till now for haplotype inference may find haplotypes that are not necessarily plausible, i.e., very rare haplotypes or haplotypes that were never observed in the population. In order to overcome this disadvantage, we study in this paper, a new constrained version of HIP under the above-mentioned models. In this new version, a pool of plausible haplotypes H is given together with the set of genotypes G, and the goal is to find a subset H ⊆ H that resolves G. For constrained perfect phlogeny haplotyping (CPPH), we provide initial insights and polynomial-time algorithms for some restricted cases of the problem. For constrained parsimony haplotyping (CPH), we show that the problem is fixed parameter tractable when parameterized by the size of the solution set of haplotypes.

  18. Analysis of Amblyomma sculptum haplotypes in an area endemic for Brazilian spotted fever.

    PubMed

    Bitencourth, K; Voloch, C M; Serra-Freire, N M; Machado-Ferreira, E; Amorim, M; Gazêta, G S

    2016-09-01

    Amblyomma sculptum (Ixodida: Ixodidae) Berlese, 1888, a member of the Amblyomma cajennense complex, is the major vector of Brazilian spotted fever (BSF) in southeastern Brazil. In this study, the genetic diversity of A. sculptum populations in the state of Rio de Janeiro (RJ), Brazil, was investigated because genetic variability in tick populations may be related to vector competence. Samples of A. sculptum from 19 municipalities in 7 regions of RJ were subjected to DNA extraction, amplification and sequencing of D-loop, cytochrome oxidase II and 12S rDNA mitochondrial genes. These sequences were used to map the genetic diversity of this tick. Amblyomma sculptum populations are genetically diverse in RJ, especially in the South Centre and Highland regions. Few unique haplotypes were observed in all populations, and the majority of genetic variation found was among ticks within each population. Phylogenetic reconstruction reinforced the assumption that all the haplotypes identified in RJ belong to A. sculptum. However, some RJ haplotypes are closer to A. sculptum from Argentina than to A. sculptum from elsewhere in Brazil. In RJ, A. sculptum has high genetic diversity, although little genetic differentiation. Observations also indicated a high level of gene flow among the studied populations and no evidence of population structure according to region in RJ. PMID:27120044

  19. Twelve short tandem repeat loci Y chromosome haplotypes: genetic analysis on populations residing in North America.

    PubMed

    Budowle, Bruce; Adamowicz, Mike; Aranda, Xavier G; Barna, Charles; Chakraborty, Ranajit; Cheswick, Dan; Dafoe, Bradley; Eisenberg, Arthur; Frappier, Roger; Gross, Ann Marie; Ladd, Carll; Lee, Hee-Suk; Milne, Scott C; Meyers, Carole; Prinz, Mechthild; Richard, Melanie L; Saldanha, Gabriela; Tierney, Amy A; Viculis, Lori; Krenke, Benjamin E

    2005-05-28

    A total of 2443 male individuals, previously typed for the 13 CODIS STR loci, distributed across the five North American population groups African American, Asian, Caucasian, Hispanic, and Native American were typed for the Y-STR loci DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 using the PowerPlex Y System. All population samples were highly polymorphic for the 12 Y-STR loci with the marker DYS385a/b being the most polymorphic across all sample populations. The Native American population groups demonstrated the lowest genetic diversity, most notably at the DYS393 and DYS437 loci. Almost all of the 12-locus haplotypes observed in the sample populations were represented only once in the database. Haplotype diversities were greater than 99.6% for the African Americans, Caucasians, Hispanics, and Asians. The Native Americans had the lowest haplotype diversities (Apaches, 97.0%; Navajo, 98.1%). Population substructure effects were greater for Y-haplotypes, compared with that for the autosomal loci. For the apportionment of variance for the 12 Y-STRs, the within sample population variation was the largest component (>98% for each major population group and approximately 97% in Native Americans), and the variance component contributed by the major population groups was less than the individual component, but much greater than among sample populations within a major group (11.79% versus 1.02% for African Americans/Caucasians/Hispanics and 15.35% versus 1.25% for all five major populations). When each major population is analyzed individually, the R(ST) values were low but showed significant among group heterogeneity. In 692 confirmed father-son pairs, 14 mutation events were observed with the average rate of 1.57x10(-3)/locus/generation (a 95% confidence bound of 0.83x10(-3) to 2.69x10(-3)). Since the Y-STR loci reside on the non-recombining region of the Y chromosome, the counting method is one approach suggested for conveying

  20. Twelve short tandem repeat loci Y chromosome haplotypes: genetic analysis on populations residing in North America.

    PubMed

    Budowle, Bruce; Adamowicz, Mike; Aranda, Xavier G; Barna, Charles; Chakraborty, Ranajit; Cheswick, Dan; Dafoe, Bradley; Eisenberg, Arthur; Frappier, Roger; Gross, Ann Marie; Ladd, Carll; Lee, Hee-Suk; Milne, Scott C; Meyers, Carole; Prinz, Mechthild; Richard, Melanie L; Saldanha, Gabriela; Tierney, Amy A; Viculis, Lori; Krenke, Benjamin E

    2005-05-28

    A total of 2443 male individuals, previously typed for the 13 CODIS STR loci, distributed across the five North American population groups African American, Asian, Caucasian, Hispanic, and Native American were typed for the Y-STR loci DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 using the PowerPlex Y System. All population samples were highly polymorphic for the 12 Y-STR loci with the marker DYS385a/b being the most polymorphic across all sample populations. The Native American population groups demonstrated the lowest genetic diversity, most notably at the DYS393 and DYS437 loci. Almost all of the 12-locus haplotypes observed in the sample populations were represented only once in the database. Haplotype diversities were greater than 99.6% for the African Americans, Caucasians, Hispanics, and Asians. The Native Americans had the lowest haplotype diversities (Apaches, 97.0%; Navajo, 98.1%). Population substructure effects were greater for Y-haplotypes, compared with that for the autosomal loci. For the apportionment of variance for the 12 Y-STRs, the within sample population variation was the largest component (>98% for each major population group and approximately 97% in Native Americans), and the variance component contributed by the major population groups was less than the individual component, but much greater than among sample populations within a major group (11.79% versus 1.02% for African Americans/Caucasians/Hispanics and 15.35% versus 1.25% for all five major populations). When each major population is analyzed individually, the R(ST) values were low but showed significant among group heterogeneity. In 692 confirmed father-son pairs, 14 mutation events were observed with the average rate of 1.57x10(-3)/locus/generation (a 95% confidence bound of 0.83x10(-3) to 2.69x10(-3)). Since the Y-STR loci reside on the non-recombining region of the Y chromosome, the counting method is one approach suggested for conveying

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

    USGS Publications Warehouse

    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.

  2. A systematic search for SNPs/haplotypes associated with disease phenotypes using a haplotype-based stepwise procedure

    PubMed Central

    Yang, Yin; Li, Shuying Sue; Chien, Jason W; Andriesen, Jessica; Zhao, Lue Ping

    2008-01-01

    Background Genotyping technologies enable us to genotype multiple Single Nucleotide Polymorphisms (SNPs) within selected genes/regions, providing data for haplotype association analysis. While haplotype-based association analysis is powerful for detecting untyped causal alleles in linkage-disequilibrium (LD) with neighboring SNPs/haplotypes, the inclusion of extraneous SNPs could reduce its power by increasing the number of haplotypes with each additional SNP. Methods Here, we propose a haplotype-based stepwise procedure (HBSP) to eliminate extraneous SNPs. To evaluate its properties, we applied HBSP to both simulated and real data, generated from a study of genetic associations of the bactericidal/permeability-increasing (BPI) gene with pulmonary function in a cohort of patients following bone marrow transplantation. Results Under the null hypothesis, use of the HBSP gave results that retained the desired false positive error rates when multiple comparisons were considered. Under various alternative hypotheses, HBSP had adequate power to detect modest genetic associations in case-control studies with 500, 1,000 or 2,000 subjects. In the current application, HBSP led to the identification of two specific SNPs with a positive validation. Conclusion These results demonstrate that HBSP retains the essence of haplotype-based association analysis while improving analytic power by excluding extraneous SNPs. Minimizing the number of SNPs also enables simpler interpretation and more cost-effective applications. PMID:19102730

  3. An integrative variant analysis pipeline for accurate genotype/haplotype inference in population NGS data

    PubMed Central

    Wang, Yi; Lu, James; Yu, Jin; Gibbs, Richard A.; Yu, Fuli

    2013-01-01

    Next-generation sequencing is a powerful approach for discovering genetic variation. Sensitive variant calling and haplotype inference from population sequencing data remain challenging. We describe methods for high-quality discovery, genotyping, and phasing of SNPs for low-coverage (approximately 5×) sequencing of populations, implemented in a pipeline called SNPTools. Our pipeline contains several innovations that specifically address challenges caused by low-coverage population sequencing: (1) effective base depth (EBD), a nonparametric statistic that enables more accurate statistical modeling of sequencing data; (2) variance ratio scoring, a variance-based statistic that discovers polymorphic loci with high sensitivity and specificity; and (3) BAM-specific binomial mixture modeling (BBMM), a clustering algorithm that generates robust genotype likelihoods from heterogeneous sequencing data. Last, we develop an imputation engine that refines raw genotype likelihoods to produce high-quality phased genotypes/haplotypes. Designed for large population studies, SNPTools' input/output (I/O) and storage aware design leads to improved computing performance on large sequencing data sets. We apply SNPTools to the International 1000 Genomes Project (1000G) Phase 1 low-coverage data set and obtain genotyping accuracy comparable to that of SNP microarray. PMID:23296920

  4. The haplotype-relative-risk (HRR) method for analysis of association in nuclear families

    SciTech Connect

    Knapp, M.; Seuchter, S.A.; Baur, M.P. )

    1993-06-01

    One major problem in studying an association between a marker locus and a disease is the selection of an appropriate group of controls. However, this problem of population stratification can be circumvented in a quite elegant manner by family-based methods. The haplotype-relative-risk (HRR) method, which samples nuclear families with a single affected child and uses the parental haplotypes not transmitted to that child as a control individual, represents such a method for estimating the relative risk of a marker phenotype. In the special case of a recessive disease, it was already known that the equivalence of the HRR method with the classical relative risk (RR) obtained from independent samples holds only if the probability [theta] of a recombination between marker and disease locus is zero. The authors extend this result to an arbitrary mode of inheritance. Furthermore, they compare the distribution of the estimators for HRR and RR and show that, in the case of a positive linkage disequilibrium between a marker and disease allele, the distribution of the estimator for HRR is (stochastically) smaller than that for RR, irrespective of the recombination fraction. The practical implication of this result is that, for the HRR method, there is no tendency to give unduly high risk estimators, even for [theta] > 0. Finally, the authors give an expression for the standard error of the estimator for HRR by taking into account the nonindependence of transmitted and nontransmitted parental marker alleles in the case of [theta] > 0. 16 refs., 3 tabs.

  5. Haplotype hitchhiking promotes trait coselection in Brassica napus.

    PubMed

    Qian, Lunwen; Qian, Wei; Snowdon, Rod J

    2016-07-01

    Local haplotype patterns surrounding densely spaced DNA markers with significant trait associations can reveal information on selective sweeps and genome diversity associated with important crop traits. Relationships between haplotype and phenotype diversity, coupled with analysis of gene content in conserved haplotype blocks, can provide insight into coselection for nonrelated traits. We performed genome-wide analysis of haplotypes associated with the important physiological and agronomic traits leaf chlorophyll and seed glucosinolate content, respectively, in the major oilseed crop species Brassica napus. A locus on chromosome A01 showed opposite effects on leaf chlorophyll content and seed glucosinolate content, attributed to strong linkage disequilibrium (LD) between orthologues of the chlorophyll biosynthesis genes EARLY LIGHT-INDUCED PROTEIN and CHLOROPHYLL SYNTHASE, and the glucosinolate synthesis gene ATP SULFURYLASE 1. Another conserved haplotype block, on chromosome A02, contained a number of chlorophyll-related genes in LD with orthologues of the key glucosinolate biosynthesis genes METHYLTHIOALKYMALATE SYNTHASE-LIKE 1 and 3. Multigene haplogroups were found to have a significantly greater contribution to variation for chlorophyll content than haplotypes for any single gene, suggesting positive effects of additive locus accumulation. Detailed reanalysis of population substructure revealed a clade of ten related accessions exhibiting high leaf chlorophyll and low seed glucosinolate content. These accessions each carried one of the above-mentioned haplotypes from A01 or A02, generally in combination with further chlorophyll-associated haplotypes from chromosomes A05 and/or C05. The phenotypic rather than pleiotropic correlations between leaf chlorophyll content index and seed GSL suggest that LD may have led to inadvertent coselection for these two traits. PMID:26800855

  6. Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy.

    PubMed

    Saito, K; Osawa, M; Wang, Z P; Ikeya, K; Fukuyama, Y; Kondo-Iida, E; Toda, T; Ohashi, H; Kurosawa, K; Wakai, S; Kaneko, K

    2000-05-29

    In typical Fukuyama congenital muscular dystrophy (FCMD), peak motor function is usually only unassisted sitting or sliding on the buttocks, though a few patients are able to walk at some point. However, a few patients have a severe phenotype and never acquire head control. In addition, it is clinically difficult to differentiate this severe FCMD from Walker-Warburg syndrome (WWS) or from muscle-eye-brain disease (MEBD). In order to establish a genotype-phenotype correlation, we performed haplotype analysis using microsatellite markers closest to the FCMD gene (FCMD) in 56 Japanese FCMD families, including 35 families whose children were diagnosed as FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 propositi with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder (A-F) haplotype whereas the other 2 were heterozygous for the haplotype. In the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmological abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype are heterozygous for the A-F haplotype, and the other one homozygous for the haplotype. We confirmed that at least one chromosome in each of the 56 FCMD patients has the A-F haplotype. The rate of heterozygosity for the A-F haplotypes was significantly higher in severe cases than in typical or mild cases (P < 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation. Thus, the present study yielded molecular genetic evidence of a broad clinical spectrum in FCMD.

  7. Effectiveness of computational methods in haplotype prediction.

    PubMed

    Xu, Chun-Fang; Lewis, Karen; Cantone, Kathryn L; Khan, Parveen; Donnelly, Christine; White, Nicola; Crocker, Nikki; Boyd, Pete R; Zaykin, Dmitri V; Purvis, Ian J

    2002-02-01

    Haplotype analysis has been used for narrowing down the location of disease-susceptibility genes and for investigating many population processes. Computational algorithms have been developed to estimate haplotype frequencies and to predict haplotype phases from genotype data for unrelated individuals. However, the accuracy of such computational methods needs to be evaluated before their applications can be advocated. We have experimentally determined the haplotypes at two loci, the N-acetyltransferase 2 gene ( NAT2, 850 bp, n=81) and a 140-kb region on chromosome X ( n=77), each consisting of five single nucleotide polymorphisms (SNPs). We empirically evaluated and compared the accuracy of the subtraction method, the expectation-maximization (EM) method, and the PHASE method in haplotype frequency estimation and in haplotype phase prediction. Where there was near complete linkage disequilibrium (LD) between SNPs (the NAT2 gene), all three methods provided effective and accurate estimates for haplotype frequencies and individual haplotype phases. For a genomic region in which marked LD was not maintained (the chromosome X locus), the computational methods were adequate in estimating overall haplotype frequencies. However, none of the methods was accurate in predicting individual haplotype phases. The EM and the PHASE methods provided better estimates for overall haplotype frequencies than the subtraction method for both genomic regions.

  8. Haplotype analysis of Apo AI-CIII-AIV gene cluster and lipids level: Tehran Lipid and Glucose Study.

    PubMed

    Daneshpour, Maryam S; Faam, Bita; Mansournia, Mohamad Ali; Hedayati, Mehdi; Halalkhor, Sohrab; Mesbah-Namin, Seyed Alireza; Shojaei, Shahla; Zarkesh, Maryam; Azizi, Fereidoun

    2012-02-01

    Iranian populations show an increased tendency for abnormal lipid levels and high risk of Coronary artery disease. Considering the important role played by the ApoAI-CIII-AIV gene cluster in the regulation of the level and metabolism of lipids, this study aimed at elucidating the association between five single nucleotide polymorphisms on the Apo11q cluster gene and lipid levels. A cross-sectional study of 823 subjects (340 males and 483 females) from the Tehran lipid and glucose study (TLGS) was conducted. Levels of TG, Chol, HDL-C, Apo AI, Apo AIV, Apo B, and Apo CIII were measured, and the selected segments of the APOAI-CIII-AIV gene cluster were amplified by PCR and the polymorphisms were revealed by RFLP using restriction enzymes. The allele frequencies for each SNP between males and females were not significantly different. The distribution of Genotypes and alleles was in Hardy-Weinberg equilibrium except for Apo AI (+83C>T). The results showed a significant association between TG, HDL-C, HDL(2), Apo AI, and Apo B levels and the presence of some alleles in the polymorphisms studied. After haplotype analysis not only did the association between these variables and SNPs remain but also levels of Chol and LDL-C were added. This study demonstrates that the level of lipids such as TG, HDL-C, HDL(2), Apo AI, and Apo B, maybe regulated partly by genetic factors and their haplotype within the Apo11q gene cluster.

  9. Reconstruction of a historical genealogy by means of STR analysis and Y-haplotyping of ancient DNA.

    PubMed

    Gerstenberger, J; Hummel, S; Schultes, T; Häck, B; Herrmann, B

    1999-01-01

    Archaeological excavations in St Margaretha's church at Reichersdorf, Germany, in 1993 led to the discovery of eight skeletons, so far assumed to be of the Earls of Königsfeld, who used the church as a family sepulchre over a period of seven generations from 1546 to 1749. DNA-based sex testing and analysis of autosomal short tandem repeat systems (STR) was carried out to confirm the assumption of kinship. Since five of the individuals were determined as males, analysis of Y-specific STRs seemed feasible. A comparison of Y-haplotypes revealed that one individual could not be linked to the Königsfeld patrilineage, an observation supported by autosomal STR evidence. Two individuals typed as females posed an identification problem, since supposedly only male members of the family were buried in St Margaretha's. Nevertheless, these individuals could tentatively be identified as members of the House of Königsfeld through genetic fingerprinting.

  10. Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites

    SciTech Connect

    Malo, D.; Hu, Jinxin; Schurr, E.

    1994-09-01

    The mouse chromosome 1 locus Bcg (Ity, Lsh) controls the capacity of the tissue macrophage to restrict the replication of antigenically unrelated intracellular parasites and therefore determines the natural resistance (BCG-R, dominant) or susceptibility (BCG-S, recessive) of inbred mouse strains to infection with diverse pathogens. We have used a positional cloning strategy based on genetic and physical mapping, YAC cloning, and exon trapping to isolate a candidate gene for Beg (Nramp) that encodes a predicted macrophage-specific transport protein. We have analyzed a total of 27 inbred mouse strains of BCG-R and BCG-S phenotypes for the presence of nucleotide sequence variations within the coding portion of Nramp and have carried out haplotype typing of the corresponding chromosome 1 region in these mice, using 11 additional polymorphic markers mapping in the immediate vicinity of Nramp. cDNA cloning and nucleotide sequencing identified 5 nucleotide sequence variations within Nramp in the inbred strains.

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

    PubMed Central

    Saad, Mohamed N.; Mabrouk, Mai S.; Eldeib, Ayman M.; Shaker, Olfat G.

    2015-01-01

    Genetics of autoimmune diseases represent a growing domain with surpassing biomarker results with rapid progress. The exact cause of Rheumatoid Arthritis (RA) is unknown, but it is thought to have both a genetic and an environmental bases. Genetic biomarkers are capable of changing the supervision of RA by allowing not only the detection of susceptible individuals, but also early diagnosis, evaluation of disease severity, selection of therapy, and monitoring of response to therapy. This review is concerned with not only the genetic biomarkers of RA but also the methods of identifying them. Many of the identified genetic biomarkers of RA were identified in populations of European and Asian ancestries. The study of additional human populations may yield novel results. Most of the researchers in the field of identifying RA biomarkers use single nucleotide polymorphism (SNP) approaches to express the significance of their results. Although, haplotype block methods are expected to play a complementary role in the future of that field. PMID:26843965

  12. A Cladistic Analysis of Phenotypic Associations with Haplotypes Inferred from Restriction Endonuclease Mapping. IV. Nested Analyses with Cladogram Uncertainty and Recombination

    PubMed Central

    Templeton, A. R.; Sing, C. F.

    1993-01-01

    We previously developed an analytical strategy based on cladistic theory to identify subsets of haplotypes that are associated with significant phenotypic deviations. Our initial approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site data to estimate the evolutionary steps that interrelate the observed haplotypes to one another. The cladogram is then used to define a nested statistical design for identifying mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that a mutation responsible for a particular phenotypic effect is embedded within the evolutionary history that is represented by the cladogram. The power of this approach depends on the accuracy of the cladogram in portraying the evolutionary history of the DNA region. This accuracy can be diminished both by recombination and by uncertainty in the estimated cladogram topology. In a previous paper, we presented an algorithm for estimating the set of likely cladograms and recombination events. In this paper we present an algorithm for defining a nested statistical design under cladogram uncertainty and recombination. Given the nested design, phenotypic associations can be examined using either a nested analysis of variance (for haploids or homozygous strains) or permutation testing (for outcrossed, diploid gene regions). In this paper we also extend this analytical strategy to include categorical phenotypes in addition to quantitative phenotypes. Some worked examples are presented using Drosophila data sets. These examples illustrate that having some recombination may actually enhance the biological inferences that may derived from a cladistic analysis. In particular, recombination can be used to assign a physical localization to a given subregion for mutations responsible for significant phenotypic effects. PMID:8100789

  13. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. IV. Nested analyses with cladogram uncertainty and recombination.

    PubMed

    Templeton, A R; Sing, C F

    1993-06-01

    We previously developed an analytical strategy based on cladistic theory to identify subsets of haplotypes that are associated with significant phenotypic deviations. Our initial approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site data to estimate the evolutionary steps that interrelate the observed haplotypes to one another. The cladogram is then used to define a nested statistical design for identifying mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that a mutation responsible for a particular phenotypic effect is embedded within the evolutionary history that is represented by the cladogram. The power of this approach depends on the accuracy of the cladogram in portraying the evolutionary history of the DNA region. This accuracy can be diminished both by recombination and by uncertainty in the estimated cladogram topology. In a previous paper, we presented an algorithm for estimating the set of likely claodgrams and recombination events. In this paper we present an algorithm for defining a nested statistical design under cladogram uncertainty and recombination. Given the nested design, phenotypic associations can be examined using either a nested analysis of variance (for haploids or homozygous strains) or permutation testing (for outcrossed, diploid gene regions). In this paper we also extend this analytical strategy to include categorical phenotypes in addition to quantitative phenotypes. Some worked examples are presented using Drosophila data sets. These examples illustrate that having some recombination may actually enhance the biological inferences that may derived from a cladistic analysis. In particular, recombination can be used to assign a physical localization to a given subregion for mutations responsible for significant phenotypic effects.

  14. A global analysis of Y-chromosomal haplotype diversity for 23 STR loci.

    PubMed

    Purps, Josephine; Siegert, Sabine; Willuweit, Sascha; Nagy, Marion; Alves, Cíntia; Salazar, Renato; Angustia, Sheila M T; Santos, Lorna H; Anslinger, Katja; Bayer, Birgit; Ayub, Qasim; Wei, Wei; Xue, Yali; Tyler-Smith, Chris; Bafalluy, Miriam Baeta; Martínez-Jarreta, Begoña; Egyed, Balazs; Balitzki, Beate; Tschumi, Sibylle; Ballard, David; Court, Denise Syndercombe; Barrantes, Xinia; Bäßler, Gerhard; Wiest, Tina; Berger, Burkhard; Niederstätter, Harald; Parson, Walther; Davis, Carey; Budowle, Bruce; Burri, Helen; Borer, Urs; Koller, Christoph; Carvalho, Elizeu F; Domingues, Patricia M; Chamoun, Wafaa Takash; Coble, Michael D; Hill, Carolyn R; Corach, Daniel; Caputo, Mariela; D'Amato, Maria E; Davison, Sean; Decorte, Ronny; Larmuseau, Maarten H D; Ottoni, Claudio; Rickards, Olga; Lu, Di; Jiang, Chengtao; Dobosz, Tadeusz; Jonkisz, Anna; Frank, William E; Furac, Ivana; Gehrig, Christian; Castella, Vincent; Grskovic, Branka; Haas, Cordula; Wobst, Jana; Hadzic, Gavrilo; Drobnic, Katja; Honda, Katsuya; Hou, Yiping; Zhou, Di; Li, Yan; Hu, Shengping; Chen, Shenglan; Immel, Uta-Dorothee; Lessig, Rüdiger; Jakovski, Zlatko; Ilievska, Tanja; Klann, Anja E; García, Cristina Cano; de Knijff, Peter; Kraaijenbrink, Thirsa; Kondili, Aikaterini; Miniati, Penelope; Vouropoulou, Maria; Kovacevic, Lejla; Marjanovic, Damir; Lindner, Iris; Mansour, Issam; Al-Azem, Mouayyad; Andari, Ansar El; Marino, Miguel; Furfuro, Sandra; Locarno, Laura; Martín, Pablo; Luque, Gracia M; Alonso, Antonio; Miranda, Luís Souto; Moreira, Helena; Mizuno, Natsuko; Iwashima, Yasuki; Neto, Rodrigo S Moura; Nogueira, Tatiana L S; Silva, Rosane; Nastainczyk-Wulf, Marina; Edelmann, Jeanett; Kohl, Michael; Nie, Shengjie; Wang, Xianping; Cheng, Baowen; Núñez, Carolina; Pancorbo, Marian Martínez de; Olofsson, Jill K; Morling, Niels; Onofri, Valerio; Tagliabracci, Adriano; Pamjav, Horolma; Volgyi, Antonia; Barany, Gusztav; Pawlowski, Ryszard; Maciejewska, Agnieszka; Pelotti, Susi; Pepinski, Witold; Abreu-Glowacka, Monica; Phillips, Christopher; Cárdenas, Jorge; Rey-Gonzalez, Danel; Salas, Antonio; Brisighelli, Francesca; Capelli, Cristian; Toscanini, Ulises; Piccinini, Andrea; Piglionica, Marilidia; Baldassarra, Stefania L; Ploski, Rafal; Konarzewska, Magdalena; Jastrzebska, Emila; Robino, Carlo; Sajantila, Antti; Palo, Jukka U; Guevara, Evelyn; Salvador, Jazelyn; Ungria, Maria Corazon De; Rodriguez, Jae Joseph Russell; Schmidt, Ulrike; Schlauderer, Nicola; Saukko, Pekka; Schneider, Peter M; Sirker, Miriam; Shin, Kyoung-Jin; Oh, Yu Na; Skitsa, Iulia; Ampati, Alexandra; Smith, Tobi-Gail; Calvit, Lina Solis de; Stenzl, Vlastimil; Capal, Thomas; Tillmar, Andreas; Nilsson, Helena; Turrina, Stefania; De Leo, Domenico; Verzeletti, Andrea; Cortellini, Venusia; Wetton, Jon H; Gwynne, Gareth M; Jobling, Mark A; Whittle, Martin R; Sumita, Denilce R; Wolańska-Nowak, Paulina; Yong, Rita Y Y; Krawczak, Michael; Nothnagel, Michael; Roewer, Lutz

    2014-09-01

    In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend toward smaller genetic distances resulting from larger numbers of markers became apparent. PMID:24854874

  15. Functional variation in promoter region of monoamine oxidase A and subtypes of alcoholism: haplotype analysis.

    PubMed

    Parsian, Abbas; Cloninger, C Robert; Sinha, Rashmi; Zhang, Zhen Hua

    2003-02-01

    Monoamine oxidase (MAO) is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines. MAO-A, due to its function in central nervous system, has been one of the important candidate genes involved in the development of neuropsychiatric disorders. A functional polymorphism in the promoter region of the MAO-A gene has been identified. This variation affects the transcriptional efficiency of the gene. To determine the role of this MAO-A functional polymorphism in the development of subtypes of alcoholism, a sample of alcoholics and normal controls were screened with this marker. The allele frequency differences between total alcoholics, Types I and II alcoholics, and normal controls was not significant. Comparison of male alcoholics to male normal controls for the frequencies of two-loci and three-loci haplotypes was statistically significant. After Bonferroni's correction for multiple tests none of the results remained significant at P < 0.05. Our results indicate that MAO-A may play a role in the development of alcoholism but the gene effect is very small.

  16. A global analysis of Y-chromosomal haplotype diversity for 23 STR loci

    PubMed Central

    Purps, Josephine; Siegert, Sabine; Willuweit, Sascha; Nagy, Marion; Alves, Cíntia; Salazar, Renato; Angustia, Sheila M.T.; Santos, Lorna H.; Anslinger, Katja; Bayer, Birgit; Ayub, Qasim; Wei, Wei; Xue, Yali; Tyler-Smith, Chris; Bafalluy, Miriam Baeta; Martínez-Jarreta, Begoña; Egyed, Balazs; Balitzki, Beate; Tschumi, Sibylle; Ballard, David; Court, Denise Syndercombe; Barrantes, Xinia; Bäßler, Gerhard; Wiest, Tina; Berger, Burkhard; Niederstätter, Harald; Parson, Walther; Davis, Carey; Budowle, Bruce; Burri, Helen; Borer, Urs; Koller, Christoph; Carvalho, Elizeu F.; Domingues, Patricia M.; Chamoun, Wafaa Takash; Coble, Michael D.; Hill, Carolyn R.; Corach, Daniel; Caputo, Mariela; D’Amato, Maria E.; Davison, Sean; Decorte, Ronny; Larmuseau, Maarten H.D.; Ottoni, Claudio; Rickards, Olga; Lu, Di; Jiang, Chengtao; Dobosz, Tadeusz; Jonkisz, Anna; Frank, William E.; Furac, Ivana; Gehrig, Christian; Castella, Vincent; Grskovic, Branka; Haas, Cordula; Wobst, Jana; Hadzic, Gavrilo; Drobnic, Katja; Honda, Katsuya; Hou, Yiping; Zhou, Di; Li, Yan; Hu, Shengping; Chen, Shenglan; Immel, Uta-Dorothee; Lessig, Rüdiger; Jakovski, Zlatko; Ilievska, Tanja; Klann, Anja E.; García, Cristina Cano; de Knijff, Peter; Kraaijenbrink, Thirsa; Kondili, Aikaterini; Miniati, Penelope; Vouropoulou, Maria; Kovacevic, Lejla; Marjanovic, Damir; Lindner, Iris; Mansour, Issam; Al-Azem, Mouayyad; Andari, Ansar El; Marino, Miguel; Furfuro, Sandra; Locarno, Laura; Martín, Pablo; Luque, Gracia M.; Alonso, Antonio; Miranda, Luís Souto; Moreira, Helena; Mizuno, Natsuko; Iwashima, Yasuki; Neto, Rodrigo S. Moura; Nogueira, Tatiana L.S.; Silva, Rosane; Nastainczyk-Wulf, Marina; Edelmann, Jeanett; Kohl, Michael; Nie, Shengjie; Wang, Xianping; Cheng, Baowen; Núñez, Carolina; Pancorbo, Marian Martínez de; Olofsson, Jill K.; Morling, Niels; Onofri, Valerio; Tagliabracci, Adriano; Pamjav, Horolma; Volgyi, Antonia; Barany, Gusztav; Pawlowski, Ryszard; Maciejewska, Agnieszka; Pelotti, Susi; Pepinski, Witold; Abreu-Glowacka, Monica; Phillips, Christopher; Cárdenas, Jorge; Rey-Gonzalez, Danel; Salas, Antonio; Brisighelli, Francesca; Capelli, Cristian; Toscanini, Ulises; Piccinini, Andrea; Piglionica, Marilidia; Baldassarra, Stefania L.; Ploski, Rafal; Konarzewska, Magdalena; Jastrzebska, Emila; Robino, Carlo; Sajantila, Antti; Palo, Jukka U.; Guevara, Evelyn; Salvador, Jazelyn; Ungria, Maria Corazon De; Rodriguez, Jae Joseph Russell; Schmidt, Ulrike; Schlauderer, Nicola; Saukko, Pekka; Schneider, Peter M.; Sirker, Miriam; Shin, Kyoung-Jin; Oh, Yu Na; Skitsa, Iulia; Ampati, Alexandra; Smith, Tobi-Gail; Calvit, Lina Solis de; Stenzl, Vlastimil; Capal, Thomas; Tillmar, Andreas; Nilsson, Helena; Turrina, Stefania; De Leo, Domenico; Verzeletti, Andrea; Cortellini, Venusia; Wetton, Jon H.; Gwynne, Gareth M.; Jobling, Mark A.; Whittle, Martin R.; Sumita, Denilce R.; Wolańska-Nowak, Paulina; Yong, Rita Y.Y.; Krawczak, Michael; Nothnagel, Michael; Roewer, Lutz

    2014-01-01

    In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend toward smaller genetic distances resulting from larger numbers of markers became apparent. PMID:24854874

  17. A Cladistic Analysis of Phenotypic Associations with Haplotypes Inferred from Restriction Endonuclease Mapping. I. Basic Theory and an Analysis of Alcohol Dehydrogenase Activity in Drosophila

    PubMed Central

    Templeton, Alan R.; Boerwinkle, Eric; Sing, Charles F.

    1987-01-01

    Because some genes have been cloned that have a known biochemical or physiological function, genetic variation can be measured in a population at loci that may directly influence a phenotype of interest. With this measured genotype approach, specific alleles or haplotypes in the probed DNA region can be assigned phenotypic effects. In this paper we address several problems encountered in implementing the measured genotype approach with restriction site data. A number of analytical problems arise in part as a consequence of the linkage disequilibrium that is commonly encountered when dealing with small DNA regions: 1) different restriction site polymorphisms are not statistically independent, 2) the sites being measured are not likely to be the direct cause of the associated phenotypic effects, 3) haplotype classes may be phenotypically heterogeneous, and 4) the sites that are most strongly associated with phenotypic effects are not necessarily the most closely linked to the actual genetic cause of the effects. When recombination and gene conversion are rare, the primary cause of linkage disequilibrium is history (mutational origin, genetic drift, hitchhiking, etc.). We deal with historical association directly by producing a cladogram that partially reconstructs the evolutionary history of the present-day haplotype variability. The cladogram defines a nested analysis of variance that simultaneously detects phenotypic effects, localizes the effects within the cladogram, and identifies haplotypes that are potentially heterogeneous in their phenotypic associations. The power of this approach is illustrated by an analysis of the associations between alcohol dehydrogenase (ADH) activity and restriction site variability in a 13-kb fragment surrounding the ADH locus in Drosophila melanogaster. PMID:2822535

  18. Whole-genome haplotyping approaches and genomic medicine.

    PubMed

    Glusman, Gustavo; Cox, Hannah C; Roach, Jared C

    2014-01-01

    Genomic information reported as haplotypes rather than genotypes will be increasingly important for personalized medicine. Current technologies generate diploid sequence data that is rarely resolved into its constituent haplotypes. Furthermore, paradigms for thinking about genomic information are based on interpreting genotypes rather than haplotypes. Nevertheless, haplotypes have historically been useful in contexts ranging from population genetics to disease-gene mapping efforts. The main approaches for phasing genomic sequence data are molecular haplotyping, genetic haplotyping, and population-based inference. Long-read sequencing technologies are enabling longer molecular haplotypes, and decreases in the cost of whole-genome sequencing are enabling the sequencing of whole-chromosome genetic haplotypes. Hybrid approaches combining high-throughput short-read assembly with strategic approaches that enable physical or virtual binning of reads into haplotypes are enabling multi-gene haplotypes to be generated from single individuals. These techniques can be further combined with genetic and population approaches. Here, we review advances in whole-genome haplotyping approaches and discuss the importance of haplotypes for genomic medicine. Clinical applications include diagnosis by recognition of compound heterozygosity and by phasing regulatory variation to coding variation. Haplotypes, which are more specific than less complex variants such as single nucleotide variants, also have applications in prognostics and diagnostics, in the analysis of tumors, and in typing tissue for transplantation. Future advances will include technological innovations, the application of standard metrics for evaluating haplotype quality, and the development of databases that link haplotypes to disease. PMID:25473435

  19. Beta S haplotypes in various world populations.

    PubMed

    Oner, C; Dimovski, A J; Olivieri, N F; Schiliro, G; Codrington, J F; Fattoum, S; Adekile, A D; Oner, R; Yüregir, G T; Altay, C

    1992-04-01

    We have determined the beta S haplotypes in 709 patients with sickle cell anemia, 30 with SC disease, 91 with S-beta-thalassemia, and in 322 Hb S heterozygotes from different countries. The methodology concerned the detection of mutations in the promoter sequences of the G gamma- and A gamma-globin genes through dot blot analysis of amplified DNA with 32P-labeled probes, and an analysis of isolated Hb F by reversed phase high performance liquid chromatography to detect the presence of the A gamma T chain [A gamma 75(E19)Ile----Thr] that is characteristic for haplotype 17 (Cameroon). The results support previously published data obtained with conventional methodology that indicates that the beta S gene arose separately in different locations. The present methodology has the advantage of being relatively inexpensive and fast, allowing the collection of a vast body of data in a short period of time. It also offers the opportunity of identifying unusual beta S haplotypes that may be associated with a milder expression of the disease. The numerous blood samples obtained from many SS patients living in different countries made it possible to compare their hematological data. Such information is included (as average values) for 395 SS patients with haplotype 19/19, for 2 with haplotype 17/17, for 50 with haplotype 20/20, for 2 with haplotype 3/3, and for 37 with haplotype 31/31. Some information on haplotype characteristics of normal beta A chromosomes is also presented.

  20. Analysis of the adequate size of a cord blood bank and comparison of HLA haplotype distributions between four populations.

    PubMed

    Haimila, Katri; Penttilä, Antti; Arvola, Anne; Auvinen, Marja-Kaisa; Korhonen, Matti

    2013-02-01

    The number of units and especially the number of different HLA haplotypes present in a cord blood (CB) bank is a crucial determinant of its usefulness. We generated data relevant to the development of our national CB in Finland. The HLA haplotype distribution was examined between specific populations. We developed graphical ways of data presentation that enable easy visualization of differences. First, we estimated the optimal size of a CB bank for Finland and found that approximately 1700 units are needed to provide a 5/6 HLA-matched donor for 80% of Finnish patients. Secondly, we evaluated HLA haplotype distributions between four locations, Finland, Japan, Sweden and Belgium. Our results showed that the Japanese Tokyo Cord Blood Bank differs in both the frequency and distribution of haplotypes from the European banks. The European banks (Finnish Cord Blood Registry, The Swedish National Cord Blood Bank, and Marrow Donor Program-Belgium) have similar frequencies of common haplotypes, but 26% of the haplotypes in the Finnish CB bank are unique, which justifies the existence of a national bank. The tendency to a homogenous HLA haplotype distribution in banks underlines the need for targeting recruitment at the poorly represented minority populations.

  1. Evidences for multiple maternal lineages of Caryocar brasiliense populations in the Brazilian Cerrado based on the analysis of chloroplast DNA sequences and microsatellite haplotype variation.

    PubMed

    Collevatti, Rosane G; Grattapaglia, Dario; Hay, John D

    2003-01-01

    In this work we report on the phylogeography of the endangered tree species Caryocar brasiliense based on variability in two classes of maternally inherited chloroplast DNA sequences with different rates of molecular evolution. Eleven sequence haplotypes of a noncoding region between the genes trnT and trnF and 21 distinct 10-locus microsatellite haplotypes could be identified in a total of 160 individuals, collected in 10 widespread populations of C. brasiliense. An amova indicated that most of the variation can be attributed to differences among populations, both for DNA sequence (87.51%) and microsatellites (84.38%). Phylogeography based on a median-joining network analysis of the noncoding region showed a sharp difference from the analysis of microsatellite haplotypes. Nevertheless, both analyses indicated that multiple lineages may have contributed to the origin of C. brasiliense populations in Brazilian Cerrado. Incongruences in the microsatellite haplotypes network suggest that homoplasy, which emerged from recurrent and independent mutations, greatly influenced the evolution of the C. brasiliense chloroplast genome. We hypothesize that our results may show the outcome of the restriction of ancient relic populations to moist refugias during extended droughts coinciding with glaciation in the northern hemisphere. The subsequent spread to favourable areas throughout Central Brazil may have caused contact between different lineages during the interglacial periods. The extinction of megafauna dispersers in the last glaciation may have caused a restriction in seed movement and currently, gene flow has been occurring mainly by pollen movement.

  2. Toward localization of the Werner syndrome gene by linkage disequilibrium and ancestral haplotyping: Lessons learned from analysis of 35 chromosome 8p11.1-21.1 markers

    SciTech Connect

    Goddard, K.A.B.; Wijsman, E.M.; Martin, G.M.

    1996-06-01

    Werner syndrome (WS) is an autosomal recessive disorder characterized by premature onset of a number of age-related diseases. The gene for WS, WRN, has been mapped to the 8p11.1-21.1 region with further localization through linkage disequilibrium mapping. Here we present the results of linkage disequilibrium and ancestral haplotype analyses of 35 markers to further refine the location of WRN. We identified an interval in this region in which 14 of 18 markers tested show significant evidence of linkage disequilibrium in at least one of the two populations tested. Analysis of extended and partial haplotypes covering 21 of the markers studied supports the existence of both obligate and probable ancestral recombinant events which localize WRN almost certainly to the interval between DSS2196 and D8S2186, and most likely to the narrower interval between D8S2168 and D8S2186. These haplotype analyses also suggest that there are multiple WRN mutations in each of the two populations under study. We also present a comparison of approaches to performing disequilibrium tests with multiallelic markers, and show that some commonly used approximations for such tests perform poorly in comparison to exact probability tests. Finally, we discuss some of the difficulties introduced by the high mutation rate at microsatellite markers which influence our ability to use ancestral haplotype analysis to localize disease genes. 51 refs., 6 figs., 7 tabs.

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

    PubMed Central

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

    2002-01-01

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

  4. Linkage disequilibrium analysis reveals an albuminuria risk haplotype containing three missense mutations in the cubilin gene with striking differences among European and African ancestry populations

    PubMed Central

    2012-01-01

    Background A recent meta-analysis described a variant (p.Ile2984Val) in the cubilin gene (CUBN) that is associated with levels of albuminuria in the general population and in diabetics. Methods We implemented a Linkage Disequilibrium (LD) search with data from the 1000 Genomes Project, on African and European population genomic sequences. Results We found that the p.Ile2984Val variation is part of a larger haplotype in European populations and it is almost absent in west Africans. This haplotype contains 19 single nucleotide polymorphisms (SNPs) in very high LD, three of which are missense mutations (p.Leu2153Phe, p.Ile2984Val, p.Glu3002Gly), and two have not been previously reported. Notably, this European haplotype is absent in west African populations, and the frequency of each individual polymorphism differs significantly in Africans. Conclusions Genotyping of these variants in existing African origin sample sets coupled to measurements of urine albumin excretion levels should reveal which is the most likely functional candidate for albuminuria risk. The unique haplotypic structure of CUBN in different populations may leverage the effort to identify the functional variant and to shed light on evolution of the CUBN gene locus. PMID:23114252

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

    PubMed

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

    2011-02-01

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

  6. Analysis of DNA haplotypes suggests a genetic predisposition to trisomy 21 associated with DNA sequences on chromosome 21.

    PubMed Central

    Antonarakis, S E; Kittur, S D; Metaxotou, C; Watkins, P C; Patel, A S

    1985-01-01

    To test the hypothesis that there is a genetic predisposition to nondisjunction and trisomy 21 associated with DNA sequences on chromosome 21, we used DNA polymorphism haplotypes for chromosomes 21 to examine the distribution of different chromosomes 21 in Down syndrome and control families from the same ethnic group. The chromosomes 21 from 20 Greek families with a Down syndrome child and 27 control Greek families have been examined for DNA polymorphism haplotypes by using four common polymorphic sites adjacent to two closely linked single-copy DNA sequences (namely pW228C and pW236B), which map somewhere near the proximal long arm of chromosome 21. Three haplotypes, +, +---, and - with respective frequencies of 43/108, 24/108, and 23/108, account for the majority of chromosomes 21 in the control families. However, haplotype - was found to be much more commonly associated with chromosomes 21 that underwent nondisjunction in the Down syndrome families (frequency of 21/50; X2 for the two distributions is 9.550; P = 0.023; degrees of freedom, 3). The two populations (control and trisomic families) did not differ in the distribution of haplotypes for two DNA polymorphisms on chromosome 17. The data from this initial study suggest that the chromosome 21, which is marked in Greeks with haplotype - for the four above described polymorphic sites, is found more commonly in chromosomes that participate in nondisjunction than in controls. We propose an increased tendency for nondisjunction due to DNA sequences associated with a subset of chromosomes 21 bearing this haplotype. Images PMID:2987923

  7. Analysis of the S-locus structure in Prunus armeniaca L. Identification of S-haplotype specific S-RNase and F-box genes.

    PubMed

    Romero, C; Vilanova, S; Burgos, L; Martínez-Calvo, J; Vicente, M; Llácer, G; Badenes, M L

    2004-09-01

    The gametophytic self-incompatibility (GSI) system in Rosaceae has been proposed to be controlled by two genes located in the S -locusan S-RNase and a recently described pollen expressed S -haplotype specific F-box gene (SFB). However, in apricot (Prunus armeniaca L.) these genes had not been identified yet. We have sequenced 21 kb in total of the S -locus region in 3 different apricot S -haplotypes. These fragments contain genes homologous to the S-RNase and F-box genes found in other Prunus species, preserving their basic gene structure features and defined amino acid domains. The physical distance between the F-box and the S-RNase genes was determined exactly in the S2-haplotype (2.9 kb) and inferred approximately in the S 1-haplotype (< 49 kb) confirming that these genes are linked. Sequence analysis of the 5' flanking regions indicates the presence of a conserved region upstream of the putative TATA box in the S-RNase gene. The three identified S-RNase alleles (S1, S2 and S4) had a high allelic sequence diversity (75.3 amino acid identity), and the apricot F-box allelic variants (SFB1, SFB2 and SFB4) were also highly haplotype-specific (79.4 amino acid identity). Organ specific-expression was also studied, revealing that S1- and S2-RNases are expressed in style tissues, but not in pollen or leaves. In contrast, SFB1 and SFB2 are only expressed in pollen, but not in styles or leaves. Taken together, these results support these genes as candidates for the pistil and pollen S-determinants of GSI in apricot.

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

    PubMed

    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.

  9. Comparative analysis of the S-intergenic region in class-II S haplotypes of self-incompatible Brassica rapa (syn. campestris).

    PubMed

    Kakizaki, Tomohiro; Takada, Yoshinobu; Fujioka, Tomoaki; Suzuki, Go; Satta, Yoko; Shiba, Hiroshi; Isogai, Akira; Takayama, Seiji; Watanabe, Masao

    2006-02-01

    In the Brassica self-incompatibility (SI) system, a pollen determinant, SP11, is involved in dominance/recessive relationships in pollen SI phenotypes. In order to gain some insights into the genomic structure around the SP11 and the mechanisms that give dominance/recessive relationships, we characterized the genomic region containing SP11 and SRK genes in three pollen recessive class-II S haplotypes. The direction of transcription of S genes was completely conserved among class-II S haplotypes. However, the region between SP11 and SRK (S-intergenic region) was highly polymorphic without short repetitive sequences. In addition, we found a sequence similarity between the short repetitive sequence and 5'-upstream region of SP11. This sequence similarity was found to be potentially related to the expression of dominance relationships through the change of chromatin structure.

  10. Analysis of BRCA1 and mtDNA haplotypes and mtDNA polymorphism in familial breast cancer.

    PubMed

    Gutiérrez Povedano, Cristina; Salgado, Josefa; Gil, Carmen; Robles, Maitane; Patiño-García, Ana; García-Foncillas, Jesús

    2015-04-01

    Mitochondrial DNA (mtDNA) defects have been postulated to play an important role in the modulation and/or progression of cancer. In the past decade, a wide spectrum of mtDNA variations have been suggested as potentially sensitive and specific biomarkers for several human cancer types. In this context, single nucleotide polymorphisms (SNPs) described as protective or risk variants have been published, in particular in breast cancer, though not without controversy. Moreover, many mtDNA haplogroups have been associated with different phenotypes and diseases. We genotyped 18 SNPs, 15 of them defining European mtDNA haplogroups, including SNPs described as protective or risk variants, 7 SNPs that determine BRCA1 haplotypes and a BRCA1 intron 7 polymorphism. We included in this study 90 Caucasian unrelated women with breast cancer with familial criteria and 96 controls. Our aim was to clarify the importance of any of these SNPs, mitochondrial haplogroups and BRCA1 haplotypes in the modulation of breast cancer. We detected no significant differences in the distribution of BRCA1 haplotypes between patients and controls. Haplogroup U and the 12308G variant of mtDNA were overrepresented within the control group (p = 0.005 and p = 0.036, respectively) compared to breast cancer. Finally, we identified a significant association between the BRCA1 intron 7 polymorphism and BRCA1 haplotypes. Specifically, (TTC)6/6 and (TTC)6/7 genotypes with the seven polymorphic site cassette of "H2-like" haplotypes, and the (TTC)7/7 genotype associated with the "H1-like" haplotypes (p < 0.001).

  11. Polymorphism of the HLA-D region in American blacks. A DR3 haplotype generated by recombination.

    PubMed

    Hurley, C K; Gregersen, P; Steiner, N; Bell, J; Hartzman, R; Nepom, G; Silver, J; Johnson, A H

    1988-02-01

    The polymorphism of HLA class II molecules in man is particularly evident when comparisons between population groups are made. This study describes a DR3 haplotype commonly present in the American black population. Unlike the Northern European population in which almost all DR3 individuals are DQw2, approximately 50% of DR3-positive American blacks express a serologically undefined DQ allelic product. DNA restriction fragment analysis with the use of several unrelated individuals and an informative family has allowed us to identify unique DQ alpha- and beta-fragments associated with the DR3, DQw- haplotype. Based on fragment size, the DQ alpha genes of the DR3, DQw- and DRw8, DQw- haplotypes are similar as are the DQ beta genes of DR3, DQw-; DRw8, DQw-; and DR4, DQw- haplotypes. In addition, a DX beta gene polymorphism has been identified which is associated with some DR3 haplotypes including the American black DR3, DQw- haplotype. cDNA sequence analysis has revealed a DQw2-like alpha gene and a DQ beta gene which is similar to that previously described for a DR4, DQw- haplotype. It is postulated that recombination between DQ alpha and DQ beta genes and between the DQ and DX subregions has generated the various DR3 haplotypes and has played an important role in creating diversity in the HLA-D region. PMID:2892884

  12. Separating Population Structure from Population History: A Cladistic Analysis of the Geographical Distribution of Mitochondrial DNA Haplotypes in the Tiger Salamander, Ambystoma Tigrinum

    PubMed Central

    Templeton, A. R.; Routman, E.; Phillips, C. A.

    1995-01-01

    Nonrandom associations of alleles or haplotypes with geographical location can arise from restricted gene flow, historical events (fragmentation, range expansion, colonization), or any mixture of these factors. In this paper, we show how a nested cladistic analysis of geographical distances can be used to test the null hypothesis of no geographical association of haplotypes, test the hypothesis that significant associations are due to restricted gene flow, and identify patterns of significant association that are due to historical events. In this last case, criteria are given to discriminate among contiguous range expansion, long-distance colonization, and population fragmentation. The ability to make these discriminations depends critically upon an adequate geographical sampling design. These points are illustrated with a worked example: mitochondrial DNA haplotypes in the salamander Ambystoma tigrinum. For this example, prior information exists about restricted gene flow and likely historical events, and the nested cladistic analyses were completely concordant with this prior information. This concordance establishes the plausibility of this nested cladistic approach, but much future work will be necessary to demonstrate robustness and to explore the power and accuracy of this procedure. PMID:7498753

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

    PubMed Central

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

    2010-01-01

    The H1 locus confers resistance to the potato cyst nematode Globodera rostochiensis pathotypes 1 and 4. It is positioned at the distal end of chromosome V of the diploid Solanum tuberosum genotype SH83-92-488 (SH) on an introgression segment derived from S. tuberosum ssp. andigena. Markers from a high-resolution genetic map of the H1 locus (Bakker et al. in Theor Appl Genet 109:146–152, 2004) were used to screen a BAC library to construct a physical map covering a 341-kb region of the resistant haplotype coming from SH. For comparison, physical maps were also generated of the two haplotypes from the diploid susceptible genotype RH89-039-16 (S. tuberosum ssp. tuberosum/S. phureja), spanning syntenic regions of 700 and 319 kb. Gene predictions on the genomic segments resulted in the identification of a large cluster consisting of variable numbers of the CC-NB-LRR type of R genes for each haplotype. Furthermore, the regions were interspersed with numerous transposable elements and genes coding for an extensin-like protein and an amino acid transporter. Comparative analysis revealed a major lack of gene order conservation in the sequences of the three closely related haplotypes. Our data provide insight in the evolutionary mechanisms shaping the H1 locus and will facilitate the map-based cloning of the H1 resistance gene. Electronic supplementary material The online version of this article (doi:10.1007/s00122-010-1472-9) contains supplementary material, which is available to authorized users. PMID:21049265

  14. Detection of novel sequence heterogeneity and haplotypic diversity of HLA class II genes.

    PubMed

    Santamaria, P; Boyce-Jacino, M T; Lindstrom, A L; Barbosa, J J; Faras, A J; Rich, S S

    1991-01-01

    Nucleic acid sequences of the second exons of HLA-DRB1, -DRB3/4/5, -DQB1, and -DQA1 genes were determined from 43 homozygous cell lines, representing each of the known class II haplotypes, and from 30 unrelated Caucasian subjects, comprising 60 haplotypes. This systematic sequence analysis was undertaken in order to a) determine the existence of sequence microheterogeneity among cell lines which type as identical by methods other than sequencing; b) determine whether direct sequencing of class II genes will identify the presence of more extensive sequence polymorphism at the population level than that identified with other typing methods; c) accurately determine the molecular composition of the known class II haplotypes; and d) study their evolutionary relatedness by maximum parsimony analysis. The identification of seven previously unidentified haplotypes carrying five new allelic amino acid sequences suggests that sequence microheterogeneity at the population level may be more frequent than previously thought. Maximum parsimony analysis of these haplotypes allowed their evolutionary classification and indicates that the higher mutation rate at DRB1 compared to DQB1 loci in most haplotypic groups is inversed in specific haplotype lineages. Furthermore, the extent and localization of gene conversions and point mutations at class II loci in the evolution of these haplotypes is significantly different at each locus. Identification of additional HLA class II molecular microheterogeneity suggests that direct sequence analysis of class II HLA genes can uncover new allelic sequences in the population and may represent a useful alternative to current typing methodologies to study the effects of sequence allelism in organ transplantation.

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

    PubMed Central

    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

  16. Interpreting Y chromosome STR haplotype mixture.

    PubMed

    Ge, Jianye; Budowle, Bruce; Chakraborty, Ranajit

    2010-05-01

    Mixture interpretation is a challenging problem in forensic DNA analyses. The interpretation of Y short tandem repeat (STR) haplotype mixtures, due to a lack of recombination, differs somewhat from that of the autosomal DNA markers and is more complex. We describe approaches for calculating the probability of exclusion (PE) and likelihood ratio (LR) methods to interpret Y-STR mixture evidence with population substructure incorporated. For a mixture sample, first, all possible contributor haplotypes in a reference database are listed as a candidate list. The PE is the complement of the summation of the frequencies of haplotypes in the candidate list. The LR method compares the probabilities of the evidence given alternative hypotheses. The hypotheses are possible explanations for the mixture. Population substructure may be further incorporated in likelihood calculation. The maximum number of contributors is based on the candidate list and the computing complexity is polynomial. Additionally, mixtures were simulated by combining two or three 16 Y-STR marker haplotypes derived from the US forensic Y-STR database. The average PE was related to the size of database. With a database comprised of 500 haplotypes an average PE value of at least 0.995 can be obtained for two-person mixtures. The PE decreases with an increasing number of contributors to the mixture. Using the total sample population, the average number of candidate haplotypes of two-person mixtures is 3.73 and 95% mixtures have less than or equal to 10 candidate haplotypes. More than 98.7% of two-person mixtures can only be explained by the haplotype combinations that mixtures are composed. These values are generally higher for three-person mixtures. A small proportion of three-person mixture can also be explained by only two haplotypes.

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

    Analysis of DNA sequence diversity at the 12S to 16S mitochondrial genes of 165 African lions (Panthera leo) from five main areas in Zambia has uncovered haplotypes which link Southern Africa with East Africa. Phylogenetic analysis suggests Zambia may serve as a bridge connecting the lion populations in southern Africa to eastern Africa, supporting earlier hypotheses that eastern-southern Africa may represent the evolutionary cradle for the species. Overall gene diversity throughout the Zambian lion population was 0.7319 +/- 0.0174 with eight haplotypes found; three haplotypes previously described and the remaining five novel. The addition of these five novel haplotypes, so far only found within Zambia, nearly doubles the number of haplotypes previously reported for any given geographic location of wild lions. However, based on an AMOVA analysis of these haplotypes, there is little to no matrilineal gene flow (Fst = 0.47) when the eastern and western regions of Zambia are considered as two regional sub-populations. Crossover haplotypes (H9, H11, and Z1) appear in both populations as rare in one but common in the other. This pattern is a possible result of the lion mating system in which predominately males disperse, as all individuals with crossover haplotypes were male. The determination and characterization of lion sub-populations, such as done in this study for Zambia, represent a higher-resolution of knowledge regarding both the genetic health and connectivity of lion populations, which can serve to inform conservation and management of this iconic species. PMID:26674533

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

    PubMed

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

    2015-01-01

    Analysis of DNA sequence diversity at the 12S to 16S mitochondrial genes of 165 African lions (Panthera leo) from five main areas in Zambia has uncovered haplotypes which link Southern Africa with East Africa. Phylogenetic analysis suggests Zambia may serve as a bridge connecting the lion populations in southern Africa to eastern Africa, supporting earlier hypotheses that eastern-southern Africa may represent the evolutionary cradle for the species. Overall gene diversity throughout the Zambian lion population was 0.7319 +/- 0.0174 with eight haplotypes found; three haplotypes previously described and the remaining five novel. The addition of these five novel haplotypes, so far only found within Zambia, nearly doubles the number of haplotypes previously reported for any given geographic location of wild lions. However, based on an AMOVA analysis of these haplotypes, there is little to no matrilineal gene flow (Fst = 0.47) when the eastern and western regions of Zambia are considered as two regional sub-populations. Crossover haplotypes (H9, H11, and Z1) appear in both populations as rare in one but common in the other. This pattern is a possible result of the lion mating system in which predominately males disperse, as all individuals with crossover haplotypes were male. The determination and characterization of lion sub-populations, such as done in this study for Zambia, represent a higher-resolution of knowledge regarding both the genetic health and connectivity of lion populations, which can serve to inform conservation and management of this iconic species. PMID:26674533

  20. Assessment of genetic diversity of accessions in Brassicaceae genetic resources by frequency distribution analysis of S haplotypes.

    PubMed

    Takuno, S; Oikawa, E; Kitashiba, H; Nishio, T

    2010-04-01

    Plant genetic resources are important sources of genetic variation for improving crop varieties as breeding materials. Conservation of such resources of allogamous species requires maintenance of the genetic diversity within each accession to avoid inbreeding depression and loss of rare alleles. For assessment of genetic diversity in the self-incompatibility locus (S locus), which is critically involved in the chance of mating, we developed a dot-blot genotyping method for self-incompatibility (S) haplotypes and applied it to indigenous, miscellaneous landraces of Brassica rapa, provided by the IPK Gene Bank (Gatersleben, Germany) and the Tohoku University Brassica Seed Bank (Sendai, Japan), in which landraces are maintained using different population sizes. This method effectively determined S genotypes of more than 500 individuals from the focal landraces. Although our results suggest that these landraces might possess sufficient numbers of S haplotypes, the strong reduction of frequencies of recessive S haplotypes occurred, probably owing to genetic drift. Based on these results, we herein discuss an appropriate way to conserve genetic diversity of allogamous plant resources in a gene bank.

  1. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: Results of an international study

    SciTech Connect

    Neuhausen, S.L.; Skolnick, M.H.; Goldgar, D.E.

    1996-02-01

    Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events. 22 refs., 1 fig., 4 tab.

  2. A Cladistic Analysis of Phenotypic Associations with Haplotypes Inferred from Restriction Endonuclease Mapping and DNA Sequence Data. III. Cladogram Estimation

    PubMed Central

    Templeton, A. R.; Crandall, K. A.; Sing, C. F.

    1992-01-01

    We previously developed a cladistic approach to identify subsets of haplotypes defined by restriction endonuclease mapping or DNA sequencing that are associated with significant phenotypic deviations. Our approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site or sequence data that represents the evolutionary steps that interrelate the observed haplotypes. The cladogram is used to define a nested statistical design to identify mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that any undetected mutation causing a phenotypic effect is embedded within the same evolutionary history that is represented by the cladogram. The power of this approach depends upon the confidence one has in the particular cladogram used to draw inferences. In this paper, we present a strategy for estimating the set of cladograms that are consistent with a particular sample of either restriction site or nucleotide sequence data and that includes the possibility of recombination. We first evaluate the limits of parsimony in constructing cladograms. Once these limits have been determined, we construct the set of parsimonious and nonparsimonious cladograms that is consistent with these limits. Our estimation procedure also identifies haplotypes that are candidates for being products of recombination. If recombination is extensive, our algorithm subdivides the DNA region into two or more subsections, each having little or no internal recombination. We apply this estimation procedure to three data sets to illustrate varying degrees of cladogram ambiguity and recombination. PMID:1385266

  3. Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes

    PubMed Central

    2004-01-01

    To dissect the haplotype structure of candidate genes for disease association studies, it is important to understand the nature of genetic variation at these loci in different populations. We present a survey of haplotype structure and linkage disequilibrium of chemokine and chemokine receptor genes in 11 geographically-distinct population samples (n = 728). Chemokine proteins are involved in intercellular signalling and the immune response. These molecules are important modulators of human immunodeficiency virus (HIV)-1 infection and the progression of the acquired immune deficiency syndrome, tumour development and the metastatic process of cancer. To study the extent of genetic variation in this gene family, single nucleotide polymorphisms (SNPs) from 13 chemokine and chemokine receptor genes were genotyped using the 5' nuclease assay (TaqMan). SNP haplotypes, estimated from unphased genotypes using the Expectation-Maximization-algorithm, are described in a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21, and a cluster of three CC-chemokine genes [MPIF-1 (CCL23) PARC (CCL18) and MIP- 1α (CCL3)] on chromosome 17q11-12. The 32 base pair (bp) deletion in exon 4 of CCR5 was also included in the haplotype analysis of 3p21. A total of 87.5 per cent of the variation of 14 biallelic loci scattered over 150 kilobases of 3p21 is explained by 11 haplotypes which have a frequency of at least 1 per cent in the total sample. An analysis of haplotype blocks in this region indicates recombination between CCR2 and CCR5, although long-range pairwise linkage disequilibrium across the region appears to remain intact on two common haplotypes. A reduced-median network demonstrates a clear relationship between 3p21 haplotypes, rooted by the putative ancestral haplotype determined by direct sequencing of four primate species. Analysis of six SNPs on 17q11-12 indicates that 97.5 per cent of the variation is explained by 15 haplotypes

  4. Analysis of Y chromosome STR haplotypes in the European part of Russia reveals high diversities but non-significant genetic distances between populations.

    PubMed

    Roewer, Lutz; Willuweit, Sascha; Krüger, Carmen; Nagy, Marion; Rychkov, Sergey; Morozowa, Irina; Naumova, Oksana; Schneider, Yuriy; Zhukova, Olga; Stoneking, Mark; Nasidze, Ivan

    2008-05-01

    A total of 17 Y-specific STR loci were studied in 12 districts of the European part of Russia aiming to ascertain the amount of substructure required for the construction of a representative regional database. All groups exhibited high haplotype diversities but low inter-population variance as measured by an analysis of molecular variance. However, when Western Russia is taken as a whole, the genetic distances to the neighbouring populations were significant. Whereas gradual change in the Y chromosome pool exists between Russia and the Slavic-speaking populations to the West, remarkable discontinuities were observed with neighbouring populations in the East, North and South.

  5. Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels

    PubMed Central

    2014-01-01

    Introduction MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this. Methods We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer’s Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated. Results H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03). Conclusions These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest

  6. Probabilistic Multilocus Haplotype Reconstruction in Outcrossing Tetraploids.

    PubMed

    Zheng, Chaozhi; Voorrips, Roeland E; Jansen, Johannes; Hackett, Christine A; Ho, Julie; Bink, Marco C A M

    2016-05-01

    For both plant (e.g., potato) and animal (e.g., salmon) species, unveiling the genetic architecture of complex traits is key to the genetic improvement of polyploids in agriculture. F1 progenies of a biparental cross are often used for quantitative trait loci (QTL) mapping in outcrossing polyploids, where haplotype reconstruction by identifying the parental origins of marker alleles is necessary. In this paper, we build a novel and integrated statistical framework for multilocus haplotype reconstruction in a full-sib tetraploid family from biallelic marker dosage data collected from single-nucleotide polymorphism (SNP) arrays or next-generation sequencing technology given a genetic linkage map. Compared to diploids, in tetraploids, additional complexity needs to be addressed, including double reduction and possible preferential pairing of chromosomes. We divide haplotype reconstruction into two stages: parental linkage phasing for reconstructing the most probable parental haplotypes and ancestral inference for probabilistically reconstructing the offspring haplotypes conditional on the reconstructed parental haplotypes. The simulation studies and the application to real data from potato show that the parental linkage phasing is robust to, and that the subsequent ancestral inference is accurate for, complex chromosome pairing behaviors during meiosis, various marker segregation types, erroneous genetic maps except for long-range disturbances of marker ordering, various amounts of offspring dosage errors (up to ∼20%), and various fractions of missing data in parents and offspring dosages. PMID:26920758

  7. The single nucleotide polymorphism and haplotype analysis of MDR1 in Chinese diffuse large B cell lymphoma patients.

    PubMed

    Ni, Ying; Xiao, Zhengrui; Yin, Guangli; Fan, Lei; Wang, Li; Zhu, Huayuan; Wu, Hanxin; Qian, Sixuan; Xu, Wei; Li, Jianyong; Miao, Kourong

    2015-07-01

    We investigated whether the MDR1 (multidrug resistance 1) gene single nucleotide polymorphism (SNP) and haplotype variants were associated with the susceptibility to diffuse large B-cell lymphoma (DLBCL). A total of 129 DLBCL patients and 208 healthy controls from Jiangsu Han population were enrolled in this study. They were genotyped by polymerase chain reaction-allele specific primers (PCR-ASP) method or DNA direct sequencing at three common loci: C1236T, G2677T/A and C3435T. At locus G2677T/A, allele G and genotype GT were significantly more common in DLBCL (G: OR=1.48, 95% CI: 1.08-2.02, Pc=0.03; GT: OR=1.96, 95% CI: 1.25-3.07, Pc<0.01), while genotype AT in this locus seemed to be protective (OR=0.29, 95% CI: 0.02-0.72, Pc=0.03). TT genotype at locus C3435T showed a risk factor in DLBCL (OR=2.38, 95% CI: 1.52-3.74, Pc<0.01). The frequency of T-G-T haplotype was significantly increased in DLBCL group (OR=5.21, 95% CI: 2.58-10.54, Pc<0.01); haplotype of G-T in 2677-3435 and diplotype of 2677GT/3435TT were significantly more frequent in DLBCL group (G-T: OR=3.97, 95% CI: 2.31-6.85, Pc<0.01; 2677GT/3435TT: OR=4.55, 95% CI: 2.02-10.22, Pc<0.01). Our findings demonstrate that G, GT at locus G2677T/A, and TT at locus C3435T might contribute to the susceptibility to DLBCL, as well as haplotype of T-G-T, G-T in 2677-3435 and diplotype of 2677GT/3435TT, while AT at locus G2677T/A might be a protective genotype. These findings could provide evidence that the MDR1 SNPs may modify the susceptibility to DLBCL and shade new lights in disease association studies.

  8. Genetic mapping of the Batten disease locus (CLN3) to the interval D16S288-D16S383 by analysis of haplotypes and allelic association

    SciTech Connect

    Mitchison, H.M.; O`Rawe, A.M.; Gardiner, R.M.

    1994-07-15

    CLN3, the gene for juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or Batten disease, has been localized by genetic linkage analysis to chromosome 16p between loci D16S297 and D16S57. The authors have now further refined the localization of CLN3 by haplotype analysis using two new microsatellite markers from loci D16S383 and SPN in the D16S297-D16S57 interval on a larger collaborative family resource consisting of 142 JNCL pedigrees. Crossover events in 3 maternal meioses define new flanking markers for CLN3 and localize the gene to the interval at 16p12.1-11.2 between D16S288 and D16S383, which corresponds to a genetic distance of 2.1 cM. Within this interval 4 microsatellite loci are in strong linkage disequilibrium with CLN3, and extended haplotype analysis of the associated alleles indicates that CLN3 is in closest proximity to loci D16S299 and D16S298. 6 refs., 1 fig., 2 tabs.

  9. Additional EIPC Study Analysis. Final Report

    SciTech Connect

    Hadley, Stanton W; Gotham, Douglas J.; Luciani, Ralph L.

    2014-12-01

    Between 2010 and 2012 the Eastern Interconnection Planning Collaborative (EIPC) conducted a major long-term resource and transmission study of the Eastern Interconnection (EI). With guidance from a Stakeholder Steering Committee (SSC) that included representatives from the Eastern Interconnection States Planning Council (EISPC) among others, the project was conducted in two phases. Phase 1 involved a long-term capacity expansion analysis that involved creation of eight major futures plus 72 sensitivities. Three scenarios were selected for more extensive transmission- focused evaluation in Phase 2. Five power flow analyses, nine production cost model runs (including six sensitivities), and three capital cost estimations were developed during this second phase. The results from Phase 1 and 2 provided a wealth of data that could be examined further to address energy-related questions. A list of 14 topics was developed for further analysis. This paper brings together the earlier interim reports of the first 13 topics plus one additional topic into a single final report.

  10. Genetic association analysis of 300 genes identifies a risk haplotype in SLC18A2 for post-traumatic stress disorder in two independent samples.

    PubMed

    Solovieff, Nadia; Roberts, Andrea L; Ratanatharathorn, Andrew; Haloosim, Michelle; De Vivo, Immaculata; King, Anthony P; Liberzon, Israel; Aiello, Allison; Uddin, Monica; Wildman, Derek E; Galea, Sandro; Smoller, Jordan W; Purcell, Shaun M; Koenen, Karestan C

    2014-07-01

    The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N=2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR)=1.4, p=2.1E-05) in SLC18A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC18A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p=0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p=0.049; N=748, men and women). SLC18A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (p<0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects. PMID:24525708

  11. Genetic Association Analysis of 300 Genes Identifies a Risk Haplotype in SLC18A2 for Post-traumatic Stress Disorder in Two Independent Samples

    PubMed Central

    Solovieff, Nadia; Roberts, Andrea L; Ratanatharathorn, Andrew; Haloosim, Michelle; De Vivo, Immaculata; King, Anthony P; Liberzon, Israel; Aiello, Allison; Uddin, Monica; Wildman, Derek E; Galea, Sandro; Smoller, Jordan W; Purcell, Shaun M; Koenen, Karestan C

    2014-01-01

    The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N=2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR)=1.4, p=2.1E-05) in SLC18A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC18A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p=0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p=0.049; N=748, men and women). SLC18A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (p<0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects. PMID:24525708

  12. Fine mapping and haplotype analysis of the locus for congenital nephrotic syndrome on chromosome 19q13.1

    SciTech Connect

    Maennikkoe, M.; Kestilae, M.; Tryggvason, K.

    1995-12-01

    We have recently localized the gene for congenital nephrotic syndrome of the Finnish type (CNF) to chromosome 19q12-13.1. On the basis of observed recombination events, the gene was localized between markers D19S416/D19S425/D19S213/D19S208/D19S191 and D19S224. Here we have extended the mapping efforts, on the basis of a detailed physical map of the region. By means of three new polymorphic markers - D19S608, D19S609, and D19S610 - developed in this study, the critical candidate region could be further restricted. Significant linkage disequilibrium was observed with marker D19S610, D19S608, D19S224, and D19S220, the strongest allelic association being 84% with marker D19S610 at 19q13.1. This suggests that the CNF gene locus lies in close proximity to marker D19S610. Combination of the informative markers revealed four main haplotype categories. Different geographic distribution was observed between these haplotype groups when they were placed on the map of Finland according to the birthplaces of grandparents. 38 refs., 2 figs., 4 tabs.

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

    PubMed

    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. Assigning linkage haplotypes from parent and progeny genotypes

    SciTech Connect

    Nejati-Javaremi, A.; Smith, C.

    1996-04-01

    Given the genotypes of parents and progeny, their haplotypes over several or many linked loci can be easily assigned by listing the allele type at each locus along the haplotype known to be from each parent. Only a small number (5-10) of progeny per family is usually needed to assign the parental and progeny haplotypes. Any gaps left in the haplotypes may be filled in from the assigned haplotypes of relatives. The process is facilitated by having multiple alleles at the loci and by using more linked loci in the haplotype and with more progeny from the mating. Crossover haplotypes in the progeny can be identified by their being unique or uncommon, and the crossover point can often be detected if the locus linkage map order is known. The haplotyping method applies to outbreeding populations in plants, animals, and man, as well as to traditional experimental crosses of inbred lines. The method also applies to half-sib families, whether the genotype of the mates are known or unknown. The haplotyping procedure is already used in linkage analysis but does not seem to have been published. It should be useful in teaching and in genetic applications of haplotypes. 15 refs., 5 tabs.

  15. Haplotype Fine Mapping by Evolutionary Trees

    PubMed Central

    Lam, Johnny C.; Roeder, Kathryn; Devlin, B.

    2000-01-01

    Summary To refine the location of a disease gene within the bounds provided by linkage analysis, many scientists use the pattern of linkage disequilibrium between the disease allele and alleles at nearby markers. We describe a method that seeks to refine location by analysis of “disease” and “normal” haplotypes, thereby using multivariate information about linkage disequilibrium. Under the assumption that the disease mutation occurs in a specific gap between adjacent markers, the method first combines parsimony and likelihood to build an evolutionary tree of disease haplotypes, with each node (haplotype) separated, by a single mutational or recombinational step, from its parent. If required, latent nodes (unobserved haplotypes) are incorporated to complete the tree. Once the tree is built, its likelihood is computed from probabilities of mutation and recombination. When each gap between adjacent markers is evaluated in this fashion and these results are combined with prior information, they yield a posterior probability distribution to guide the search for the disease mutation. We show, by evolutionary simulations, that an implementation of these methods, called “FineMap,” yields substantial refinement and excellent coverage for the true location of the disease mutation. Moreover, by analysis of hereditary hemochromatosis haplotypes, we show that FineMap can be robust to genetic heterogeneity. PMID:10677324

  16. Allelic association and extended haplotype analysis of the spinal muscular atrophy (SMA) candidate region in the French Candadian population

    SciTech Connect

    Simard, L.R.; Prescott, G.; Rochette, C. |

    1994-09-01

    SMA is a common lower motor neuron disease characterized by progressive proximal limb and trunk muscle weakness. Despite the wide range in phenotypic severity, all three clinical types of childhood SMAs map to chromosome 5q11.2-5q13.3. The proximal (D5S557) flanking markers span about 1 Mb. We have previously demonstrated significant linkage disequilibrium between D5S125, D5S435, D5S351, JK53CA1/2 and SMA in the French Canadian population. We now present data for three new DNA markers mapping between D5S435 and D5S557 kindly provided to us by Drs. B. Wirth (A31), A. Burghes (Ag1) and A. MacKenzie (CATT-40G1). We identified 10 different A31 Alleles whose frequencies were similar for both normal and SMA chromosomes. Ag1 is a complex multi-allelic marker and specific primers amplified 1 (Class I), 2 or rarely 3 (Class II) alleles per chromosome. We observed significant association between Ag1 and SMA. For example, the 100 bp Ag1 fragment was typed on 20 of 73 SMA chromosomes and 0 of 74 normal chromosomes (p=<10{sup -4}). We also observed significant association between Ag1 Class genotypes and phenotypic severity. Class I chromosomes predominated in Type I SMA (p=.001) while Type II SMA individuals were generally heterozygous Class I/Class II (p=.001). Finally, we provide evidence for allelic association between Type I SMA and CATT-40G1, a tri-allelic sublocus of CATT-1. All of our Type I SMA chromosomes (n=20) carried a null allele compared to 40% of normal chromosomes (p=<10{sup -4}). Extended haplotype analyses indicated that > 19% of French Canadian SMA chromosomes appear to be ancestrally related to two unique haplotypes indicating their utility for linkage disequilibrium mapping.

  17. Hybrid origin of European commercial pigs examined by an in-depth haplotype analysis on chromosome 1

    PubMed Central

    Bosse, Mirte; Madsen, Ole; Megens, Hendrik-Jan; Frantz, Laurent A. F.; Paudel, Yogesh; Crooijmans, Richard P. M. A.; Groenen, Martien A. M.

    2014-01-01

    Although all farm animals have an original source of domestication, a large variety of modern breeds exist that are phenotypically highly distinct from the ancestral wild population. This phenomenon can be the result of artificial selection or gene flow from other sources into the domesticated population. The Eurasian wild boar (Sus scrofa) has been domesticated at least twice in two geographically distinct regions during the Neolithic revolution when hunting shifted to farming. Prior to the establishment of the commercial European pig breeds we know today, some 200 years ago Chinese pigs were imported into Europe to improve local European pigs. Commercial European domesticated pigs are genetically more diverse than European wild boars, although historically the latter represents the source population for domestication. In this study we examine the cause of the higher diversity within the genomes of European commercial pigs compared to their wild ancestors by testing two different hypotheses. In the first hypothesis we consider that European commercial pigs are a mix of different European wild populations as a result of movement throughout Europe, hereby acquiring haplotypes from all over the European continent. As an alternative hypothesis, we examine whether the introgression of Asian haplotypes into European breeds during the Industrial Revolution caused the observed increase in diversity. By using re-sequence data for chromosome 1 of 136 pigs and wild boars, we show that an Asian introgression of about 20% into the genome of European commercial pigs explains the majority of the increase in genetic diversity. These findings confirm that the Asian hybridization, that was used to improve production traits of local breeds, left its signature in the genome of the commercial pigs we know today. PMID:25601878

  18. Use of haplotypes to predict selection limits and Mendelian sampling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Limits to selection and Mendelian sampling terms can be calculated using haplotypes, which are sums of individual additive effects on a chromosome. Haplotypes were imputed for 43,385 actual markers of 3,765 Jerseys using the Fortran program findhap.f90, which combines population and pedigree haploty...

  19. Fine genetic mapping of the Batten disease locus (CLN3) by haplotype analysis and demonstration of allelic association with chromosome 16p microsatellite loci

    SciTech Connect

    Mitchison, H.M.; McKay, T.R.; Thompson, A.D.; Mulley, J.C.; Kozman, H.M.; Richards, R.I.; Callen, D.F.; Stallings, R.L.; Doggett, N.A.; Attwood, J.

    1993-05-01

    Batten disease, juvenile onset neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder characterized by accumulation of autofluorescent lipopigment in neurons and other cell types. The disease locus (CLN3) has previously been assigned to chromosome 16p. The genetic localization of CLN3 has been refined by analyzing 70 families using a high-resolution map of 15 marker loci encompassing the CLN3 region on 16p. Crossovers in three maternal meioses allowed localization of CLN3 to the interval between D16S297 and D16S57. Within that interval alleles at three highly polymorphic dinucleotide repeat loci (D16S288, D16S298, D16S299) were found to be in strong linkage disequilibrium with CLN3. Analysis of haplotypes suggests that a majority of CLN3 chromosomes have arisen from a single founder mutation. 15 refs., 2 figs., 5 tabs.

  20. Acid Rain Analysis by Standard Addition Titration.

    ERIC Educational Resources Information Center

    Ophardt, Charles E.

    1985-01-01

    The standard addition titration is a precise and rapid method for the determination of the acidity in rain or snow samples. The method requires use of a standard buret, a pH meter, and Gran's plot to determine the equivalence point. Experimental procedures used and typical results obtained are presented. (JN)

  1. Electrophoretic analysis of Allium alien addition lines.

    PubMed

    Peffley, E B; Corgan, J N; Horak, K E; Tanksley, S D

    1985-12-01

    Meiotic pairing in an interspecific triploid of Allium cepa and A. fistulosum, 'Delta Giant', exhibits preferential pairing between the two A. cepa genomes, leaving the A. fistulosum genome as univalents. Multivalent pairing involving A. fistulosum chromosomes occurs at a low level, allowing for recombination between the genomes. Ten trisomies were recovered from the backcross of 'Delta Giant' x A. cepa cv., 'Temprana', representing a minimum of four of the eight possible alien addition lines. The alien addition lines possessed different A. fistulosum enzyme markers. Those markers, Adh-1, Idh-1 and Pgm-1 reside on different A. fistulosum chromosomes, whereas Pgi-1 and Idh-1 may be linked. Diploid, trisomic and hyperploid progeny were recovered that exhibited putative pink root resistance. The use of interspecific plants as a means to introgress A. fistulosum genes into A. cepa appears to be successful at both the trisomic and the diploid levels. If introgression can be accomplished using an interspecific triploid such as 'Delta Giant' to generate fertile alien addition lines and subsequent fertile diploids, or if introgression can be accomplished directly at the diploid level, this will have accomplished gene flow that has not been possible at the interspecific diploid level.

  2. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  3. Genome-Wide Association Studies Using Haplotypes and Individual SNPs in Simmental Cattle

    PubMed Central

    Wu, Yang; Fan, Huizhong; Wang, Yanhui; Zhang, Lupei; Gao, Xue; Chen, Yan; Li, Junya; Ren, HongYan; Gao, Huijiang

    2014-01-01

    Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components. PMID:25330174

  4. Genome-wide association studies using haplotypes and individual SNPs in Simmental cattle.

    PubMed

    Wu, Yang; Fan, Huizhong; Wang, Yanhui; Zhang, Lupei; Gao, Xue; Chen, Yan; Li, Junya; Ren, HongYan; Gao, Huijiang

    2014-01-01

    Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components. PMID:25330174

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

    PubMed Central

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

    2012-01-01

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

  6. Chromosomal Haplotypes by Genetic Phasing of Human Families

    PubMed Central

    Roach, Jared C.; Glusman, Gustavo; Hubley, Robert; Montsaroff, Stephen Z.; Holloway, Alisha K.; Mauldin, Denise E.; Srivastava, Deepak; Garg, Vidu; Pollard, Katherine S.; Galas, David J.; Hood, Leroy; Smit, Arian F.A.

    2011-01-01

    Assignment of alleles to haplotypes for nearly all the variants on all chromosomes can be performed by genetic analysis of a nuclear family with three or more children. Whole-genome sequence data enable deterministic phasing of nearly all sequenced alleles by permitting assignment of recombinations to precise chromosomal positions and specific meioses. We demonstrate this process of genetic phasing on two families each with four children. We generate haplotypes for all of the children and their parents; these haplotypes span all genotyped positions, including rare variants. Misassignments of phase between variants (switch errors) are nearly absent. Our algorithm can also produce multimegabase haplotypes for nuclear families with just two children and can handle families with missing individuals. We implement our algorithm in a suite of software scripts (Haploscribe). Haplotypes and family genome sequences will become increasingly important for personalized medicine and for fundamental biology. PMID:21855840

  7. Haplotype map of sickle cell anemia in Tunisia.

    PubMed

    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.

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

    PubMed

    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%).

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

    PubMed

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

    2008-10-01

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

  10. Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients

    PubMed Central

    Mwinyi, Jessica; Wenger, Christa; Eloranta, Jyrki J; Kullak-Ublick, Gerd A

    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, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically significant association with glucocorticoid therapy success. CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome. PMID:20712049

  11. Analysis of DNA polymorphism haplotypes linked to the cystic fibrosis locus in North American black and Caucasian families supports the existence of multiple mutations of the cystic fibrosis gene.

    PubMed Central

    Cutting, G R; Antonarakis, S E; Buetow, K H; Kasch, L M; Rosenstein, B J; Kazazian, H H

    1989-01-01

    Strong linkage disequilibrium (LD) was found between DNA marker XV2c and the cystic fibrosis (CF) locus (delta = 0.46) and between DNA marker KM19 and CF (delta = 0.67) in 157 CF and 138 normal chromosomes from U.S. Caucasians. DNA haplotypes with nine polymorphic sites were created in 54 Caucasian families. There is a strong LD between the haplotypes and the presence of the mutant CF genes. This implies that the DNA polymorphisms examined are close to the CF gene and that one mutation of the CF gene predominates in the Caucasian population. Haplotype analysis can also be used to refine estimates of CF carrier risk in Caucasians. Data for XV2c and MET markers in 16 American black patients and their families revealed a different haplotype distribution and LD pattern with the CF locus. These data suggest that racial admixture alone does not explain the occurrence of CF in American blacks and that multiple alleles of the CF gene may exist in this population. PMID:2563631

  12. Analysis of FMR1 (CGG)n alleles and FRAXA microsatellite haplotypes in the population of Greenland: implications for the population of the New World from Asia.

    PubMed

    Larsen, L A; Armstrong, J S; Grønskov, K; Hjalgrim, H; Brøndum-Nielsen, K; Hasholt, L; Nørgaard-Pedersen, B; Vuust, J

    1999-01-01

    The fragile X syndrome is caused by the expansion of a polymorphic (CGG)n tract in the promoter region of the FMR1 gene. Apparently the incidence of fragile X syndrome is rare in the population of Greenland. In order to examine population-related factors involved in stability of the (CGG)n sequence, DNA samples obtained randomly from the Greenlandic population were analysed for size and AGG interspersion pattern of the FMR1 (CGG)n region and associated DXS548-FRAXAC1 haplotypes. In addition a large Greenland family with unstable transmission in the premutation range was analysed. The (CGG)n allele sizes in the Greenland population showed a narrow distribution similar to that reported for Asian populations. DNA sequencing of alleles with 36 CGG repeats revealed an AGG(CGG)6 insertion previously reported exclusively in Asian populations and a high frequency of alleles with a (CGG)10AGG(CGG)9AGG(CGG)9 or (CGG)9AGG(CGG)9AGG(CGG)6AGG(CGG)9 sequence pattern was found. Thus the data confirm the Asian origin of the Greenlandic (Eskimo) population and indicates that some (CGG)n alleles have remained stable for 15-30,000 years, since the population of the New World arrived from Asia via the Bering Strait. PMID:10573009

  13. An Analysis of HLA-A, -B, and -DRB1 Allele and Haplotype Frequencies of 21,918 Residents Living in Liaoning, China

    PubMed Central

    Li, Xiao-Feng; Zhang, Xu; Chen, Yang; Zhang, Kun-Lian; Liu, Xiang-Jun; Li, Jian-Ping

    2014-01-01

    HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics. PMID:24691290

  14. The S haplotype-specific F-box protein gene, SFB, is defective in self-compatible haplotypes of Prunus avium and P. mume.

    PubMed

    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. PMID:15272875

  15. Additive interaction in survival analysis: use of the additive hazards model.

    PubMed

    Rod, Naja Hulvej; Lange, Theis; Andersen, Ingelise; Marott, Jacob Louis; Diderichsen, Finn

    2012-09-01

    It is a widely held belief in public health and clinical decision-making that interventions or preventive strategies should be aimed at patients or population subgroups where most cases could potentially be prevented. To identify such subgroups, deviation from additivity of absolute effects is the relevant measure of interest. Multiplicative survival models, such as the Cox proportional hazards model, are often used to estimate the association between exposure and risk of disease in prospective studies. In Cox models, deviations from additivity have usually been assessed by surrogate measures of additive interaction derived from multiplicative models-an approach that is both counter-intuitive and sometimes invalid. This paper presents a straightforward and intuitive way of assessing deviation from additivity of effects in survival analysis by use of the additive hazards model. The model directly estimates the absolute size of the deviation from additivity and provides confidence intervals. In addition, the model can accommodate both continuous and categorical exposures and models both exposures and potential confounders on the same underlying scale. To illustrate the approach, we present an empirical example of interaction between education and smoking on risk of lung cancer. We argue that deviations from additivity of effects are important for public health interventions and clinical decision-making, and such estimations should be encouraged in prospective studies on health. A detailed implementation guide of the additive hazards model is provided in the appendix.

  16. A Cladistic Analysis of Phenotypic Associations with Haplotypes Inferred from Restriction Endonuclease Mapping or DNA Sequencing. V. Analysis of Case/Control Sampling Designs: Alzheimer's Disease and the Apoprotein E Locus

    PubMed Central

    Templeton, A. R.

    1995-01-01

    Present-day associations between haplotypes at a candidate locus and phenotypes exist when phenotypically important mutations occurred at some point during the evolution of the current array of genetic variation. A cladistic statistical design can be defined that focuses power by using the evolutionary history of the candidate DNA region. This paper shows how cladistic methodology is used for the analysis of case/control data, a common sampling design in genetic/disease association studies. A worked example is presented of the associations for sporadic early and late-onset forms of Alzheimer's disease with the 19q13.2 chromosomal region that includes the loci for apoproteins E, CI, and CII. This analysis confirms earlier reports of a strong association of the ApoE &4 allele with Alzheimer's disease but indicates that it is premature to condsider this association causal, particularly for early onset cases. Associations were also found with the &2 allele, as previously reported, and with the 1 allele at the ApoCI locus. However, this analysis indicates that it is inappropriate both statistically and medically to use single markers as risk predictors when haplotype data are available, even when the mutation leading to the marker is identified as having a strong phenotypic association. PMID:7635303

  17. Understanding Y haplotype matching probability.

    PubMed

    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. Polymorphic DNA haplotypes at the LDL receptor locus.

    PubMed Central

    Leitersdorf, E; Chakravarti, A; Hobbs, H H

    1989-01-01

    Mutations in the low-density lipoprotein (LDL) receptor gene result in the autosomal dominant disorder familial hypercholesterolemia (FH). Many different LDL receptor mutations have been identified and characterized, demonstrating a high degree of allelic heterogeneity at this locus. The ability to identify mutant LDL receptor genes for prenatal diagnosis of homozygous FH or to study the role of the LDL receptor gene in polygenic hypercholesterolemia requires the use of closely linked RFLPs. In the present study we used 10 different RFLPs, including three newly described polymorphisms, to construct 123 independent haplotypes from 20 Caucasian American pedigrees. Our sample contained 31 different haplotypes varying in frequency from 0.8% to 29.3%; the five most common haplotypes account for 67.5% of the sample. The heterozygosity and PIC of each site were determined, and these values disclosed that eight of the RFLPs were substantially polymorphic. Linkage-disequilibrium analysis of the haplotype data revealed strong nonrandom associations among all 10 RFLPs, especially among those sites clustered in the 3' region of the gene. Evolutionary analysis suggests the occurrence of both mutational and recombinational events in the generation of the observed haplotypes. A strategy for haplotype analysis of the LDL receptor gene in individuals of Caucasian American descent is presented. Images Figure 2 Figure 3 PMID:2563635

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

    PubMed

    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.

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

    PubMed

    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. PMID:26006006

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

    PubMed

    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.

  2. The Huntington's disease candidate region exhibits many different haplotypes.

    PubMed

    MacDonald, M E; Novelletto, A; Lin, C; Tagle, D; Barnes, G; Bates, G; Taylor, S; Allitto, B; Altherr, M; Myers, R

    1992-05-01

    Analysis of 78 Huntington's disease (HD) chromosomes with multi-allele markers revealed 26 different haplotypes, suggesting a variety of independent HD mutations. The most frequent haplotype, accounting for about one third of disease chromosomes, suggests that the disease gene is between D4S182 and D4S180. However, the paucity of an expected class of chromosomes that can be related to this major haplotype by assuming single crossovers may reflect the operation of other mechanisms in creating haplotype diversity. Some of these mechanisms sustain alternative scenarios that do not require a multiple mutational origin for HD and/or its positioning between D4S182 and D4S180.

  3. Haplotype Map of Sickle Cell Anemia in Tunisia

    PubMed Central

    Ben Mustapha, Maha; Zorai, Amine; Ben Mansour, Ikbel; 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 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 (Gγ and Aγ) 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. PMID:25197158

  4. The Wilson disease gene: Haplotypes and mutations

    SciTech Connect

    Thomas, G.R.; Roberts, E.A.; Cox, D.W.; Walshe, J.M.

    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.

  5. Haplotype inference from unphased SNP data in heterozygous polyploids based on SAT

    PubMed Central

    Neigenfind, Jost; Gyetvai, Gabor; Basekow, Rico; Diehl, Svenja; Achenbach, Ute; Gebhardt, Christiane; Selbig, Joachim; Kersten, Birgit

    2008-01-01

    Background Haplotype inference based on unphased SNP markers is an important task in population genetics. Although there are different approaches to the inference of haplotypes in diploid species, the existing software is not suitable for inferring haplotypes from unphased SNP data in polyploid species, such as the cultivated potato (Solanum tuberosum). Potato species are tetraploid and highly heterozygous. Results Here we present the software SATlotyper which is able to handle polyploid and polyallelic data. SATlo-typer uses the Boolean satisfiability problem to formulate Haplotype Inference by Pure Parsimony. The software excludes existing haplotype inferences, thus allowing for calculation of alternative inferences. As it is not known which of the multiple haplotype inferences are best supported by the given unphased data set, we use a bootstrapping procedure that allows for scoring of alternative inferences. Finally, by means of the bootstrapping scores, it is possible to optimise the phased genotypes belonging to a given haplotype inference. The program is evaluated with simulated and experimental SNP data generated for heterozygous tetraploid populations of potato. We show that, instead of taking the first haplotype inference reported by the program, we can significantly improve the quality of the final result by applying additional methods that include scoring of the alternative haplotype inferences and genotype optimisation. For a sub-population of nineteen individuals, the predicted results computed by SATlotyper were directly compared with results obtained by experimental haplotype inference via sequencing of cloned amplicons. Prediction and experiment gave similar results regarding the inferred haplotypes and phased genotypes. Conclusion Our results suggest that Haplotype Inference by Pure Parsimony can be solved efficiently by the SAT approach, even for data sets of unphased SNP from heterozygous polyploids. SATlotyper is freeware and is distributed as

  6. Genetic epidemiology of Paget's disease of bone in italy: sequestosome1/p62 gene mutational test and haplotype analysis at 5q35 in a large representative series of sporadic and familial Italian cases of Paget's disease of bone.

    PubMed

    Falchetti, Alberto; Di Stefano, Marco; Marini, Francesca; Ortolani, Sergio; Ulivieri, Massimo Fabio; Bergui, Simona; Masi, Laura; Cepollaro, Chiara; Benucci, Maurizio; Di Munno, Ombretta; Rossini, Maurizio; Adami, Silvano; Del Puente, Antonio; Isaia, Giancarlo; Torricelli, Francesca; Brandi, Maria Luisa

    2009-01-01

    Families affected by Paget's disease of bone frequently harbor mutations in the SQSTM1/p62 gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3, D335E, A381V, and Y383X, external to the UBA domain. Subjects with truncating mutations, E396X, showed a significantly younger age at clinical diagnosis, while the Y383X subjects had a higher average number of affected skeletal sites. All the mutants exhibited the CGTG-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common SQSTM1/p62 mutation for each P392L, M404V, and G425R group. Since the CGTG-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the SQSTM1/p62 locus, from chromosome 5q35, other than the exon 6 and 3'UTR polymorphisms. All mutant carriers from two of the three M404V families and from the G425R families exhibited common extended chromosome 5q35 haplotypes, IT01 and IT02, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population.

  7. Relative efficiency of ambiguous vs. directly measured haplotype frequencies.

    PubMed

    Schaid, Daniel J

    2002-11-01

    Haplotypes are useful for both fine-mapping of susceptibility loci and evaluation of sequence variation at multiple sites along a chromosome. However, they are difficult to directly measure over long stretches of DNA in diploid organisms. Consequently, multiple genetic markers are typically measured, without linkage phase information, giving rise to a subject's diplotype. From diplotype data, haplotypes are often inferred by pedigree information, or treated as partially missing data when haplotype frequencies are estimated among unrelated subjects. This latter ambiguity can increase the variance of the estimated haplotype frequencies. Douglas et al. ([2001] Nat. Genet. 28:361-364) recently quantified the relative efficiency of estimating haplotype frequencies from the diplotypes of unrelated subjects, relative to directly measured haplotypes via somatic cell hybrids (conversion technology), and demonstrated that unknown linkage phase can lead to a large loss of efficiency. However, their results were based on linkage equilibrium among marker loci, which may not be realistic for closely linked markers. We extend their relative efficiency calculations by several aspects: 1) allowance for linkage disequilbrium (LD) among marker loci; 2) evaluation of different patterns of LD; and 3) evaluation of nuclear families with and without parents. We show that although the loss in efficiency of haplotype frequencies among unrelated subjects decreases as LD increases to its maximum value, the general conclusions of Douglas et al. ([2001] Nat. Genet. 28:361-364) hold true for a variety of LD patterns and magnitudes. However, our results also demonstrate that trios of parents+one child are highly efficient for haplotype frequency estimation, that additional children offer little information, and that siblings without parents can be grossly inefficient. Genet. Epidemiol. 23:426-443, 2002. PMID:12432508

  8. Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility.

    PubMed

    Cole, J B; Null, D J; VanRaden, P M

    2016-09-01

    Phenotypes from the August 2015 US national genetic evaluation were used to compute phenotypic effects of 18 recessive haplotypes in Ayrshire (n=1), Brown Swiss (n=5), Holstein (n=10), and Jersey (n=2) cattle on milk, fat, and protein yields, somatic cell score (SCS), single-trait productive life (PL), daughter pregnancy rate (DPR), heifer conception rate (HCR), and cow conception rate (CCR). The haplotypes evaluated were Ayrshire haplotype 1, Brown Swiss haplotypes 1 and 2, spinal dysmyelination, spinal muscular atrophy, Weaver Syndrome, brachyspina, Holstein cholesterol deficiency, Holstein haplotypes 1 to 5, bovine leukocyte adhesion deficiency, complex vertebral malformation, mulefoot (syndactyly), and Jersey haplotypes 1 and 2. When causal variants are unknown and tests are based only on single nucleotide polymorphism haplotypes, it can sometimes be difficult to accurately determine carrier status. For example, 2 Holstein haplotypes for cholesterol deficiency have the same single nucleotide polymorphism genotype, but only one of them carries the causative mutation. Genotyped daughters of carrier bulls included in the analysis ranged from 8 for Weaver Syndrome to 17,869 for Holstein haplotype 3. Lactation records preadjusted for nongenetic factors and direct genomic values (DGV) were used to estimate phenotypic and genetic effects of recessive haplotypes, respectively. We found no phenotypic or genetic differences between carriers and noncarriers of Ayrshire or Brown Swiss defects. Several associations were noted for Holstein haplotypes, including fat and HCR for Holstein haplotype 0 carriers; milk, protein, SCS, PL, and fertility for Holstein haplotype 1; protein, PL, CCR, and HCR for Holstein haplotype 2; milk, protein, and fertility for Holstein haplotype 4; and protein yield and DPR for Holstein haplotype 5. There were no differences among bovine leukocyte adhesion deficiency carriers, but complex vertebral malformation affected fat yield and mulefoot

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

    PubMed

    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.

  10. Direct micro-haplotyping by multiple double PCR amplifications of specific alleles (MD-PASA)

    PubMed Central

    Eitan, Yuval; Kashi, Yechezkel

    2002-01-01

    Analysis of haplotypes is an important tool in population genetics, familial heredity and gene mapping. Determination of haplotypes of multiple single nucleotide polymorphisms (SNPs) or other simple mutations is time consuming and expensive when analyzing large populations, and often requires the help of computational and statistical procedures. Based on double PCR amplification of specific alleles, described previously, we have developed a simple, rapid and low-cost method for direct haplotyping of multiple SNPs and simple mutations found within relatively short specific regions or genes (micro-haplotypes). Using this method, it is possible to directly determine the physical linkage of multiple heterozygous alleles, by conducting a series of double allele-specific PCR amplification sets with simple analysis by gel electrophoresis. Application of the method requires prior information as to the sequence of the segment to be haplotyped, including the polymorphic sites. We applied the method to haplotyping of nine sites in the chicken HSP108 gene. One of the haplotypes in the population apparently arose by recombination between two existing haplotypes, and we were able to locate the point of recombination within a segment of 19 bp. We anticipate rapidly growing needs for SNP haplotyping in human (medical and pharmacogenetics), animal and plant genetics; in this context, the multiple double PCR amplifications of specific alleles (MD-PASA) method offers a useful haplotyping tool. PMID:12060700

  11. COI haplotype groups in Mesocriconema (Nematoda: Criconematidae) and their morphospecies associations.

    PubMed

    Powers, T O; Bernard, E C; Harris, T; Higgins, R; Olson, M; Lodema, M; Mullin, P; Sutton, L; Powers, K S

    2014-07-03

    Discocriconemella inarata is transferred to Mesocriconema inaratum based on its phylogenetic position on the COI tree as well as previous phylogenetic analyses using 18S, ITS1, and cytochrome b nucleotide sequences. This study indicates that some of the species considered cosmopolitan in their distribution are actually multispecies polyphyletic groupings and an accurate assessment of Mesocriconema species distributions will benefit from molecular determination of haplotype relationships. The groups revealed by COI analysis should provide a useful framework for the evaluation of additional Mesocriconema species and will improve the reliability of designating taxonomic units in studies of nematode biodiversity. 

  12. Annotated definition of BCL11A and HMIP-2 haplotypes through the analysis of sicilian β-thalassemia patients with high levels of fetal hemoglobin.

    PubMed

    Buccheri, Maria A; Spina, Sonia; Ruberto, Concetta; Lombardo, Turi; Labie, Dominique; Ragusa, And Angela

    2013-01-01

    Fetal hemoglobin (Hb F) is the principal ameliorating factor of β-thalassemia (β-thal) and sickle cell disease. Persistent production in adult life is a quantitative trait regulated by loci inside or outside the β-globin gene cluster. From genome-wide association studies, principal quantitative trait loci (QTL) (accounting for 50.0% of Hb F variability in different populations) have been identified in the BCL11A gene, HBS1L-MYB intergenic polymorphism and the β-globin gene cluster itself. In this study, we analyzed quantitative trait haplotypes in two Sicilian families with extremely mild β-thal and unusually high Hb F expression, in order to examine possible genetic background variations in a similar β-thalassemic phenotype. This study redefines the linkage disequilibrium blocks at these loci, but also shows slight differences between probands in haplotype combinations which could reflect different mechanisms of high Hb F production in patients with β-thal. We proposed a haplotype-based approach as a useful tool for the understanding of β-thal phenotype variation in patients with similar β-thalassemic backgrounds in an attempt to answer the recurring question of why patients with the same β-thalassemic genotype show different phenotypes.

  13. Mitochondrial coding genome analysis of tropical root-knot nematodes (Meloidogyne) supports haplotype based diagnostics and reveals evidence of recent reticulate evolution

    PubMed Central

    Janssen, Toon; Karssen, Gerrit; Verhaeven, Myrtle; Coyne, Danny; Bert, Wim

    2016-01-01

    The polyphagous parthenogenetic root-knot nematodes of the genus Meloidogyne are considered to be the most significant nematode pest in sub-tropical and tropical agriculture. Despite the crucial need for correct diagnosis, identification of these pathogens remains problematic. The traditionally used diagnostic strategies, including morphometrics, host-range tests, biochemical and molecular techniques, now appear to be unreliable due to the recently-suggested hybrid origin of root-knot nematodes. In order to determine a suitable barcode region for these pathogens nine quickly-evolving mitochondrial coding genes were screened. Resulting haplotype networks revealed closely related lineages indicating a recent speciation, an anthropogenic-aided distribution through agricultural practices, and evidence for reticulate evolution within M. arenaria. Nonetheless, nucleotide polymorphisms harbor enough variation to distinguish these closely-related lineages. Furthermore, completeness of lineage sorting was verified by screening 80 populations from widespread geographical origins and variable hosts. Importantly, our results indicate that mitochondrial haplotypes are strongly linked and consistent with traditional esterase isozyme patterns, suggesting that different parthenogenetic lineages can be reliably identified using mitochondrial haplotypes. The study indicates that the barcode region Nad5 can reliably identify the major lineages of tropical root-knot nematodes. PMID:26940543

  14. Genetic analysis of haplotype data for 23 Y-chromosome short tandem repeat loci in the Turkish population recently settled in Sarajevo, Bosnia and Herzegovina

    PubMed Central

    Dogan, Serkan; Primorac, Dragan; Marjanović, Damir

    2014-01-01

    Aim To explore the distribution and polymorphisms of 23 short tandem repeat (STR) loci on the Y chromosome in the Turkish population recently settled in Sarajevo, Bosnia and Herzegovina and to investigate its genetic relationships with the homeland Turkish population and neighboring populations. Methods This study included 100 healthy unrelated male individuals from the Turkish population living in Sarajevo. Buccal swab samples were collected as a DNA source. Genomic DNA was extracted using the salting out method and amplification was performed using PowerPlex Y 23 amplification kit. The studied population was compared to other populations using pairwise genetic distances, which were represented with a multi-dimensional scaling plot. Results Haplotype and allele frequencies of the sample population were calculated and the results showed that all 100 samples had unique haplotypes. The most polymorphic locus was DYS458, and the least polymorphic DYS391. The observed haplotype diversity was 1.0000 ± 0.0014, with a discrimination capacity of 1.00 and the match probability of 0.01. Rst values showed that our sample population was closely related in both dimensions to the Lebanese and Iraqi populations, while it was more distant from Bosnian, Croatian, and Macedonian populations. Conclusion Turkish population residing in Sarajevo could be observed as a representative Turkish population, since our results were consistent with those previously published for the homeland Turkish population. Also, this study once again proved that geographically close populations were genetically more related to each other. PMID:25358886

  15. Computed Tomography Inspection and Analysis for Additive Manufacturing Components

    NASA Technical Reports Server (NTRS)

    Beshears, Ronald D.

    2016-01-01

    Computed tomography (CT) inspection was performed on test articles additively manufactured from metallic materials. Metallic AM and machined wrought alloy test articles with programmed flaws were inspected using a 2MeV linear accelerator based CT system. Performance of CT inspection on identically configured wrought and AM components and programmed flaws was assessed using standard image analysis techniques to determine the impact of additive manufacturing on inspectability of objects with complex geometries.

  16. Additivity in the Analysis and Design of HIV Protease Inhibitors

    PubMed Central

    Jorissen, Robert N.; Kiran Kumar Reddy, G. S.; Ali, Akbar; Altman, Michael D.; Chellappan, Sripriya; Anjum, Saima G.; Tidor, Bruce; Schiffer, Celia A.; Rana, Tariq M.; Gilson, Michael K.

    2009-01-01

    We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors, whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridge-regression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease-inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis. PMID:19193159

  17. Croatian national reference Y-STR haplotype database.

    PubMed

    Mršić, Gordan; Gršković, Branka; Vrdoljak, Andro; Popović, Maja; Valpotić, Ivica; Anđelinović, Šimun; Stenzl, Vlastimil; Ehler, Edvard; Urban, Ludvik; Lacković, Gordana; Underhill, Peter; Primorac, Dragan

    2012-07-01

    A reference Y-chromosome short tandem repeat (STR) haplotype database is needed for Y-STR match interpretation as well as for national and regional characterization of populations. The aim of this study was to create a comprehensive Y-STR haplotype database of the Croatian contemporary population and to analyze substructure between the five Croatian regions. We carried out a statistical analysis of the data from previously performed genetic analyses collected during routine forensic work by the Forensic Science Centre "Ivan Vučetić". A total of 1,100 unrelated men from eastern, western, northern, southern and central Croatia were selected for the purpose of this study. Y-STRs were typed using the AmpFISTR Yfiler PCR amplification kit. Analysis of molecular variance calculated with the Y chromosome haplotype reference database online analysis tool included 16 population samples with 20,247 haplotypes. A total of 947 haplotypes were recorded, 848 of which were unique (89.5%). Haplotype diversity was 0.998, with the most frequent haplotype found in 9 of 1,100 men (0.82%). Locus diversity varied from 0.266 for DYS392 to 0.868 for DYS385. Discrimination capacity was 86.1%. Our results suggested high level of similarity among regional subpopulations within Croatia, except for mildly different southern Croatia. Relative resemblance was found with Bosnia and Herzegovina and Serbia. Whit Atheys' Haplogroup Predictor was used to estimate the frequencies of Y-chromosome haplogroups. I2a, R1a, E1b1b and R1b haplogroups were most frequent in all Croatian regions. These results are important in forensics and contribute to the population genetics and genetic background of the contemporary Croatian population. PMID:22391654

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

    SciTech Connect

    Eisensmith, R.C.; Woo, S.L.C. )

    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.

  19. Optimal Multicomponent Analysis Using the Generalized Standard Addition Method.

    ERIC Educational Resources Information Center

    Raymond, Margaret; And Others

    1983-01-01

    Describes an experiment on the simultaneous determination of chromium and magnesium by spectophotometry modified to include the Generalized Standard Addition Method computer program, a multivariate calibration method that provides optimal multicomponent analysis in the presence of interference and matrix effects. Provides instructions for…

  20. Detecting structure of haplotypes and local ancestry

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. A global analysis of soil acidification caused by nitrogen addition

    NASA Astrophysics Data System (ADS)

    Tian, Dashuan; Niu, Shuli

    2015-02-01

    Nitrogen (N) deposition-induced soil acidification has become a global problem. However, the response patterns of soil acidification to N addition and the underlying mechanisms remain far from clear. Here, we conducted a meta-analysis of 106 studies to reveal global patterns of soil acidification in responses to N addition. We found that N addition significantly reduced soil pH by 0.26 on average globally. However, the responses of soil pH varied with ecosystem types, N addition rate, N fertilization forms, and experimental durations. Soil pH decreased most in grassland, whereas boreal forest was not observed a decrease to N addition in soil acidification. Soil pH decreased linearly with N addition rates. Addition of urea and NH4NO3 contributed more to soil acidification than NH4-form fertilizer. When experimental duration was longer than 20 years, N addition effects on soil acidification diminished. Environmental factors such as initial soil pH, soil carbon and nitrogen content, precipitation, and temperature all influenced the responses of soil pH. Base cations of Ca2+, Mg2+ and K+ were critical important in buffering against N-induced soil acidification at the early stage. However, N addition has shifted global soils into the Al3+ buffering phase. Overall, this study indicates that acidification in global soils is very sensitive to N deposition, which is greatly modified by biotic and abiotic factors. Global soils are now at a buffering transition from base cations (Ca2+, Mg2+ and K+) to non-base cations (Mn2+ and Al3+). This calls our attention to care about the limitation of base cations and the toxic impact of non-base cations for terrestrial ecosystems with N deposition.

  2. Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5-6.0 Hz polyspike waves.

    PubMed

    Wight, Jenny E; Nguyen, Viet-Huong; Medina, Marco T; Patterson, Christopher; Durón, Reyna M; Molina, Yolly; Lin, Yu-Chen; Martínez-Juárez, Iris E; Ochoa, Adriana; Jara-Prado, Aurelio; Tanaka, Miyabi; Bai, Dongsheng; Aftab, Sumaya; Bailey, Julia N; Delgado-Escueta, Antonio V

    2016-03-01

    Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5-6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two-point parametric linkage analyses were performed with 5185 single-nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2-q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage (Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3-q31.2 (Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease-causing genes, favoring the concept of JME as several distinct diseases. Whole-exome sequencing will likely identify a CAE/JME gene in 2q21.2-2q31.1, a JME/pA gene in 13q13.3-q31.2, and a cJME gene in 17q12. PMID:27066514

  3. [Kinetic analysis of additive effect on desulfurization activity].

    PubMed

    Han, Kui-hua; Zhao, Jian-li; Lu, Chun-mei; Wang, Yong-zheng; Zhao, Gai-ju; Cheng, Shi-qing

    2006-02-01

    The additive effects of A12O3, Fe2O3 and MnCO3 on CaO sulfation kinetics were investigated by thermogravimetic analysis method and modified grain model. The activation energy (Ea) and the pre-exponential factor (k0) of surface reaction, the activation energy (Ep) and the pre-exponential factor (D0) of product layer diffusion reaction were calculated according to the model. Additions of MnCO3 can enhance the initial reaction rate, product layer diffusion and the final CaO conversion of sorbents, the effect mechanism of which is similar to that of Fe2O3. The method based isokinetic temperature Ts and activation energy can not estimate the contribution of additive to the sulfation reactivity, the rate constant of the surface reaction (k), and the effective diffusivity of reactant in the product layer (Ds) under certain experimental conditions can reflect the effect of additives on the activation. Unstoichiometric metal oxide may catalyze the surface reaction and promote the diffusivity of reactant in the product layer by the crystal defect and distinct diffusion of cation and anion. According to the mechanism and effect of additive on the sulfation, the effective temperature and the stoichiometric relation of reaction, it is possible to improve the utilization of sorbent by compounding more additives to the calcium-based sorbent.

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

    PubMed

    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.

  5. Rare variant phasing and haplotypic expression from RNA sequencing with phASER.

    PubMed

    Castel, Stephane E; Mohammadi, Pejman; Chung, Wendy K; Shen, Yufeng; Lappalainen, Tuuli

    2016-01-01

    Haplotype phasing of genetic variants is important for clinical interpretation of the genome, population genetic analysis and functional genomic analysis of allelic activity. Here we present phASER, an accurate approach for phasing variants that are overlapped by sequencing reads, including those from RNA sequencing (RNA-seq), which often span multiple exons due to splicing. Using diverse RNA-seq data we demonstrate that this provides more accurate phasing of rare variants compared with population-based phasing and allows phasing of variants in the same gene up to hundreds of kilobases away that cannot be obtained from DNA sequencing (DNA-seq) reads. We show that in the context of medical genetic studies this improves the resolution of compound heterozygotes. Additionally, phASER provides measures of haplotypic expression that increase power and accuracy in studies of allelic expression. In summary, phasing using RNA-seq and phASER is accurate and improves studies where rare variant haplotypes or allelic expression is needed. PMID:27605262

  6. Rare variant phasing and haplotypic expression from RNA sequencing with phASER

    PubMed Central

    Castel, Stephane E.; Mohammadi, Pejman; Chung, Wendy K.; Shen, Yufeng; Lappalainen, Tuuli

    2016-01-01

    Haplotype phasing of genetic variants is important for clinical interpretation of the genome, population genetic analysis and functional genomic analysis of allelic activity. Here we present phASER, an accurate approach for phasing variants that are overlapped by sequencing reads, including those from RNA sequencing (RNA-seq), which often span multiple exons due to splicing. Using diverse RNA-seq data we demonstrate that this provides more accurate phasing of rare variants compared with population-based phasing and allows phasing of variants in the same gene up to hundreds of kilobases away that cannot be obtained from DNA sequencing (DNA-seq) reads. We show that in the context of medical genetic studies this improves the resolution of compound heterozygotes. Additionally, phASER provides measures of haplotypic expression that increase power and accuracy in studies of allelic expression. In summary, phasing using RNA-seq and phASER is accurate and improves studies where rare variant haplotypes or allelic expression is needed. PMID:27605262

  7. Development of a simultaneous high resolution typing method for three SLA class II genes, SLA-DQA, SLA-DQB1, and SLA-DRB1 and the analysis of SLA class II haplotypes.

    PubMed

    Le, MinhThong; Choi, Hojun; Choi, Min-Kyeung; Cho, Hyesun; Kim, Jin-Hoi; Seo, Han Geuk; Cha, Se-Yeon; Seo, Kunho; Dadi, Hailu; Park, Chankyu

    2015-06-15

    The characterization of the genetic variations of major histocompatibility complex (MHC) is essential to understand the relationship between the genetic diversity of MHC molecules and disease resistance and susceptibility in adaptive immunity. We previously reported the development of high-resolution individual locus typing methods for three of the most polymorphic swine leukocyte antigens (SLA) class II loci, namely, SLA-DQA, SLA-DQB1, and SLA-DRB1. In this study, we extensively modified our previous protocols and developed a method for the simultaneous amplification of the three SLA class II genes and subsequent analysis of individual loci using direct sequencing. The unbiased and simultaneous amplification of alleles from the all three hyper-polymorphic and pseudogene containing genes such as MHC genes is extremely challenging. However, using this method, we demonstrated the successful typing of SLA-DQA, SLA-DQB1, and SLA-DRB1 for 31 selected individuals comprising 26 different SLA class II haplotypes which were identified from 700 animals using the single locus typing methods. The results were identical to the known genotypes from the individual locus typing. The new method has significant benefits over the individual locus typing, including lower typing cost, use of less biomaterial, less effort and fewer errors in handling large samples for multiple loci. We also extensively characterized the haplotypes of SLA class II genes and reported three new haplotypes. Our results should serve as a basis to investigate the possible association between polymorphisms of MHC class II and differences in immune responses to exogenous antigens.

  8. ANALYSIS OF MPC ACCESS REQUIREMENTS FOR ADDITION OF FILLER MATERIALS

    SciTech Connect

    W. Wallin

    1996-09-03

    This analysis is prepared by the Mined Geologic Disposal System (MGDS) Waste Package Development Department (WPDD) in response to a request received via a QAP-3-12 Design Input Data Request (Ref. 5.1) from WAST Design (formerly MRSMPC Design). The request is to provide: Specific MPC access requirements for the addition of filler materials at the MGDS (i.e., location and size of access required). The objective of this analysis is to provide a response to the foregoing request. The purpose of this analysis is to provide a documented record of the basis for the response. The response is stated in Section 8 herein. The response is based upon requirements from an MGDS perspective.

  9. Ehapp2: Estimate haplotype frequencies from pooled sequencing data with prior database information.

    PubMed

    Cao, Chang-Chang; Sun, Xiao

    2016-08-01

    To reduce the cost of large-scale re-sequencing, multiple individuals are pooled together and sequenced called pooled sequencing. Pooled sequencing could provide a cost-effective alternative to sequencing individuals separately. To facilitate the application of pooled sequencing in haplotype-based diseases association analysis, the critical procedure is to accurately estimate haplotype frequencies from pooled samples. Here we present Ehapp2 for estimating haplotype frequencies from pooled sequencing data by utilizing a database which provides prior information of known haplotypes. We first translate the problem of estimating frequency for each haplotype into finding a sparse solution for a system of linear equations, where the NNREG algorithm is employed to achieve the solution. Simulation experiments reveal that Ehapp2 is robust to sequencing errors and able to estimate the frequencies of haplotypes with less than 3% average relative difference for pooled sequencing of mixture of real Drosophila haplotypes with 50× total coverage even when the sequencing error rate is as high as 0.05. Owing to the strategy that proportions for local haplotypes spanning multiple SNPs are accurately calculated first, Ehapp2 retains excellent estimation for recombinant haplotypes resulting from chromosomal crossover. Comparisons with present methods reveal that Ehapp2 is state-of-the-art for many sequencing study designs and more suitable for current massive parallel sequencing. PMID:27216711

  10. Haplotype combination of the bovine CFL2 gene sequence variants and association with growth traits in Qinchuan cattle.

    PubMed

    Sun, Yujia; Lan, Xianyong; Lei, Chuzhao; Zhang, Chunlei; Chen, Hong

    2015-06-01

    The aim of this study was to examine the association of cofilin2 (CFL2) gene polymorphisms with growth traits in Chinese Qinchuan cattle. Three single nucleotide polymorphisms (SNPs) were identified in the bovine CFL2 gene using DNA sequencing and (forced) PCR-RFLP methods. These polymorphisms included a missense mutation (NC_007319.5: g. C 2213 G) in exon 4, one synonymous mutation (NC_007319.5: g. T 1694 A) in exon 4, and a mutation (NC_007319.5: g. G 1500 A) in intron 2, respectively. In addition, we evaluated the haplotype frequency and linkage disequilibrium coefficient of three sequence variants in 488 individuals in QC cattle. All the three SNPs in QC cattle belonged to an intermediate level of genetic diversity (0.25Haplotype analysis of three SNPs showed that 8 different haplotypes were identified in all, but only 5 haplotypes were listed except for those with a frequency of <0.03. Hap4 (-GTC-) had the highest haplotype frequencies (34.70%). However in the three SNPs there were no significant associations between the 13 combined genotypes of the CFL2 gene and growth traits. LD analysis showed that the SNP T 1694 A and C 2213 G loci had a strong linkage (r(2)>0.33). Association analysis indicated that SNP G 1500 A, T 1694 A and C 2213 G were significantly associated with growth traits in the QC population. The results of our study suggest that the CFL2 gene may be a strong candidate gene that affects growth traits in the QC cattle breeding program.

  11. Estimating KIR Haplotype Frequencies on a Cohort of 10,000 Individuals: A Comprehensive Study on Population Variations, Typing Resolutions, and Reference Haplotypes

    PubMed Central

    Jayaraman, Jyothi; Trowsdale, John; Traherne, James; Kuang, Rui; Spellman, Stephen; Maiers, Martin

    2016-01-01

    The killer cell immunoglobulin-like receptors (KIR) mediate human natural killer (NK) cell cytotoxicity via activating or inhibiting signals. Although informative and functional haplotype patterns have been reported, most genotyping has been performed at resolutions that are structurally ambiguous. In order to leverage structural information given low-resolution genotypes, we performed experiments to quantify the effects of population variations, reference haplotypes, and genotyping resolutions on population-level haplotype frequency estimations as well as predictions of individual haplotypes. We genotyped 10,157 unrelated individuals in 5 populations (518 African American[AFA], 258 Asian or Pacific Islander[API], 8,245 European[EUR], 1,073 Hispanic[HIS], and 63 Native American[NAM]) for KIR gene presence/absence (PA), and additionally half of the AFA samples for KIR gene copy number variation (CNV). A custom EM algorithm was used to estimate haplotype frequencies for each population by interpretation in the context of three sets of reference haplotypes. The algorithm also assigns each individual the haplotype pairs of maximum likelihood. Generally, our haplotype frequency estimates agree with similar previous publications to within <5% difference for all haplotypes. The exception is that estimates for NAM from the U.S. showed higher frequency association of cB02 with tA01 (+14%) instead of tB01 (-8.5%) compared to a previous study of NAM from south of the U.S. The higher-resolution CNV genotyping on the AFA samples allowed unambiguous haplotype-pair assignments for the majority of individuals, resulting in a 22% higher median typing resolution score (TRS), which measures likelihood of self-match in the context of population-specific haplo- and geno-types. The use of TRS to quantify reduced ambiguity with CNV data clearly revealed the few individuals with ambiguous genotypes as outliers. It is observed that typing resolution and reference haplotype set influence

  12. Beta-globin gene evolution in the ruminants: evidence for an ancient origin of sheep haplotype B.

    PubMed

    Jiang, Y; Wang, X; Kijas, J W; Dalrymple, B P

    2015-10-01

    Domestic sheep (Ovis aries) can be divided into two groups with significantly different responses to hypoxic environments, determined by two allelic beta-globin haplotypes. Haplotype A is very similar to the goat beta-globin locus, whereas haplotype B has a deletion spanning four globin genes, including beta-C globin, which encodes a globin with high oxygen affinity. We surveyed the beta-globin locus using resequencing data from 70 domestic sheep from 42 worldwide breeds and three Ovis canadensis and two Ovis dalli individuals. Haplotype B has an allele frequency of 71.4% in O. aries and was homozygous (BB) in all five wild sheep. This shared ancestry indicates haplotype B is at least 2-3 million years old. Approximately 40 kb of the sequence flanking the ~37-kb haplotype B deletion had unexpectedly low identity between haplotypes A and B. Phylogenetic analysis showed that the divergent region of sheep haplotype B is remarkably distinct from the beta-globin loci in goat and cattle but still groups with the Ruminantia. We hypothesize that this divergent ~40-kb region in haplotype B may be from an unknown ancestral ruminant and was maintained in the lineage to O. aries, but not other Bovidae, evolving independently of haplotype A. Alternatively, the ~40-kb sequence in haplotype B was more recently acquired by an ancestor of sheep from an unknown non-Bovidae ruminant, replacing part of haplotype A. Haplotype B has a lower nucleotide diversity than does haplotype A, suggesting a recent bottleneck, whereas the higher frequency of haplotype B suggests a subsequent spread through the global population of O. aries.

  13. Beta-globin gene evolution in the ruminants: evidence for an ancient origin of sheep haplotype B.

    PubMed

    Jiang, Y; Wang, X; Kijas, J W; Dalrymple, B P

    2015-10-01

    Domestic sheep (Ovis aries) can be divided into two groups with significantly different responses to hypoxic environments, determined by two allelic beta-globin haplotypes. Haplotype A is very similar to the goat beta-globin locus, whereas haplotype B has a deletion spanning four globin genes, including beta-C globin, which encodes a globin with high oxygen affinity. We surveyed the beta-globin locus using resequencing data from 70 domestic sheep from 42 worldwide breeds and three Ovis canadensis and two Ovis dalli individuals. Haplotype B has an allele frequency of 71.4% in O. aries and was homozygous (BB) in all five wild sheep. This shared ancestry indicates haplotype B is at least 2-3 million years old. Approximately 40 kb of the sequence flanking the ~37-kb haplotype B deletion had unexpectedly low identity between haplotypes A and B. Phylogenetic analysis showed that the divergent region of sheep haplotype B is remarkably distinct from the beta-globin loci in goat and cattle but still groups with the Ruminantia. We hypothesize that this divergent ~40-kb region in haplotype B may be from an unknown ancestral ruminant and was maintained in the lineage to O. aries, but not other Bovidae, evolving independently of haplotype A. Alternatively, the ~40-kb sequence in haplotype B was more recently acquired by an ancestor of sheep from an unknown non-Bovidae ruminant, replacing part of haplotype A. Haplotype B has a lower nucleotide diversity than does haplotype A, suggesting a recent bottleneck, whereas the higher frequency of haplotype B suggests a subsequent spread through the global population of O. aries. PMID:26096044

  14. Detecting disease-predisposing variants: The haplotype method

    SciTech Connect

    Valdes, A.M.; Thomson, G.

    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.

  15. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

    PubMed Central

    Lambert, J-C; Grenier-Boley, B; Harold, D; Zelenika, D; Chouraki, V; Kamatani, Y; Sleegers, K; Ikram, M A; Hiltunen, M; Reitz, C; Mateo, I; Feulner, T; Bullido, M; Galimberti, D; Concari, L; Alvarez, V; Sims, R; Gerrish, A; Chapman, J; Deniz-Naranjo, C; Solfrizzi, V; Sorbi, S; Arosio, B; Spalletta, G; Siciliano, G; Epelbaum, J; Hannequin, D; Dartigues, J-F; Tzourio, C; Berr, C; Schrijvers, E M C; Rogers, R; Tosto, G; Pasquier, F; Bettens, K; Van Cauwenberghe, C; Fratiglioni, L; Graff, C; Delepine, M; Ferri, R; Reynolds, C A; Lannfelt, L; Ingelsson, M; Prince, J A; Chillotti, C; Pilotto, A; Seripa, D; Boland, A; Mancuso, M; Bossù, P; Annoni, G; Nacmias, B; Bosco, P; Panza, F; Sanchez-Garcia, F; Del Zompo, M; Coto, E; Owen, M; O'Donovan, M; Valdivieso, F; Caffara, P; Scarpini, E; Combarros, O; Buée, L; Campion, D; Soininen, H; Breteler, M; Riemenschneider, M; Van Broeckhoven, C; Alpérovitch, A; Lathrop, M; Trégouët, D-A; Williams, J; Amouyel, P

    2013-01-01

    Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10−10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10−7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD. PMID:22430674

  16. Results of Expedicion Humana. I. Analysis of HLA class II (DRB1-DQA1-DPB1) alleles and DR-DQ haplotypes in nine Amerindian populations from Colombia.

    PubMed

    Trachtenberg, E A; Keyeux, G; Bernal, J E; Rhodas, M C; Erlich, H A

    1996-09-01

    HLA class II variation was analyzed in nine Native American populations of Colombia using PCR/SSOP typing methods. Under the auspices of the Expedition Humana, approximately 30 unrelated native Colombia Indian samples each from the Tule (NW Pacific Coast), Kogui (Sierra Nevada). Ijka (Sierra Nevada), Ingano (Amazonas), Coreguaje (Amazonas), Nukak (Amazonas), Waunana (Pacific), Embera (Pacific) and Sikuani (Northeastern Plains) were collected and analyzed at the DRBI, DQA1, DQB1 and DPB1 loci. The number of different DRB1, DQA1, DQB1 and DPB1 alleles in the Colombian Indians is markedly reduced in comparison with neighboring African Colombian populations, which exhibit a very high degree of class II variability, as discussed in an accompanying paper. In the Colombian Amerindian groups, DR2 (DRB1*1602), DR4 (DRB1*0407, *0404, *0403 AND *0411), DR6 (DRB1*1402) and DR8 (DRB1*0802) comprise > 95% of all DRB1 alleles. We also found an absence of DR3 in all populations, and DR1, DR7 and DR9 allelic groups were either very rare or absent. Each Colombian Amerindian population has a predominant DRB1 allele (f = approximately 0.22-0.65) and DRB1-DQA1-DQB1 haplotype. Several novel DR-DQ haplotypes were also found. At the DPB1 locus, DPB1*0402 (f = 0.28-0.82), *1401 (f = 0.03-0.45), and *3501 (f = 0.03-0.27), were the three most prevalent alleles, each population maintaining one of these three alleles as the predominant (f > 0.26) DPB1 allele. The reduction of diversity for the HLA class II alleles in the Colombian Indians is suggestive of a population bottleneck during the colonization of the Americans, with little to no subsequent admixture with neighboring African Colombian populations in the last approximately 300 years. PMID:8896175

  17. Identification of PKD2 mutations in human preimplantation embryos in vitro using a combination of targeted next-generation sequencing and targeted haplotyping.

    PubMed

    Chen, Song-Chang; Xu, Xiao-Li; Zhang, Jun-Yu; Ding, Guo-Lian; Jin, Li; Liu, Bei; Sun, Dong-Mei; Mei, Chang-Lin; Yang, Xiao-Nan; Huang, He-Feng; Xu, Chen-Ming

    2016-01-01

    Here, we evaluate the applicability of a new method that combines targeted next-generation sequencing (NGS) with targeted haplotyping in identifying PKD2 gene mutations in human preimplantation embryos in vitro. To achieve this goal, a proband family with a heterozygous deletion of c.595_595 + 14delGGTAAGAGCGCGCGA in exon 1 of the PKD2 gene was studied. A total of 10 samples were analyzed, including 7 embryos. An array-based gene chip was designed to capture all of the exons of 21 disease-related genes, including PKD2. We performed Sanger sequencing combined with targeted haplotyping to evaluate the feasibility of this new method. A total of 7.09 G of data were obtained from 10 samples by NGS. In addition, 24,142 informative single-nucleotide polymorphisms (SNPs) were identified. Haplotyping analysis of several informative SNPs of PKD2 that we selected revealed that embryos 3, 5, and 6 did not inherit the mutation haplotypes of the PKD2 gene, a finding that was 100% accurate and was consistent with Sanger sequencing. Our results demonstrate that targeted NGS combined with targeted haplotyping can be used to identify PKD2 gene mutations in human preimplantation embryos in vitro with high sensitivity, fidelity, throughput and speed. PMID:27150309

  18. Identification of PKD2 mutations in human preimplantation embryos in vitro using a combination of targeted next-generation sequencing and targeted haplotyping

    PubMed Central

    Chen, Song-Chang; Xu, Xiao-Li; Zhang, Jun-Yu; Ding, Guo-Lian; Jin, Li; Liu, Bei; Sun, Dong-Mei; Mei, Chang-Lin; Yang, Xiao-Nan; Huang, He-Feng; Xu, Chen-Ming

    2016-01-01

    Here, we evaluate the applicability of a new method that combines targeted next-generation sequencing (NGS) with targeted haplotyping in identifying PKD2 gene mutations in human preimplantation embryos in vitro. To achieve this goal, a proband family with a heterozygous deletion of c.595_595 + 14delGGTAAGAGCGCGCGA in exon 1 of the PKD2 gene was studied. A total of 10 samples were analyzed, including 7 embryos. An array-based gene chip was designed to capture all of the exons of 21 disease-related genes, including PKD2. We performed Sanger sequencing combined with targeted haplotyping to evaluate the feasibility of this new method. A total of 7.09 G of data were obtained from 10 samples by NGS. In addition, 24,142 informative single-nucleotide polymorphisms (SNPs) were identified. Haplotyping analysis of several informative SNPs of PKD2 that we selected revealed that embryos 3, 5, and 6 did not inherit the mutation haplotypes of the PKD2 gene, a finding that was 100% accurate and was consistent with Sanger sequencing. Our results demonstrate that targeted NGS combined with targeted haplotyping can be used to identify PKD2 gene mutations in human preimplantation embryos in vitro with high sensitivity, fidelity, throughput and speed. PMID:27150309

  19. Evidence for high-risk haplotypes and (CGG)n expansion in fragile X syndrome in the Hellenic population of Greece and Cyprus

    SciTech Connect

    Syrrou, M.; Georgiou, I.; Pagoulatos, G.

    1996-07-12

    The expansion of the trinucleotide repeat (CGG){sub n} in successive generations through maternal meiosis is the cause of fragile X syndrome. Analysis of CA repeat polymorphisms flanking the FMR-1 gene provides evidence of a limited number of {open_quotes}founder{close_quotes} chromosomes and predisposing high-risk haplotypes related to the mutation. To investigate the origin of mutations in the fragile X syndrome in the Hellenic populations of Greece and Cyprus, we studied the alleles and haplotypes at DXS548 and FRAXAC2 loci of 16 independent fragile X and 70 normal control chromosomes. In addition, we studied 191 unrelated normal X chromosomes for the distribution and frequencies of CGG alleles. At DXS548, 6 alleles were found, 2 (194 and 196) of which were represented on fragile X chromosomes. At FRAXAC2, 6 alleles were found, 4 of which were present on fragile X chromosomes. Sixteen haplotypes were identified, but only 5 were present on fragile X chromosomes. The highest number of CGG repeats ({ge} 33) were associated with haplotypes 194-147, 194-151, 194-153, and 204-155. The data provide evidence for founder chromosomes and high-risk haplotypes in the Hellenic population. 20 refs., 3 figs., 2 tabs.

  20. Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women.

    PubMed

    Pan, Z; Fu, Z; Song, Q; Cao, W; Cheng, W; Xu, X

    2016-01-01

    Sex hormones play important roles in breast cancer (BC) development. This study investigated associations between BC risk and hormone-related gene variants in Chinese women. In a cohort of 336 patients with histopathologically confirmed BC and 390 age-matched controls, we genotyped seven single nucleotide polymorphisms (SNPs) in five hormone-related genes: estrogen receptor-α (ESR1), aromatase (CYP19), catechol-O-methyl transferase (COMT), sex hormone-binding globulin (SHBG), and glutathione S-transferase (GSTP1). Among these seven SNPs, the SNPs in GSTP1 rs1695 [A/G; odds ratio (OR): 1.68; 95% confidence interval (CI): 1.23-2.30] and ESR1 rs2046210 (C/T; OR: 1.39; 95%CI = 1.02-1.91) were associated with an increased risk among heterozygote carriers. Homozygotes of minor alleles of CYP19 rs10046 (CC) were associated with a reduced risk of BC with OR: 0.61 (95%CI = 0.39-0.95). In addition, a stratified analysis by menopausal status indicated that the association of the CYP19 polymorphisms (rs10046 and rs700519) with BC risk was mainly evident in premenopausal women, and the association of CYP19 rs700519 with BC risk was significant in women less than 50 years old. Haplotype analysis identified 15 common haplotypes (>1%). The haplotype TGGGGTC was significantly associated with BC risk compared with the reference haplotype CGAGGTC (OR > 1000, P < 0.0001). Our data demonstrate that these ESR1, GSTP1, and CYP19 polymorphisms are associated with risk of BC, and the risk haplotype TGGGGTC could help to identify populations with high susceptibility to BC in Chinese women. PMID:27323034

  1. SNP Haplotype Mapping in a Small ALS Family

    PubMed Central

    Krueger, Katherine A. Dick; Tsuji, Shoji; Fukuda, Yoko; Takahashi, Yuji; Goto, Jun; Mitsui, Jun; Ishiura, Hiroyuki; Dalton, Joline C.; Miller, Michael B.; Day, John W.; Ranum, Laura P. W.

    2009-01-01

    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. PMID:19479031

  2. Spectroscopic analysis and DFT calculations of a food additive Carmoisine

    NASA Astrophysics Data System (ADS)

    Snehalatha, M.; Ravikumar, C.; Hubert Joe, I.; Sekar, N.; Jayakumar, V. S.

    2009-04-01

    FT-IR and Raman techniques were employed for the vibrational characterization of the food additive Carmoisine (E122). The equilibrium geometry, various bonding features, and harmonic vibrational wavenumbers have been investigated with the help of density functional theory (DFT) calculations. A good correlation was found between the computed and experimental wavenumbers. Azo stretching wavenumbers have been lowered due to conjugation and π-electron delocalization. Predicted electronic absorption spectra from TD-DFT calculation have been analysed comparing with the UV-vis spectrum. The first hyperpolarizability of the molecule is calculated. Intramolecular charge transfer (ICT) responsible for the optical nonlinearity of the dye molecule has been discussed theoretically and experimentally. Stability of the molecule arising from hyperconjugative interactions, charge delocalization and C-H⋯O, improper, blue shifted hydrogen bonds have been analysed using natural bond orbital (NBO) analysis.

  3. [Analysis of constituents in urushi wax, a natural food additive].

    PubMed

    Jin, Zhe-Long; Tada, Atsuko; Sugimoto, Naoki; Sato, Kyoko; Masuda, Aino; Yamagata, Kazuo; Yamazaki, Takeshi; Tanamoto, Kenichi

    2006-08-01

    Urushi wax is a natural gum base used as a food additive. In order to evaluate the quality of urushi wax as a food additive and to obtain information useful for setting official standards, we investigated the constituents and their concentrations in urushi wax, using the same sample as scheduled for toxicity testing. After methanolysis of urushi wax, the composition of fatty acids was analyzed by GC/MS. The results indicated that the main fatty acids were palmitic acid, oleic acid and stearic acid. LC/MS analysis of urushi wax provided molecular-related ions of the main constituents. The main constituents were identified as triglycerides, namely glyceryl tripalmitate (30.7%), glyceryl dipalmitate monooleate (21.2%), glyceryl dioleate monopalmitate (2.1%), glyceryl monooleate monopalmitate monostearate (2.6%), glyceryl dipalmitate monostearate (5.6%), glyceryl distearate monopalmitate (1.4%). Glyceryl dipalmitate monooleate isomers differing in the binding sites of each constituent fatty acid could be separately determined by LC/MS/MS. PMID:16984037

  4. Decreasing Cloudiness Over China: An Updated Analysis Examining Additional Variables

    SciTech Connect

    Kaiser, D.P.

    2000-01-14

    As preparation of the IPCC's Third Assessment Report takes place, one of the many observed climate variables of key interest is cloud amount. For several nations of the world, there exist records of surface-observed cloud amount dating back to the middle of the 20th Century or earlier, offering valuable information on variations and trends. Studies using such databases include Sun and Groisman (1999) and Kaiser and Razuvaev (1995) for the former Soviet Union, Angel1 et al. (1984) for the United States, Henderson-Sellers (1986) for Europe, Jones and Henderson-Sellers (1992) for Australia, and Kaiser (1998) for China. The findings of Kaiser (1998) differ from the other studies in that much of China appears to have experienced decreased cloudiness over recent decades (1954-1994), whereas the other land regions for the most part show evidence of increasing cloud cover. This paper expands on Kaiser (1998) by analyzing trends in additional meteorological variables for Chi na [station pressure (p), water vapor pressure (e), and relative humidity (rh)] and extending the total cloud amount (N) analysis an additional two years (through 1996).

  5. Sensitivity analysis of geometric errors in additive manufacturing medical models.

    PubMed

    Pinto, Jose Miguel; Arrieta, Cristobal; Andia, Marcelo E; Uribe, Sergio; Ramos-Grez, Jorge; Vargas, Alex; Irarrazaval, Pablo; Tejos, Cristian

    2015-03-01

    Additive manufacturing (AM) models are used in medical applications for surgical planning, prosthesis design and teaching. For these applications, the accuracy of the AM models is essential. Unfortunately, this accuracy is compromised due to errors introduced by each of the building steps: image acquisition, segmentation, triangulation, printing and infiltration. However, the contribution of each step to the final error remains unclear. We performed a sensitivity analysis comparing errors obtained from a reference with those obtained modifying parameters of each building step. Our analysis considered global indexes to evaluate the overall error, and local indexes to show how this error is distributed along the surface of the AM models. Our results show that the standard building process tends to overestimate the AM models, i.e. models are larger than the original structures. They also show that the triangulation resolution and the segmentation threshold are critical factors, and that the errors are concentrated at regions with high curvatures. Errors could be reduced choosing better triangulation and printing resolutions, but there is an important need for modifying some of the standard building processes, particularly the segmentation algorithms.

  6. A haplotype map of the human genome

    PubMed Central

    2007-01-01

    Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution. PMID:16255080

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

    PubMed

    Gilmore, Simon; Peakall, Rod; Robertson, James

    2007-10-25

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

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

    PubMed

    Nadeau, J H; Phillips, S J

    1987-11-01

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

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

    PubMed

    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

  10. COMT haplotype analyses in Malaysians with schizophrenia.

    PubMed

    Tee, Shiau Foon; Tang, Pek Yee; Loh, Han Chern

    2012-01-30

    The present study included a total 261 patients with schizophrenia and 261 healthy controls to replicate the genetic association between the cathechol-o-methyltransferase gene and schizophrenia using a haplotype block-based gene-tagging. The G-G-G haplotype was found to show a highly significant association with schizophrenia.

  11. Filling in missing genotypes using haplotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Unknown genotypes can be made known (imputed) from observed genotypes at the same or nearby loci of relatives using pedigree haplotyping, or from matching allele patterns (regardless of pedigree) using population haplotyping. Fortran program findhap.f90 was designed to combine population and pedigre...

  12. GABRB2 Haplotype Association with Heroin Dependence in Chinese Population

    PubMed Central

    Kim, Yung Su; Yang, Mei; Mat, Wai-Kin; Tsang, Shui-Ying; Su, Zhonghua; Jiang, Xianfei; Ng, Siu-Kin; Liu, Siyu; Hu, Taobo; Pun, Frank; Liao, Yanhui; Tang, Jinsong; Chen, Xiaogang; Hao, Wei; Xue, Hong

    2015-01-01

    Substance dependence is a frequently observed comorbid disorder in schizophrenia, but little is known about genetic factors possibly shared between the two psychotic disorders. GABRB2, a schizophrenia candidate gene coding for GABAA receptor β2 subunit, is examined for possible association with heroin dependence in Han Chinese population. Four single nucleotide polymorphisms (SNPs) in GABRB2, namely rs6556547 (S1), rs1816071 (S3), rs18016072 (S5), and rs187269 (S29), previously associated with schizophrenia, were examined for their association with heroin dependence. Two additional SNPs, rs10051667 (S31) and rs967771 (S32), previously associated with alcohol dependence and bipolar disorder respectively, were also analyzed. The six SNPs were genotyped by direct sequencing of PCR amplicons of target regions for 564 heroin dependent individuals and 498 controls of Han Chinese origin. Interestingly, it was found that recombination between the haplotypes of all-derived-allele (H1; OR = 1.00) and all-ancestral-allele (H2; OR = 0.74) at S5-S29 junction generated two recombinants H3 (OR = 8.51) and H4 (OR = 5.58), both conferring high susceptibility to heroin dependence. Additional recombination between H2 and H3 haplotypes at S1-S3 junction resulted in a risk-conferring haplotype H5 (OR = 1.94x109). In contrast, recombination between H1 and H2 haplotypes at S3-S5 junction rescued the risk-conferring effect of recombination at S5-S29 junction, giving rise to the protective haplotype H6 (OR = 0.68). Risk-conferring effects of S1-S3 and S5-S29 crossovers and protective effects of S3-S5 crossover were seen in both pure heroin dependent and multiple substance dependence subgroups. In conclusion, significant association was found with haplotypes of the S1-S29 segment in GABRB2 for heroin dependence in Han Chinese population. Local recombination was an important determining factor for switching haplotypes between risk-conferring and protective statuses. The present study

  13. Nonparametric survival analysis using Bayesian Additive Regression Trees (BART).

    PubMed

    Sparapani, Rodney A; Logan, Brent R; McCulloch, Robert E; Laud, Purushottam W

    2016-07-20

    Bayesian additive regression trees (BART) provide a framework for flexible nonparametric modeling of relationships of covariates to outcomes. Recently, BART models have been shown to provide excellent predictive performance, for both continuous and binary outcomes, and exceeding that of its competitors. Software is also readily available for such outcomes. In this article, we introduce modeling that extends the usefulness of BART in medical applications by addressing needs arising in survival analysis. Simulation studies of one-sample and two-sample scenarios, in comparison with long-standing traditional methods, establish face validity of the new approach. We then demonstrate the model's ability to accommodate data from complex regression models with a simulation study of a nonproportional hazards scenario with crossing survival functions and survival function estimation in a scenario where hazards are multiplicatively modified by a highly nonlinear function of the covariates. Using data from a recently published study of patients undergoing hematopoietic stem cell transplantation, we illustrate the use and some advantages of the proposed method in medical investigations. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26854022

  14. Effects of IL-10 haplotype and atomic bomb radiation exposure on gastric cancer risk.

    PubMed

    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.

  15. Association of Nrf2 Polymorphism Haplotypes with Acute Lung Injury Phenotypes in Inbred Strains of Mice

    PubMed Central

    Jedlicka, Anne E.; Gladwell, Wesley; Marzec, Jacqui; McCaw, Zackary R.; Bienstock, Rachelle J.; Kleeberger, Steven R.

    2015-01-01

    Abstract Aims: Nrf2 is a master transcription factor for antioxidant response element (ARE)-mediated cytoprotective gene induction. A protective role for pulmonary Nrf2 was determined in model oxidative disorders, including hyperoxia-induced acute lung injury (ALI). To obtain additional insights into the function and genetic regulation of Nrf2, we assessed functional single nucleotide polymorphisms (SNPs) of Nrf2 in inbred mouse strains and tested whether sequence variation is associated with hyperoxia susceptibility. Results: Nrf2 SNPs were compiled from publicly available databases and by re-sequencing DNA from inbred strains. Hierarchical clustering of Nrf2 SNPs categorized the strains into three major haplotypes. Hyperoxia susceptibility was greater in haplotypes 2 and 3 strains than in haplotype 1 strains. A promoter SNP −103 T/C adding an Sp1 binding site in haplotype 2 diminished promoter activation basally and under hyperoxia. Haplotype 3 mice bearing nonsynonymous coding SNPs located in (1862 A/T, His543Gln) and adjacent to (1417 T/C, Thr395Ile) the Neh1 domain showed suppressed nuclear transactivation of pulmonary Nrf2 relative to other strains, and overexpression of haplotype 3 Nrf2 showed lower ARE responsiveness than overexpression of haplotype 1 Nrf2 in airway cells. Importantly, we found a significant correlation of Nrf2 haplotypes and hyperoxic lung injury phenotypes. Innovation and Conclusion: The results indicate significant influence of Nrf2 polymorphisms and haplotypes on gene function and hyperoxia susceptibility. Our findings further support Nrf2 as a genetic determinant in ALI pathogenesis and provide useful tools for investigators who use mouse strains classified by Nrf2 haplotypes to elucidate the role for Nrf2 in oxidative disorders. Antioxid. Redox Signal. 22, 325–338. PMID:25268541

  16. Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in European families with phenylketonuria (PKU).

    PubMed

    Daiger, S P; Chakraborty, R; Reed, L; Fekete, G; Schuler, D; Berenssi, G; Nasz, I; Brdicka, R; Kamarýt, J; Pijácková, A

    1989-08-01

    DNA haplotype data from the phenylalanine hydroxylase (PAH) locus are available from a number of European populations as a result of RFLP testing for genetic counseling in families with phenylketonuria (PKU). We have analyzed data from Hungary and Czechoslovakia together with published data from five additional countries--Denmark, Switzerland, Scotland, Germany, and France--representing a broad geographic and ethnographic range. The data include 686 complete chromosomal haplotypes for eight RFLP sites assayed in 202 unrelated Caucasian families with PKU. Forty-six distinct RFLP haplotypes have been observed to date, 10 unique to PKU-bearing chromosomes, 12 unique to non-PKU chromosomes, and the remainder found in association with both types. Despite the large number of haplotypes observed (still much less than the theoretical maximum of 384), five haplotypes alone account for more than 76% of normal European chromosomes and four haplotypes alone account for more than 80% of PKU-bearing chromosomes. We evaluated the distribution of haplotypes and alleles within these populations and calculated pairwise disequilibrium values between RFLP sites and between these sites and a hypothetical PKU "locus." These are statistically significant differences between European populations in the frequencies of non-PKU chromosomal haplotypes (P = .025) and PKU chromosomal haplotypes (P much less than .001). Haplotype frequencies of the PKU and non-PKU chromosomes also differ significantly (P much less than .001. Disequilibrium values are consistent with the PAH physical map and support the molecular evidence for multiple, independent PKU mutations in Caucasians. However, the data do not support a single geographic origin for these mutations.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Private haplotypes can reveal local adaptation

    PubMed Central

    2014-01-01

    Background Genome-wide scans for regions that demonstrate deviating patterns of genetic variation have become common approaches for finding genes targeted by selection. Several genomic patterns have been utilized for this purpose, including deviations in haplotype homozygosity, frequency spectra and genetic differentiation between populations. Results We describe a novel approach based on the Maximum Frequency of Private Haplotypes – MFPH – to search for signals of recent population-specific selection. The MFPH statistic is straightforward to compute for phased SNP- and sequence-data. Using both simulated and empirical data, we show that MFPH can be a powerful statistic to detect recent population-specific selection, that it performs at the same level as other commonly used summary statistics (e.g. FST, iHS and XP-EHH), and that MFPH in some cases capture signals of selection that are missed by other statistics. For instance, in the Maasai, MFPH reveals a strong signal of selection in a region where other investigated statistics fail to pick up a clear signal that contains the genes DOCK3, MAPKAPK3 and CISH. This region has been suggested to affect height in many populations based on phenotype-genotype association studies. It has specifically been suggested to be targeted by selection in Pygmy groups, which are on the opposite end of the human height spectrum compared to the Maasai. Conclusions From the analysis of both simulated and publicly available empirical data, we show that MFPH represents a summary statistic that can provide further insight concerning population-specific adaptation. PMID:24885734

  18. Sequence analysis of the fragile X trinucleotide repeat: Correlations with stability and haplotype and implications for the origin of fragile X alleles

    SciTech Connect

    Snow, K.; Tester, D.J.; Kruckeberg, K.E.; Thibodeau, S.N.

    1994-09-01

    Fragile X (FX) syndrome is associated with amplification of a CGG trinucleotide repeat in the 5{prime} untranslated region of the gene FMR-1. To address mechanism of instability and concern related to overlap between sizes of normal stable alleles and FX unstable alleles, we have sequenced 165 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines instability. For 17 stably transmitted alleles with total repeat lengths between 33 and 51, the longest stretch of uninterrupted CGGs was 41. In contrast, for 13 premutation alleles, the shortest stretch of uninterrupted CGGs was 48, suggesting a threshold for expansion between 41 and 48 pure CGGs. For expansion from a premutation to a full mutation, the threshold appears to be {ge}70 uninterrupted repeats. Interestingly, an AGG was detected in some carriers of a full mutation. Comparison of the number of {open_quote}shadow bands{close_quote} in PCR products from similar size alleles with different AGG interruption patterns supports replication slippage as a potential mechanism, i.e. replication slippage occurs more readily as the length of pure repeat increases. Alleles with high total repeat lengths but up to 3 AGGs may be relatively protected against expansion, whereas smaller alleles with pure CGG sequence could be at higher risk for instability. Comparison of sequence data and DXS548 (CA)n data revealed specific sequence trends for each of the DXS548 alleles, explaining the previously reported haplotype association with FX. Incorporating these observations into models for the origin of FX alleles, we consider replication slippage, unequal crossover within the CGG repeat region, recombination between FMR-1 and DXS548, and loss of AGGs by A to C transversion.

  19. Comparison of haplotype frequencies differentiate fall armyworm (Lepidoptera: Noctuidae) corn-strain populations from Florida and Brazil.

    PubMed

    Nagoshi, Rod N; Silvie, Pierre; Meagher, Robert L

    2007-06-01

    Fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a major economic pest throughout the Western Hemisphere. Populations can be subdivided into two morphologically identical but genetically distinct strains (corn-strain and rice-strain) that differ in their host plant preferences. These strains can be distinguished by using polymorphisms in the mitochondrial cytochrome oxidase 1 gene. Additional sequence analysis of this locus identified two sites that were highly polymorphic in the corn-strain population and that produced four different haplotype subgroups. Comparisons of the frequency distribution of these haplotypes found no seasonal or plant host specificities, but they did demonstrate that the Brazil corn-strain population is different from corn-strain fall armyworm found in Florida. The development of a rapid means of distinguishing fall armyworm populations originating from Brazil versus Florida provides an opportunity for investigating and comparing the genetic complexity and long-range movements of this important agricultural pest.

  20. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

    PubMed Central

    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

  1. TNF-alpha SNP haplotype frequencies in equidae.

    PubMed

    Brown, J J; Ollier, W E R; Thomson, W; Matthews, J B; Carter, S D; Binns, M; Pinchbeck, G; Clegg, P D

    2006-05-01

    Tumour necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that plays a crucial role in the regulation of inflammatory and immune responses. In all vertebrate species the genes encoding TNF-alpha are located within the major histocompatability complex. In the horse TNF-alpha has been ascribed a role in a variety of important disease processes. Previously two single nucleotide polymorphisms (SNPs) have been reported within the 5' un-translated region of the equine TNF-alpha gene. We have examined the equine TNF-alpha promoter region further for additional SNPs by analysing DNA from 131 horses (Equus caballus), 19 donkeys (E. asinus), 2 Grant's zebras (E. burchellii boehmi) and one onager (E. hemionus). Two further SNPs were identified at nucleotide positions 24 (T/G) and 452 (T/C) relative to the first nucleotide of the 522 bp polymerase chain reaction product. A sequence variant at position 51 was observed between equidae. SNaPSHOT genotyping assays for these and the two previously reported SNPs were performed on 457 horses comprising seven different breeds and 23 donkeys to determine the gene frequencies. SNP frequencies varied considerably between different horse breeds and also between the equine species. In total, nine different TNF-alpha promoter SNP haplotypes and their frequencies were established amongst the various equidae examined, with some haplotypes being found only in horses and others only in donkeys or zebras. The haplotype frequencies observed varied greatly between different horse breeds. Such haplotypes may relate to levels of TNF-alpha production and disease susceptibility and further investigation is required to identify associations between particular haplotypes and altered risk of disease.

  2. Precessing rotating flows with additional shear: Stability analysis

    NASA Astrophysics Data System (ADS)

    Salhi, A.; Cambon, C.

    2009-03-01

    We consider unbounded precessing rotating flows in which vertical or horizontal shear is induced by the interaction between the solid-body rotation (with angular velocity Ω0 ) and the additional “precessing” Coriolis force (with angular velocity -ɛΩ0 ), normal to it. A “weak” shear flow, with rate 2ɛ of the same order of the Poincaré “small” ratio ɛ , is needed for balancing the gyroscopic torque, so that the whole flow satisfies Euler’s equations in the precessing frame (the so-called admissibility conditions). The base flow case with vertical shear (its cross-gradient direction is aligned with the main angular velocity) corresponds to Mahalov’s [Phys. Fluids A 5, 891 (1993)] precessing infinite cylinder base flow (ignoring boundary conditions), while the base flow case with horizontal shear (its cross-gradient direction is normal to both main and precessing angular velocities) corresponds to the unbounded precessing rotating shear flow considered by Kerswell [Geophys. Astrophys. Fluid Dyn. 72, 107 (1993)]. We show that both these base flows satisfy the admissibility conditions and can support disturbances in terms of advected Fourier modes. Because the admissibility conditions cannot select one case with respect to the other, a more physical derivation is sought: Both flows are deduced from Poincaré’s [Bull. Astron. 27, 321 (1910)] basic state of a precessing spheroidal container, in the limit of small ɛ . A Rapid distortion theory (RDT) type of stability analysis is then performed for the previously mentioned disturbances, for both base flows. The stability analysis of the Kerswell base flow, using Floquet’s theory, is recovered, and its counterpart for the Mahalov base flow is presented. Typical growth rates are found to be the same for both flows at very small ɛ , but significant differences are obtained regarding growth rates and widths of instability bands, if larger ɛ values, up to 0.2, are considered. Finally, both flow cases

  3. HapCompass: A Fast Cycle Basis Algorithm for Accurate Haplotype Assembly of Sequence Data

    PubMed Central

    Aguiar, Derek

    2012-01-01

    Abstract Genome assembly methods produce haplotype phase ambiguous assemblies due to limitations in current sequencing technologies. Determining the haplotype phase of an individual is computationally challenging and experimentally expensive. However, haplotype phase information is crucial in many bioinformatics workflows such as genetic association studies and genomic imputation. Current computational methods of determining haplotype phase from sequence data—known as haplotype assembly—have difficulties producing accurate results for large (1000 genomes-type) data or operate on restricted optimizations that are unrealistic considering modern high-throughput sequencing technologies. We present a novel algorithm, HapCompass, for haplotype assembly of densely sequenced human genome data. The HapCompass algorithm operates on a graph where single nucleotide polymorphisms (SNPs) are nodes and edges are defined by sequence reads and viewed as supporting evidence of co-occurring SNP alleles in a haplotype. In our graph model, haplotype phasings correspond to spanning trees. We define the minimum weighted edge removal optimization on this graph and develop an algorithm based on cycle basis local optimizations for resolving conflicting evidence. We then estimate the amount of sequencing required to produce a complete haplotype assembly of a chromosome. Using these estimates together with metrics borrowed from genome assembly and haplotype phasing, we compare the accuracy of HapCompass, the Genome Analysis ToolKit, and HapCut for 1000 Genomes Project and simulated data. We show that HapCompass performs significantly better for a variety of data and metrics. HapCompass is freely available for download (www.brown.edu/Research/Istrail_Lab/). PMID:22697235

  4. Haplotype Phasing and Inheritance of Copy Number Variants in Nuclear Families

    PubMed Central

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

    2015-01-01

    DNA copy number variants (CNVs) that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i) phase normal and CNV-carrying haplotypes in the copy number variable regions, ii) resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii) infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring. PMID:25853576

  5. Phylogeographic study of Chinese seabuckthorn (Hippophae rhamnoides subsp. sinensis Rousi) reveals two distinct haplotype groups and multiple microrefugia on the Qinghai-Tibet Plateau

    PubMed Central

    Wang, Hongfang; Liu, Han; Yang, Mingbo; Bao, Lei; Ge, Jianping

    2014-01-01

    Historical climate change can shape the genetic pattern of a species. Studies on this phenomenon provide great advantage in predicting the response of species to current and future global climate change. Chinese seabuckthorn (Hippophae rhamnoides subsp. sinensis) is one of the most important cultivated plants in Northwest China. However, the subspecies history and the potential genetic resources within the subspecies range remain unclear. In this study, we utilized two intergenic chloroplast regions to characterize the spatial genetic distribution of the species. We found 19 haplotypes in total, 12 of which were unique to the Chinese seabuckthorn. The populations observed on the Qinghai-Tibet Plateau (QTP) consisted of most of the haplotypes, while in the northeast of the range of the subspecies, an area not on the QTP, only four haplotypes were detected. Our study also revealed two distinct haplotype groups of the subspecies with a sharp transition region located in the south of the Zoige Basin. 89.96% of the genetic variation located between the regions. Mismatch analysis indicated old expansions of these two haplotype groups, approximately around the early stage of Pleistocene. Additional morphological proofs from existing studies and habitat differentiation supported a long independent colonization history among the two regions. Potential adaptation probably occurred but needs more genome and morphology data in future. Chinese seabuckthorn have an older population expansion compared with subspecies in Europe. The lack of large land ice sheets and the heterogeneous landscape of the QTP could have provided extensive microrefugia for Chinese seabuckthorn during the glaciation period. Multiple localities sustaining high-frequency private haplotypes support this hypothesis. Our study gives clear insight into the distribution of genetic resources and the evolutionary history of Chinese seabuckthorn. PMID:25540697

  6. Inferring Selection Intensity and Allele Age from Multilocus Haplotype Structure

    PubMed Central

    Chen, Hua; Slatkin, Montgomery

    2013-01-01

    It is a challenging task to infer selection intensity and allele age from population genetic data. Here we present a method that can efficiently estimate selection intensity and allele age from the multilocus haplotype structure in the vicinity of a segregating mutant under positive selection. We use a structured-coalescent approach to model the effect of directional selection on the gene genealogies of neutral markers linked to the selected mutant. The frequency trajectory of the selected allele follows the Wright-Fisher model. Given the position of the selected mutant, we propose a simplified multilocus haplotype model that can efficiently model the dynamics of the ancestral haplotypes under the joint influence of selection and recombination. This model approximates the ancestral genealogies of the sample, which reduces the number of states from an exponential function of the number of single-nucleotide polymorphism loci to a quadratic function. That allows parameter inference from data covering DNA regions as large as several hundred kilo-bases. Importance sampling algorithms are adopted to evaluate the probability of a sample by exploring the space of both allele frequency trajectories of the selected mutation and gene genealogies of the linked sites. We demonstrate by simulation that the method can accurately estimate selection intensity for moderate and strong positive selection. We apply the method to a data set of the G6PD gene in an African population and obtain an estimate of 0.0456 (95% confidence interval 0.0144−0.0769) for the selection intensity. The proposed method is novel in jointly modeling the multilocus haplotype pattern caused by recombination and mutation, allowing the analysis of haplotype data in recombining regions. Moreover, the method is applicable to data from populations under exponential growth and a variety of other demographic histories. PMID:23797107

  7. Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation.

    PubMed

    Oueslati, S; Hadj Fredj, S; Belhaj, R; Siala, H; Bibi, A; Messaoud, Taieb

    2015-03-01

    The analysis of some extra- and intragenic markers within or closely linked to the cystic fibrosis transmembrane regulator (CFTR) gene is useful as a molecular method in clinical linkage analysis. Indeed, knowing that the molecular basis of cystic fibrosis (CF) is highly heterogeneous in our population, the study of haplotype association with normal and CF chromosomes could be very helpful in cases where one or both mutations remain unidentified. In this study, we analysed with PCR-RFLP and capillary electrophoresis some extra (pJ3.11, KM19 and XV2C) and intragenic (IVS8CA, IVS17bTA and IVS17bCA) polymorphic markers in 50 normal and 10 Tunisian patients carrying the rare E1104X mutation in order to determine the haplotype associated with this mutation. For the extragenic markers, 8 haplotypes were identified. The most frequent of them are the 221 and 112 accounting for 80% of total haplotypes. For the intragenic markers, five haplotypes were present on the E1104X chromosomes. One of them 16-31-13 accounted for 50%. To our knowledge, this is the first work to be interested to the haplotypes linked to the E1104X mutation. This preliminary study of haplotypes could be a helpful method to determine the molecular lesions responsible of this pathology.

  8. Hybrid Additive Manufacturing Technologies - An Analysis Regarding Potentials and Applications

    NASA Astrophysics Data System (ADS)

    Merklein, Marion; Junker, Daniel; Schaub, Adam; Neubauer, Franziska

    Imposing the trend of mass customization of lightweight construction in industry, conventional manufacturing processes like forming technology and chipping production are pushed to their limits for economical manufacturing. More flexible processes are needed which were developed by the additive manufacturing technology. This toolless production principle offers a high geometrical freedom and an optimized utilization of the used material. Thus load adjusted lightweight components can be produced in small lot sizes in an economical way. To compensate disadvantages like inadequate accuracy and surface roughness hybrid machines combining additive and subtractive manufacturing are developed. Within this paper the principles of mainly used additive manufacturing processes of metals and their possibility to be integrated into a hybrid production machine are summarized. It is pointed out that in particular the integration of deposition processes into a CNC milling center supposes high potential for manufacturing larger parts with high accuracy. Furthermore the combination of additive and subtractive manufacturing allows the production of ready to use products within one single machine. Additionally actual research for the integration of additive manufacturing processes into the production chain will be analyzed. For the long manufacturing time of additive production processes the combination with conventional manufacturing processes like sheet or bulk metal forming seems an effective solution. Especially large volumes can be produced by conventional processes. In an additional production step active elements can be applied by additive manufacturing. This principle is also investigated for tool production to reduce chipping of the high strength material used for forming tools. The aim is the addition of active elements onto a geometrical simple basis by using Laser Metal Deposition. That process allows the utilization of several powder materials during one process what

  9. GISH analysis of disomic Brassica napus-Crambe abyssinica chromosome addition lines produced by microspore culture from monosomic addition lines.

    PubMed

    Wang, Youping; Sonntag, Karin; Rudloff, Eicke; Wehling, Peter; Snowdon, Rod J

    2006-02-01

    Two Brassica napus-Crambe abyssinica monosomic addition lines (2n=39, AACC plus a single chromosome from C. abyssinca) were obtained from the F(2) progeny of the asymmetric somatic hybrid. The alien chromosome from C. abyssinca in the addition line was clearly distinguished by genomic in situ hybridization (GISH). Twenty-seven microspore-derived plants from the addition lines were obtained. Fourteen seedlings were determined to be diploid plants (2n=38) arising from spontaneous chromosome doubling, while 13 seedlings were confirmed as haploid plants. Doubled haploid plants produced after treatment with colchicine and two disomic chromosome addition lines (2n=40, AACC plus a single pair of homologous chromosomes from C. abyssinca) could again be identified by GISH analysis. The lines are potentially useful for molecular genetic analysis of novel C. abyssinica genes or alleles contributing to traits relevant for oilseed rape (B. napus) breeding.

  10. The Role of MAPT Haplotype H2 and Isoform 1N/4R in Parkinsonism of Older Adults

    PubMed Central

    Oliveira-Filho, Jamary; White, Charles C.; Yu, Lei; Schneider, Julie A.; Buchman, Aron S.; Shulman, Joshua M.; Bennett, David A.; De Jager, Philip L.

    2016-01-01

    Background and Objective Recently, we have shown that the Parkinson’s disease (PD) susceptibility locus MAPT (microtubule associated protein tau) is associated with parkinsonism in older adults without a clinical diagnosis of PD. In this study, we investigated the relationship between parkinsonian signs and MAPT transcripts by assessing the effect of MAPT haplotypes on alternative splicing and expression levels of the most common isoforms in two prospective clinicopathologic studies of aging. Materials and Methods using regression analysis, controlling for age, sex, study and neuropathology, we evaluated 976 subjects with clinical, genotyping and brain pathology data for haplotype analysis. For transcript analysis, we obtained MAPT gene and isoform-level expression from the dorsolateral prefrontal cortex for 505 of these subjects. Results The MAPT H2 haplotype was associated with lower total MAPT expression (p = 1.2x10-14) and global parkinsonism at both study entry (p = 0.001) and proximate to death (p = 0.050). Specifically, haplotype H2 was primarily associated with bradykinesia in both assessments (p<0.001 and p = 0.008). MAPT total expression was associated with age and decreases linearly with advancing age (p<0.001). Analysing MAPT alternative splicing, the expression of 1N/4R isoform was inversely associated with global parkinsonism (p = 0.008) and bradykinesia (p = 0.008). Diminished 1N/4R isoform expression was also associated with H2 (p = 0.001). Conclusions Overall, our results suggest that age and H2 are associated with higher parkinsonism score and decreased total MAPT RNA expression. Additionally, we found that H2 and parkinsonism are associated with altered expression levels of specific isoforms. These findings may contribute to the understanding of the association between MAPT locus and parkinsonism in elderly subjects and in some extent to age-related neurodegenerative diseases. PMID:27458716

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27221742

  13. ACC interleukin-10 gene promoter haplotype as a breast cancer risk factor predictor among Jordanian females

    PubMed Central

    Atoum, Manar Fayiz

    2016-01-01

    Introduction Interleukin-10 (IL-10) is a multifactorial cytokine with a complex biological role in breast cancer. The aims of this study were to investigate any association between IL-10 gene promoter polymorphisms, 1082A>/G, −819T>C, and −592A>C, or haplotypes and breast cancer risk among Jordanian women and to evaluate any association between the most common haplotype with clinicopathological features of breast cancer. Patients and methods A total of 202 breast cancer patients and 210 age-matched healthy control subjects were genotyped for −1082A/G, −819T/C, and −592A/C single nucleotide polymorphisms in the promoter region of the IL-10 gene by polymerase chain reaction-restriction fragment length polymorphism. Study patients and control subjects were recruited from Prince Hamzah Hospital, Amman, Jordan (2012–2013). Ethical approval and signed consent forms were signed by all participants. DNA was extracted, and polymerase chain reaction fragments were amplified and restriction digested by MnII, MaeIII, and RsaI. Results This study showed no statistically significant difference between −1082A/G, −819T/C, and −592A/C IL-10 genotypes or alleles among breast cancer patients or controls. Four different haplotypes ATA, ACC, GTA, and ACA within the IL-10 promoter gene were determined among both breast cancer and control groups. The most frequent haplotype was ACC among breast cancer patients and controls (41.6% and 40.7%, respectively). No statistical differences in these haplotypes among breast cancer patients or controls were determined. Analysis of the most common ACC haplotype showed statistical difference in positive estrogen receptor (P=0.022), positive progesterone receptor (P=0.004), cancer grade (P=0.0001), and cancer stage (P=0.009) among the ACC haplotype compared to non-ACC haplotype. Conclusion To our knowledge, this is the first report studying the association of IL-10 haplotype with breast cancer risk events among Jordanian females. The

  14. Linked vs unlinked markers: multilocus microsatellite haplotype-sharing as a tool to estimate gene flow and introgression.

    PubMed

    Koopman, Wim J M; Li, Yinghui; Coart, Els; van de Weg, W Eric; Vosman, Ben; Roldán-Ruiz, Isabel; Smulders, Marinus J M

    2007-01-01

    We have explored the use of multilocus microsatellite haplotypes to study introgression from cultivated (Malus domestica) into wild apple (Malus sylvestris), and to study gene flow among remnant populations of M. sylvestris. A haplotype consisted of alleles at microsatellite loci along one chromosome. As destruction of haplotypes through recombination occurs much faster than loss of alleles due to genetic drift, the lifespan of a multilocus haplotype is much shorter than that of the underlying alleles. When different populations share the same haplotype, this may indicate recent gene flow between populations. Similarly, haplotypes shared between two species would be a strong signal for introgression. As the expected lifespan of a haplotype depends on the strength of the linkage, the length [in centiMorgans (cM)] of the haplotype shared contains information on the number of generations passed. This application of shared haplotypes is distinct from using haplotype-sharing to detect association between markers and a certain trait. We inferred haplotypes for four to eight microsatellite loci on Linkage Group 10 of apple from genotype data using the program phase, and then identified those haplotypes shared between populations and species. Compared with a Bayesian analysis of unlinked microsatellite loci using the program structure, haplotype-sharing detected a partially different set of putative hybrids. Cultivated haplotypes present in M. sylvestris were short (< 1.5 cM), indicating that introgression had taken place many generations ago, except for two Belgian plants that contained a haplotype of 47.1 cM, indicating recent introgression. In the estimation of gene flow, F(ST) based on unlinked loci indicated small (0.032-0.058) but statistically significant differentiation between some populations only. However, various M. sylvestris haplotypes were shared in nearly all pairwise comparisons of populations, and their length indicated recent gene flow. Hence, all Dutch

  15. JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women.

    PubMed

    Rojano-Mejía, David; Coral-Vázquez, Ramón M; Espinosa, Leticia Cortes; López-Medina, Guillermo; Aguirre-García, María C; Coronel, Agustín; Canto, Patricia

    2013-04-01

    Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r (2), and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P = 0.021). In addition, analysis of the haplotype of COL1A1 showed that the G-G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.

  16. Factors associated with regional bias of pfcrt (plasmodium falciparum chloroquine resistance transporter) haplotypes in Nepal.

    PubMed

    Banjara, Megha Raj; Imwong, Mallika; Petmitr, Songsak; Sirawaraporn, Worachart; Joshi, Anand B; Chavalitshewinkoon-Petmitr, Porntip

    2011-01-01

    Evidences of reappearance of chloroquine sensitive Plasmodium falciparum haplotypes after cessation of chloroquine in many countries provide a rationale for the search of chloroquine sensitive haplotypes in P. falciparum isolates in Nepal where the use of chloroquine for falciparum malaria treatment has been ceased since 1988. P. falciparum chloroquine resistant transporter gene (pfcrt) haplotypes were determined and the factors associated with pfcrt haplotypes in the Eastern and Central regions of Nepal were identified. Blood samples from 106 microscopy-positive falciparum malaria patients (62 from the Eastern and 44 from the Central region) were collected on filter paper. Pfcrt region covering codons 72-76 was amplified by PCR and sequenced. SVMNT haplotype was predominant in the Central region, whereas CVIET haplotype significantly more common in the Eastern region. In multivariable analysis of factors associated with CVIET haplotype, the Eastern region and parasite isolates from patients visiting India within one month are significant at 5% level of significance. These findings suggest that antimalarial pressure is different between Eastern and Central regions of Nepal and there is a need of an effective malaria control program in the border areas between India and Nepal.

  17. Casein haplotypes and their association with milk production traits in the Finnish Ayrshire cattle.

    PubMed

    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).

  18. Practical interpretation of CYP2D6 haplotypes: Comparison and integration of automated and expert calling.

    PubMed

    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.

  19. Characterization of swine leukocyte antigen alleles and haplotypes on a novel miniature pig line, Microminipig.

    PubMed

    Ando, A; Imaeda, N; Ohshima, S; Miyamoto, A; Kaneko, N; Takasu, M; Shiina, T; Kulski, J K; Inoko, H; Kitagawa, H

    2014-12-01

    Microminipigs are extremely small-sized, novel miniature pigs that were recently developed for medical research. The inbred Microminipigs with defined swine leukocyte antigen (SLA) haplotypes are expected to be useful for allo- and xenotransplantation studies and also for association analyses between SLA haplotypes and immunological traits. To establish SLA-defined Microminipig lines, we characterized the polymorphic SLA alleles for three class I (SLA-1, SLA-2 and SLA-3) and two class II (SLA-DRB1 and SLA-DQB1) genes of 14 parental Microminipigs using a high-resolution nucleotide sequence-based typing method. Eleven class I and II haplotypes, including three recombinant haplotypes, were found in the offspring of the parental Microminipigs. Two class I and class II haplotypes, Hp-31.0 (SLA-1*1502-SLA-3*070102-SLA-2*1601) and Hp-0.37 (SLA-DRB1*0701-SLA-DQB1*0502), are novel and have not so far been reported in other pig breeds. Crossover regions were defined by the analysis of 22 microsatellite markers within the SLA class III region of three recombinant haplotypes. The SLA allele and haplotype information of Microminipigs in this study will be useful to establish SLA homozygous lines including three recombinants for transplantation and immunological studies.

  20. Multiple divergent haplotypes express completely distinct sets of class I MHC genes in zebrafish.

    PubMed

    McConnell, Sean C; Restaino, Anthony C; de Jong, Jill L O

    2014-03-01

    The zebrafish is an important animal model for stem cell biology, cancer, and immunology research. Histocompatibility represents a key intersection of these disciplines; however, histocompatibility in zebrafish remains poorly understood. We examined a set of diverse zebrafish class I major histocompatibility complex (MHC) genes that segregate with specific haplotypes at chromosome 19, and for which donor-recipient matching has been shown to improve engraftment after hematopoietic transplantation. Using flanking gene polymorphisms, we identified six distinct chromosome 19 haplotypes. We describe several novel class I U lineage genes and characterize their sequence properties, expression, and haplotype distribution. Altogether, ten full-length zebrafish class I genes were analyzed, mhc1uba through mhc1uka. Expression data and sequence properties indicate that most are candidate classical genes. Several substitutions in putative peptide anchor residues, often shared with deduced MHC molecules from additional teleost species, suggest flexibility in antigen binding. All ten zebrafish class I genes were uniquely assigned among the six haplotypes, with dominant or codominant expression of one to three genes per haplotype. Interestingly, while the divergent MHC haplotypes display variable gene copy number and content, the different genes appear to have ancient origin, with extremely high levels of sequence diversity. Furthermore, haplotype variability extends beyond the MHC genes to include divergent forms of psmb8. The many disparate haplotypes at this locus therefore represent a remarkable form of genomic region configuration polymorphism. Defining the functional MHC genes within these divergent class I haplotypes in zebrafish will provide an important foundation for future studies in immunology and transplantation. PMID:24291825

  1. The S haplotypes lacking SLG in the genome of Brassica rapa.

    PubMed

    Suzuki, G; Kakizaki, T; Takada, Y; Shiba, H; Takayama, S; Isogai, A; Watanabe, M

    2003-06-01

    Self-incompatibility (SI) discriminating self- and non-self pollen is regulated by S-locus genes in Brassica. In most of the S haplotypes, a highly polymorphic S-locus glycoprotein ( SLG) gene is tightly linked to genes for the SI determinants, S-receptor kinase ( SRK) and SP11, although the precise function of SLG in SI has not been clarified. In the present study, we performed DNA gel blot analysis for S(32), S(33), and S(36) haplotypes of Brassica rapa showing normal SI phenotypes and concluded that there might be no SLG in their genome. RNA gel blot analysis of the SLG-less S haplotypes indicated the possible existence of eSRK transcripts in the stigma. These three S haplotypes are useful resources to discern the molecular mechanism of the SI reaction without SLG.

  2. Haplotype diversity of 17 Y-chromosomal STR loci in the Bangladeshi population.

    PubMed

    Alam, Shafiul; Ali, Md Eunus; Ferdous, Ahmad; Hossain, Tania; Hasan, Md Mahamud; Akhteruzzaman, Sharif

    2010-02-01

    Haplotype and allele frequencies of 17 Y-chromosomal STR loci were determined in 216 unrelated Bangladeshi males. AmpFlSTR Y-filer PCR Amplification kit (Applied Biosystems) was used to type the following Y-STR markers: DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS438, DYS439, DYS437, DYS448, DYS458, DYS456, DYS635, and Y-GATA-H4. A total of 211 haplotypes for the 17 Y-STR markers were detected and, of these, 206 haplotypes were unique. The haplotype diversity was 0.9998, indicating a high potential for differentiating between male individuals in this population. Comparison analysis via Analysis of Molecular Variance (AMOVA) and construction of Neighbor Joining Tree revealed a close association of Bangladeshi population with Indian Gaddi and Southern Indian populations. PMID:20129457

  3. Approaches for identifying multiple-SNP haplotype blocks for use in human identification.

    PubMed

    Hiroaki, Nakahara; Koji, Fujii; Tetsushi, Kitayama; Kazumasa, Sekiguchi; Hiroaki, Nakanishi; Kazuyuki, Saito

    2015-09-01

    Single nucleotide polymorphism (SNP) discrimination effectiveness is low due to the bi-allelic nature of SNPs, and large numbers of loci must be analyzed for human identification in forensic casework. To resolve these issues, the authors support the use of multiple SNP haplotypes that will generate many haplotypes based on the combination of SNP alleles. First, 27 regions were selected from the JSNP database (http://snp.ims.u-tokyo.ac.jp) according to the following criteria: (1) 3 or more SNP loci within 100bp; (2) on-intron or out-of-gene location; and (3) frequency of more than 40% for each SNP allele. PCR amplification and high-resolution melting curve (HRM) analysis were then carried out for all selected regions to determine variation in the haplotypes of each. HRM analysis indicated that 7 regions (1q25, 1q42.2, 3p24, 10p13, 11p15.1, 14q12-q13, and 20q12) containing 3 SNP loci had more than 2 haplotypes. The frequencies of the haplotypes for each region were observed via direct sequencing of more than 100 individuals. Not only haplotyping increases the effectiveness of individual identification but also the analysis region is shorter than in common short tandem repeat analysis, representing a further advantage for fragmented DNA samples in SNP typing.

  4. Forensic analysis of polymorphism and regional stratification of Y-chromosomal microsatellites in Belarus.

    PubMed

    Rebała, Krzysztof; Tsybovsky, Iosif S; Bogacheva, Anna V; Kotova, Svetlana A; Mikulich, Alexei I; Szczerkowska, Zofia

    2011-01-01

    Nine loci defining minimal haplotypes and four other Y-chromosomal short tandem repeats (Y-STRs) DYS437, DYS438, DYS439 and GATA H4.1 were analysed in 414 unrelated males residing in four regions of Belarus. Haplotypes of 328 males were further extended by 7 additional Y-STRs: DYS388, DYS426, DYS448, DYS456, DYS458, DYS460 and DYS635. The 13-locus haplotype diversity was 0.9978 and discrimination capacity was 78.7%, indicating presence of identical haplotypes among unrelated males. Seven additional Y-STRs enabled almost complete discrimination of undifferentiated 13-locus haplotypes, increasing haplotype diversity to 0.9998 and discrimination capacity to 97.9%. Analysis of molecular variance of minimal haplotypes excluded the use of a Y-STR database for Belarusians residing in northeastern Poland as representative for the Belarusian population in forensic practice, and revealed regional stratification within the country. However, four additional markers (DYS437, DYS438, DYS439 and GATA H4.1) were shown to eliminate the observed geographical substructure among Belarusian males. The results imply that in case of minimal and PowerPlex Y haplotypes, a separate frequency database should be used for northern Belarus to estimate Y-STR profile frequencies in forensic casework. In case of Yfiler haplotypes, regional stratification within Belarus may be neglected.

  5. Antigenic peptide molecular recognition by the DRB1-DQB1 haplotype modulates multiple sclerosis susceptibility.

    PubMed

    Kumar, Amit; Melis, Paola; Genna, Vito; Cocco, Eleonora; Marrosu, Maria Giovanna; Pieroni, Enrico

    2014-08-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that has a notably high incidence in Sardinia. Our study focuses on two HLA class II haplotypes associated with the disease in Sardinia, the rare predisposing DRB1*15:01-DQB1*06:02 and the widespread protective DRB1*16:01-DQB1*05:02. This framework enabled the highlighting of HLA binding pocket specificity and peptide recognition mechanisms by employing molecular dynamics simulations of the whole DRB1-DQB1 haplotype interacting with MBP- and EBV-derived peptides. We analyzed peptide-protein interaction networks and temporal evolution of the original complexes and after key amino acid mutations. The mutation G86V of the protective DRB1 allele exerted its effect mainly in the presence of the EBV viral peptide, with local and long range outcomes. However, the V38A mutation of the protective DQB1 showed a long range effect only in the case of the MBP myelin peptide. Our findings also demonstrate a DRB1/DQB1 complementary molecular recognition of peptides. This mechanism could provide a robust synergistic action and a differential role of DRB1 and DQB1 in tissues and in the time-steps towards autoimmunity. In addition, we demonstrate that negatively charged residues in pockets 4 and 9 play a role in MS susceptibility. Our findings are supported by recent experiments using a closely related MS animal model. Overall, our analysis confirms the role of the DRB1-DQB1 haplotype in conferring disease predisposition and could provide a valuable aid in designing optimal therapeutic peptides for MS therapy.

  6. Porosity Measurements and Analysis for Metal Additive Manufacturing Process Control.

    PubMed

    Slotwinski, John A; Garboczi, Edward J; Hebenstreit, Keith M

    2014-01-01

    Additive manufacturing techniques can produce complex, high-value metal parts, with potential applications as critical metal components such as those found in aerospace engines and as customized biomedical implants. Material porosity in these parts is undesirable for aerospace parts - since porosity could lead to premature failure - and desirable for some biomedical implants - since surface-breaking pores allows for better integration with biological tissue. Changes in a part's porosity during an additive manufacturing build may also be an indication of an undesired change in the build process. Here, we present efforts to develop an ultrasonic sensor for monitoring changes in the porosity in metal parts during fabrication on a metal powder bed fusion system. The development of well-characterized reference samples, measurements of the porosity of these samples with multiple techniques, and correlation of ultrasonic measurements with the degree of porosity are presented. A proposed sensor design, measurement strategy, and future experimental plans on a metal powder bed fusion system are also presented.

  7. Porosity Measurements and Analysis for Metal Additive Manufacturing Process Control.

    PubMed

    Slotwinski, John A; Garboczi, Edward J; Hebenstreit, Keith M

    2014-01-01

    Additive manufacturing techniques can produce complex, high-value metal parts, with potential applications as critical metal components such as those found in aerospace engines and as customized biomedical implants. Material porosity in these parts is undesirable for aerospace parts - since porosity could lead to premature failure - and desirable for some biomedical implants - since surface-breaking pores allows for better integration with biological tissue. Changes in a part's porosity during an additive manufacturing build may also be an indication of an undesired change in the build process. Here, we present efforts to develop an ultrasonic sensor for monitoring changes in the porosity in metal parts during fabrication on a metal powder bed fusion system. The development of well-characterized reference samples, measurements of the porosity of these samples with multiple techniques, and correlation of ultrasonic measurements with the degree of porosity are presented. A proposed sensor design, measurement strategy, and future experimental plans on a metal powder bed fusion system are also presented. PMID:26601041

  8. Porosity Measurements and Analysis for Metal Additive Manufacturing Process Control

    PubMed Central

    Slotwinski, John A; Garboczi, Edward J; Hebenstreit, Keith M

    2014-01-01

    Additive manufacturing techniques can produce complex, high-value metal parts, with potential applications as critical metal components such as those found in aerospace engines and as customized biomedical implants. Material porosity in these parts is undesirable for aerospace parts - since porosity could lead to premature failure - and desirable for some biomedical implants - since surface-breaking pores allows for better integration with biological tissue. Changes in a part’s porosity during an additive manufacturing build may also be an indication of an undesired change in the build process. Here, we present efforts to develop an ultrasonic sensor for monitoring changes in the porosity in metal parts during fabrication on a metal powder bed fusion system. The development of well-characterized reference samples, measurements of the porosity of these samples with multiple techniques, and correlation of ultrasonic measurements with the degree of porosity are presented. A proposed sensor design, measurement strategy, and future experimental plans on a metal powder bed fusion system are also presented. PMID:26601041

  9. Additional EIPC Study Analysis: Interim Report on High Priority Topics

    SciTech Connect

    Hadley, Stanton W

    2013-11-01

    Between 2010 and 2012 the Eastern Interconnection Planning Collaborative (EIPC) conducted a major long-term resource and transmission study of the Eastern Interconnection (EI). With guidance from a Stakeholder Steering Committee (SSC) that included representatives from the Eastern Interconnection States Planning Council (EISPC) among others, the project was conducted in two phases. Phase 1 involved a long-term capacity expansion analysis that involved creation of eight major futures plus 72 sensitivities. Three scenarios were selected for more extensive transmission- focused evaluation in Phase 2. Five power flow analyses, nine production cost model runs (including six sensitivities), and three capital cost estimations were developed during this second phase. The results from Phase 1 and 2 provided a wealth of data that could be examined further to address energy-related questions. A list of 13 topics was developed for further analysis; this paper discusses the first five.

  10. Disclosure of hydraulic fracturing fluid chemical additives: analysis of regulations.

    PubMed

    Maule, Alexis L; Makey, Colleen M; Benson, Eugene B; Burrows, Isaac J; Scammell, Madeleine K

    2013-01-01

    Hydraulic fracturing is used to extract natural gas from shale formations. The process involves injecting into the ground fracturing fluids that contain thousands of gallons of chemical additives. Companies are not mandated by federal regulations to disclose the identities or quantities of chemicals used during hydraulic fracturing operations on private or public lands. States have begun to regulate hydraulic fracturing fluids by mandating chemical disclosure. These laws have shortcomings including nondisclosure of proprietary or "trade secret" mixtures, insufficient penalties for reporting inaccurate or incomplete information, and timelines that allow for after-the-fact reporting. These limitations leave lawmakers, regulators, public safety officers, and the public uninformed and ill-prepared to anticipate and respond to possible environmental and human health hazards associated with hydraulic fracturing fluids. We explore hydraulic fracturing exemptions from federal regulations, as well as current and future efforts to mandate chemical disclosure at the federal and state level.

  11. Disclosure of hydraulic fracturing fluid chemical additives: analysis of regulations.

    PubMed

    Maule, Alexis L; Makey, Colleen M; Benson, Eugene B; Burrows, Isaac J; Scammell, Madeleine K

    2013-01-01

    Hydraulic fracturing is used to extract natural gas from shale formations. The process involves injecting into the ground fracturing fluids that contain thousands of gallons of chemical additives. Companies are not mandated by federal regulations to disclose the identities or quantities of chemicals used during hydraulic fracturing operations on private or public lands. States have begun to regulate hydraulic fracturing fluids by mandating chemical disclosure. These laws have shortcomings including nondisclosure of proprietary or "trade secret" mixtures, insufficient penalties for reporting inaccurate or incomplete information, and timelines that allow for after-the-fact reporting. These limitations leave lawmakers, regulators, public safety officers, and the public uninformed and ill-prepared to anticipate and respond to possible environmental and human health hazards associated with hydraulic fracturing fluids. We explore hydraulic fracturing exemptions from federal regulations, as well as current and future efforts to mandate chemical disclosure at the federal and state level. PMID:23552653

  12. Risk analysis of sulfites used as food additives in China.

    PubMed

    Zhang, Jian Bo; Zhang, Hong; Wang, Hua Li; Zhang, Ji Yue; Luo, Peng Jie; Zhu, Lei; Wang, Zhu Tian

    2014-02-01

    This study was to analyze the risk of sulfites in food consumed by the Chinese people and assess the health protection capability of maximum-permitted level (MPL) of sulfites in GB 2760-2011. Sulfites as food additives are overused or abused in many food categories. When the MPL in GB 2760-2011 was used as sulfites content in food, the intake of sulfites in most surveyed populations was lower than the acceptable daily intake (ADI). Excess intake of sulfites was found in all the surveyed groups when a high percentile of sulfites in food was in taken. Moreover, children aged 1-6 years are at a high risk to intake excess sulfites. The primary cause for the excess intake of sulfites in Chinese people is the overuse and abuse of sulfites by the food industry. The current MPL of sulfites in GB 2760-2011 protects the health of most populations.

  13. Haplotype diversity of 17 Y-chromosomal STRs in three native Sarawak populations (Iban, Bidayuh and Melanau) in East Malaysia.

    PubMed

    Chang, Yuet Meng; Swaran, Yuvaneswari; Phoon, Yoong Keat; Sothirasan, Kavin; Sim, Hang Thiew; Lim, Kong Boon; Kuehn, Daniel

    2009-06-01

    17 Y-STRs (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385a/b, DYS393, DYS391, DYS439, DYS635 or Y-GATA C4, DYS392, Y-GATA H4, DYS437, DYS438 and DYS448) have been analyzed in 320 male individuals from Sarawak, an eastern state of Malaysia on the Borneo island using the AmpFlSTR Y-filer (Applied Biosystems, Foster City, CA). These individuals were from three indigenous ethnic groups in Sarawak comprising of 103 Ibans, 113 Bidayuhs and 104 Melanaus. The observed 17-loci haplotypes and the individual allele frequencies for each locus were estimated, whilst the locus diversity, haplotype diversity and discrimination capacity were calculated in the three groups. Analysis of molecular variance (AMOVA) indicated that 87.6% of the haplotypic variation was found within population and 12.4% between populations (fixation index F(ST)=0.124, p=0.000). This study has revealed that the indigenous populations in Sarawak are distinctly different to each other, and to the three major ethnic groups in Malaysia (Malays, Chinese and Indians), with the Melanaus having a strikingly high degree of shared haplotypes within. There are rare unusual variants and microvariants that were not present in Malaysian Malay, Chinese or Indian groups. In addition, occurrences of DYS385 duplications which were only noticeably present in Chinese group previously was also observed in the Iban group whilst null alleles were detected at several Y-loci (namely DYS19, DYS392, DYS389II and DYS448) in the Iban and Melanau groups. PMID:19414156

  14. Verticillium dahliae populations from mint and potato are genetically divergent with predominant haplotypes.

    PubMed

    Dung, Jeremiah K S; Peever, Tobin L; Johnson, Dennis A

    2013-05-01

    In total, 286 Verticillium dahliae isolates from mint, potato, and other hosts and substrates were characterized for mating type, vegetative compatibility group (VCG), and multilocus microsatellite haplotype to determine population genetic structure among populations infecting mint and potato. Populations from mint and potato fit a clonal reproductive model, with all isolates a single mating type (MAT1-2) and multiple occurrences of the same haplotypes. Haplotype H02 represented 88% of mint isolates and was primarily VCG2B, while haplotype H04 represented 70% of potato isolates and was primarily VCG4A. Haplotypes H02 and H04 typically caused severe disease on mint and potato, respectively, in greenhouse assays regardless of host origin. Principal coordinate analysis and analysis of molecular variance indicated that mint and potato populations were significantly genetically diverged (P = 0.02), and identification of private alleles and estimation of migration rates suggested restricted gene flow. Migration was detected between infected potato plants and seed tubers, infested tare soil, and field soils. Genetic differentiation of V. dahliae from mint and potato may be due to the occurrence of a single mating type and differences in VCG. Populations of V. dahliae in potato and mint were characterized by the presence of aggressive, clonally reproducing haplotypes which are widely distributed in commercial mint and potato production.

  15. References for Haplotype Imputation in the Big Data Era

    PubMed Central

    Li, Wenzhi; Xu, Wei; Li, Qiling; Ma, Li; Song, Qing

    2016-01-01

    Imputation is a powerful in silico approach to fill in those missing values in the big datasets. This process requires a reference panel, which is a collection of big data from which the missing information can be extracted and imputed. Haplotype imputation requires ethnicity-matched references; a mismatched reference panel will significantly reduce the quality of imputation. However, currently existing big datasets cover only a small number of ethnicities, there is a lack of ethnicity-matched references for many ethnic populations in the world, which has hampered the data imputation of haplotypes and its downstream applications. To solve this issue, several approaches have been proposed and explored, including the mixed reference panel, the internal reference panel and genotype-converted reference panel. This review article provides the information and comparison between these approaches. Increasing evidence showed that not just one or two genetic elements dictate the gene activity and functions; instead, cis-interactions of multiple elements dictate gene activity. Cis-interactions require the interacting elements to be on the same chromosome molecule, therefore, haplotype analysis is essential for the investigation of cis-interactions among multiple genetic variants at different loci, and appears to be especially important for studying the common diseases. It will be valuable in a wide spectrum of applications from academic research, to clinical diagnosis, prevention, treatment, and pharmaceutical industry. PMID:27274952

  16. Mitochondrial Haplotypes Influence Metabolic Traits in Porcine Transmitochondrial Cybrids.

    PubMed

    Yu, Guanghui; Xiang, Hai; Tian, Jianhui; Yin, Jingdong; Pinkert, Carl A; Li, Qiuyan; Zhao, Xingbo

    2015-01-01

    In farm animals, mitochondrial DNA mutations exist widely across breeds and individuals. In order to identify differences among mtDNA haplotypes, two porcine transmitochondrial cybrids were generated by fusion of a Lantang pig cell line devoid of mitochondrial DNA with enucleated cytoplasm from either a Large White pig or a Xiang pig harboring potentially divergent mitochondrial haplotypes. These cybrid cells were subjected to mitochondrial genome sequencing, copy number detecting and analysis of biochemical traits including succinate dehydrogenase (SDH) activity, ATP content and susceptibility to reactive oxygen species (ROS). The Lantang and Xiang mitochondrial genomes were highly homologous with only 18 polymorphic sites, and differed radically from the Large White with 201 and 198 mutations respectively. The Large White and Xiang cybrids exhibited similar mtDNA copy numbers and different values among biochemical traits, generated greater ROS production (P < 0.05) and less SDH activity (P < 0.05) and a lesser ATP content (P < 0.05). The results show that functional differences exist between cybrid cells which differ in mitochondrial genomic background. In conclusion, transmitochondrial cybrids provide the first direct evidence on pig biochemical traits linking different mitochondrial genome haplotypes. PMID:26285652

  17. Reflections on ancestral haplotypes: medical genomics, evolution, and human individuality.

    PubMed

    Steele, Edward J

    2014-01-01

    The major histocompatibility complex (MHC), once labelled the "sphinx of immunology" by Jan Klein, provides powerful challenges to evolutionary thinking. This essay highlights the main discoveries that established the block ancestral haplotype structure of the MHC and the wider genome, focusing on the work by the Perth (Australia) group, led by Roger Dawkins, and the Boston group, led by Chester Alper and Edmond Yunis. Their achievements have been overlooked in the rush to sequence the first and subsequent drafts of the human genome. In Caucasoids, where most of the detailed work has been done, about 70% of all known allelic MHC diversity can be accounted for by 30 or so ancestral haplotypes (AHs), or conserved sequences of many mega-bases, and their recombinants. The block haplotype structure of the genome, as shown for the MHC (and other genetic regions), is a story that needs to be understood in its own right, particularly given the promotion of the "HapMap" project and single nucleotide polymorphism (SNP) linkage disequilibrium (LD) analysis, which has been wrongly touted as the only way to pinpoint those genes that are important in genetic disorders or other desired (qualitative) characteristics. PMID:25544323

  18. Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes.

    PubMed

    Lam, Tze Hau; Tay, Matthew Zirui; Wang, Bei; Xiao, Ziwei; Ren, Ee Chee

    2015-11-23

    Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases.

  19. Mitochondrial Haplotypes Influence Metabolic Traits in Porcine Transmitochondrial Cybrids

    PubMed Central

    Yu, Guanghui; Xiang, Hai; Tian, Jianhui; Yin, Jingdong; Pinkert, Carl A.; Li, Qiuyan; Zhao, Xingbo

    2015-01-01

    In farm animals, mitochondrial DNA mutations exist widely across breeds and individuals. In order to identify differences among mtDNA haplotypes, two porcine transmitochondrial cybrids were generated by fusion of a Lantang pig cell line devoid of mitochondrial DNA with enucleated cytoplasm from either a Large White pig or a Xiang pig harboring potentially divergent mitochondrial haplotypes. These cybrid cells were subjected to mitochondrial genome sequencing, copy number detecting and analysis of biochemical traits including succinate dehydrogenase (SDH) activity, ATP content and susceptibility to reactive oxygen species (ROS). The Lantang and Xiang mitochondrial genomes were highly homologous with only 18 polymorphic sites, and differed radically from the Large White with 201 and 198 mutations respectively. The Large White and Xiang cybrids exhibited similar mtDNA copy numbers and different values among biochemical traits, generated greater ROS production (P < 0.05) and less SDH activity (P < 0.05) and a lesser ATP content (P < 0.05). The results show that functional differences exist between cybrid cells which differ in mitochondrial genomic background. In conclusion, transmitochondrial cybrids provide the first direct evidence on pig biochemical traits linking different mitochondrial genome haplotypes. PMID:26285652

  20. Delineation of the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a small region of 11q13, through linkage and haplotype analysis of 91 pedigrees.

    PubMed

    Katsanis, N; Lewis, R A; Stockton, D W; Mai, P M; Baird, L; Beales, P L; Leppert, M; Lupski, J R

    1999-12-01

    Bardet-Biedl syndrome (BBS) is a genetically heterogeneous recessive disease characterized primarily by atypical retinitis pigmentosa, obesity, polydactyly, hypogenitalism, and mental retardation. Despite the presence of at least five loci in the human genome, on chromosomes 2q, 3p, 11q, 15q and 16q, as many as 50% of the mutations appear to map to the BBS1 locus on 11q13. The recessive mode of inheritance and the genetic heterogeneity of the syndrome, as well as the inability to distinguish between different genetic loci by phenotypic analyses, have hindered efforts to delineate the 11q13 region as a first step toward cloning the mutated gene. To circumvent these difficulties, we collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis, using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in two consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944. The identification of multiple recombinants at the same position forms the basis for physical mapping efforts, coupled with mutation analysis of candidate genes, to identify the gene for BBS1.

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

    SciTech Connect

    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.

  2. Additional challenges for uncertainty analysis in river engineering

    NASA Astrophysics Data System (ADS)

    Berends, Koen; Warmink, Jord; Hulscher, Suzanne

    2016-04-01

    the proposed intervention. The implicit assumption underlying such analysis is that both models are commensurable. We hypothesize that they are commensurable only to a certain extent. In an idealised study we have demonstrated that prediction performance loss should be expected with increasingly large engineering works. When accounting for parametric uncertainty of floodplain roughness in model identification, we see uncertainty bounds for predicted effects of interventions increase with increasing intervention scale. Calibration of these types of models therefore seems to have a shelf-life, beyond which calibration does not longer improves prediction. Therefore a qualification scheme for model use is required that can be linked to model validity. In this study, we characterize model use along three dimensions: extrapolation (using the model with different external drivers), extension (using the model for different output or indicators) and modification (using modified models). Such use of models is expected to have implications for the applicability of surrogating modelling for efficient uncertainty analysis as well, which is recommended for future research. Warmink, J. J.; Straatsma, M. W.; Huthoff, F.; Booij, M. J. & Hulscher, S. J. M. H. 2013. Uncertainty of design water levels due to combined bed form and vegetation roughness in the Dutch river Waal. Journal of Flood Risk Management 6, 302-318 . DOI: 10.1111/jfr3.12014

  3. Association of the arginine vasopressin receptor 1A (AVPR1A) haplotypes with listening to music.

    PubMed

    Ukkola-Vuoti, Liisa; Oikkonen, Jaana; Onkamo, Päivi; Karma, Kai; Raijas, Pirre; Järvelä, Irma

    2011-04-01

    Music is listened in all cultures. We hypothesize that willingness to produce and perceive sound and music is social communication that needs musical aptitude. Here, listening to music was surveyed using a web-based questionnaire and musical aptitude using the auditory structuring ability test (Karma Music test) and Carl Seashores tests for pitch and for time. Three highly polymorphic microsatellite markers (RS3, RS1 and AVR) of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with social communication and attachment, were genotyped and analyzed in 31 Finnish families (n=437 members) using family-based association analysis. A positive association between the AVPR1A haplotype (RS1 and AVR) and active current listening to music (permuted P=0.0019) was observed. Other AVPR1A haplotype (RS3 and AVR) showed association with lifelong active listening to music (permuted P=0.0022). In addition to AVPR1A, two polymorphisms (5-HTTLPR and variable number of tandem repeat) of human serotonin transporter gene (SLC6A4), a candidate gene for many neuropsychiatric disorders and previously associated with emotional processing, were analyzed. No association between listening to music and the polymorphisms of SLC6A4 were detected. The results suggest that willingness to listen to music is related to neurobiological pathways affecting social affiliation and communication.

  4. Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

    PubMed

    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. PMID:24842889

  5. Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction.

    PubMed

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

    PubMed Central

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

    2013-01-01

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

  7. Kinetic analysis of microbial respiratory response to substrate addition

    NASA Astrophysics Data System (ADS)

    Blagodatskaya, Evgenia; Blagodatsky, Sergey; Yuyukina, Tatayna; Kuzyakov, Yakov

    2010-05-01

    Heterotrophic component of CO2 emitted from soil is mainly due to the respiratory activity of soil microorganisms. Field measurements of microbial respiration can be used for estimation of C-budget in soil, while laboratory estimation of respiration kinetics allows the elucidation of mechanisms of soil C sequestration. Physiological approaches based on 1) time-dependent or 2) substrate-dependent respiratory response of soil microorganisms decomposing the organic substrates allow to relate the functional properties of soil microbial community with decomposition rates of soil organic matter. We used a novel methodology combining (i) microbial growth kinetics and (ii) enzymes affinity to the substrate to show the shift in functional properties of the soil microbial community after amendments with substrates of contrasting availability. We combined the application of 14C labeled glucose as easily available C source to soil with natural isotope labeling of old and young soil SOM. The possible contribution of two processes: isotopic fractionation and preferential substrate utilization to the shifts in δ13C during SOM decomposition in soil after C3-C4 vegetation change was evaluated. Specific growth rate (µ) of soil microorganisms was estimated by fitting the parameters of the equation v(t) = A + B * exp(µ*t), to the measured CO2 evolution rate (v(t)) after glucose addition, and where A is the initial rate of non-growth respiration, B - initial rate of the growing fraction of total respiration. Maximal mineralization rate (Vmax), substrate affinity of microbial enzymes (Ks) and substrate availability (Sn) were determined by Michaelis-Menten kinetics. To study the effect of plant originated C on δ13C signature of SOM we compared the changes in isotopic composition of different C pools in C3 soil under grassland with C3-C4 soil where C4 plant Miscanthus giganteus was grown for 12 years on the plot after grassland. The shift in 13δ C caused by planting of M. giganteus

  8. Proposal for an allele nomenclature system based on the evolutionary divergence of haplotypes.

    PubMed

    Nebert, Daniel W

    2002-12-01

    The classical view of what constitutes an "allele" has been challenged by recent findings of a great deal of human genetic variability, i.e., we can expect, on average, one variant site every 100-250 bases of our haploid genome. The haplotype is defined as "the patterns of co-occurrence of variant sites on the same chromosome" (and therefore within each particular gene). Sufficient evidence exists for the divergence of haplotypes during evolution of Homo sapiens sapiens, and the total number of haplotypes per gene will reflect the amount of time any particular ethnic group has existed on the planet, e.g., greatest in Africans, fewer in East Asians, and still fewer in Caucasians. If the average gene spans 30 kb, we can expect approximately 170 polymorphic variant sites per gene in the world population. We do not see 2(170) haplotypes, however; we might find only 10 to 200 haplotypes (depending on the gene's size and degree of conservation of the gene product). This finite number allows for a reasonable haplotype nomenclature system for each gene, based on evolutionary divergence. For polymorphic variants (i.e., frequency > or = 0.01), I propose using Arabic numerals for the major clades (e.g., *1, *2, em leader *20, *21), capital letters for sublineages (e.g., *2A, *2B, *2C), and Arabic numerals for sub-sublineages (e.g., *22G12, *22G13); additional subcategories may be added, in an alternating number/letter/number/letter sequence, depending on the complexity of present-day haplotypes of a particular gene. Web sites with a web master and external advisory committee should be set up for each gene superfamily, family, or individual gene (depending on complexity), and an international haplotype nomenclature committee, perhaps comprised of several dozen of these web masters, should oversee haplotype nomenclature for the entire human genome. The higher heterozygosity and multiallelic nature makes haplotypes more informative than biallelic SNPs. Ultimately, our knowledge

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

    SciTech Connect

    Martinson, J.J.; Clegg, J.B.; Boyce, A.J.

    1994-09-01

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

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

    PubMed

    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.

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

    PubMed Central

    Gutiérrez-López, Nidia; Ovando-Medina, Isidro; Salvador-Figueroa, Miguel; Molina-Freaner, Francisco; Avendaño-Arrazate, Carlos H.

    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 (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. PMID:27076998

  12. Extended haplotypes in rheumatoid arthritis and preliminary evidence for an interaction with immunoglobulin genes.

    PubMed

    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.

  13. Difference in number of loci of swine leukocyte antigen classical class I genes among haplotypes.

    PubMed

    Tanaka-Matsuda, Maiko; Ando, Asako; Rogel-Gaillard, Claire; Chardon, Patrick; Uenishi, Hirohide

    2009-03-01

    The structure of the entire genomic region of swine leukocyte antigen (SLA)-the porcine major histocompatibility complex--was recently elucidated in a particular haplotype named Hp-1.0 (H01). However, it has been suggested that there are differences in the number of loci of SLA genes, particularly classical class I genes, among haplotypes. To clarify the between-haplotype copy number variance in genes of the SLA region, we sequenced the genomic region carrying SLA classical class I genes on two different haplotypes, revealing increments of up to six in the number of classical class I genes in a single haplotype. All of the SLA-1(-like) (SLA-1 and newly designated SLA-12) and SLA-3 genes detected in the haplotypes thus analyzed were transcribed in the individual. The process by which duplication of SLA classical class I genes was likely to have occurred was interpreted from an analysis of repetitive sequences adjacent to the duplicated class I genes.

  14. Interactions “Candidatus Liberibacter solanacearum”—Bactericera cockerelli: Haplotype Effect on Vector Fitness and Gene Expression Analyses

    PubMed Central

    Yao, Jianxiu; Saenkham, Panatda; Levy, Julien; Ibanez, Freddy; Noroy, Christophe; Mendoza, Azucena; Huot, Ordom; Meyer, Damien F.; Tamborindeguy, Cecilia

    2016-01-01

    “Candidatus Liberibacter solanacearum” (Lso) has emerged as a serious threat world-wide. Five Lso haplotypes have been identified so far. Haplotypes A and B are present in the Americas and/or New Zealand, where they are vectored to solanaceous plants by the potato psyllid, Bactericera cockerelli (Šulc) (Hemiptera: Triozidae). The fastidious nature of these pathogens has hindered the study of the interactions with their eukaryotic hosts (vector and plant). To understand the strategies used by these pathogens to infect their vector, the effects of each Lso haplotype (A or B) on psyllid fitness was investigated, and genome-wide transcriptomic and RT-qPCR analyses were performed to evaluate Lso gene expression in association with its vector. Results showed that psyllids infected with haplotype B had significantly lower percentage of nymphal survival compared to psyllids infected with haplotype A. Although overall gene expression across Lso genome was similar between the two Lso haplotypes, differences in the expression of key candidate genes were found. Among the 16 putative type IV effector genes tested, four of them were differentially expressed between Lso haplotypes, while no differences in gene expression were measured by qPCR or transcriptomic analysis for the rest of the genes. This study provides new information regarding the pathogenesis of Lso haplotypes in their insect vector. PMID:27376032

  15. Inheritance of Hetero-Diploid Pollen S-Haplotype in Self-Compatible Tetraploid Chinese Cherry (Prunus pseudocerasus Lindl)

    PubMed Central

    Gu, Chao; Liu, Qing-Zhong; Yang, Ya-Nan; Zhang, Shu-Jun; Khan, Muhammad Awais; Wu, Jun; Zhang, Shao-Ling

    2013-01-01

    The breakdown of self-incompatibility, which could result from the accumulation of non-functional S-haplotypes or competitive interaction between two different functional S-haplotypes, has been studied extensively at the molecular level in tetraploid Rosaceae species. In this study, two tetraploid Chinese cherry (Prunus pseudocerasus) cultivars and one diploid sweet cherry (Prunus avium) cultivar were used to investigate the ploidy of pollen grains and inheritance of pollen-S alleles. Genetic analysis of the S-genotypes of two intercross-pollinated progenies showed that the pollen grains derived from Chinese cherry cultivars were hetero-diploid, and that the two S-haplotypes were made up of every combination of two of the four possible S-haplotypes. Moreover, the distributions of single S-haplotypes expressed in self- and intercross-pollinated progenies were in disequilibrium. The number of individuals of the two different S-haplotypes was unequal in two self-pollinated and two intercross-pollinated progenies. Notably, the number of individuals containing two different S-haplotypes (S1- and S5-, S5- and S8-, S1- and S4-haplotype) was larger than that of other individuals in the two self-pollinated progenies, indicating that some of these hetero-diploid pollen grains may have the capability to inactivate stylar S-RNase inside the pollen tube and grow better into the ovaries. PMID:23596519

  16. Applications of haplotypes in dairy farm management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Haplotypes from genomic tests are now available for almost 100,000 dairy cows and heifers in the U.S.. Genomic EBV values are accelerating the rate of genetic improvement in dairy cattle, but genomic information also is useful for making improved decisions on the farm. Mate selection strategies have...

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

    PubMed

    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.

  18. Effects of IL-10 haplotype and atomic bomb radiation exposure on gastric cancer risk.

    PubMed

    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. PMID:23772925

  19. Y-chromosomal STR haplotypes in Central Thai population.

    PubMed

    Siriboonpiputtana, T; Jomsawat, U; Rinthachai, T; Thanakitgosate, J; Shotivaranon, J; Limsuwanachot, N; Polyorat, P; Rerkamnuaychoke, B

    2010-04-01

    12 Y-STR loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS438, DYS439 and DYS437) were typed with PowerPlex Y System (Promega, USA) in a total sample of 501 unrelated males from the central part of Thailand. Allele frequencies and gene diversity for each Y-STR locus were determined. Haplotype diversity from the combined 12 Y-STR loci was 0.9996. The present results can be used as Thai ethnic genetic information resources in routine forensic analysis. PMID:20215020

  20. 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

    PubMed Central

    Pyo, Chul-Woo; Guethlein, Lisbeth A.; Vu, Quyen; Wang, Ruihan; Abi-Rached, Laurent; Norman, Paul J.; Marsh, Steven G. E.; Miller, Jeffrey S.; Parham, Peter; Geraghty, Daniel E.

    2010-01-01

    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. PMID:21206914

  1. Expression levels of JNK associated with polymorphic lactotransferrin haplotypes in human nasopharyngeal carcinoma

    PubMed Central

    Luo, Gengqiu; Zhou, Yanhong; Yi, Wei; Yi, Hong

    2016-01-01

    Lactotransferrin (LTF), a member of the transferrin family, serves a role in the innate immune response and is involved in anti-inflammatory, anti-microbial and anti-tumor activity. Alterations in the LTF gene are associated with an increased incidence of cancer. The LTF gene is polymorphic, and several common alleles may be observed in the general population. Our previous study identified a lower rate of occurrence of the ‘A-G-G-T’ haplotype (constructed with rs1126477, rs1126478, rs2073495 and rs9110) in nasopharyngeal carcinoma (NPC) patients compared with controls. In the present study, in order to elucidate a possible mechanism of LTF-mediated anti-tumor activity in NPC, the protein profiles of NPC and non-tumorous nasopharyngeal epithelium tissues with/without the ‘A-G-G-T’ haplotype were constructed using LTQ Orbitrap technology. The results revealed that c-Jun N-terminal kinase 2 (JNK2) was highly expressed in NPC tissues and non-tumor nasopharyngeal epithelium tissues without the ‘A-G-G-T’ haplotype. These results were confirmed by western blot analysis. Furthermore, microRNA (miRNA) microarray analysis was conducted to investigate the differential miRNA profiles of NPC and non-tumor nasopharyngeal epithelium tissues with/without the ‘A-G-G-T’ haplotype. It was observed that hsa-miR-1256 and hsa-miR-659, which are potentially targeted to the JNK2 gene, were downregulated in NPC tissues without the ‘A-G-G-T’ haplotype. Hsa-miR-298, another miRNA potentially targeted to the JNK2 gene, was downregulated in non-tumor nasopharyngeal epithelium tissues without the ‘A-G-G-T’ haplotype. In summary, these results suggested that the expression levels of JNK2 may be associated with polymorphic LTF haplotypes in human NPC. PMID:27446399

  2. Y chromosome STR allelic and haplotype diversity in a Rwanda population from East Central Africa.

    PubMed

    Balamurugan, Kuppareddi; Duncan, George

    2012-03-01

    We have analyzed 17 Y-chromosomal STR loci in a population sample of 69 unrelated male individuals of the Rwanda-Hutu population from East Central Africa using an AmpFlSTR® Yfiler™ PCR amplification kit. A total of 62 unique haplotypes were identified among the 69 individuals studied. The haplotype diversity was found to be 0.9970 for this population. The gene diversity ranged from 0.1130 (DYS392) to 0.7722 (DYS385). Comparison of populations in this study with twenty-five other national and global populations using Principal Co-ordinate Analysis (PCA) and phylogenetic molecular analysis using a genetic distance matrix indicates a delineation of all the African populations from other unrelated populations. The results of population pair-wise Fst p values indicate statistically significant differentiation of the Rwandan population when compared with 25 other global populations including four African populations (p=0.0000). Analysis of Molecular Variance (AMOVA) of the Rwanda population with four other African populations indicated a 93% variance within populations and 7% variance among the five populations. A data base search of the 62 haplotypes yielded only one non-African haplotype match, suggesting these haplotypes are unique to the African continent. PMID:22285642

  3. Interleukin-6 (IL-6) haplotypes and the response to therapy of chronic hepatitis C virus infection

    PubMed Central

    Yee, Leland J.; Im, KyungAh; Borg, Brian; Yang, Huiying; Liang, T. Jake

    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 viral response (SVR) to therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) (RR=0.80; 95%C.I.: 0.66– 0.98; p=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95%C.I.: 0.66–0.94; p=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95%C.I.: 0.66–0.94; p=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% C.I.: 0.62–1.0; p=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy. PMID:19387461

  4. HapRice, an SNP haplotype database and a web tool for rice.

    PubMed

    Yonemaru, Jun-ichi; Ebana, Kaworu; Yano, Masahiro

    2014-01-01

    Genome-wide single nucleotide polymorphism (SNP) analysis is a promising tool to examine the genetic diversity of rice populations and genetic traits of scientific and economic importance. Next-generation sequencing technology has accelerated the re-sequencing of diverse rice varieties and the discovery of genome-wide SNPs. Notably, validation of these SNPs by a high-throughput genotyping system, such as an SNP array, could provide a manageable and highly accurate SNP set. To enhance the potential utility of genome-wide SNPs for geneticists and breeders, analysis tools need to be developed. Here, we constructed an SNP haplotype database, which allows visualization of the allele frequency of all SNPs in the genome browser. We calculated the allele frequencies of 3,334 SNPs in 76 accessions from the world rice collection and 3,252 SNPs in 177 Japanese rice accessions; all these SNPs have been validated in our previous studies. The SNP haplotypes were defined by the allele frequency in each cultivar group (aus, indica, tropical japonica and temperate japonica) for the world rice accessions, and in non-irrigated and three irrigated groups (three variety registration periods) for Japanese rice accessions. We also developed web tools for finding polymorphic SNPs between any two rice accessions and for the primer design to develop cleaved amplified polymorphic sequence markers at any SNP. The 'HapRice' database and the web tools can be accessed at http://qtaro.abr.affrc.go.jp/index.html. In addition, we established a core SNP set consisting of 768 SNPs uniformly distributed in the rice genome; this set is of a practically appropriate size for use in rice genetic analysis.

  5. Recombination of haplotypes leads to biased estimates of admixture proportions in human populations

    SciTech Connect

    Chakraborty, R.; Smouse, P.E.

    1988-05-01

    A population formed by genetic admixture of two or more source populations may exhibit considerable linkage disequilibrium between genetic loci. In the presence of recombination, this linkage disequilibrium declines with time, a fact that is often ignored when considering haplotypes of closely linked systems (e.g., Gm serum group (gamma globulins), HLA and, more recently, restriction fragment length polymorphisms). Recombination alters haplotype frequencies over time, and the haplotype-derived measures of admixture proportions from haplotype frequencies in generations following the admixture event become progressively more biased. The direction and extent of this bias can be predicted only when the history of admixture is known. Numerical illustration suggests that this bias is problematic whenever rt > 0.05, where r is the recombination rate between linked loci and t is the time (in generations) that has elapsed since the admixture extent. In general, even the haplotype frequencies defined by multiple restriction fragment length polymorphisms should be used with caution for admixture analysis. When recombination rates or the time since admixture are not precisely known, it is advantageous to consider each restriction fragment length polymorphism site separately for admixture analysis.

  6. Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas.

    PubMed

    Hackinger, Sophie; Kraaijenbrink, Thirsa; Xue, Yali; Mezzavilla, Massimo; Asan; van Driem, George; Jobling, Mark A; de Knijff, Peter; Tyler-Smith, Chris; Ayub, Qasim

    2016-04-01

    High-altitude adaptation in Tibetans is influenced by introgression of a 32.7-kb haplotype from the Denisovans, an extinct branch of archaic humans, lying within the endothelial PAS domain protein 1 (EPAS1), and has also been reported in Sherpa. We genotyped 19 variants in this genomic region in 1507 Eurasian individuals, including 1188 from Bhutan and Nepal residing at altitudes between 86 and 4550 m above sea level. Derived alleles for five SNPs characterizing the core Denisovan haplotype (AGGAA) were present at high frequency not only in Tibetans and Sherpa, but also among many populations from the Himalayas, showing a significant correlation with altitude (Spearman's correlation coefficient = 0.75, p value 3.9 × 10(-11)). Seven East- and South-Asian 1000 Genomes Project individuals shared the Denisovan haplotype extending beyond the 32-kb region, enabling us to refine the haplotype structure and identify a candidate regulatory variant (rs370299814) that might be interacting in an additive manner with the derived G allele of rs150877473, the variant previously associated with high-altitude adaptation in Tibetans. Denisovan-derived alleles were also observed at frequencies of 3-14% in the 1000 Genomes Project African samples. The closest African haplotype is, however, separated from the Asian high-altitude haplotype by 22 mutations whereas only three mutations, including rs150877473, separate the Asians from the Denisovan, consistent with distant shared ancestry for African and Asian haplotypes and Denisovan adaptive introgression.

  7. Association of Extrarenal Adverse Effects of Posttransplant Immunosuppression With Sex and ABCB1 Haplotypes

    PubMed Central

    Venuto, Rocco C.; Meaney, Calvin J.; Chang, Shirley; Leca, Nicolae; Consiglio, Joseph D.; Wilding, Gregory E.; Brazeau, Daniel; Gundroo, Aijaz; Nainani, Neha; Morse, Sarah E.; Cooper, Louise M.; Tornatore, Kathleen M.

    2015-01-01

    Abstract Extrarenal adverse effects (AEs) associated with calcineurin inhibitor (CNI) and mycophenolic acid (MPA) occur frequently but are unpredictable posttransplant complications. AEs may result from intracellular CNI accumulation and low activity of P-glycoprotein, encoded by the ABCB1 gene. Since ABCB1 single nucleotide polymorphisms (SNPs) and sex influence P-glycoprotein, we investigated haplotypes and extrarenal AEs. A prospective, cross-sectional study evaluated 149 patients receiving tacrolimus and enteric coated mycophenolate sodium or cyclosporine and mycophenolate mofetil. Immunosuppressive AE assessment determined individual and composite gastrointestinal, neurologic, aesthetic, and cumulative AEs. Lipids were quantitated after 12-hour fast. ABCB1 SNPs: c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642) were determined with haplotype associations computed using the THESIAS program, and evaluated by immunosuppression, sex and race using multivariate general linear models. Tacrolimus patients exhibited more frequent and higher gastrointestinal AE scores compared with cyclosporine with association to CTT (P = 0.018) and sex (P = 0.01). Aesthetic AE score was 3 times greater for cyclosporine with TTC haplotype (P = 0.005). Females had higher gastrointestinal (P = 0.022), aesthetic (P < 0.001), neurologic (P = 0.022), and cumulative AE ratios (P < 0.001). Total cholesterol (TCHOL), low-density lipoproteins (LDL), and triglycerides were higher with cyclosporine. The TTC haplotype had higher TCHOL (P < 0.001) and LDL (P = 0.005). Higher triglyceride (P = 0.034) and lower high-density lipoproteins (P = 0.057) were associated with TTT with sex-adjusted analysis. ABCB1 haplotypes and sex were associated with extrarenal AEs. Using haplotypes, certain female patients manifested more AEs regardless of CNI. Haplotype testing may identify patients with greater susceptibility to AEs and facilitate CNI

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

    PubMed Central

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

    2012-01-01

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

  9. Beta S-gene-cluster haplotypes in sickle cell anemia: clinical implications.

    PubMed

    Powars, D R; Chan, L; Schroeder, W A

    1990-01-01

    Restriction endonuclease analysis was used to detect alpha-gene deletions and to determine the haplotypes in the DNA of the beta S-gene-cluster [Benin, Central African Republic (CAR), and Senegal] in 221 patients with sickle cell anemia (SS). The clinical expression of SS was modified by the beta S-gene-cluster polymorphisms and the alpha-gene status (alpha-thalassemia-2). The overall risk of soft tissue organ failure caused by the obliterative sickle vasculopathy (including stroke, renal failure, chronic lung disease with cor pulmonale, leg ulcers, and young adult death) was increased threefold in those with a CAR haplotype and was decreased in those with a Senegalese chromosome (p = 0.003). In the presence of a Senegalese haplotype, the patient's health is better, and with the CAR haplotype it is always worse. With the Benin, it is intermediate. Acute recurrent clinical events including hospitalized sickle cell crisis, bone infarction, and infection are decreased in frequency in those with a Senegalese haplotype. The risk of most acute events including acute chest syndrome is equivalent in those with Benin or CAR haplotypes. In the United States, alpha-thalassemia-2 is co-inherited randomly among the beta S-gene-cluster haplotypes. Acute events occurring during childhood are minimally effected by this co-inheritance. The risk of soft tissue organ failure is decreased. After the age of 20 years, painful episodes of the lumbar dorsal area are increased in patients who had alpha-thalassemia-2 in association with degenerative bone disease.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Dried blood spot analysis of creatinine with LC-MS/MS in addition to immunosuppressants analysis.

    PubMed

    Koster, Remco A; Greijdanus, Ben; Alffenaar, Jan-Willem C; Touw, Daan J

    2015-02-01

    In order to monitor creatinine levels or to adjust the dosage of renally excreted or nephrotoxic drugs, the analysis of creatinine in dried blood spots (DBS) could be a useful addition to DBS analysis. We developed a LC-MS/MS method for the analysis of creatinine in the same DBS extract that was used for the analysis of tacrolimus, sirolimus, everolimus, and cyclosporine A in transplant patients with the use of Whatman FTA DMPK-C cards. The method was validated using three different strategies: a seven-point calibration curve using the intercept of the calibration to correct for the natural presence of creatinine in reference samples, a one-point calibration curve at an extremely high concentration in order to diminish the contribution of the natural presence of creatinine, and the use of creatinine-[(2)H3] with an eight-point calibration curve. The validated range for creatinine was 120 to 480 μmol/L (seven-point calibration curve), 116 to 7000 μmol/L (1-point calibration curve), and 1.00 to 400.0 μmol/L for creatinine-[(2)H3] (eight-point calibration curve). The precision and accuracy results for all three validations showed a maximum CV of 14.0% and a maximum bias of -5.9%. Creatinine in DBS was found stable at ambient temperature and 32 °C for 1 week and at -20 °C for 29 weeks. Good correlations were observed between patient DBS samples and routine enzymatic plasma analysis and showed the capability of the DBS method to be used as an alternative for creatinine plasma measurement.

  11. Haplotype-assisted accurate non-invasive fetal whole genome recovery through maternal plasma sequencing

    PubMed Central

    2013-01-01

    Background The applications of massively parallel sequencing technology to fetal cell-free DNA (cff-DNA) have brought new insight to non-invasive prenatal diagnosis. However, most previous research based on maternal plasma sequencing has been restricted to fetal aneuploidies. To detect specific parentally inherited mutations, invasive approaches to obtain fetal DNA are the current standard in the clinic because of the experimental complexity and resource consumption of previously reported non-invasive approaches. Methods Here, we present a simple and effective non-invasive method for accurate fetal genome recovery-assisted with parental haplotypes. The parental haplotype were firstly inferred using a combination strategy of trio and unrelated individuals. Assisted with the parental haplotype, we then employed a hidden Markov model to non-invasively recover the fetal genome through maternal plasma sequencing. Results Using a sequence depth of approximately 44X against a an approximate 5.69% cff-DNA concentration, we non-invasively inferred fetal genotype and haplotype under different situations of parental heterozygosity. Our data show that 98.57%, 95.37%, and 98.45% of paternal autosome alleles, maternal autosome alleles, and maternal chromosome X in the fetal haplotypes, respectively, were recovered accurately. Additionally, we obtained efficient coverage or strong linkage of 96.65% of reported Mendelian-disorder genes and 98.90% of complex disease-associated markers. Conclusions Our method provides a useful strategy for non-invasive whole fetal genome recovery. PMID:23445748

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

    PubMed

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

    2011-11-01

    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.

  13. Haplotype-based approach for noninvasive prenatal diagnosis of congenital adrenal hyperplasia by maternal plasma DNA sequencing.

    PubMed

    Ma, Dingyuan; Ge, Huijuan; Li, Xuchao; Jiang, Tao; Chen, Fang; Zhang, Yanyan; Hu, Ping; Chen, Shengpei; Zhang, Jingjing; Ji, Xiuqing; Xu, Xun; Jiang, Hui; Chen, Minfeng; Wang, Wei; Xu, Zhengfeng

    2014-07-10

    Prenatal diagnosis of congenital adrenal hyperplasia (CAH) is of clinical significance because in utero treatment is available to prevent virilization of an affected female fetus. However, traditional prenatal diagnosis of CAH relies on genetic testing of fetal genomic DNA obtained using amniocentesis or chorionic villus sampling, which is associated with an increased risk of miscarriage. The aim of this study was to demonstrate the feasibility of a new haplotype-based approach for the noninvasive prenatal testing of CAH due to 21-hydroxylase deficiency. Parental haplotypes were constructed using target-region sequencing data of the parents and the proband. With the assistance of the parental haplotypes, we recovered fetal haplotypes using a hidden Markov model (HMM) through maternal plasma DNA sequencing. In the genomic region around the CYP21A2 gene, the fetus inherited the paternal haplotype '0' alleles linked to the mutant CYP21A2 gene, but the maternal haplotype '1' alleles linked to the wild-type gene. The fetus was predicted to be an unaffected carrier of CAH, which was confirmed by genetic analysis of fetal genomic DNA from amniotic fluid cells. This method was further validated by comparing the inferred SNP genotypes with the direct sequencing data of fetal genomic DNA. The result showed an accuracy of 96.41% for the inferred maternal alleles and an accuracy of 97.81% for the inferred paternal alleles. The haplotype-based approach is feasible for noninvasive prenatal testing of CAH.

  14. Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments.

    PubMed

    Palo, Outi M; Antila, Mervi; Silander, Kaisa; Hennah, William; Kilpinen, Helena; Soronen, Pia; Tuulio-Henriksson, Annamari; Kieseppä, Tuula; Partonen, Timo; Lönnqvist, Jouko; Peltonen, Leena; Paunio, Tiina

    2007-10-15

    Bipolar disorder (BPD) and schizophrenia (SCZ) have at least a partially convergent aetiology and thus may share genetic susceptibility loci. Multiple lines of evidence emphasize the role of disrupted-in-schizophrenia-1 (DISC1) gene in psychotic disorders such as SCZ. We monitored the association of allelic variants of translin-associated factor X (TSNAX)/DISC1 gene cluster using 13 single-nucleotide polymorphisms (SNPs) in 723 members of 179 Finnish BPD families. Consistent with an earlier finding in Finnish SCZ families, the haplotype T-A of rs751229 and rs3738401 at the 5' end of DISC1 was over-transmitted to males with psychotic disorder (P = 0.008; for an extended haplotype P = 0.0007 with both genders). Haplotypes at the 3' end of DISC1 associated with bipolar spectrum disorder (P = 0.0002 for an under-transmitted haplotype T-T of rs821616 and rs1411771, for an extended haplotype P = 0.0001), as did a two-SNP risk haplotype at the 5' end of TSNAX (P = 0.007). The risk haplotype for psychotic disorder also associated to perseverations (P = 0.035; for rs751229 alone P = 0.0012), and a protective haplotype G-T-G with rs1655285 in addition to auditory attention (P = 0.0059). The 3' end variants associated with several cognitive traits, with the most robust signal for rs821616 and verbal fluency and rs980989 and psychomotor processing speed (P = 0.011 for both). These results support involvement of DISC1 in the genetic aetiology of BPD and suggest that its distinct variants contribute to variation in the dimensional features of psychotic and bipolar spectrum disorders. Finding of alternative associating haplotypes in the same set of BPD families gives evidence for allelic heterogeneity within DISC1, eventually leading to heterogeneity in the clinical outcome as well.

  15. A haplotype-based algorithm for multilocus linkage disequilibrium mapping of quantitative trait loci with epistasis.

    PubMed Central

    Lou, Xiang-Yang; Casella, George; Littell, Ramon C; Yang, Mark C K; Johnson, Julie A; Wu, Rongling

    2003-01-01

    For tightly linked loci, cosegregation may lead to nonrandom associations between alleles in a population. Because of its evolutionary relationship with linkage, this phenomenon is called linkage disequilibrium. Today, linkage disequilibrium-based mapping has become a major focus of recent genome research into mapping complex traits. In this article, we present a new statistical method for mapping quantitative trait loci (QTL) of additive, dominant, and epistatic effects in equilibrium natural populations. Our method is based on haplotype analysis of multilocus linkage disequilibrium and exhibits two significant advantages over current disequilibrium mapping methods. First, we have derived closed-form solutions for estimating the marker-QTL haplotype frequencies within the maximum-likelihood framework implemented by the EM algorithm. The allele frequencies of putative QTL and their linkage disequilibria with the markers are estimated by solving a system of regular equations. This procedure has significantly improved the computational efficiency and the precision of parameter estimation. Second, our method can detect marker-QTL disequilibria of different orders and QTL epistatic interactions of various kinds on the basis of a multilocus analysis. This can not only enhance the precision of parameter estimation, but also make it possible to perform whole-genome association studies. We carried out extensive simulation studies to examine the robustness and statistical performance of our method. The application of the new method was validated using a case study from humans, in which we successfully detected significant QTL affecting human body heights. Finally, we discuss the implications of our method for genome projects and its extension to a broader circumstance. The computer program for the method proposed in this article is available at the webpage http://www.ifasstat.ufl.edu/genome/~LD. PMID:12702696

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

    PubMed

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

    2010-09-01

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

  17. Impact of haplotypes of TNF in the natural course of infective endocarditis.

    PubMed

    Giannitsioti, E; Damoraki, G; Rokkas, C; Tsaganos, T; Fragou, A; Kannelaki, S; Athanasia, S; Giamarellos-Bourboulis, E J

    2014-05-01

    Based on previous findings for the role of single nucleotide polymorphisms (SNPs) of TNF for the predisposition for bloodstream infections, this study investigates the role of these SNPs at the promoter positions -376, -308, -238 in infective endocarditis (IE). In a case-control study, 83 patients with IE and 83 controls were enrolled. Blood genotyping for the presence of G or A alleles of the three SNPs was carried out using restriction fragment length polymorphisms. Haplotypes were calculated. Patients were mostly infected by Staphylococcus aureus (32.5%) and by species of enterococci (14.3%) and streptococci (14.3%). Carriage of the minor frequency A alleles at -238 of the promoter region of TNF was greater than in controls (8.4% versus 1.2%, p 0.003). The presence of any of the three GGA/GAA/AGA haplotypes was more frequent in patients with IE (OR 8.22, 95CI% 1.8-37.4, p 0.001). After multivariate logistic regression analysis, it was found that the only factor related to fatal outcome was carriage of the wild-type GGG haplotype (OR, 3.29, 95CI%, 1.05-10.29, p 0.04). GGA, AGA and GAA haplotypes were more frequent in patients with IE than in controls, suggesting a predisposition for IE and a potential protective role against fatal outcome, as the wild-type GGG haplotype was independently related with death. PMID:24165416

  18. Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

    PubMed Central

    Alper, C A; Fleischnick, E; Awdeh, Z; Katz, A J; Yunis, E J

    1987-01-01

    We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SC01] and [HLA-B44, DR7, FC31] which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena. PMID:3793924

  19. Assembly of a large Y-STR haplotype database for the Czech population and investigation of its substructure.

    PubMed

    Zastera, Jan; Roewer, Lutz; Willuweit, Sascha; Sekerka, Patrik; Benesova, Lucie; Minarik, Marek

    2010-04-01

    Twelve Y-chromosomal short tandem repeats (Y-STR) (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a, DYS385b, DYS437, DYS438, and DYS439) included in the PowerPlex Y Kit (Promega Corporation, Madison, USA) were studied for 1750 unrelated males living in 14 regions of the Czech Republic. A total of 1148 different haplotypes were found. The overall haplotype diversity (HD) was determined as 0.998. Analysis of Molecular Variance (AMOVA) reveals non-significant distances between regions concerning their haplotype distribution, thus allowing to use the whole sample as a representative reference database of the Czech Republic. Median network analysis shows a remarkable bipartite composition of the Czech haplotypes, falling in distinct clusters with Eastern and Western European roots. PMID:20215022

  20. Haplotypes of PADI4 susceptible to rheumatoid arthritis are also associated with ulcerative colitis in the Japanese population.

    PubMed

    Chen, Chun Chuan; Isomoto, Hajime; Narumi, Yukiko; Sato, Kayoko; Oishi, Yuuki; Kobayashi, Tsutomu; Yanagihara, Katsunori; Mizuta, Yohei; Kohno, Shigeru; Tsukamoto, Kazuhiro

    2008-02-01

    Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disorder characterized by intractable inflammation specific to the gastrointestinal tract. The precise etiology of IBD remains unknown. Recently, haplotypes of peptidylarginine deiminase type 4 (PADI4) have been identified as the rheumatoid arthritis (RA)-susceptible gene. PADI4 is located at 1p36, which is one of chromosomal loci susceptible for IBD. Then, we examined whether haplotypes and diplotypes of PADI4 are associated with IBD in the Japanese population. We studied haplotypes of PADI4 in 114 patients with UC, 83 patients with CD, and 200 gender-matched healthy controls by PCR-restriction fragment length polymorphism. Frequencies and distributions of haplotypes and diplotypes were compared statistically between patients and controls by logistic regression analysis. The frequency of haplotype 1 was significantly decreased in patients with UC, compared to that in controls (P=0.037; odds ratio (OR)=0.702). In contrast, the frequency of haplotype 2 in patients with UC was significantly higher than that in controls (P=0.003; OR=1.722). Moreover, of a total of 114 patients with UC, 15 (13.2%) had a diplotype homozygous for haplotype 2, the frequency being significantly higher than in controls (9/200, 4.5%; P=0.008, OR=3.215). Our results indicate that haplotype 1 of PADI4 is associated with non-susceptibility to UC, whereas haplotype 2 is susceptible to UC. Thus, it is likely that PADI4 is one of genetic determinants of UC in the Japanese population.

  1. A CCL5 Haplotype Is Associated with Low Seropositivity Rate of HCV Infection in People Who Inject Drugs

    PubMed Central

    Huik, Kristi; Avi, Radko; Pauskar, Merit; Kallas, Eveli; Jõgeda, Ene-Ly; Karki, Tõnis; Rüütel, Kristi; Talu, Ave; Abel-Ollo, Katri; Uusküla, Anneli; Carrillo, Andrew; Ahuja, Sunil K.; He, Weijing; Lutsar, Irja

    2016-01-01

    Objective The role of CC chemokine receptor 5 (CCR5) and its ligand CCL5 on the pathogenesis of HIV infection has been well studied but not for HCV infection. Here, we investigated whether CCL5 haplotypes influence HIV and HCV seropositivity among 373 Caucasian people who inject drugs (PWID) from Estonia. Methods Study included 373 PWID; 56% were HIV seropositive, 44% HCV seropositive and 47% co-infected. Four CCL5 haplotypes (A-D) were derived from three CCL5 polymorphisms (rs2107538/rs2280788/rs2280789) typed by Taqman allelic discrimination assays. The data of CCR5 haplotypes were used from our previous study. The association between CCL5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis. Results Possessing CCL5 haplotype D (defined by rs2107538A/rs2280788G/rs2280789C) decreased the odds of HCV seropositivity compared to those not possessing it (OR = 0.19; 95% CI 0.09–0.40), which remained significant after adjustment to co-variates (OR = 0.08; 95% CI 0.02–0.29). An association of this haplotype with HIV seropositivity was not found. In step-wise logistic regression with backward elimination CCL5 haplotype D and CCR5 HHG*1 had reduced odds for HCV seropositivity (OR = 0.28 95% CI 0.09–0.92; OR = 0.23 95% CI 0.08–0.68, respectively) compared to those who did not possess these haplotypes, respectively. Conclusions Our results suggest that among PWID CCL5 haplotype D and CCR5 HHG*1 independently protects against HCV. Our findings highlight the importance of CCL5 genetic variability and CCL5-CCR5 axis on the susceptibility to HCV. PMID:27304910

  2. Brief communication: mitochondrial haplotype C4c confirmed as a founding genome in the Americas.

    PubMed

    Malhi, Ripan S; Cybulski, Jerome S; Tito, Raul Y; Johnson, Jesse; Harry, Harold; Dan, Carrie

    2010-03-01

    Mitochondrial DNA analysis of 31 unrelated Shuswap speakers from a previously poorly sampled region of North America revealed two individuals with haplogroups rarely found in the Americas, C4c and C1d. Comparison of the complete genomes of the two individuals with others found in the literature confirms that C4c is a founding haplotype and gives insight into the evolution of the C1d haplotype. This study demonstrates the importance of collecting and analyzing data from Native North Americans when addressing hypotheses about the peopling of the Americas.

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

    PubMed

    An, Qing-Ming; Zhou, Hui-Tong; Hu, Jiang; Luo, Yu-Zhu; Hickford, Jon G H

    2015-01-01

    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. PMID:26610572

  4. MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.

    PubMed

    Pastor, Pau; Moreno, Fermín; Clarimón, Jordi; Ruiz, Agustín; Combarros, Onofre; Calero, Miguel; López de Munain, Adolfo; Bullido, Maria J; de Pancorbo, Marian M; Carro, Eva; Antonell, Anna; Coto, Eliecer; Ortega-Cubero, Sara; Hernandez, Isabel; Tárraga, Lluís; Boada, Mercè; Lleó, Alberto; Dols-Icardo, Oriol; Kulisevsky, Jaime; Vázquez-Higuera, José Luis; Infante, Jon; Rábano, Alberto; Fernández-Blázquez, Miguel Ángel; Valentí, Meritxell; Indakoetxea, Begoña; Barandiarán, Myriam; Gorostidi, Ana; Frank-García, Ana; Sastre, Isabel; Lorenzo, Elena; Pastor, María A; Elcoroaristizabal, Xabier; Lennarz, Martina; Maier, Wolfang; Rámirez, Alfredo; Serrano-Ríos, Manuel; Lee, Suzee E; Sánchez-Juan, Pascual

    2015-01-01

    The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD. PMID:26444794

  5. MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.

    PubMed

    Pastor, Pau; Moreno, Fermín; Clarimón, Jordi; Ruiz, Agustín; Combarros, Onofre; Calero, Miguel; López de Munain, Adolfo; Bullido, Maria J; de Pancorbo, Marian M; Carro, Eva; Antonell, Anna; Coto, Eliecer; Ortega-Cubero, Sara; Hernandez, Isabel; Tárraga, Lluís; Boada, Mercè; Lleó, Alberto; Dols-Icardo, Oriol; Kulisevsky, Jaime; Vázquez-Higuera, José Luis; Infante, Jon; Rábano, Alberto; Fernández-Blázquez, Miguel Ángel; Valentí, Meritxell; Indakoetxea, Begoña; Barandiarán, Myriam; Gorostidi, Ana; Frank-García, Ana; Sastre, Isabel; Lorenzo, Elena; Pastor, María A; Elcoroaristizabal, Xabier; Lennarz, Martina; Maier, Wolfang; Rámirez, Alfredo; Serrano-Ríos, Manuel; Lee, Suzee E; Sánchez-Juan, Pascual

    2015-01-01

    The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

  6. Analysis methods for the determination of anthropogenic additions of P to agricultural soils

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phosphorus additions and measurement in soil is of concern on lands where biosolids have been applied. Colorimetric analysis for plant-available P may be inadequate for the accurate assessment of soil P. Phosphate additions in a regulatory environment need to be accurately assessed as the reported...

  7. On the Minimum Error Correction Problem for Haplotype Assembly in Diploid and Polyploid Genomes.

    PubMed

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

    2016-09-01

    In diploid genomes, haplotype assembly is the computational problem of reconstructing the two parental copies, called haplotypes, of each chromosome starting from sequencing reads, called fragments, possibly affected by sequencing errors. Minimum error correction (MEC) is a prominent computational problem for haplotype assembly and, given a set of fragments, aims at reconstructing the two haplotypes by applying the minimum number of base corrections. MEC is computationally hard to solve, but some approximation-based or fixed-parameter approaches have been proved capable of obtaining accurate results on real data. In this work, we expand the current characterization of the computational complexity of MEC from the approximation and the fixed-parameter tractability point of view. In particular, we show that MEC is not approximable within a constant factor, whereas it is approximable within a logarithmic factor in the size of the input. Furthermore, we answer open questions on the fixed-parameter tractability for parameters of classical or practical interest: the total number of corrections and the fragment length. In addition, we present a direct 2-approximation algorithm for a variant of the problem that has also been applied in the framework of clustering data. Finally, since polyploid genomes, such as those of plants and fishes, are composed of more than two copies of the chromosomes, we introduce a novel formulation of MEC, namely the k-ploid MEC problem, that extends the traditional problem to deal with polyploid genomes. We show that the novel formulation is still both computationally hard and hard to approximate. Nonetheless, from the parameterized point of view, we prove that the problem is tractable for parameters of practical interest such as the number of haplotypes and the coverage, or the number of haplotypes and the fragment length. PMID:27280382

  8. Vitamin D Binding Protein Haplotype is Associated with Hospitalization for RSV Bronchiolitis

    PubMed Central

    Randolph, Adrienne G.; Yip, Wai-Ki; Falkenstein-Hagander, Kathy; Weiss, Scott T.; Janssen, Riny; Keisling, Shannon; Bont, Louis

    2014-01-01

    Background Between 75,000–125,000 U.S. infants are hospitalized for respiratory syncytial virus (RSV) bronchiolitis each year. Up to half will be diagnosed with asthma in later childhood. Vitamin D deficiency has been associated with susceptibility to asthma and respiratory infections. Measured vitamin D is largely bound to vitamin D binding protein (VDBP); VDBP levels are influenced by its gene (GC) haplotype. Objective We assessed the relationship between polymorphisms rs7041 and rs4588, which define haplotypes GC1s, GC1f, and GC2, and RSV bronchiolitis susceptibility and subsequent asthma. Methods We retrospectively recruited 198 otherwise healthy children (93% White) hospitalized for severe RSV bronchiolitis in Boston and 333 parents into a follow up study to assess asthma diagnosis. Data were analyzed using family-based genetic association tests. We independently validated our results in 465 White children hospitalized with RSV bronchiolitis and 930 White population controls from the Netherlands. Results The rs7041_C allele (denoting haplotype GC1s) was overtransmitted (P=0.02, additive model) in the entire Boston cohort, and in Whites (P=0.03), and in those subsequently diagnosed with asthma (P=0.006). The GC1f haplotype was undertransmitted in the White and asthma subgroups (both P=0.05). The rs7041_C allele was also more frequent in the RSV bronchiolitis group compared to controls (OR 1.12, 95% CI 1.02, 1.4, P=0.03) in the Netherlands; especially in mechanically ventilated patients (P=0.009). Conclusion and Clinical Relevance GC1s haplotype carriage may increase the risk of RSV bronchiolitis in infancy and subsequent asthma development. The GC1s haplotype is associated with higher VDBP levels, resulting in less freely-available vitamin D. PMID:24447085

  9. On the Minimum Error Correction Problem for Haplotype Assembly in Diploid and Polyploid Genomes.

    PubMed

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

    2016-09-01

    In diploid genomes, haplotype assembly is the computational problem of reconstructing the two parental copies, called haplotypes, of each chromosome starting from sequencing reads, called fragments, possibly affected by sequencing errors. Minimum error correction (MEC) is a prominent computational problem for haplotype assembly and, given a set of fragments, aims at reconstructing the two haplotypes by applying the minimum number of base corrections. MEC is computationally hard to solve, but some approximation-based or fixed-parameter approaches have been proved capable of obtaining accurate results on real data. In this work, we expand the current characterization of the computational complexity of MEC from the approximation and the fixed-parameter tractability point of view. In particular, we show that MEC is not approximable within a constant factor, whereas it is approximable within a logarithmic factor in the size of the input. Furthermore, we answer open questions on the fixed-parameter tractability for parameters of classical or practical interest: the total number of corrections and the fragment length. In addition, we present a direct 2-approximation algorithm for a variant of the problem that has also been applied in the framework of clustering data. Finally, since polyploid genomes, such as those of plants and fishes, are composed of more than two copies of the chromosomes, we introduce a novel formulation of MEC, namely the k-ploid MEC problem, that extends the traditional problem to deal with polyploid genomes. We show that the novel formulation is still both computationally hard and hard to approximate. Nonetheless, from the parameterized point of view, we prove that the problem is tractable for parameters of practical interest such as the number of haplotypes and the coverage, or the number of haplotypes and the fragment length.

  10. FokI Polymorphism, Vitamin D Receptor, and Interleukin-1 Receptor Haplotypes Are Associated with Type 1 Diabetes in the Dalmatian Population

    PubMed Central

    Zemunik, Tatijana; Škrabić, Veselin; Boraska, Vesna; Diklić, Dijaneta; Terzić, Ivana Marinović; Čapkun, Vesna; Peruzović, Marijana; Terzić, Janoš

    2005-01-01

    Vitamin D and interleukin (IL)-1 have been suggested to function in the pathogenesis of type 1 diabetes mellitus (T1DM). Therefore, we examined the influence of gene polymorphisms in vitamin D receptor (VDR) and interleukin-1 receptor type I (IL-1-R1) on susceptibility to T1DM in the Dalmatian population of South Croatia. We genotyped 134 children with T1DM and 132 controls; for FokI polymorphism studies, we extended the control group to an additional 102 patients. The VDR gene polymorphism FokI displayed unequal distribution (P = 0.0049) between T1DM and control groups, with the ff genotype occurring more frequently in T1DM individuals whereas the VDR gene polymorphism Tru9I did not differ in frequency between studied groups. All tested polymorphisms of the IL-1-R1 gene [PstI, HinfI, and AluI (promoter region) and PstI-e (exon 1B region)] displayed no differences between cases and controls. Haplotype analysis of the VDR gene (FokI, BsmI, ApaI, TaqI, Tru9I) and of the IL-1-R1 gene (PstI, HinfI, AluI, PstI-e) found haplotypes VDR FbATu (P = 0.0388) and IL-1-R1 phap’ (P = 0.0419) to be more frequent in T1DM patients whereas the BatU haplotype occurred more often in controls (P = 0.0064). Our findings indicate that the VDR FokI polymorphism and several VDR and IL-1-R1 haplotypes are associated with susceptibility to T1DM in the Dalmatian population. PMID:16258158

  11. Genome-wide association scan and phased haplotype construction for quantitative trait loci affecting boar taint in three pig breeds

    PubMed Central

    2012-01-01

    Background Boar taint is the undesirable smell and taste of pork meat derived from some entire male pigs. The main causes of boar taint are the two compounds androstenone and skatole (3-methyl-indole). The steroid androstenone is a sex pheromone produced in the testis of the boars. Skatole is produced from tryptophan by bacteria in the intestine of the pigs. In many countries pigs are castrated as piglets to avoid boar taint, however, this is undesirable for animal welfare reasons. Genetic variations affecting the level of boar taint have previously been demonstrated in many breeds. In the study presented in this paper, markers and haplotypes, which can be applied to DNA-based selection schemes in order to reduce or eliminate the boar taint problem, are identified. Results Approximately 30,000 SNPs segregating in 923 boars from three Danish breeds; Duroc, Landrace, and Yorkshire, were used to conduct genome wide association studies of boar taint compounds. At 46 suggestive quantitative trait loci (QTL), 25 haplotypes and three single markers with effects were identified. Furthermore, 40% of the haplotypes mapped to previously identified regions. Haplotypes were also analysed for effects of slaughter weight and meat content. The most promising haplotype was identified on Sus scrofa chromosome 1. The gain in fixed effect of having this haplotype on level of androstenone in Landrace was identified to be high (1.279 μg/g). In addition, this haplotype explained 16.8% of the phenotypic variation within the trait. The haplotype was identified around the gene CYB5A which is known to have an indirect impact on the amount of androstenone. In addition to CYB5A, the genes SRD5A2, LOC100518755, and CYP21A2 are candidate genes for other haplotypes affecting androstenone, whereas, candidate genes for the indolic compounds were identified to be SULT1A1 and CYP2E1. Conclusions Despite the small sample size, a total of 25 haplotypes and three single markers were identified

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

    PubMed Central

    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

  13. Quantitative Analysis of Polymer Additives with MALDI-TOF MS Using an Internal Standard Approach

    NASA Astrophysics Data System (ADS)

    Schwarzinger, Clemens; Gabriel, Stefan; Beißmann, Susanne; Buchberger, Wolfgang

    2012-06-01

    MALDI-TOF MS is used for the qualitative analysis of seven different polymer additives directly from the polymer without tedious sample pretreatment. Additionally, by using a solid sample preparation technique, which avoids the concentration gradient problems known to occur with dried droplets and by adding tetraphenylporphyrine as an internal standard to the matrix, it is possible to perform quantitative analysis of additives directly from the polymer sample. Calibration curves for Tinuvin 770, Tinuvin 622, Irganox 1024, Irganox 1010, Irgafos 168, and Chimassorb 944 are presented, showing coefficients of determination between 0.911 and 0.990.

  14. Quantitative analysis of polymer additives with MALDI-TOF MS using an internal standard approach.

    PubMed

    Schwarzinger, Clemens; Gabriel, Stefan; Beißmann, Susanne; Buchberger, Wolfgang

    2012-06-01

    MALDI-TOF MS is used for the qualitative analysis of seven different polymer additives directly from the polymer without tedious sample pretreatment. Additionally, by using a solid sample preparation technique, which avoids the concentration gradient problems known to occur with dried droplets and by adding tetraphenylporphyrine as an internal standard to the matrix, it is possible to perform quantitative analysis of additives directly from the polymer sample. Calibration curves for Tinuvin 770, Tinuvin 622, Irganox 1024, Irganox 1010, Irgafos 168, and Chimassorb 944 are presented, showing coefficients of determination between 0.911 and 0.990.

  15. Variants and Haplotypes in Angiotensinogen Gene Are Associated With Plasmatic Angiotensinogen Level in Mexican Population

    PubMed Central

    Balam-Ortiz, Eros; Esquivel-Villarreal, Adolfo; Alfaro-Ruiz, Luis; Carrillo, Karol; Elizalde, Adela; Gil, Trinidad; Urushihara, Maki; Kobori, Hiroyuki; Jimenez-Sanchez, Gerardo

    2011-01-01

    Introduction The plasmatic angiotensinogen (AGT) level has been associated with essential hypertension. Linkage analysis has found a relationship between the AGT gene locus and hypertension in the Mexican-American population, but studies have failed to identify genetic variants associated with hypertension or plasma AGT levels. This study analyzes the relationship between polymorphisms in the AGT gene and plasmatic AGT levels in Mexican population. Methods Nine polymorphisms in AGT gene were genotyped, and plasma AGT level was determined by enzyme-linked immunosorbent assay. Results Differences in AGT plasma levels were associated with 2 polymorphisms: T-20G, TT = 25.3 ± 8.3 versus TG + GG = 21.6 ± 8.8 μg/mL; P = 0.008 and C3389T (T174M), CC = 25.8 ± 9.9 versus TC + TT = 20.5 ± 5.4 μg/mL; P = 0.0002. Haplotype 2 was associated with low plasma AGT (−5.1 μg/mL [95% confidence interval: −8.6 to −1.6], P = 0.004) and Haplotype 8 was associated with high plasma AGT (6.5 μg/mL [95% confidence interval: 2.5 to 10.6], P = 0.001). This association remained after adjustment for covariates. A Likelihood Ratio Test for haplotype-phenotype association adjusted for covariates resulted in χ2 = 38.9, P = 0.0005. The total effect of the haplotypes on plasma AGT level variance was 19.5%. No association was identified between haplotypes and quantitative traits of blood pressure. Conclusions Two polymorphisms (T-20G and C3389T) and 2 haplotypes (H2 and H8) showed an association with plasma AGT levels in Mexican population. PMID:21629041

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

    PubMed

    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. PMID:27076998

  17. Haplotype data for 23 Y-chromosome markers in a reference sample from Bosnia and Herzegovina

    PubMed Central

    Kovačević, Lejla; Fatur-Cerić, Vera; Hadžić, Negra; Čakar, Jasmina; Primorac, Dragan; Marjanović, Damir

    2013-01-01

    Aim To detect polymorphisms of 23 Y-chromosomal short tandem repeat (STR) loci, including 6 new loci, in a reference database of male population of Bosnia and Herzegovina, as well as to assess the importance of increasing the number of Y-STR loci utilized in forensic DNA analysis. Methods The reference sample consisted of 100 healthy, unrelated men originating from Bosnia and Herzegovina. Sample collection using buccal swabs was performed in all geographical regions of Bosnia and Herzegovina in the period from 2010 to 2011. DNA samples were typed for 23 Y STR loci, including 6 new loci: DYS576, DYS481, DYS549, DYS533, DYS570, and DYS643, which are included in the new PowerPlex® Y 23 amplification kit. Results The absolute frequency of generated haplotypes was calculated and results showed that 98 samples had unique Y 23 haplotypes, and that only two samples shared the same haplotype. The most polymorphic locus was DYS418, with 14 detected alleles and the least polymorphic loci were DYS389I, DYS391, DYS437, and DYS393. Conclusion This study showed that by increasing the number of highly polymorphic Y STR markers, to include those tested in our analysis, leads to a reduction of repeating haplotypes, which is very important in the application of forensic DNA analysis. PMID:23771760

  18. B haplotype influence on the relative efficacy of Marek's disease vaccines in commercial chickens.

    PubMed

    Bacon, L D; Witter, R L

    1994-04-01

    The objectives were to investigate whether or not B haplotypes influence vaccinal immunity against Marek's disease (MD) in commercial chickens and to evaluate whether retrospective analysis would detect the influence. This method involved evaluating the B haplotypes of turkey herpesvirus (HVT)-vaccinated sick vs normal chickens from a flock afflicted with MD symptoms. An analysis of the retrospective data disclosed that MD symptoms were present in a higher proportion of B2B19 than B2B21 chickens. A prospective study was then conducted with blood-typed chickens of the strain vaccinated with HVT or HVT + 301B bivalent MD vaccines prior to inoculation of the very virulent Md5 virus. The bivalent vaccine provided better protection than HVT alone, but with either vaccine fewer B2B21 chickens developed MD lesions. We conclude that the B haplotype influence on vaccinal immunity against MD previously demonstrated in B-congenic strains of chickens is also significant in commercial chickens and that the influence can be detected through analysis of B haplotypes in sick vs normal chickens of an affected flock.

  19. Haplotype diversity of 13 RM Y-STRs in Chinese Han population and an update on the allele designation of DYF403S1.

    PubMed

    Zhang, Wenqiong; Xiao, Chao; Wei, Tian; Pan, Chao; Yi, Shaohua; Huang, Daixin

    2016-07-01

    Rapidly mutating Y-STRs (RM Y-STRs) have been paid much attention in recent years. The 13 RM Y-STRs have been proved to have substantially higher haplotype diversity and discrimination capacity than conventionally used Y-STRs, indicating the considerable power in paternal lineage differentiation. To investigate the haplotype diversity in Chinese Han population, we collected 252 unrelated male samples and tested the genotype of the 13 RM Y-STRs. Among 252 male individuals, a total of 250 haplotypes were observed in which only 2 haplotypes were shared by 2 males respectively. The haplotype diversity reached 0.999937 and the discrimination capacity was 99.21%, showing a great discrimination power in Chinese Han population. In addition, an update on the allele designation of DYF403S1 was proposed.

  20. The haplotype analyses using multiple markers of the apolipoprotein B gene in patients with coronary artery disease.

    PubMed Central

    Hong, S. H.; Song, J.; Kim, J. Q.

    2001-01-01

    The high level of low density lipoprotein (LDL) is a risk factor for cardiovascular disease. Apolipoprotein (apo) B is a major protein component of LDL and plays an important role in the maintenance of cholesterol homeostasis. In this study, six polymorphic sites of the apoB gene were anlaysed in 235 patients with coronary artery disease (CAD) and 216 normal control subjects. There were no significant differences in the allele frequencies of apoB polymorphisms between the control and patient groups. However, haplotype frequencies were significantly different between the CAD patients and control (p<0.05). In addition, the allelic distributions of both EcoRI and MspI polymorphisms in Koreans were similar to those in Chinese but significantly different from those in Caucasians. ApoB polymorphisms showed no association with plasma lipid levels. In conclusion, haplotype analysis of the apoB gene using multiple diallelic markers might be a useful marker for Korean CAD patients. PMID:11748351

  1. Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

    PubMed Central

    Hawwa, Ahmed F; McKiernan, Patrick J; Shields, Michael; Millership, Jeff S; Collier, Paul S; McElnay, James C

    2009-01-01

    AIMS The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation. METHODS Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes. RESULTS The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (≥30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677->T variant allele also had a significant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were significantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation. CONCLUSIONS These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post-transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and

  2. The mutated S1-haplotype in sour cherry has an altered S-haplotype-specific F-box protein gene.

    PubMed

    Hauck, Nathanael R; Ikeda, Kazuo; Tao, Ryutaro; Iezzoni, Amy F

    2006-01-01

    Gametophytic self-incompatibility (GSI) is an outcrossing mechanism in flowering plants that is genetically controlled by 2 separate genes located at the highly polymorphic S-locus, termed S-haplotype. This study characterizes a pollen part mutant of the S(1)-haplotype present in sour cherry (Rosaceae, Prunus cerasus L.) that contributes to the loss of GSI. Inheritance of S-haplotypes from reciprocal interspecific crosses between the self-compatible sour cherry cultivar Ujfehértói Fürtös carrying the mutated S(1)-haplotype (S(1)'S(4)S(d)S(null)) and the self-incompatible sweet cherry (Prunus avium L.) cultivars carrying the wild-type S(1)-haplotype revealed that the mutated S(1)-haplotype confers unilateral incompatibility with a functional pistil component and a nonfunctional pollen component. The altered sour cherry S(1)-haplotype pollen part mutant, termed S(1)', contains a 615-bp Ds-like element within the S(1)-haplotype-specific F-box protein gene (SFB(1)'). This insertion generates a premature in-frame stop codon that would result in a putative truncated SFB(1) containing only 75 of the 375 amino acids present in the wild-type SFB(1). S(1)' along with 2 other previously characterized Prunus S-haplotype mutants, S(f) and S(6m), illustrate that mobile element insertion is an evolutionary force contributing to the breakdown of GSI. PMID:16985081

  3. Microsatellites haplotyping of CF chromosomes shows linkage disequilibrium and several founder effects in Brittany (France)

    SciTech Connect

    Raguenes, O.; Ferec, C.; Mercier, B.

    1994-09-01

    A large study on cystic fibrosis (CF) is underway in Brittany (France). It is based on 902 CF patients distributed in 795 families who were or are still followed at the {open_quotes}Centre Helio-Marin{close_quotes} in Roscoff and/or were subjected to a molecular analysis at the {open_quotes}Centre de Biogenetique{close_quotes} in Brest. At present, the CF mutations have been identified in 309 patients born in Brittany, most of them of Celtic origin. A microsatellite (MS) study using IVS 17b TA, IVS 17b CA and IVS 8 CA was also completed in 63 CF patients and their parents (carriers of the {Delta}F508 mutation or the G551D mutation or the 1078delT mutation or the W846X mutation). All the 21 chromosomes carrying the 1078delT mutation had the same MS haplotype (16-21-13), which was also found on 9 of the 83 non-CF chromosomes analyzed. All the 16 chromosomes with the G551D mutation carried another MS haplotype (16-7-17), which was also found on 13.3% of the non-CF chromosomes. All the 6 chromosomes with the W846X mutation carried the 16-32-13 haplotype, also found on 6.0% of the non-CF chromosomes. Sixteen different MS haplotypes were found among the 74 chromosomes carrying the{Delta}F508 mutation, three of them representing 74.3% (55/74) of the chromosomes. These were the 23-31-13 haplotype (31/74 - 41.9%), the 17-31-13 haplotype (11/74 - 14.9%), and the 17-32-13 haplotype (13/74 - 17.6%). These results show that the CF mutations observed in Brittany are in linkage disequilibrium with the MS haplotypes. They also suggest that their presence in Brittany is the consequence of several founder effects.

  4. Interaction between HLA-DRB1-DQB1 haplotypes in Sardinian multiple sclerosis population.

    PubMed

    Cocco, Eleonora; Murru, Raffaele; Costa, Gianna; Kumar, Amit; Pieroni, Enrico; Melis, Cristina; Barberini, Luigi; Sardu, Claudia; Lorefice, Lorena; Fenu, Giuseppe; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Marrosu, Maria Giovanna

    2013-01-01

    We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13:03-*03:01 OR = 3.3, Pc 5.1 × 10(-5), *04:05-*03:01 OR = 2.1, Pc 9.7 × 10(-8), *15:01-*06:02 OR = 2.0, Pc = 9.1 × 10(-3), *03:01-*02:01 OR = 1.7 Pc = 7.9 × 10(-22)) and protection (*11, OR = 0.8, Pc = 2.7 × 10(-2), *16:01-*05:02 OR = 0.6, Pc = 4.8 × 10(-16), *14:01-4-*05:031 = OR = 0.5, Pc = 9.8 × 10(-4) and *15:02-*06:01 OR = 0.4, Pc = 5.1 × 10(-4)). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14:01, *04:05, *13∶03, *08:01 and *03:01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85-99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms.

  5. ADRB2 haplotype is associated with glucose tolerance and insulin sensitivity in obese postmenopausal women.

    PubMed

    Prior, Steven J; Goldberg, Andrew P; Ryan, Alice S

    2011-02-01

    The β(2)-adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resistance. We examined the hypothesis that ADRB2 Arg16Gly-Gln27Glu haplotype is associated with body composition, glucose tolerance, and insulin sensitivity in obese, postmenopausal women. Obese (>35% body fat), postmenopausal (age 45-75 years) women (n = 123) underwent genotyping, dual-energy X-ray absorptiometry, and computed tomography scans, exercise testing (VO(2(max))), 2-h oral glucose tolerance tests (OGTTs), and hyperinsulinemic-euglycemic clamps (80 mU/m(2)/min). Analysis of covariance (ANCOVA) tested for differences among haplotypes, with race, % body fat, and VO(2(max)) as covariates. We found that ADRB2 haplotype was independently associated with % body fat, abdominal fat distribution, VO(2(max)), insulin sensitivity (M/ΔInsulin), and glucose tolerance (ANOVA, P < 0.05 for all). Women homozygous for Gly16-Gln27 haplotype had the highest % body fat (52.7 ± 1.9%), high abdominal fat, low M/ΔInsulin (0.49 ± 0.08 mg/kg/min/pmol/l/10(2)), and impaired glucose tolerance (IGT) during an OGTT (G(120) = 10.2 ± 0.9 mmol/l). Women homozygous for Gly16-Glu27 haplotype also had low M/ΔInsulin (0.51 ± 0.05 mg/kg/min/pmol/l/10(2)) and IGT (G(120) = 8.2 ± 0.7 mmol/l). Subjects with Arg16-Gln27/Gly16-Gln27 haplotype combination had the highest VO(2(max)) (1.84 ± 0.07 l/min) and M/ΔInsulin (0.7 ± 0.04 mg/kg/min/pmol/l/10(2)), and normal glucose tolerance (G(120) = 6.4 ± 0.4 mmol/l), despite being obese. These data show associations of the ADRB2 Arg16Gly-Gln27Glu haplotype with VO(2(max)) and body composition, and an independent association with glucose metabolism, which persists after controlling for body composition and fitness. This suggests that ADRB2 haplotypes may mediate insulin action, glucose tolerance, and potentially risk for type 2 diabetes mellitus (T2DM) in obese, postmenopausal women.

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

    PubMed

    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.

  7. Haplotype-tagging single nucleotide polymorphisms in the GSTP1 gene promoter and susceptibility to lung cancer☆

    PubMed Central

    Tan, Xiang-Lin; Moslehi, Roxana; Han, WeiGuo; Spivack, Simon D.

    2013-01-01

    Background Glutathione S-transferase (GST) P1 is a major phase II xenobiotic-metabolizing enzyme in the human lung. Our laboratory had previously identified nine single nucleotide polymorphisms (SNPs) in the GSTP1 gene promoter, which were then grouped into three main haplotypes (Hap1, Hap2, and Hap3) based on statistical inference. Hap3 was found to display a high expression phenotype. The main objective of the current study was to test the association between GSTP1 promoter haplotypes with the risk of lung cancer after determining the promoter haplotypes experimentally through cloning and sequencing. Methods We conducted a case–control analysis of 150 subjects with lung cancer and 329 controls with no personal history of the disease. The three statistically inferred GSTP1 promoter haplotypes were confirmed experimentally through cloning and sequencing. Haplotype-tagging SNPs were selected and GSTP1 haplotypes were tested for genetic association to lung cancer using unconditional logistic regression after adjusting for confounders. Statistical interaction between GSTP1 promoter haplotypes with either cigarette smoking or dietary fruit and vegetable intake were tested using the likelihood ratio test. Results We did not find protective effects of Hap3 against lung cancer, despite an adequately powered design for this main effect. Homozygous variants of tagSNPs –1738 T >A and –354 G > T, which tag Hap2, showed an increased (but statistically non-significant) risk of lung cancer among all subjects as well as among individuals with low fruit and vegetable intake, compared to homozygous wildtypes for these SNPs. We did not find significant interactions between Hap2 and dietary intake of fruits and vegetables. Conclusions Our results do not support significant main and modifying effects for GSTP1 promoter haplotypes on susceptibility to lung cancer in this population, but reinforce the protective effects of dietary intake of fruits and vegetables. PMID:19282111

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

    SciTech Connect

    Shuguang Leng; Juan Cheng; Linyuan Zhang; Yong Niu; Yufei Dai; Zufei Pan; Bin Li; Fengsheng He; Yuxin Zheng

    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.

  9. p53 polymorphisms in Russia and Belarus: correlation of the 2-1-1 haplotype frequency with longitude.

    PubMed

    Khrunin, A V; Tarskaia, L A; Spitsyn, V A; Lylova, O I; Bebyakova, N A; Mikulich, A I; Limborska, S A

    2005-02-01

    Four different polymorphisms in the human p53 gene (a 16-bp duplication in intron 3, and three RFLPs: for Bsh1236I at codon 72, for MspI in intron 6 and for BamHI in the 3' flanking region) and extended haplotypes were studied in nine geographically diverse populations from Russia and Belarus. The Yakuts differed from all other populations, as they had a significantly higher frequency of the BamHI A1 allele. Most populations did not differ significantly from each other in the frequency of the Bsh1236I polymorphism. The 16-bp duplication A1 allele and MspI A2 allele frequencies were significantly higher in the Yakut and Khant populations. Linkage disequilibrium values (D') between BamHI and other polymorphic sites were not significant in many cases; for this reason we have used the 16 bp-Bsh1236I-MspI haplotype frequencies only. Of eight possible haplotypes, five were observed in the populations investigated. Haplotype 1-2-2 was the most frequent in all populations. The next most common haplotype, 1-1-2, was present at very similar frequencies among the Byelorussians and Russians from Smolensk, but was more frequent in other populations. The frequency of haplotype 2-1-1 showed a nearly continuous decrease from West to East (from 17.857% among the Byelorussians to 0.685% in the Yakuts from the Verkhoyansk) and correlated with longitude (Spearman's r = -0.8667, P = 0.0025), which may be due to natural selection and adaptation. The relationships among populations were evaluated by means of Nei's D(A) distances for the 16 bp-Bsh1236I-MspI haplotype frequencies. Based on the multidimensional scaling analysis a correlation between p53 haplotype frequencies and ethnicity is supposed.

  10. Haplotype diversity in mitochondrial DNA hypervariable region in a population of southeastern Brazil.

    PubMed

    Fridman, C; Gonzalez, R S; Pereira, A C; Cardena, M M S G

    2014-07-01

    Brazilian population derives from Native Amerindians, Europeans, and Africans. Southeastern Brazil is the most populous region of the country. The present study intended to characterize the maternal genetic ancestry of 290 individuals from southeastern (Brazil) population. Thus, we made the sequencing of the three hypervariable regions (HV1, HV2, and HV3) of the mitochondrial DNA (mtDNA). The statistical analyses were made using Arlequin software, and the median-joining haplotype networks were generated using Network software. The analysis of three hypervariable regios showed 230 (79.3 %) unique haplotypes and the most common haplotype was "263G" carried by 12 (4.1 %) individuals. The strikingly high variability generated by intense gene flow is mirrored in a high sequence diversity (0.9966 ± 0.0010), and the probability of two random individuals showing identical mtDNA haplotypes were 0.0068. The analysis of haplogroup distribution revealed that 36.9 % (n = 107) presented Amerindian haplogroups, 35.2 % (n = 102) presented African haplogroups, 27.6 % (n = 80) presented European haplogroups, and one (0.3 %) individual presented East Asian haplogroup, evidencing that the southeastern population is extremely heterogeneous and the coexistence of matrilineal lineages with three different phylogeographic origins. The genetic diversity found in the mtDNA control region in the southeastern Brazilian population reinforces the importance of increased national database in order to be important and informative in forensic cases.

  11. Patterns of haplotypes for 92 cystic fibrosis mutations: Variability, association and recurrence

    SciTech Connect

    Morral, N.; Llevadot, R.; Estivill, X.

    1994-09-01

    Most CFTR mutations are very uncommon among the cystic fibrosis population, with frequencies of less than 1%, and many are found only in specific areas. We have analyzed 92 CF mutations for several markers (4 microsatellites and 3 other polymorphisms) scattered in the CFTR gene. Haplotypes associated with these mutations can be used as a framework in the screening of chromosomes carrying unknown mutations. The association between mutation and haplotype reduces the number of mutations it is necessary to search for to a maximum of 16 for the same haplotype. Only mutations {triangle}F508, G542X and N1303K are associated with more than one haplotype as a result of slippage at more than one microsatellite loci, suggesting that these three are the most ancient CF mutations. Recurrence has been found for at least 7 mutations: H199Y, R347P, L558S, R553X, 2184insA, 3272-26A{r_arrow}G, 3849+10kbC{r_arrow}T and R1162X. Also microsatellite analysis of chromosomes of several ethnic origins (Czech, Italian, Russian, Slovac and Spanish) suggested that possibility of three or more independent origins for mutations R334W, R347P, R1162X, and 3849+10kbC{r_arrow}T, which was confirmed by analysis of markers flanking these mutations.

  12. HLA-A, HLA-B, HLA-DRB1 allele and haplotype frequencies in 6384 umbilical cord blood units and transplantation matching and engraftment statistics in the Zhejiang cord blood bank of China.

    PubMed

    Wang, F; He, J; Chen, S; Qin, F; Dai, B; Zhang, W; Zhu, F M; Lv, H J

    2014-02-01

    Umbilical cord blood (UCB) is a widely accepted source of progenitor cells, and now, many cord blood banks were established. Here, we analysed the HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies, HLA matching possibilities for searching potential donors and outcome of UCB transplantations in Zhejiang cord blood bank of China. A total of 6384 UCB units were characterized for 17 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles at the first field resolution level. Additionally, B*14, B*15 and B*40 were typed to the second field level. A total of 1372 distinct A-B-DRB1 haplotypes were identified. The frequencies of 7 haplotypes were more than 1%, and 439 haplotypes were <0.01%. A*02-B*46-DRB1*09, A*33-B*58-DRB1*03 and A*30-B*13-DRB1*07 were the most common haplotypes, with frequencies of 4.4%, 3.3%, and 2.9%, respectively. Linkage disequilibrium(LD) analysis showed that there were 83 A-B, 106 B-DRB1, 54 A-DRB1 haplotypes with positive LD, in which 51 A-B, 60 B-DRB1, 32 A-DRB1 haplotypes exhibited a significant LD (P < 0.05). In 682 search requests, 12.9%, 40.0% and 42.7% of patients were found to have 6 of 6, 5 of 6 and 4 of 6 HLA-A, HLA-B and HLA-DRB1 matching donors, respectively. A total of 30 UCB units were transplanted to 24 patients (3 patients not evaluated due to early death); 14 of 21 patients (66.7%) engrafted. This study reveals the HLA distribution and its transplantation application in the cord blood bank of Zhejiang province. These data can help to select potential UCB donors for transplantation and used to assess the scale of new cord blood banking endeavours.

  13. Haplotypes for 13 Y-chromosomal STR loci in South Tunisian population (Sfax region).

    PubMed

    Ayadi, Imen; Ammar-Keskes, Leila; Rebai, Ahmed

    2006-12-20

    Nine Y-STR loci from the "minimal haplotype" (DYS19, DYS385a/b, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393) included in Y-STR Haplotype Reference Databases (YHRD) with 4 additional Y-STRs (DYS436, DYS437, DYS438, DYS439) were analyzed by PCR using duplex and Y-PLEX 12 kit, followed by automatic genotyping in a sample of 105 Tunisian males originating from Sfax region (south Tunisia). Allelic frequencies and gene diversities for each Y-STR locus were determined. The high haplotype diversity (0.9932) and discrimination capacity (0.7714) show the usefulness of these loci for human identification in forensic studies and paternity tests in Tunisia. The most common haplotype was shared by 4.7% (5 individuals) of the sample was only found in samples from the Tunisian population reported in YHRD. One private allele for DYS392 (allele 17) was discovered and duplications were observed for five loci (DYS19, DYS389I, DYS393, DYS437 and DYS439).

  14. Use of haplotypes to estimate Mendelian sampling effects and selection limits.

    PubMed

    Cole, J B; VanRaden, P M

    2011-12-01

    Limits to selection and Mendelian sampling (MS) terms can be calculated using haplotypes by summing the individual additive effects on each chromosome. Haplotypes were imputed for 43 382 single-nucleotide polymorphisms (SNP) in 1455 Brown Swiss, 40 351 Holstein and 4064 Jersey bulls and cows using the Fortran program findhap.f90, which combines population and pedigree haplotyping methods. Lower and upper bounds of MS variance were calculated for daughter pregnancy rate (a measure of fertility), milk yield, lifetime net merit (a measure of profitability) and protein yield assuming either no or complete linkage among SNP on the same chromosome. Calculated selection limits were greater than the largest direct genomic values observed in all breeds studied. The best chromosomal genotypes generally consisted of two copies of the same haplotype even after adjustment for inbreeding. Selection of animals rather than chromosomes may result in slower progress, but limits may be the same because most chromosomes will become homozygous with either strategy. Selection on functions of MS could be used to change variances in later generations. PMID:22059578

  15. Dispersion of human Y chromosome haplotypes based on five microsatellites in global populations.

    PubMed

    Deka, R; Jin, L; Shriver, M D; Yu, L M; Saha, N; Barrantes, R; Chakraborty, R; Ferrell, R E

    1996-12-01

    We have analyzed five microsatellite loci from the nonrecombining portion of the human Y chromosome in 15 diverse human populations to evaluate their usefulness in the reconstruction of human evolution and early male migrations. The results show that, in general, most populations have the same set of the most frequent alleles at these loci. Hypothetical ancestral haplotypes, reconstructed on the basis of these alleles and their close derivatives, are shared by multiple populations across racial and geographical boundaries. A network of the observed haplotypes is characterized by a lack of clustering of geographically proximal populations. In spite of this, few distinct clusters of closely related populations emerged in the network, which are associated with population-specific alleles. A tree based on allele frequencies also shows similar results. Lack of haplotypic structure associated with the presumed ancestral haplotypes consisting of individuals from almost all populations indicate a recent common ancestry and/or extensive male migration during human evolutionary history. The convergent nature of microsatellite mutation confounds population relationships. Optimum resolution of Y chromosome evolution will require the use of additional microsatellite loci and diallelic genetic markers with lower mutation rates. PMID:8973912

  16. Development of an Italian RM Y-STR haplotype database: Results of the 2013 GEFI collaborative exercise.

    PubMed

    Robino, C; Ralf, A; Pasino, S; De Marchi, M R; Ballantyne, K N; Barbaro, A; Bini, C; Carnevali, E; Casarino, L; Di Gaetano, C; Fabbri, M; Ferri, G; Giardina, E; Gonzalez, A; Matullo, G; Nutini, A L; Onofri, V; Piccinini, A; Piglionica, M; Ponzano, E; Previderè, C; Resta, N; Scarnicci, F; Seidita, G; Sorçaburu-Cigliero, S; Turrina, S; Verzeletti, A; Kayser, M

    2015-03-01

    Recently introduced rapidly mutating Y-chromosomal short tandem repeat (RM Y-STR) loci, displaying a multiple-fold higher mutation rate relative to any other Y-STRs, including those conventionally used in forensic casework, have been demonstrated to improve the resolution of male lineage differentiation and to allow male relative separation usually impossible with standard Y-STRs. However, large and geographically-detailed frequency haplotype databases are required to estimate the statistical weight of RM Y-STR haplotype matches if observed in forensic casework. With this in mind, the Italian Working Group (GEFI) of the International Society for Forensic Genetics launched a collaborative exercise aimed at generating an Italian quality controlled forensic RM Y-STR haplotype database. Overall 1509 male individuals from 13 regional populations covering northern, central and southern areas of the Italian peninsula plus Sicily were collected, including both "rural" and "urban" samples classified according to population density in the sampling area. A subset of individuals was additionally genotyped for Y-STR loci included in the Yfiler and PowerPlex Y23 (PPY23) systems (75% and 62%, respectively), allowing the comparison of RM and conventional Y-STRs. Considering the whole set of 13 RM Y-STRs, 1501 unique haplotypes were observed among the 1509 sampled Italian men with a haplotype diversity of 0.999996, largely superior to Yfiler and PPY23 with 0.999914 and 0.999950, respectively. AMOVA indicated that 99.996% of the haplotype variation was within populations, confirming that genetic-geographic structure is almost undetected by RM Y-STRs. Haplotype sharing among regional Italian populations was not observed at all with the complete set of 13 RM Y-STRs. Haplotype sharing within Italian populations was very rare (0.27% non-unique haplotypes), and lower in urban (0.22%) than rural (0.29%) areas. Additionally, 422 father-son pairs were investigated, and 20.1% of them could

  17. Development of an Italian RM Y-STR haplotype database: Results of the 2013 GEFI collaborative exercise.

    PubMed

    Robino, C; Ralf, A; Pasino, S; De Marchi, M R; Ballantyne, K N; Barbaro, A; Bini, C; Carnevali, E; Casarino, L; Di Gaetano, C; Fabbri, M; Ferri, G; Giardina, E; Gonzalez, A; Matullo, G; Nutini, A L; Onofri, V; Piccinini, A; Piglionica, M; Ponzano, E; Previderè, C; Resta, N; Scarnicci, F; Seidita, G; Sorçaburu-Cigliero, S; Turrina, S; Verzeletti, A; Kayser, M

    2015-03-01

    Recently introduced rapidly mutating Y-chromosomal short tandem repeat (RM Y-STR) loci, displaying a multiple-fold higher mutation rate relative to any other Y-STRs, including those conventionally used in forensic casework, have been demonstrated to improve the resolution of male lineage differentiation and to allow male relative separation usually impossible with standard Y-STRs. However, large and geographically-detailed frequency haplotype databases are required to estimate the statistical weight of RM Y-STR haplotype matches if observed in forensic casework. With this in mind, the Italian Working Group (GEFI) of the International Society for Forensic Genetics launched a collaborative exercise aimed at generating an Italian quality controlled forensic RM Y-STR haplotype database. Overall 1509 male individuals from 13 regional populations covering northern, central and southern areas of the Italian peninsula plus Sicily were collected, including both "rural" and "urban" samples classified according to population density in the sampling area. A subset of individuals was additionally genotyped for Y-STR loci included in the Yfiler and PowerPlex Y23 (PPY23) systems (75% and 62%, respectively), allowing the comparison of RM and conventional Y-STRs. Considering the whole set of 13 RM Y-STRs, 1501 unique haplotypes were observed among the 1509 sampled Italian men with a haplotype diversity of 0.999996, largely superior to Yfiler and PPY23 with 0.999914 and 0.999950, respectively. AMOVA indicated that 99.996% of the haplotype variation was within populations, confirming that genetic-geographic structure is almost undetected by RM Y-STRs. Haplotype sharing among regional Italian populations was not observed at all with the complete set of 13 RM Y-STRs. Haplotype sharing within Italian populations was very rare (0.27% non-unique haplotypes), and lower in urban (0.22%) than rural (0.29%) areas. Additionally, 422 father-son pairs were investigated, and 20.1% of them could

  18. [Highly efficient and rapid capillary electrophoretic analysis of seven organic acid additives in beverages using polymeric ionic liquid as additive].

    PubMed

    Han, Haifeng; Wang, Qing; Liu, Xi; Jiang, Shengxiang

    2012-05-01

    A new capillary electrophoretic method for the rapid and direct separation of seven organic acids in beverages was developed, with poly (1-vinyl-3-butylimidazolium bromide) as the reliable background electrolyte modifier to reverse the direction of anode electroosmotic flow (EOF) severely. Several factors that affected the separation efficiency were investigated in detail. The optimal running buffer consisted of 125 mmol/L sodium dihydrogen phosphate (pH 6.5) and 0.01 g/L poly (1-vinyl-3-butylimidazolium bromide). Highly efficient separation (105,000 to 636,000 plates/m) was achieved within 4 min and standard deviations of the migration times (n=3) were lower than 0.0213 min under optimal conditions. The limits of detection (S/N = 3) ranged from 0.001 to 0.05 g/L. The present method was applied to determine a beverage sample (Mirinda) for sodium citrate, benzoic acid and sorbic acid with concentration of 2.64, 0.10 and 0.08 g/L, respectively. The recoveries of the three analytes in the sample were 100.3%, 100.7% and 131.7%, respectively. The method is simple, rapid, inexpensive, and can be applied to determine organic acids as additives in beverages.

  19. Mathematical properties and bounds on haplotyping populations by pure parsimony.

    PubMed

    Wang, I-Lin; Chang, Chia-Yuan

    2011-06-01

    Although the haplotype data can be used to analyze the function of DNA, due to the significant efforts required in collecting the haplotype data, usually the genotype data is collected and then the population haplotype inference (PHI) problem is solved to infer haplotype data from genotype data for a population. This paper investigates the PHI problem based on the pure parsimony criterion (HIPP), which seeks the minimum number of distinct haplotypes to infer a given genotype data. We analyze the mathematical structure and properties for the HIPP problem, propose techniques to reduce the given genotype data into an equivalent one of much smaller size, and analyze the relations of genotype data using a compatible graph. Based on the mathematical properties in the compatible graph, we propose a maximal clique heuristic to obtain an upper bound, and a new polynomial-sized integer linear programming formulation to obtain a lower bound for the HIPP problem.

  20. Association between mitochondrial DNA haplotype compatibility and increased efficiency of bovine intersubspecies cloning.

    PubMed

    Yan, Hao; Yan, Zhonghai; Ma, Qingwen; Jiao, Fei; Huang, Shuzhen; Zeng, Fanyi; Zeng, Yitao

    2011-01-01

    Reconstructed embryos derived from intersubspecies somatic cell nuclear transfer (SCNT) have poorer developmental potential than those from intrasubspecies SCNT. Based on our previous study that Holstein dairy bovine (HD) mitochondrial DNA (mtDNA) haplotype compatibility between donor karyoplast and recipient cytoplast is crucial for SCNT embryo development, we performed intersubspecies SCNT using HD as donor karyoplast and Luxi yellow heifer (LY) as recipient cytoplast according to mtDNA haplotypes determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results demonstrated that intersubspecies mtDNA homotype SCNT embryos had higher pre- and post-implantation developmental competence than intrasubspecies mtDNA heterotype embryos as well as improved blastocyst reprogramming status, including normal H3K9 dimethylation pattern and promoter hypomethylation of pluripotent genes such as Oct4 and Sox2, suggesting that intersubspecies SCNT using LY oocytes maintains HD cloning efficiency and may reprogram HD nuclei to develop into a normal cloned animal ultimately. Our results indicated that karyoplast-cytoplast interactions and mtDNA haplotype compatibility may affect bovine intersubspecies SCNT efficiency. This study on bovine intersubspecies SCNT is valuable for understanding the mechanisms of mtDNA haplotype compatibility between karyoplast and cytoplast impacting the bovine SCNT efficiency, and provides an alternative and economic resource for HD cloning.

  1. Concurrent Whole-Genome Haplotyping and Copy-Number Profiling of Single Cells

    PubMed Central

    Zamani Esteki, Masoud; Dimitriadou, Eftychia; Mateiu, Ligia; Melotte, Cindy; Van der Aa, Niels; Kumar, Parveen; Das, Rakhi; Theunis, Koen; Cheng, Jiqiu; Legius, Eric; Moreau, Yves; Debrock, Sophie; D’Hooghe, Thomas; Verdyck, Pieter; De Rycke, Martine; Sermon, Karen; Vermeesch, Joris R.; Voet, Thierry

    2015-01-01

    Methods for haplotyping and DNA copy-number typing of single cells are paramount for studying genomic heterogeneity and enabling genetic diagnosis. Before analyzing the DNA of a single cell by microarray or next-generation sequencing, a whole-genome amplification (WGA) process is required, but it substantially distorts the frequency and composition of the cell’s alleles. As a consequence, haplotyping methods suffer from error-prone discrete SNP genotypes (AA, AB, BB) and DNA copy-number profiling remains difficult because true DNA copy-number aberrations have to be discriminated from WGA artifacts. Here, we developed a single-cell genome analysis method that reconstructs genome-wide haplotype architectures as well as the copy-number and segregational origin of those haplotypes by employing phased parental genotypes and deciphering WGA-distorted SNP B-allele fractions via a process we coin haplarithmisis. We demonstrate that the method can be applied as a generic method for preimplantation genetic diagnosis on single cells biopsied from human embryos, enabling diagnosis of disease alleles genome wide as well as numerical and structural chromosomal anomalies. Moreover, meiotic segregation errors can be distinguished from mitotic ones. PMID:25983246

  2. Origins of Wohlfahrtia magnifica in Italy based on the identification of mitochondrial cytochrome b gene haplotypes.

    PubMed

    Marangi, Marianna; Hall, Martin J R; Aitken, Alex; Ready, Paul D; Giangaspero, Annunziata

    2016-02-01

    To identify the geographical origins of larvae of Wohlfahrtia magnifica (Diptera: Sarcophagidae) causing myiasis of sheep in Italy, comparative DNA sequence analysis of the mitochondrial cytochrome b gene was performed, based on gene fragments amplified by PCR from genomic DNA isolated from individual specimens. DNA extractions of 19 larvae from Lazio, Molise, Puglia, and Sicilia generated 17 readable sequences homologous to 2 haplotypes, either CB_magn01 or CB_magn02; DNA extracts from 4 adult flies from Calabria (reared from larvae) produced 4 readable sequences belonging to the haplotype CB_magn01. The two haplotypes found represent both the East and West phylogenetic lineages of W. magnifica, which is consistent with the species' arrival from central/southeast Europe (East lineage) and/or from southwest Europe/northwest Africa (West lineage). This is the first report of the sympatric occurrence of the two lineages, which could have resulted from natural or human-assisted dispersal. Polymorphic nuclear loci will have to be characterized in order to explain the origins and lack of mitochondrial haplotype diversity of this pest in Italy, where it poses increasing veterinary problems.

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

    PubMed

    Catanzaro, Daniele; Labbé, Martine; Porretta, Luciano

    2011-01-01

    The Pure Parsimony Haplotyping (PPH) problem is a NP-hard combinatorial optimization problem that consists of finding the minimum number of haplotypes necessary to explain a given set of genotypes. PPH has attracted more and more attention in recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from mapping complex disease genes to inferring population histories, passing through designing drugs, functional genomics and pharmacogenetics. In this article we investigate, for the first time, a recent version of PPH called the Pure Parsimony Haplotype problem under Uncertain Data (PPH-UD). This version mainly arises when the input genotypes are not accurate, i.e., when some single nucleotide polymorphisms are missing or affected by errors. We propose an exact approach to solution of PPH-UD based on an extended version of Catanzaro et al.[1] class representative model for PPH, currently the state-of-the-art integer programming model for PPH. The model is efficient, accurate, compact, polynomial-sized, easy to implement, solvable with any solver for mixed integer programming, and usable in all those cases for which the parsimony criterion is well suited for haplotype estimation. PMID:21464966

  4. Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy.

    PubMed

    Vasconcellos, Vivian; Lacchini, Riccardo; Jacob-Ferreira, Anna L B; Sales, Maria L; Ferreira-Sae, Maria C; Schreiber, Roberto; Nadruz, Wilson; Tanus-Santos, Jose E

    2010-04-01

    Left ventricular hypertrophy (LVH) is a complication that may result from chronic hypertension. While nitric oxide (NO) deficiency has been associated with LVH, inconsistent results have been reported with regards to the association of endothelial NO synthase (eNOS) polymorphisms and LVH in hypertensive patients. This study aims to assess whether eNOS haplotypes are associated with LVH in hypertensive patients. This study included 101 healthy controls and 173 hypertensive patients submitted to echocardiography examination. Genotypes for three eNOS polymorphisms were determined: a single-nucleotide polymorphism in the promoter region (T-786C) and in exon 7 (Glu298Asp), and variable number of tandem repeats in intron 4. We found no significant association between eNOS genotypes and hypertension or with LVH (all p > 0.05). However, while we found two eNOS haplotypes associated with variable risk of hypertension (all p < 0.05), we found no significant associations between eNOS haplotypes and LVH (all p > 0.05), even after adjustment in multiple linear regression analysis. These findings suggest that eNOS haplotypes that have been associated with variable susceptibility to hypertension were not associated with LVH in hypertensive patients. Further studies are necessary to examine whether other genes downstream may interact with eNOS polymorphisms and predispose to LVH in hypertensive patients. PMID:20070154

  5. Inference of population structure using dense haplotype data.

    PubMed

    Lawson, Daniel John; Hellenthal, Garrett; Myers, Simon; Falush, Daniel

    2012-01-01

    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 available from http://www.paintmychromosomes.com/.

  6. Multivariate qualitative analysis of banned additives in food safety using surface enhanced Raman scattering spectroscopy

    NASA Astrophysics Data System (ADS)

    He, Shixuan; Xie, Wanyi; Zhang, Wei; Zhang, Liqun; Wang, Yunxia; Liu, Xiaoling; Liu, Yulong; Du, Chunlei

    2015-02-01

    A novel strategy which combines iteratively cubic spline fitting baseline correction method with discriminant partial least squares qualitative analysis is employed to analyze the surface enhanced Raman scattering (SERS) spectroscopy of banned food additives, such as Sudan I dye and Rhodamine B in food, Malachite green residues in aquaculture fish. Multivariate qualitative analysis methods, using the combination of spectra preprocessing iteratively cubic spline fitting (ICSF) baseline correction with principal component analysis (PCA) and discriminant partial least squares (DPLS) classification respectively, are applied to investigate the effectiveness of SERS spectroscopy for predicting the class assignments of unknown banned food additives. PCA cannot be used to predict the class assignments of unknown samples. However, the DPLS classification can discriminate the class assignment of unknown banned additives using the information of differences in relative intensities. The results demonstrate that SERS spectroscopy combined with ICSF baseline correction method and exploratory analysis methodology DPLS classification can be potentially used for distinguishing the banned food additives in field of food safety.

  7. Multivariate qualitative analysis of banned additives in food safety using surface enhanced Raman scattering spectroscopy.

    PubMed

    He, Shixuan; Xie, Wanyi; Zhang, Wei; Zhang, Liqun; Wang, Yunxia; Liu, Xiaoling; Liu, Yulong; Du, Chunlei

    2015-02-25

    A novel strategy which combines iteratively cubic spline fitting baseline correction method with discriminant partial least squares qualitative analysis is employed to analyze the surface enhanced Raman scattering (SERS) spectroscopy of banned food additives, such as Sudan I dye and Rhodamine B in food, Malachite green residues in aquaculture fish. Multivariate qualitative analysis methods, using the combination of spectra preprocessing iteratively cubic spline fitting (ICSF) baseline correction with principal component analysis (PCA) and discriminant partial least squares (DPLS) classification respectively, are applied to investigate the effectiveness of SERS spectroscopy for predicting the class assignments of unknown banned food additives. PCA cannot be used to predict the class assignments of unknown samples. However, the DPLS classification can discriminate the class assignment of unknown banned additives using the information of differences in relative intensities. The results demonstrate that SERS spectroscopy combined with ICSF baseline correction method and exploratory analysis methodology DPLS classification can be potentially used for distinguishing the banned food additives in field of food safety.

  8. Multivariate qualitative analysis of banned additives in food safety using surface enhanced Raman scattering spectroscopy.

    PubMed

    He, Shixuan; Xie, Wanyi; Zhang, Wei; Zhang, Liqun; Wang, Yunxia; Liu, Xiaoling; Liu, Yulong; Du, Chunlei

    2015-02-25

    A novel strategy which combines iteratively cubic spline fitting baseline correction method with discriminant partial least squares qualitative analysis is employed to analyze the surface enhanced Raman scattering (SERS) spectroscopy of banned food additives, such as Sudan I dye and Rhodamine B in food, Malachite green residues in aquaculture fish. Multivariate qualitative analysis methods, using the combination of spectra preprocessing iteratively cubic spline fitting (ICSF) baseline correction with principal component analysis (PCA) and discriminant partial least squares (DPLS) classification respectively, are applied to investigate the effectiveness of SERS spectroscopy for predicting the class assignments of unknown banned food additives. PCA cannot be used to predict the class assignments of unknown samples. However, the DPLS classification can discriminate the class assignment of unknown banned additives using the information of differences in relative intensities. The results demonstrate that SERS spectroscopy combined with ICSF baseline correction method and exploratory analysis methodology DPLS classification can be potentially used for distinguishing the banned food additives in field of food safety. PMID:25300041

  9. Stimulation of terrestrial ecosystem carbon storage by nitrogen addition: a meta-analysis

    NASA Astrophysics Data System (ADS)

    Yue, Kai; Peng, Yan; Peng, Changhui; Yang, Wanqin; Peng, Xin; Wu, Fuzhong

    2016-01-01

    Elevated nitrogen (N) deposition alters the terrestrial carbon (C) cycle, which is likely to feed back to further climate change. However, how the overall terrestrial ecosystem C pools and fluxes respond to N addition remains unclear. By synthesizing data from multiple terrestrial ecosystems, we quantified the response of C pools and fluxes to experimental N addition using a comprehensive meta-analysis method. Our results showed that N addition significantly stimulated soil total C storage by 5.82% ([2.47%, 9.27%], 95% CI, the same below) and increased the C contents of the above- and below-ground parts of plants by 25.65% [11.07%, 42.12%] and 15.93% [6.80%, 25.85%], respectively. Furthermore, N addition significantly increased aboveground net primary production by 52.38% [40.58%, 65.19%] and litterfall by 14.67% [9.24%, 20.38%] at a global scale. However, the C influx from the plant litter to the soil through litter decomposition and the efflux from the soil due to microbial respiration and soil respiration showed insignificant responses to N addition. Overall, our meta-analysis suggested that N addition will increase soil C storage and plant C in both above- and below-ground parts, indicating that terrestrial ecosystems might act to strengthen as a C sink under increasing N deposition.

  10. Stimulation of terrestrial ecosystem carbon storage by nitrogen addition: a meta-analysis

    PubMed Central

    Yue, Kai; Peng, Yan; Peng, Changhui; Yang, Wanqin; Peng, Xin; Wu, Fuzhong

    2016-01-01

    Elevated nitrogen (N) deposition alters the terrestrial carbon (C) cycle, which is likely to feed back to further climate change. However, how the overall terrestrial ecosystem C pools and fluxes respond to N addition remains unclear. By synthesizing data from multiple terrestrial ecosystems, we quantified the response of C pools and fluxes to experimental N addition using a comprehensive meta-analysis method. Our results showed that N addition significantly stimulated soil total C storage by 5.82% ([2.47%, 9.27%], 95% CI, the same below) and increased the C contents of the above- and below-ground parts of plants by 25.65% [11.07%, 42.12%] and 15.93% [6.80%, 25.85%], respectively. Furthermore, N addition significantly increased aboveground net primary production by 52.38% [40.58%, 65.19%] and litterfall by 14.67% [9.24%, 20.38%] at a global scale. However, the C influx from the plant litter to the soil through litter decomposition and the efflux from the soil due to microbial respiration and soil respiration showed insignificant responses to N addition. Overall, our meta-analysis suggested that N addition will increase soil C storage and plant C in both above- and below-ground parts, indicating that terrestrial ecosystems might act to strengthen as a C sink under increasing N deposition. PMID:26813078

  11. Gender-Dimorphic Impact of PXR Genotype and Haplotype on Hepatotoxicity During Antituberculosis Treatment

    PubMed Central

    Wang, Jann Yuan; Tsai, Ching Hui; Lee, Yungling Leo; Lee, Li Na; Hsu, Chia Lin; Chang, Hsiu Ching; Chen, Jong Ming; Hsu, Cheng An; Yu, Chong Jen; Yang, Pan Chyr

    2015-01-01

    Abstract Women have a higher risk of drug-induced hepatotoxicity during antituberculosis treatment (HATT) than men. We hypothesized that single nucleotide polymorphism (SNP) genotype and derived haplotype of pregnane X receptor (PXR) gene, which could regulate the expression of phase I enzyme cytochrome P450 (CYP) 3A4, had a sex-specific influence on the risk of HATT. Six SNPs of the PXR gene were sequenced. Genotypes and haplotypes of the PXR SNPs, and other potential risk factors for HATT were compared between pulmonary TB patients with and those without HATT. HATT was defined as an increase in serum transaminase level >3 times the upper limit of normal (ULN) with symptoms, or >5 times ULN without symptoms. We performed the study in a derivation and a validation cohort. Among the 355 patients with pulmonary TB in the derivation cohort, 70 (19.7%) developed HATT. Logistic regression analysis revealed the risk of HATT increased in female genotype AA at rs2461823 (OR: 6.87 [2.55–18.52]) and decreased in female genotype AA at rs7643645 (OR: 0.14 [0.02–1.02]) of PXR gene. Haplotype analysis showed that female h001101 (OR: 2.30 [1.22–4.32]) and female h000110 (OR: 2.25 [1.08–4.69]) haplotype were associated with increased HATT risk. The identified predictors were also significantly associated with female HATT risk among the 182 patients in the validation cohort. Two PXR SNP genotypes and 2 haplotypes influenced the risk of HATT only in females. The PXR SNP showed a sex-specific impact that contributed to an increased HATT risk in females.

  12. Gender-Dimorphic Impact of PXR Genotype and Haplotype on Hepatotoxicity During Antituberculosis Treatment

    PubMed Central

    Wang, Jann Yuan; Tsai, Ching Hui; Lee, Yungling Leo; Lee, Li Na; Hsu, Chia Lin; Chang, Hsiu Ching; Chen, Jong Ming; Hsu, Cheng An; Yu, Chong Jen; Yang, Pan Chyr

    2015-01-01

    Abstract Women have a higher risk of drug-induced hepatotoxicity during antituberculosis treatment (HATT) than men. We hypothesized that single nucleotide polymorphism (SNP) genotype and derived haplotype of pregnane X receptor (PXR) gene, which could regulate the expression of phase I enzyme cytochrome P450 (CYP) 3A4, had a sex-specific influence on the risk of HATT. Six SNPs of the PXR gene were sequenced. Genotypes and haplotypes of the PXR SNPs, and other potential risk factors for HATT were compared between pulmonary TB patients with and those without HATT. HATT was defined as an increase in serum transaminase level >3 times the upper limit of normal (ULN) with symptoms, or >5 times ULN without symptoms. We performed the study in a derivation and a validation cohort. Among the 355 patients with pulmonary TB in the derivation cohort, 70 (19.7%) developed HATT. Logistic regression analysis revealed the risk of HATT increased in female genotype AA at rs2461823 (OR: 6.87 [2.55–18.52]) and decreased in female genotype AA at rs7643645 (OR: 0.14 [0.02–1.02]) of PXR gene. Haplotype analysis showed that female h001101 (OR: 2.30 [1.22–4.32]) and female h000110 (OR: 2.25 [1.08–4.69]) haplotype were associated with increased HATT risk. The identified predictors were also significantly associated with female HATT risk among the 182 patients in the validation cohort. Two PXR SNP genotypes and 2 haplotypes influenced the risk of HATT only in females. The PXR SNP showed a sex-specific impact that contributed to an increased HATT risk in females. PMID:26091473

  13. Gender-Dimorphic Impact of PXR Genotype and Haplotype on Hepatotoxicity During Antituberculosis Treatment.

    PubMed

    Wang, Jann Yuan; Tsai, Ching Hui; Lee, Yungling Leo; Lee, Li Na; Hsu, Chia Lin; Chang, Hsiu Ching; Chen, Jong Ming; Hsu, Cheng An; Yu, Chong Jen; Yang, Pan Chyr

    2015-06-01

    Women have a higher risk of drug-induced hepatotoxicity during antituberculosis treatment (HATT) than men. We hypothesized that single nucleotide polymorphism (SNP) genotype and derived haplotype of pregnane X receptor (PXR) gene, which could regulate the expression of phase I enzyme cytochrome P450 (CYP) 3A4, had a sex-specific influence on the risk of HATT. Six SNPs of the PXR gene were sequenced. Genotypes and haplotypes of the PXR SNPs, and other potential risk factors for HATT were compared between pulmonary TB patients with and those without HATT. HATT was defined as an increase in serum transaminase level >3 times the upper limit of normal (ULN) with symptoms, or >5 times ULN without symptoms. We performed the study in a derivation and a validation cohort. Among the 355 patients with pulmonary TB in the derivation cohort, 70 (19.7%) developed HATT. Logistic regression analysis revealed the risk of HATT increased in female genotype AA at rs2461823 (OR: 6.87 [2.55-18.52]) and decreased in female genotype AA at rs7643645 (OR: 0.14 [0.02-1.02]) of PXR gene. Haplotype analysis showed that female h001101 (OR: 2.30 [1.22-4.32]) and female h000110 (OR: 2.25 [1.08-4.69]) haplotype were associated with increased HATT risk. The identified predictors were also significantly associated with female HATT risk among the 182 patients in the validation cohort. Two PXR SNP genotypes and 2 haplotypes influenced the risk of HATT only in females. The PXR SNP showed a sex-specific impact that contributed to an increased HATT risk in females.

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

    SciTech Connect

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

    1991-02-15

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

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

    PubMed Central

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

    1991-01-01

    The probable ancestral haplotype for human apolipoprotein B (apoB) has been identified through immunological analysis of chimpanzee and gorilla serum and sequence analysis of their DNA. Moreover, the frequency of this ancestral apoB haplotype among different human populations provides strong support for the African origin of Homo sapiens sapiens and their subsequent migration from Africa to Europe and to the Pacific. The approach used here for the identification of the ancestral human apoB haplotype is likely to be applicable to many other genes. PMID:1996341

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

    PubMed

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

    1991-02-15

    The probable ancestral haplotype for human apolipoprotein B (apoB) has been identified through immunological analysis of chimpanzee and gorilla serum and sequence analysis of their DNA. Moreover, the frequency of this ancestral apoB haplotype among different human populations provides strong support for the African origin of Homo sapiens sapiens and their subsequent migration from Africa to Europe and to the Pacific. The approach used here for the identification of the ancestral human apoB haplotype is likely to be applicable to many other genes. PMID:1996341

  17. On an Additive Semigraphoid Model for Statistical Networks With Application to Pathway Analysis

    PubMed Central

    Li, Bing; Chun, Hyonho; Zhao, Hongyu

    2014-01-01

    We introduce a nonparametric method for estimating non-gaussian graphical models based on a new statistical relation called additive conditional independence, which is a three-way relation among random vectors that resembles the logical structure of conditional independence. Additive conditional independence allows us to use one-dimensional kernel regardless of the dimension of the graph, which not only avoids the curse of dimensionality but also simplifies computation. It also gives rise to a parallel structure to the gaussian graphical model that replaces the precision matrix by an additive precision operator. The estimators derived from additive conditional independence cover the recently introduced nonparanormal graphical model as a special case, but outperform it when the gaussian copula assumption is violated. We compare the new method with existing ones by simulations and in genetic pathway analysis. PMID:26401064

  18. Analysis of occupational accidents: prevention through the use of additional technical safety measures for machinery

    PubMed Central

    Dźwiarek, Marek; Latała, Agata

    2016-01-01

    This article presents an analysis of results of 1035 serious and 341 minor accidents recorded by Poland's National Labour Inspectorate (PIP) in 2005–2011, in view of their prevention by means of additional safety measures applied by machinery users. Since the analysis aimed at formulating principles for the application of technical safety measures, the analysed accidents should bear additional attributes: the type of machine operation, technical safety measures and the type of events causing injuries. The analysis proved that the executed tasks and injury-causing events were closely connected and there was a relation between casualty events and technical safety measures. In the case of tasks consisting of manual feeding and collecting materials, the injuries usually occur because of the rotating motion of tools or crushing due to a closing motion. Numerous accidents also happened in the course of supporting actions, like removing pollutants, correcting material position, cleaning, etc. PMID:26652689

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

    PubMed Central

    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

  20. Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis.

    PubMed

    Yau, Anthony C Y; Tuncel, Jonatan; Haag, Sabrina; Norin, Ulrika; Houtman, Miranda; Padyukov, Leonid; Holmdahl, Rikard

    2016-06-28

    Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis. PMID:27303036

  1. Rapid growth of a Eurasian haplotype of Phragmites australis in a restored brackish marsh in Louisiana, USA

    USGS Publications Warehouse

    Howard, R.J.; Travis, S.E.; Sikes, B.A.

    2008-01-01

    While numerous studies have documented patterns of invasion by non-indigenous plant species, few have considered the invasive properties of non-native genotypes of native species. Characteristics associated with specific genotypes, such as tolerance to disturbance, may mistakenly be applied to an entire species in the absence of genetic information, which consequently may affect management decisions. We report here on the incidence and growth of an introduced lineage of Phragmites australis in the Gulf of Mexico coastal zone of Louisiana. P. australis was collected from nine separate locations for inclusion in a series of growth experiments. Chloroplast DNA analysis indicated that specimens collected from four locations in the Mississippi River Delta represented the introduced Eurasian haplotype; the remainder represented the gulf coast haplotype. Three distinct genotypes, or clones, were identified within each haplotype via analysis using amplified fragment length polymorphisms, which also revealed reduced genetic diversity of the gulf coast clones compared to the Eurasian clones. Clones of each haplotype were planted along with three other native macrophytes at similar densities in a restored brackish marsh and monitored for growth. After 14 months, the Eurasian haplotype had spread vegetatively to cover about 82% of the experimental plots, more than four times the coverage (18%) of the gulf coast haplotype. Thus, the use of P. australis plantings for wetland restoration should consider the genetic lineage of plants used since our results indicate the potential of the Eurasian haplotype to grow rapidly at newly restored sites. This rapid growth may limit the establishment of more slowly growing native species. ?? 2007 Springer Science+Business Media B.V.

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

    PubMed

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

    2004-10-01

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

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

    PubMed Central

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

    2004-01-01

    Introduction Oestrogen receptor α, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor α gene (ESR1) are associated with breast cancer risk. Methods We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TAn, 1514 cases and 1514 controls; c.454-397C → T, 1557 cases and 1512 controls; c.454-351A → G, 1556 cases and 1512 controls; c.729C → T, 1562 cases and 1513 controls; c.975C → G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. Results There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A → G or c.454-397C → T and c.975C → G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A → G and c.975C → G haplotype entailed an OR of 1.19 (95% CI 1.06–1.33) and two copies with an OR of 1.42 (95% CI 1.15–1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C → T and c.975C → G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. Conclusion We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women. PMID:15217512

  4. A specific haplotype at the INS/TH loci confers high susceptibility to IDDM

    SciTech Connect

    Doria, A.; Lee, J.; Warram, J.H.; Krolewski, A.S.

    1994-09-01

    Polymorphism at the insulin locus (INS) have consistently been found to be associated with insulin-dependent diabetes mellitus (IDDM). We investigated whether a combined analysis of the INS locus with the 5{prime} flanking tyrosine hydroxylase (TH) locus increases the specificity of this association. A group of 308 Caucasians (201 IDDM CASES and 107 non-diabetic CONTROLS) were genotyped for the two-allele markers, INS/1127PstI and TH/Rsal, by PCR-DGGE. INS/1127PstI allele 2 was more common in CASES than CONTROLS (0.84 vs. 0.68, p<0.0001). The relative risk of IDDM for homozygotes for this allele (2/2) was 3.3 in comparison with the other genotypes (95% CI 2.0-5.3). Similarly, homozygotes for allele 2 of TH/RsaI, which is in moderate linkage disequilibrium with INS/1127PstI ({Delta} = 0.45), had a relative risk of IDDM of 2.5 (1.6-4.2). By haplotyping individuals for the two markers, INS/1127PstI 2/2 genotypes were subdivided on the basis of their INS-TH haplotypes. The excess of INS/1127PstI 2/2 homozygotes in IDDM cases was mainly contributed by homozygotes for the INS-TH haplotype 22. Thus, among hapotypes carrying INS/1127 PstI allele 2, the INS-TH 22 haplotype is a more specific marker of IDDM risk than the INS-TH 21 haplotype. The association of the INS-TH 22/22 genotype with IDDM was independent of HLA, being similar among carriers and non-carriers of IDDM-predisposing DQ{beta} alleles 0302 and 0201-DR3.

  5. Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

    PubMed Central

    Raum, D; Awdeh, Z; Yunis, E J; Alper, C A; Gabbay, K H

    1984-01-01

    We have studied major histocompatibility complex markers in Caucasian patients with type I diabetes mellitus and their families. The frequencies of extended haplotypes that were composed of specific HLA-B, HLA-DR, BF, C2, C4A, and C4B allelic combinations, which occurred more commonly than expected, were compared on random diabetic and normal chromosomes in the study families. We demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes: [HLA B8, DR3, SC01, GLO2]; [HLA-B18, DR3, F1C30]; [HLA-B15, DR4, SC33]; and [HLA-BW38, DR4, SC21]. In fact, HLA-DR3 on nonextended haplotypes was "protective", with a relative risk considerably less than 1.0. There was a paucity or absence among diabetic patients of several extended haplotypes of normal chromosomes, notably [HLA-B7, DR2, SC31] and [HLA-BW44, DR4, SC30]. The extended haplotype [HLA-BW38, DR4, SC21] is found only in Ashkenazi Jewish patients, which suggests that extended haplotypes mark specific mutations that arise in defined ethnic groups. The data show that no known MHC allele, including HLA-DR3 and possibly HLA-DR4, is per se a marker for or itself a susceptibility gene for type I diabetes. Rather, extended haplotypes, with relatively fixed alleles, are either carriers or noncarriers of susceptibility genes for this disease. Thus, the increased frequency (association) or the decreased frequency (protection) of individual MHC alleles is largely explainable by these extended haplotypes. PMID:6746903

  6. Analysis of zinc in biological samples by flame atomic absorption spectrometry: use of addition calibration technique.

    PubMed

    Dutra, Rosilene L; Cantos, Geny A; Carasek, Eduardo

    2006-01-01

    The quantification of target analytes in complex matrices requires special calibration approaches to compensate for additional capacity or activity in the matrix samples. The standard addition is one of the most important calibration procedures for quantification of analytes in such matrices. However, this technique requires a great number of reagents and material, and it consumes a considerable amount of time throughout the analysis. In this work, a new calibration procedure to analyze biological samples is proposed. The proposed calibration, called the addition calibration technique, was used for the determination of zinc (Zn) in blood serum and erythrocyte samples. The results obtained were compared with those obtained using conventional calibration techniques (standard addition and standard calibration). The proposed addition calibration was validated by recovery tests using blood samples spiked with Zn. The range of recovery for blood serum and erythrocyte samples were 90-132% and 76-112%, respectively. Statistical studies among results obtained by the addition technique and conventional techniques, using a paired two-tailed Student's t-test and linear regression, demonstrated good agreement among them. PMID:16943611

  7. Simultaneous inference of haplotypes and alleles at a causal gene.

    PubMed

    Larribe, Fabrice; Dupont, Mathieu J; Boucher, Gabrielle

    2015-01-01

    We present a methodology which jointly infers haplotypes and the causal alleles at a gene influencing a given trait. Often in human genetic studies, the available data consists of genotypes (series of genetic markers along the chromosomes) and a phenotype. However, for many genetic analyses, one needs haplotypes instead of genotypes. Our methodology is not only able to estimate haplotypes conditionally on the disease status, but is also able to infer the alleles at the unknown disease locus. Some applications of our methodology are in genetic mapping and in genetic counseling.

  8. Short Reads Phasing to Construct Haplotypes in Genomic Regions That Are Associated with Body Mass Index in Korean Individuals

    PubMed Central

    Lee, Kichan; Han, Seonggyun; Tark, Yeonjeong

    2014-01-01

    Genome-wide association (GWA) studies have found many important genetic variants that affect various traits. Since these studies are useful to investigate untyped but causal variants using linkage disequilibrium (LD), it would be useful to explore the haplotypes of single-nucleotide polymorphisms (SNPs) within the same LD block of significant associations based on high-density variants from population references. Here, we tried to make a haplotype catalog affecting body mass index (BMI) through an integrative analysis of previously published whole-genome next-generation sequencing (NGS) data of 7 representative Korean individuals and previously known Korean GWA signals. We selected 435 SNPs that were significantly associated with BMI from the GWA analysis and searched 53 LD ranges nearby those SNPs. With the NGS data, the haplotypes were phased within the LDs. A total of 44 possible haplotype blocks for Korean BMI were cataloged. Although the current result constitutes little data, this study provides new insights that may help to identify important haplotypes for traits and low variants nearby significant SNPs. Furthermore, we can build a more comprehensive catalog as a larger dataset becomes available. PMID:25705154

  9. Annexin A5 Promoter Haplotype M2 Is Not a Risk Factor for Recurrent Pregnancy Loss in Northern Europe

    PubMed Central

    Rull, Kristiina; Christiansen, Ole B.; Nielsen, Henriette S.; Laan, Maris

    2015-01-01

    Introduction Annexin A5 is an essential component of placental integrity that may potentially mediate susceptibility to phenotypes of compromised pregnancy. A promoter haplotype termed M2 of the coding gene ANXA5 has been implicated in various pregnancy complications such as preeclampsia and recurrent pregnancy loss (RPL), however with inconclusive results. Study subjects and methods A retrospective case-control study combining resequencing and restriction fragment length polymorphism (RFLP) analysis was undertaken in 313 women with unexplained RPL and 214 fertile women from Estonia and Denmark to estimate the RPL disease risk of the M2 haplotype in Northern Europe. Comparative prevalence of the studied ANXA5 genetic variants in human populations was estimated based on the 1000 Genomes Project (n = 675, whole-genome sequencing data) and the KORA S3 500K dataset of South German samples (n = 1644, genome-wide genotyping data). Results Minor allele frequency of common polymorphisms in ANXA5 promoter was up to two-fold lower among Estonian RPL subjects than fertile controls. The M2 haplotype was not associated with RPL and a trend for decreased prevalence was observed among RPL patients compared to controls both in Estonia (8.1% vs 15.2%, respectively) and Denmark (9.7% vs 12.6%). The high M2 prevalence in fertile controls was consistent with estimations for European and East Asian populations (9.6%-16.0%). Conclusions This study cautions to consider the M2 haplotype as a deterministic factor in early pregnancy success because: i) no RPL disease risk was associated with the haplotype in two clinically well-characterized RPL case-control study samples, ii) high prevalence of the haplotype among fertile controls and world-wide populations is inconsistent with the previously proposed severe impact on early pregnancy success, iii) weak impact of M2 haplotype on the production of ANXA5 protein has been established by others. PMID:26135579

  10. Haplotype Block Partition with Limited Resources and Applications to Human Chromosome 21 Haplotype Data

    PubMed Central

    Zhang, Kui; Sun, Fengzhu; Waterman, Michael S.; Chen, Ting

    2003-01-01

    Recent studies have shown that the human genome has a haplotype block structure such that it can be decomposed into large blocks with high linkage disequilibrium (LD) and relatively limited haplotype diversity, separated by short regions of low LD. One of the practical implications of this observation is that only a small fraction of all the single-nucleotide polymorphisms (SNPs) (referred as “tag SNPs”) can be chosen for mapping genes responsible for human complex diseases, which can significantly reduce genotyping effort, without much loss of power. Algorithms have been developed to partition haplotypes into blocks with the minimum number of tag SNPs for an entire chromosome. In practice, investigators may have limited resources, and only a certain number of SNPs can be genotyped. In the present article, we first formulate this problem as finding a block partition with a fixed number of tag SNPs that can cover the maximal percentage of the whole genome, and we then develop two dynamic programming algorithms to solve this problem. The algorithms are sufficiently flexible to permit knowledge of functional polymorphisms to be considered. We apply the algorithms to a data set of SNPs on human chromosome 21, combining the information of coding and noncoding regions. We study the density of SNPs in intergenic regions, introns, and exons, and we find that the SNP density in intergenic regions is similar to that in introns and is higher than that in exons, results that are consistent with previous studies. We also calculate the distribution of block break points in intergenic regions, genes, exons, and coding regions and do not find any significant differences. PMID:12802783

  11. Y-chromosome STR haplotypes in males from Greenland.

    PubMed

    Hallenberg, Charlotte; Tomas, Carmen; Simonsen, Bo; Morling, Niels

    2009-09-01

    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. The number of haplotypes seen once was 108 and the most common haplotype was observed in 12 males. A significant F(ST) value was observed (F(ST)=0.012, P<0.00001) when comparing the population of 15 locations in Greenland assigned to 7 groups. The significance could mainly be attributed to the subpopulation of males from Tasiilaq (East of Greenland). The R(ST) value was not statistically significant (R(ST)=0.016, P=0.15). PMID:19647703

  12. Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations.

    PubMed

    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.

  13. Contribution of HLA-A/B/C/DRB1/DQB1 common haplotypes to donor search outcome in unrelated hematopoietic stem cell transplantation.

    PubMed

    Pédron, Béatrice; Guérin-El Khourouj, Valérie; Dalle, Jean-Hugues; Ouachée-Chardin, Marie; Yakouben, Karima; Corroyez, France; Auvrignon, Anne; Petit, Arnaud; Landman-Parker, Judith; Leverger, Guy; Baruchel, André; Sterkers, Ghislaine

    2011-11-01

    In unrelated hematopoietic stem cell transplantation (HSCT), the prediction of donor search outcome at the time of search initiation is of great value for the physicians to delineate the strategy of patient care. The probability of finding an unrelated donor is high for patients who carry at least 1 of the 10 most common HLA haplotypes in Caucasians. As only 10% to 20% patients respond to this criterion, here we aimed at finding additional common haplotypes to improve the prediction of a successful search. HLA broad HLA-A/B/DRB1 haplotypes that were observed with frequencies ≥0.19% in patient families of European origin and that split into ≤2 predominant 4-digit HLA-A/B/C/DRB1/DQB1 haplotypes were considered as common. Carriage of at least 1 of those in 168 patients of various geographic areas with no family donor was confronted to the chance of finding ≥9/10 HLA-matched unrelated donors. Fifty common 4-digit haplotypes were identified. A higher (P < 5 × 10(-6)) chance of finding a suitable donor was found for 55 of 170 (32%) recipients that carried at least 1 of these common haplotypes. Up to now, estimates classified patients into ≥3 groups of probability with ≥1 intermediate group of poor utility for the clinicians. Considering carriage of these common haplotypes together with the frequencies of alleles and of B/C and DRB1/DQB1 associations, which are carried by patient HLA haplotypes, we could classify the patients into 2 groups of probability with a 98% and 26% chance of finding a donor, respectively. Prediction of search outcome could be improved by including the 50 most common HLA haplotypes in the current approaches.

  14. ANALYSIS OF DISTRIBUTION FEEDER LOSSES DUE TO ADDITION OF DISTRIBUTED PHOTOVOLTAIC GENERATORS

    SciTech Connect

    Tuffner, Francis K.; Singh, Ruchi

    2011-08-09

    Distributed generators (DG) are small scale power supplying sources owned by customers or utilities and scattered throughout the power system distribution network. Distributed generation can be both renewable and non-renewable. Addition of distributed generation is primarily to increase feeder capacity and to provide peak load reduction. However, this addition comes with several impacts on the distribution feeder. Several studies have shown that addition of DG leads to reduction of feeder loss. However, most of these studies have considered lumped load and distributed load models to analyze the effects on system losses, where the dynamic variation of load due to seasonal changes is ignored. It is very important for utilities to minimize the losses under all scenarios to decrease revenue losses, promote efficient asset utilization, and therefore, increase feeder capacity. This paper will investigate an IEEE 13-node feeder populated with photovoltaic generators on detailed residential houses with water heater, Heating Ventilation and Air conditioning (HVAC) units, lights, and other plug and convenience loads. An analysis of losses for different power system components, such as transformers, underground and overhead lines, and triplex lines, will be performed. The analysis will utilize different seasons and different solar penetration levels (15%, 30%).

  15. Analysis of redox additive-based overcharge protection for rechargeable lithium batteries

    NASA Technical Reports Server (NTRS)

    Narayanan, S. R.; Surampudi, S.; Attia, A. I.; Bankston, C. P.

    1991-01-01

    The overcharge condition in secondary lithium batteries employing redox additives for overcharge protection, has been theoretically analyzed in terms of a finite linear diffusion model. The analysis leads to expressions relating the steady-state overcharge current density and cell voltage to the concentration, diffusion coefficient, standard reduction potential of the redox couple, and interelectrode distance. The model permits the estimation of the maximum permissible overcharge rate for any chosen set of system conditions. Digital simulation of the overcharge experiment leads to numerical representation of the potential transients, and estimate of the influence of diffusion coefficient and interelectrode distance on the transient attainment of the steady state during overcharge. The model has been experimentally verified using 1,1-prime-dimethyl ferrocene as a redox additive. The analysis of the experimental results in terms of the theory allows the calculation of the diffusion coefficient and the formal potential of the redox couple. The model and the theoretical results may be exploited in the design and optimization of overcharge protection by the redox additive approach.

  16. Association of a Bovine Prion Gene Haplotype with Atypical BSE

    PubMed Central

    Clawson, Michael L.; Richt, Juergen A.; Baron, Thierry; Biacabe, Anne-Gaëlle; Czub, Stefanie; Heaton, Michael P.; Smith, Timothy P. L.; Laegreid, William W.

    2008-01-01

    Background Atypical bovine spongiform encephalopathies (BSEs) are recently recognized prion diseases of cattle. Atypical BSEs are rare; approximately 30 cases have been identified worldwide. We tested prion gene (PRNP) haplotypes for an association with atypical BSE. Methodology/Principle Findings Haplotype tagging polymorphisms that characterize PRNP haplotypes from the promoter region through the three prime untranslated region of exon 3 (25.2 kb) were used to determine PRNP haplotypes of six available atypical BSE cases from Canada, France and the United States. One or two copies of a distinct PRNP haplotype were identified in five of the six cases (p = 1.3×10−4, two-tailed Fisher's exact test; CI95% 0.263–0.901, difference between proportions). The haplotype spans a portion of PRNP that includes part of intron 2, the entire coding region of exon 3 and part of the three prime untranslated region of exon 3 (13 kb). Conclusions/Significance This result suggests that a genetic determinant in or near PRNP may influence susceptibility of cattle to atypical BSE. PMID:18350166

  17. MHC Class II haplotypes of Colombian Amerindian tribes.

    PubMed

    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.

  18. MHC Class II haplotypes of Colombian Amerindian tribes

    PubMed Central

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

    2013-01-01

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

  19. "HOOF-Print" Genotyping and Haplotype Inference Discriminates among Brucella spp Isolates From a Small Spatial Scale

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We demonstrate that the “HOOF-Print” assay provides high power to discriminate among Brucella isolates collected on a small spatial scale (within Portugal). Additionally, we illustrate how haplotype identification using non-random association among markers allows resolution of B. melitensis biovars ...

  20. Measurement of haplotypic variation in Xanthomonas oryzae pv. oryzae within a single field by rep-PCR and RFLP analyses

    SciTech Connect

    Vera Cruz, C.M.; Leach, J.E.; Ardales, E.Y.; Talag, J.

    1996-12-01

    The haplotypic variation of Xanthomonas oryzae pv. oryzae in a farmer;s field that had endemic bacterial blight in the Philippines was evaluated at a single time. The genomic structure of the field population was analyzed by repetitive sequence-based polymerase chain reaction with oligonucleotide primers corresponding to interspersed repeated sequences in prokaryotic genomes and restriction fragment length polymorphism (RFLP) with the insertion sequence IS1113. The techniques and specific probes and primers were selected because they grouped consistently into the same lineages a set of 30 selected X. oryzae pv. oryzae strains that represented the four distinct RFLP lineages found in the Philippines did. Strains (155) were systematically collected from a field planted to rice cv. Sinandomeng, which is susceptible to the indigenous pathogen population. Two of the four Philippine lineages, B and C, which included race 2 and races 3 and 9, respectively, were detected in the field. Lineage C was the predominant population (74.8%). The haplotypic diversities of 10 of the 25 blocks were significantly greater than the total haplotypic diversity of the collection in the entire field; however, between individual blocks the haplotypic diversities were not significantly different. Haplo-types from both lineages were distributed randomly across the field. Analysis of genetic diversity at the microgeographic scale provided insights into the finer scale of variation of X. oryzae pv. oryzae, which are useful in designing experiments to study effects of host resistance on the population structure of the bacterial blight pathogen. 46 refs., 4 figs., 2 tabs.

  1. Analysis of the benefits of carbon credits to hydrogen addition to midsize gas turbine feedstocks.

    SciTech Connect

    Miller, J.; Towns, B.; Keller, Jay O.; Schefer, Robert W.; Skolnik, Edward G.

    2006-02-01

    The addition of hydrogen to the natural gas feedstocks of midsize (30-150 MW) gas turbines was analyzed as a method of reducing nitrogen oxides (NO{sub x}) and CO{sub 2} emissions. In particular, the costs of hydrogen addition were evaluated against the combined costs for other current NO{sub x} and CO{sub 2} emissions control technologies for both existing and new systems to determine its benefits and market feasibility. Markets for NO{sub x} emissions credits currently exist in California and the Northeast States and are expected to grow. Although regulations are not currently in place in the United States, several other countries have implemented carbon tax and carbon credit programs. The analysis thus assumes that the United States adopts future legislation similar to these programs. Therefore, potential sale of emissions credits for volunteer retrofits was also included in the study. It was found that hydrogen addition is a competitive alternative to traditional emissions abatement techniques under certain conditions. The existence of carbon credits shifts the system economics in favor of hydrogen addition.

  2. HLA-G UTR haplotype conservation in the Malian population: association with soluble HLA-G.

    PubMed

    Carlini, Federico; Traore, Karim; Cherouat, Nissem; Roubertoux, Pierre; Buhler, Stéphane; Cortey, Martì; Simon, Sophie; Doumbo, Ogobara; Chiaroni, Jacques; Picard, Christophe; Di Cristofaro, Julie

    2013-01-01

    The HLA-G molecule plays an important role in immunomodulation. In a previous study carried out on a southern French population our team showed that HLA-G haplotypes, defined by SNPs in the coding region and specific SNPs located in 5'URR and 3'UTR regulatory regions, are associated with differential soluble HLA-G expression (sHLA-G). Furthermore, the structure of these HLA-G haplotypes appears to be conserved in geographically distant populations. The aim of our study is to confirm these expectations in a sub-Saharan African population and to explore additional factors, such as HLA-A alleles, that might influence sHLA-G expression. DNA and plasma samples were collected from 229 Malians; HLA-G and HLA-A genotyping were respectively performed by the Snap Shot® method and by Luminex™ technology. sHLA-G dosage was performed using an ELISA kit. HLA-G and HLA-A allelic and haplotypic frequencies were estimated using an EM algorithm from the Gene[Rate] program. Associations between genetic and non genetic parameters with sHLA-G were performed using a non-parametric test with GRAPH PAD Prism 5. Our results reveal a good conservation of the HLA-G UTR haplotype structure in populations with different origins and demographic histories. These UTR haplotypes appear to be involved in different sHLA-G expression patterns. Specifically, the UTR-2 haplotype was associated with low sHLA-G levels, displaying a dominant negative effect. Furthermore, an allelic effect of both HLA-G and HLA-A, as well as non genetic parameters, such as age and gender possibly linked to osteogenesis and sexual hormones, also seem to be involved in the modulation of sHLA-G. These data suggest that further investigation in larger cohorts and in populations from various ethnical backgrounds is necessary not only to detect new functional polymorphism in HLA-G regulatory regions, but also to reveal the extent of biological phenomena that influence sHLA-G secretion and this might therefore have an impact

  3. Addition of three-dimensional isoparametric elements to NASA structural analysis program (NASTRAN)

    NASA Technical Reports Server (NTRS)

    Field, E. I.; Johnson, S. E.

    1973-01-01

    Implementation is made of the three-dimensional family of linear, quadratic and cubic isoparametric solid elements into the NASA Structural Analysis program, NASTRAN. This work included program development, installation, testing, and documentation. The addition of these elements to NASTRAN provides a significant increase in modeling capability particularly for structures requiring specification of temperatures, material properties, displacements, and stresses which vary throughout each individual element. Complete program documentation is presented in the form of new sections and updates for direct insertion to the three NASTRAN manuals. The results of demonstration test problems are summarized. Excellent results are obtained with the isoparametric elements for static, normal mode, and buckling analyses.

  4. A near-infrared spectroscopic study of young field ultracool dwarfs: additional analysis

    NASA Astrophysics Data System (ADS)

    Allers, K. N.; Liu, M. C.

    We present additional analysis of the classification system presented in \\citet{allers13}. We refer the reader to \\citet{allers13} for a detailed discussion of our near-IR spectral type and gravity classification system. Here, we address questions and comments from participants of the Brown Dwarfs Come of Age meeting. In particular, we examine the effects of binarity and metallicity on our classification system. We also present our classification of Pleiades brown dwarfs using published spectra. Lastly, we determine SpTs and calculate gravity-sensitive indices for the BT-Settl atmospheric models and compare them to observations.

  5. Excap: maximization of haplotypic diversity of linked markers.

    PubMed

    Kahles, André; Sarqume, Fahad; Savolainen, Peter; Arvestad, Lars

    2013-01-01

    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.

  6. Beyond clines: lineages and haplotype blocks in hybrid zones.

    PubMed

    Sedghifar, Alisa; Brandvain, Yaniv; Ralph, Peter

    2016-06-01

    Hybrid zones formed between recently diverged populations offer an opportunity to study the mechanisms underlying reproductive isolation and the process of speciation. Here, we use a combination of analytical theory and explicit forward simulations to describe how selection against hybrid genotypes impacts patterns of introgression across genomic and geographic space. By describing how lineages move across the hybrid zone, in a model without coalescence, we add to modern understanding of how clines form and how parental haplotypes are broken up during introgression. Working with lineages makes it easy to see that clines form in about 1/s generations, where s is the strength of selection against hybrids, and linked clines persist over a genomic scale of 1/T, where T is the age, in generations, of the hybrid zone. Locally disadvantageous alleles tend to exist as small families, whose lineages trace back to the side from which they originated at speed s dispersal distances per generation. The lengths of continuous tracts of ancestry provide an additional source of information: blocks of ancestry surrounding incompatibilities can be substantially longer than the genomewide average block length at the same spatial location, an observation that might be used to identify candidate targets of selection. PMID:27148805

  7. Re-analysis of survival data of cancer patients utilizing additive homeopathy.

    PubMed

    Gleiss, Andreas; Frass, Michael; Gaertner, Katharina

    2016-08-01

    In this short communication we present a re-analysis of homeopathic patient data in comparison to control patient data from the same Outpatient´s Unit "Homeopathy in malignant diseases" of the Medical University of Vienna. In this analysis we took account of a probable immortal time bias. For patients suffering from advanced stages of cancer and surviving the first 6 or 12 months after diagnosis, respectively, the results show that utilizing homeopathy gives a statistically significant (p<0.001) advantage over control patients regarding survival time. In conclusion, bearing in mind all limitations, the results of this retrospective study suggest that patients with advanced stages of cancer might benefit from additional homeopathic treatment until a survival time of up to 12 months after diagnosis. PMID:27515878

  8. A multiple additive regression tree analysis of three exposure measures during Hurricane Katrina.

    PubMed

    Curtis, Andrew; Li, Bin; Marx, Brian D; Mills, Jacqueline W; Pine, John

    2011-01-01

    This paper analyses structural and personal exposure to Hurricane Katrina. Structural exposure is measured by flood height and building damage; personal exposure is measured by the locations of 911 calls made during the response. Using these variables, this paper characterises the geography of exposure and also demonstrates the utility of a robust analytical approach in understanding health-related challenges to disadvantaged populations during recovery. Analysis is conducted using a contemporary statistical approach, a multiple additive regression tree (MART), which displays considerable improvement over traditional regression analysis. By using MART, the percentage of improvement in R-squares over standard multiple linear regression ranges from about 62 to more than 100 per cent. The most revealing finding is the modelled verification that African Americans experienced disproportionate exposure in both structural and personal contexts. Given the impact of exposure to health outcomes, this finding has implications for understanding the long-term health challenges facing this population.

  9. Towards internationally acceptable standards for food additives and contaminants based on the use of risk analysis.

    PubMed

    Huggett, A; Petersen, B J; Walker, R; Fisher, C E; Notermans, S H; Rombouts, F M; Abbott, P; Debackere, M; Hathaway, S C; Hecker, E F; Knaap, A G; Kuznesof, P M; Meyland, I; Moy, G; Narbonne, J F; Paakkanen, J; Smith, M R; Tennant, D; Wagstaffe, P; Wargo, J; Würtzen, G

    1998-06-01

    Internationally acceptable norms need to incorporate sound science and consistent risk management principles in an open and transparent manner, as set out in the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). The process of risk analysis provides a procedure to reach these goals. The interaction between risk assessors and risk managers is considered vital to this procedure. This paper reports the outcome of a meeting of risk assessors and risk managers on specific aspects of risk analysis and its application to international standard setting for food additives and contaminants. Case studies on aflatoxins and aspartame were used to identify the key steps of the interaction process which ensure scientific justification for risk management decisions. A series of recommendations were proposed in order to enhance the scientific transparency in these critical phases of the standard setting procedure.

  10. Using haplotypes to monitor the migration of fall armyworm (Lepidoptera: Noctuidae) corn-strain populations from Texas and Florida.

    PubMed

    Nagoshi, Rodney N; Meagher, Robert L; Flanders, Kathy; Gore, Jeffrey; Jackson, Ryan; Lopez, Juan; Armstrong, John S; Buntin, G David; Sansone, Chris; Leonard, B Rogers

    2008-06-01

    Fall armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae), infestations in most of North America north of Mexico arise from annual migrations of populations that overwinter in southern Texas and Florida. A comparison of the cytochrome oxidase I haplotype profiles within the fall armyworm corn-strain, the subgroup that preferentially infests corn (Zea mays L.) and sorghum (Sorghum vulgare Pers.), identified significant differences in the proportions of certain haplotypes between the Texas and Florida populations. These proportional differences were preserved as the populations migrated, providing a molecular metric by which the source of a migrant population could be identified. The migratory pattern derived from this method for several southeastern states was shown to be consistent with predictions based on analysis of historical agricultural and fall armyworm infestation data. These results demonstrate the utility of haplotype proportions to monitor fall armyworm migration, and they also introduce a potential method to predict the severity of cotton crop infestations in the short term.

  11. On the relationship between an Asian haplotype on chromosome 6 that reduces androstenone levels in boars and the differential expression of SULT2A1 in the testis

    PubMed Central

    2014-01-01

    Background Androstenone is one of the major compounds responsible for boar taint, a pronounced urine-like odor produced when cooking boar meat. Several studies have identified quantitative trait loci (QTL) for androstenone level on Sus scrofa chromosome (SSC) 6. For one of the candidate genes in the region SULT2A1, a difference in expression levels in the testis has been shown at the protein and RNA level. Results Haplotypes were predicted for the QTL region and their effects were estimated showing that haplotype 1 was consistently related with a lower level, and haplotype 2 with a higher level of androstenone. A recombinant haplotype allowed us to narrow down the QTL region from 3.75 Mbp to 1.94 Mbp. An RNA-seq analysis of the liver and testis revealed six genes that were differentially expressed between homozygotes of haplotypes 1 and 2. Genomic sequences of these differentially expressed genes were checked for variations within potential regulatory regions. We identified one variant located within a CpG island that could affect expression of SULT2A1 gene. An allele-specific expression analysis in the testis did not show differential expression between the alleles of SULT2A1 located on the different haplotypes in heterozygous animals. However a synonymous mutation C166T (SSC6: 49,117,861 bp in Sscrofa 10.2; C/T) was identified within the exon 2 of SULT2A1 for which the haplotype 2 only had the C allele which was higher expressed than the T allele, indicating haplotype-independent allelic-imbalanced expression between the two alleles. A phylogenetic analysis for the 1.94 Mbp region revealed that haplotype 1, associated with low androstenone level, originated from Asia. Conclusions Differential expression could be observed for six genes by RNA-seq analysis. No difference in the ratio of C:T expression of SULT2A1 for the haplotypes was found by the allele-specific expression analysis, however, a difference in expression between the C over T allele was found for a

  12. Allelic and haplotype variation of major histocompatibility complex class II DRB1 and DQB loci in the St Lawrence beluga (Delphinapterus leucas).

    PubMed

    1999-07-01

    In order to assess levels of major histocompatibility complex (Mhc) variation within the St Lawrence beluga (Delphinapterus leucas) the variation at the beluga Mhc DRB1 class II locus was assessed by single-strand conformation polymorphism (SSCP) analysis of the peptide-binding region for 313 whales collected from 13 sampling locations across North America. In addition, samples from west Greenland and the St Lawrence were also typed at the DQB locus, allowing comparison to a previous study and assessment of linkage disequilibrium of alleles at the two loci. Comparisons of DRB1 and DQB allele frequencies among all sampling locations indicated genetic structure (alpha < 0.005). Most of this structure resulted from differences between the different wintering groups. Significant genetic structure (alpha = 0.05) exists among each pair of the following groups at both the DRB1 and DQB loci; St Lawrence, Hudson Strait, Bering Sea, Cunningham Inlet, and Davis Strait (minus Cunningham Inlet), except the St Lawrence and Hudson Strait for the DQB locus. In the St Lawrence population, six of the eight DRB1 alleles are present representing all five known allelic lineages. Evidence of linkage disequilibrium between the DRB1 and DQB is present in two sampling locations, the St Lawrence and Nuussuaq (alpha = 0.05). Analysis of probable DRB1-DQB haplotypes among groups of beluga suggests a haplotype reduction in the St Lawrence. PMID:10447854

  13. Plasmodium falciparum: A novel method for analyzing haplotypes in mixed infections

    PubMed Central

    Certain, Laura K.; Sibley, Carol H.

    2007-01-01

    Studying the population genetics of Plasmodium falciparum is necessary for understanding the spread of drug resistance. However, these studies are hampered by the inability to determine haplotypes from patient samples that contain multiple parasite populations. Therefore, we have developed a method for separating for genetic analysis the individual strains in a mixed infection. We amplified a 6 kb region of chromosome 4, including the dihydrofolate reductase gene and upstream microsatellite markers. This PCR product was inserted by recombination into a gapped yeast shuttle plasmid containing both selectable and counter-selectable markers. Because each plasmid contains only one insert and each yeast colony contains only one plasmid, the individual strains are now separate. We analyzed mixtures of 3D7, K1, and Dd2 DNA and correctly identified a haplotype in each case. PMID:17049516

  14. Accumulating Mutations in Series of Haplotypes at the KIT and MITF Loci Are Major Determinants of White Markings in Franches-Montagnes Horses

    PubMed Central

    Haase, Bianca; Signer-Hasler, Heidi; Binns, Matthew M.; Obexer-Ruff, Gabriela; Hauswirth, Regula; Bellone, Rebecca R.; Burger, Dominik

    2013-01-01

    Coat color and pattern variations in domestic animals are frequently inherited as simple monogenic traits, but a number are known to have a complex genetic basis. While the analysis of complex trait data remains a challenge in all species, we can use the reduced haplotypic diversity in domestic animal populations to gain insight into the genomic interactions underlying complex phenotypes. White face and leg markings are examples of complex traits in horses where little is known of the underlying genetics. In this study, Franches-Montagnes (FM) horses were scored for the occurrence of white facial and leg markings using a standardized scoring system. A genome-wide association study (GWAS) was performed for several white patterning traits in 1,077 FM horses. Seven quantitative trait loci (QTL) affecting the white marking score with p-values p≤10−4 were identified. Three loci, MC1R and the known white spotting genes, KIT and MITF, were identified as the major loci underlying the extent of white patterning in this breed. Together, the seven loci explain 54% of the genetic variance in total white marking score, while MITF and KIT alone account for 26%. Although MITF and KIT are the major loci controlling white patterning, their influence varies according to the basic coat color of the horse and the specific body location of the white patterning. Fine mapping across the MITF and KIT loci was used to characterize haplotypes present. Phylogenetic relationships among haplotypes were calculated to assess their selective and evolutionary influences on the extent of white patterning. This novel approach shows that KIT and MITF act in an additive manner and that accumulating mutations at these loci progressively increase the extent of white markings. PMID:24098679

  15. Y chromosomal haplotype characteristics of domestic sheep (Ovis aries) in China.

    PubMed

    Wang, Yutao; Xu, Lei; Yan, Wei; Li, Shaobin; Wang, Jiqing; Liu, Xiu; Hu, Jiang; Luo, Yuzhu

    2015-07-10

    Investigations on the variation present at the male-specific Y chromosome region provide strong information to understand the origin and evolution of domestic sheep. One SNP OY1 (g.88A>G) in the upstream region of SRY gene, and the microsatellite SRYM18 locus within ovine Y chromosome were analyzed in one hundred and forty five samples collected from eleven breeds in China. SNP OY1 was analyzed using PCR-SSCP method and sequencing. Two different PCR-SSCP patterns represented two specific sequences with sequence analysis revealing SNP-OY1 (g.88A>G) were observed, while SNP A-OY1 showed the most common frequency (82.8%). Sequencing of the SRYM18 region revealed one novel size fragment (A2) with different repetitive units. Seven haplotypes (H4, H5, H6, H7, H8, H9 and H12) and two novel haplotypes (Ha and Hb) were established using combined genotype analysis. H6 showed the highest frequency (43.4%) across all breeds, and H8 showed the second frequency (24.1%). Ha was only found in one breed (Tan), while Hb was present in three breeds (Gansu alpine, White Suffolk and Duolang). Our findings reveal one novel allele in SRYM18 region and two novel male haplotypes of domestic sheep in China.

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

    PubMed

    Brandvain, Yaniv; Slotte, Tanja; Hazzouri, Khaled M; Wright, Stephen I; Coop, Graham

    2013-01-01

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

  17. A Fully Non-Metallic Gas Turbine Engine Enabled by Additive Manufacturing Part I: System Analysis, Component Identification, Additive Manufacturing, and Testing of Polymer Composites

    NASA Technical Reports Server (NTRS)

    Grady, Joseph E.; Haller, William J.; Poinsatte, Philip E.; Halbig, Michael C.; Schnulo, Sydney L.; Singh, Mrityunjay; Weir, Don; Wali, Natalie; Vinup, Michael; Jones, Michael G.; Patterson, Clark; Santelle, Tom; Mehl, Jeremy

    2015-01-01

    The research and development activities reported in this publication were carried out under NASA Aeronautics Research Institute (NARI) funded project entitled "A Fully Nonmetallic Gas Turbine Engine Enabled by Additive Manufacturing." The objective of the project was to conduct evaluation of emerging materials and manufacturing technologies that will enable fully nonmetallic gas turbine engines. The results of the activities are described in three part report. The first part of the report contains the data and analysis of engine system trade studies, which were carried out to estimate reduction in engine emissions and fuel burn enabled due to advanced materials and manufacturing processes. A number of key engine components were identified in which advanced materials and additive manufacturing processes would provide the most significant benefits to engine operation. The technical scope of activities included an assessment of the feasibility of using additive manufacturing technologies to fabricate gas turbine engine components from polymer and ceramic matrix composites, which were accomplished by fabricating prototype engine components and testing them in simulated engine operating conditions. The manufacturing process parameters were developed and optimized for polymer and ceramic composites (described in detail in the second and third part of the report). A number of prototype components (inlet guide vane (IGV), acoustic liners, engine access door) were additively manufactured using high temperature polymer materials. Ceramic matrix composite components included turbine nozzle components. In addition, IGVs and acoustic liners were tested in simulated engine conditions in test rigs. The test results are reported and discussed in detail.

  18. Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers

    PubMed Central

    Shankar, Suma P.; Hughbanks-Wheaton, Dianna K.; Birch, David G.; Sullivan, Lori S.; Conneely, Karen N.; Bowne, Sara J.; Stone, Edwin M.; Daiger, Stephen P.

    2016-01-01

    Purpose We determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene. Methods A total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis. Results Several distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]). Conclusions The PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets. PMID:26842753

  19. BDNF gene polymorphisms and haplotypes in relation to cognitive performance in Polish healthy subjects.

    PubMed

    Wiłkość, Monika; Szałkowska, Agnieszka; Skibińska, Maria; Zając-Lamparska, Ludmiła; Maciukiewicz, Małgorzata; Araszkiewicz, Aleksander

    2016-01-01

    The brain derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in the cell survival, axonal and dendritic growth, and synaptic plasticity. BDNF gene polymorphisms, 'functional Val66Met mainly, were shown to influence human brain structure and cognition. The aim of the study was to assess the relationship between twelve BDNF gene variants and their haplotypes and cognitive performance measured using the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), the Stroop Test which are to a large extent connected with prefrontal cortex activity. Our sample consisted of 460 healthy participants from Polish population. We detected possible association between five BDNF polymorphisms (rs11030101, rs10835210, rs2049046, rs2030324, rs2883187) and TMT_A. Additionally, one haplotype block made from eleven BDNF variants (rs2883187, rs1401635, rs2049046, rs2030324, rs11030101, rs10835210, rs1013402, rs1401635, rs1013402), as significant linkage disequilibrium appeared. We discovered possible relationships of CACCGCGTACG and CACCGCGTACG haplotypes with TMT_A and TMT_B performance respectively. Our results confirmed the involvement of BDNF in the regulation of psychomotor speed, working memory and executive function in healthy subjects measured by a task engaging visuoperceptual abilities. PMID:27102917

  20. Methods for human demographic inference using haplotype patterns from genomewide single-nucleotide polymorphism data.

    PubMed

    Lohmueller, Kirk E; Bustamante, Carlos D; Clark, Andrew G

    2009-05-01

    We propose a novel approximate-likelihood method to fit demographic models to human genomewide single-nucleotide polymorphism (SNP) data. We divide the genome into windows of constant genetic map width and then tabulate the number of distinct haplotypes and the frequency of the most common haplotype for each window. We summarize the data by the genomewide joint distribution of these two statistics-termed the HCN statistic. Coalescent simulations are used to generate the expected HCN statistic for different demographic parameters. The HCN statistic provides additional information for disentangling complex demography beyond statistics based on single-SNP frequencies. Application of our method to simulated data shows it can reliably infer parameters from growth and bottleneck models, even in the presence of recombination hotspots when properly modeled. We also examined how practical problems with genomewide data sets, such as errors in the genetic map, haplotype phase uncertainty, and SNP ascertainment bias, affect our method. Several modifications of our method served to make it robust to these problems. We have applied our method to data collected by Perlegen Sciences and find evidence for a severe population size reduction in northwestern Europe starting 32,500-47,500 years ago.

  1. Remarkable variation in maize genome structure inferred from haplotype diversity at the bz locus

    PubMed Central

    Wang, Qinghua; Dooner, Hugo K.

    2006-01-01

    Maize is probably the most diverse of all crop species. Unexpectedly large differences among haplotypes were first revealed in a comparison of the bz genomic regions of two different inbred lines, McC and B73. Retrotransposon clusters, which comprise most of the repetitive DNA in maize, varied markedly in makeup, and location relative to the genes in the region and genic sequences, later shown to be carried by two helitron transposons, also differed between the inbreds. Thus, the allelic bz regions of these Corn Belt inbreds shared only a minority of the total sequence. To investigate further the variation caused by retrotransposons, helitrons, and other insertions, we have analyzed the organization of the bz genomic region in five additional cultivars selected because of their geographic and genetic diversity: the inbreds A188, CML258, and I137TN, and the land races Coroico and NalTel. This vertical comparison has revealed the existence of several new helitrons, new retrotransposons, members of every superfamily of DNA transposons, numerous miniature elements, and novel insertions flanked at either end by TA repeats, which we call TAFTs (TA-flanked transposons). The extent of variation in the region is remarkable. In pairwise comparisons of eight bz haplotypes, the percentage of shared sequences ranges from 25% to 84%. Chimeric haplotypes were identified that combine retrotransposon clusters found in different haplotypes. We propose that recombination in the common gene space greatly amplifies the variability produced by the retrotransposition explosion in the maize ancestry, creating the heterogeneity in genome organization found in modern maize. PMID:17101975

  2. Insights into HLA-G Genetics Provided by Worldwide Haplotype Diversity

    PubMed Central

    Castelli, Erick C.; Ramalho, Jaqueline; Porto, Iane O. P.; Lima, Thálitta H. A.; Felício, Leandro P.; Sabbagh, Audrey; Donadi, Eduardo A.; Mendes-Junior, Celso T.

    2014-01-01

    Human leukocyte antigen G (HLA-G) belongs to the family of non-classical 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 non-classical 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), and (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 region (UTR)]. 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′UTRs 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. PMID:25339953

  3. inPHAP: Interactive visualization of genotype and phased haplotype data

    PubMed Central

    2014-01-01

    Background To understand individual genomes it is necessary to look at the variations that lead to changes in phenotype and possibly to disease. However, genotype information alone is often not sufficient and additional knowledge regarding the phase of the variation is needed to make correct interpretations. Interactive visualizations, that allow the user to explore the data in various ways, can be of great assistance in the process of making well informed decisions. But, currently there is a lack for visualizations that are able to deal with phased haplotype data. Results We present inPHAP, an interactive visualization tool for genotype and phased haplotype data. inPHAP features a variety of interaction possibilities such as zooming, sorting, filtering and aggregation of rows in order to explore patterns hidden in large genetic data sets. As a proof of concept, we apply inPHAP to the phased haplotype data set of Phase 1 of the 1000 Genomes Project. Thereby, inPHAP’s ability to show genetic variations on the population as well as on the individuals level is demonstrated for several disease related loci. Conclusions As of today, inPHAP is the only visual analytical tool that allows the user to explore unphased and phased haplotype data interactively. Due to its highly scalable design, inPHAP can be applied to large datasets with up to 100 GB of data, enabling users to visualize even large scale input data. inPHAP closes the gap between common visualization tools for unphased genotype data and introduces several new features, such as the visualization of phased data. inPHAP is available for download at http://bit.ly/1iJgKmX. PMID:25002076

  4. Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines

    PubMed Central

    Norman, Paul J.; Norberg, Steve; Nemat-Gorgani, Neda; Royce, Thomas; Hollenbach, Jill A.; Won, Melissa Shults; Guethlein, Lisbeth A.; Gunderson, Kevin L.; Ronaghi, Mostafa; Parham, Peter

    2015-01-01

    The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show this panel represents a significant proportion of European HLA allelic and haplotype diversity (60–95%). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21Mbp. Within HLA the mean haplotype length is 4.3Mbp, and 65% of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls. PMID:26198775

  5. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy.

    PubMed

    Toyota, Kentaro; Hashimoto, Taeko; Ogino, Daisuke; Matsunaga, Akira; Ito, Minoru; Masakane, Ikuto; Degawa, Noriyuki; Sato, Hiroshi; Shirai, Sayuri; Umetsu, Kazuo; Tamiya, Gen; Saito, Takao; Hayasaka, Kiyoshi

    2013-05-01

    Lipoprotein glomerulopathy (LPG) is a hereditary disease characterized by lipoprotein thrombi in the glomerulus, hyperlipoproteinemia, and a marked increase in serum apolipoprotein E (APOE). More than 12 APOE mutations have been identified as causes of LPG, and APOE-Sendai (Arg145Pro) mutation was frequently detected in patients from the eastern part of Japan including Yamagata prefecture. Recently, effective therapy with intensive lipid-lowering agents was established, and epidemiologic data are required for early diagnosis. We determined the haplotype structure of APOE-Sendai in 13 patients from 9 unrelated families with LPG, and found that the haplotype of all APOE-Sendai mutations was identical, suggesting that APOE-Sendai mutation is common in Japanese patients probably through a founder effect. We also studied the gene frequency of APOE-Sendai in 2023 control subjects and 418 patients receiving hemodialysis in Yamagata prefecture using the TaqMan method, but did not identify any subjects carrying the mutation, indicating that it is very rare in the general population even in the eastern part of Japan. In addition to APOE mutation, other genetic and/or epigenetic factors are considered to be involved in the pathogenesis of LPG because of its low penetrance. The patients did not have a common haplotype of the counterpart APOE allele, and some patients had the same haplotype of the counterpart APOE allele as the asymptomatic carriers. These results suggest that the counterpart APOE allele is not likely associated with the onset of LPG. Further study is required to clarify the pathogenesis of LPG.

  6. Association of genetic variants of cancer stem cell gene CD44 haplotypes with gallbladder cancer susceptibility in North Indian population.

    PubMed

    Sharma, Kiran Lata; Yadav, Anu; Gupta, Annapurna; Tulsayan, Sonam; Kumar, Vijay; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2014-03-01

    CD44 is an important marker for cancer stem cells. Germline variants in CD44 gene have been associated with susceptibility to breast and nasopharyngeal carcinomas but no study in gallbladder cancer (GBC) has been done yet. The present study included 405 GBC patients and 200 healthy controls from North India. Tagger SNPs for CD44 were selected from the GIH population data. Genotyping was carried out by PCR-RFLP and Taqman probes. Statistical analysis was done by SPSS. Bonferroni correction was applied in subgroup analysis. Logistic regression analysis showed no individual association of CD44 polymorphisms with GBC risk. However, [CCAT] haplotype was associated with overall reduced risk of GBC [P = 0.04, odds ratios (OR) = 0.47]. Gender stratification revealed that [CCAT] and [TAGT] haplotypes were significantly associated with decreased risk in female GBC patients [P = 0.022, OR = 0.38; P = 0.011, OR = 0.17, respectively]. The CAAT haplotype was marginally associated with low GBC risk in patients with co-existing gallstones [P = 0.026, OR = 0.53]. The cancer risk was not further modified with tobacco usage or age of onset. In silico analysis showed change in transcriptional regulation of selected SNPs. This study reports an important role of CD44 haplotypes with reduced risk of GBC.

  7. In Vivo Characterization of Human APOA5 Haplotypes

    SciTech Connect

    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.

  8. The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

    PubMed Central

    Nahajevszky, Sarolta; Andrikovics, Hajnalka; Batai, Arpad; Adam, Emma; Bors, Andras; Csomor, Judit; Gopcsa, Laszlo; Koszarska, Magdalena; Kozma, Andras; Lovas, Nora; Lueff, Sandor; Matrai, Zoltan; Meggyesi, Nora; Sinko, Janos; Sipos, Andrea; Varkonyi, Andrea; Fekete, Sandor; Tordai, Attila; Masszi, Tamas

    2011-01-01

    Background Prognostic risk stratification according to acquired or inherited genetic alterations has received increasing attention in acute myeloid leukemia in recent years. A germline Janus kinase 2 haplotype designated as the 46/1 haplotype has been reported to be associated with an inherited predisposition to myeloproliferative neoplasms, and also to acute myeloid leukemia with normal karyotype. The aim of this study was to assess the prognostic impact of the 46/1 haplotype on disease characteristics and treatment outcome in acute myeloid leukemia. Design and Methods Janus kinase 2 rs12343867 single nucleotide polymorphism tagging the 46/1 haplotype was genotyped by LightCycler technology applying melting curve analysis with the hybridization probe detection format in 176 patients with acute myeloid leukemia under 60 years diagnosed consecutively and treated with curative intent. Results The morphological subtype of acute myeloid leukemia with maturation was less frequent among 46/1 carriers than among non-carriers (5.6% versus 17.2%, P=0.018, cytogenetically normal subgroup: 4.3% versus 20.6%, P=0.031), while the morphological distribution shifted towards the myelomonocytoid form in 46/1 haplotype carriers (28.1% versus 14.9%, P=0.044, cytogenetically normal subgroup: 34.0% versus 11.8%, P=0.035). In cytogenetically normal cases of acute myeloid leukemia, the 46/1 carriers had a considerably lower remission rate (78.7% versus 94.1%, P=0.064) and more deaths in remission or in aplasia caused by infections (46.8% versus 23.5%, P=0.038), resulting in the 46/1 carriers having shorter disease-free survival and overall survival compared to the 46/1 non-carriers. In multivariate analysis, the 46/1 haplotype was an independent adverse prognostic factor for disease-free survival (P=0.024) and overall survival (P=0.024) in patients with a normal karyotype. Janus kinase 2 46/1 haplotype had no impact on prognosis in the subgroup with abnormal karyotype. Conclusions Janus

  9. Genetic linkage analysis to identify a gene required for the addition of phosphoethanolamine to meningococcal lipopolysaccharide.

    PubMed

    Tang, Christoph M; Stroud, Dave; Mackinnon, Fiona; Makepeace, Katherine; Plested, Joyce; Moxon, E Richard; Chalmers, Ronald

    2002-02-01

    Lipopolysaccharide (LPS) is important for the virulence of Neisseria meningitidis, and is the target of immune responses. We took advantage of a monoclonal antibody (Mab B5) that recognises phosphoethanolamine (PEtn) attached to the inner core of meningococcal LPS to identify genes required for the addition of PEtn to LPS. Insertional mutants that lost Mab B5 reactivity were isolated and characterised, but failed to yield genes directly responsible for PEtn substitution. Subsequent genetic linkage analysis was used to define a region of DNA containing a single intact open reading frame which is sufficient to confer B5 reactivity to a B5 negative meningococcal isolate. The results provide an initial characterisation of the genetic basis of a key, immunodominant epitope of meningococcal LPS.

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

    SciTech Connect

    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, 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.

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

    PubMed Central

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

    1994-01-01

    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. Images Figure 1 PMID:7913582

  12. First successful application of preimplantation genetic diagnosis and haplotyping for congenital hyperinsulinism.

    PubMed

    Qubbaj, Wafa; Al-Swaid, Abdulrahman; Al-Hassan, Saad; Awartani, Khalid; Deek, Hesham; Coskun, Serdar

    2011-01-01

    Congenital hyperinsulinism is the most common cause of persistent hypoglycaemia in infancy. Early surgical intervention is usually required to prevent brain damage. The prevention of the transmission to the offspring is important in families carrying the mutated gene. Preimplantation genetic diagnosis (PGD) is an early genetic testing procedure for couples at risk of transmitting inherited diseases. A 36-year-old Saudi woman married to her first cousin with four affected children was referred for PGD. The hyperinsulinism disease was caused by a novel homozygous mutation in the KCNJ11 gene, an arginine 301 to proline (R301P) substitution.PGD was achieved by whole genome amplification followed by mutation detection combined with short tandem repeat identifier analysis in the first cycle and with haplotyping in the second cycle. The first and second cycles resulted in the births of healthy twin girls and a boy, respectively. As far as is known, this is the first application of PGD to hyperinsulinism. A feasible strategy including whole genome amplification followed by direct mutation detection combined with haplotyping is described.Utilizing haplotyping increases the efficiency of PGD diagnosis as well as confirming the genetic diagnosis. It reveals the parental origin of each inherited chromosome.

  13. Multiple haplotype-resolved genomes reveal population patterns of gene and protein diplotypes

    PubMed Central

    Hoehe, Margret R.; Church, George M.; Lehrach, Hans; Kroslak, Thomas; Palczewski, Stefanie; Nowick, Katja; Schulz, Sabrina; Suk, Eun-Kyung; Huebsch, Thomas

    2014-01-01

    To fully understand human biology and link genotype to phenotype, the phase of DNA variants must be known. Here we present a comprehensive analysis of haplotype-resolved genomes to assess the nature and variation of haplotypes and their pairs, diplotypes, in European population samples. We use a set of 14 haplotype-resolved genomes generated by fosmid clone-based sequencing, complemented and expanded by up to 372 statistically resolved genomes from the 1000 Genomes Project. We find immense diversity of both haploid and diploid gene forms, up to 4.1 and 3.9 million corresponding to 249 and 235 per gene on average. Less than 15% of autosomal genes have a predominant form. We describe a ‘common diplotypic proteome’, a set of 4,269 genes encoding two different proteins in over 30% of genomes. We show moreover an abundance of cis configurations of mutations in the 386 genomes with an average cis/trans ratio of 60:40, and distinguishable classes of cis- versus trans-abundant genes. This work identifies key features characterizing the diplotypic nature of human genomes and provides a conceptual and analytical framework, rich resources and novel hypotheses on the functional importance of diploidy. PMID:25424553

  14. Possible Positive Selection for an Arsenic-Protective Haplotype in Humans

    PubMed Central

    Schlebusch, Carina M.; Lewis, Cecil M.; Vahter, Marie; Engström, Karin; Tito, Raúl Y.; Obregón-Tito, Alexandra J.; Huerta, Doris; Polo, Susan I.; Medina, Ángel C.; Brutsaert, Tom D.; Concha, Gabriela; Jakobsson, Mattias

    2012-01-01

    Background: Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite. Objectives: We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups. Methods: Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic. Results: We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared). Conclusions: Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis. PMID:23070617

  15. The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms

    PubMed Central

    Jones, Amy V.; Campbell, Peter J.; Beer, Philip A.; Schnittger, Susanne; Vannucchi, Alessandro M.; Zoi, Katerina; Percy, Melanie J.; McMullin, Mary Frances; Scott, Linda M.; Tapper, William; Silver, Richard T.; Oscier, David; Harrison, Claire N.; Grallert, Harald; Kisialiou, Aliaksei; Strike, Paul; Chase, Andrew J.; Green, Anthony R.

    2010-01-01

    The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms, but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n = 404) versus controls (n = 1492, P = 3.9 × 10−11). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .002), but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n = 69, P = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 cases is compatible with both the “hypermutability” and “fertile ground” hypotheses, but the excess in MPL-mutated cases argues against the former. No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle. PMID:20304805

  16. Mining of haplotype-based expressed sequence tag single nucleotide polymorphisms in citrus

    PubMed Central

    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 comparison. There were a total of 567,297 ESTs belonging to 27 cultivars in varying numbers and consequentially yielding different numbers of haplotype-based quality SNPs. Sweet orange (SO) had the most (213,830) ESTs, generating 11,182 quality SNPs in 3,327 out of 4,228 usable contigs. Summed from all the individually mining results, a total of 25,417 quality SNPs were discovered – 15,010 (59.1%) were transitions (AG and CT), 9,114 (35.9%) were transversions (AC, GT, CG, and AT), and 1,293 (5.0%) were insertion/deletions (indels). A vast majority of SNP-containing contigs consisted of only 2 haplotypes, as expected, but the percentages of 2 haplotype contigs varied widely in these citrus cultivars. BLAST of the 25,417 25-mer SNP oligos to the Clementine reference genome scaffolds revealed 2,947 SNPs had “no hits found”, 19,943 had 1 unique hit / alignment, 1,571 had one hit and 2+ alignments per hit, and 956 had 2+ hits and 1+ alignment per hit. Of the total 24,293 scaffold hits, 23,955 (98.6%) were on the main scaffolds 1 to 9, and only 338 were on 87 minor scaffolds. Most alignments had 100% (25/25) or 96% (24/25) nucleotide identities, accounting for 93% of all the alignments. Considering almost all the nucleotide discrepancies in the 24/25 alignments were at the SNP sites, it served well as in silico validation of these SNPs, in addition to and consistent with the rate (81%) validated by sequencing and SNaPshot assay. Conclusions High-quality EST-SNPs from different

  17. High diversity of {alpha}-globin haplotypes in a senegalese population, including many previously unreported variants

    SciTech Connect

    Martinson, J.J.; Swinburn, C.; Clegg, J.B.

    1995-11-01

    RFLP haplotypes at the {alpha}-globin gene complex have been examined in 190 individuals from the Niokolo Mandenka population of Senegal: haplotypes were assigned unambiguously for 210 chromosomes. The Mandenka share with other African populations a sample size-independent haplotype diversity that is much greater than that in any non-African population: the number of haplotypes observed in the Mandenka is typically twice that seen in the non-African populations sampled to date. Of these haplotypes, 17.3% had not been observed in any previous surveys, and a further 19.1% have previously been reported only in African populations. The haplotype distribution shows clear differences between African and non-African peoples, but this is on the basis of population-specific haplotypes combined with haplotypes common to all. The relationship of the newly reported haplotypes to those previously recorded suggests that several mutation processes, particularly recombination as homologous exchange or gene conversion, have been involved in their production. A computer program based on the expectation-maximization (EM) algorithm was used to obtain maximum-likelihood estimates of haplotype frequencies for the entire data set: good concordance between the unambiguous and EM-derived sets was seen for the overall haplotype frequencies. Some of the low-frequency haplotypes reported by the estimation algorithm differ greatly, in structure, from those haplotypes known to be present in human populations, and they may not represent haplotypes actually present in the sample. 43 refs., 4 figs., 4 tabs.

  18. Genomic organization of the S locus: Identification and characterization of genes in SLG/SRK region of S(9) haplotype of Brassica campestris (syn. rapa).

    PubMed

    Suzuki, G; Kai, N; Hirose, T; Fukui, K; Nishio, T; Takayama, S; Isogai, A; Watanabe, M; Hinata, K

    1999-09-01

    In Brassica, two self-incompatibility genes, encoding SLG (S locus glycoprotein) and SRK (S-receptor kinase), are located at the S locus and expressed in the stigma. Recent molecular analysis has revealed that the S locus is highly polymorphic and contains several genes, i.e., SLG, SRK, the as-yet-unidentified pollen S gene(s), and other linked genes. In the present study, we searched for expressed sequences in a 76-kb SLG/SRK region of the S(9) haplotype of Brassica campestris (syn. rapa) and identified 10 genes in addition to the four previously identified (SLG(9), SRK(9), SAE1, and SLL2) in this haplotype. This gene density (1 gene/5.4 kb) suggests that the S locus is embedded in a gene-rich region of the genome. The average G + C content in this region is 32.6%. An En/Spm-type transposon-like element was found downstream of SLG(9). Among the genes we identified that had not previously been found to be linked to the S locus were genes encoding a small cysteine-rich protein, a J-domain protein, and an antisilencing protein (ASF1) homologue. The small cysteine-rich protein was similar to a pollen coat protein, named PCP-A1, which had previously been shown to bind SLG.

  19. Genomic organization of the S locus: Identification and characterization of genes in SLG/SRK region of S(9) haplotype of Brassica campestris (syn. rapa).

    PubMed Central

    Suzuki, G; Kai, N; Hirose, T; Fukui, K; Nishio, T; Takayama, S; Isogai, A; Watanabe, M; Hinata, K

    1999-01-01

    In Brassica, two self-incompatibility genes, encoding SLG (S locus glycoprotein) and SRK (S-receptor kinase), are located at the S locus and expressed in the stigma. Recent molecular analysis has revealed that the S locus is highly polymorphic and contains several genes, i.e., SLG, SRK, the as-yet-unidentified pollen S gene(s), and other linked genes. In the present study, we searched for expressed sequences in a 76-kb SLG/SRK region of the S(9) haplotype of Brassica campestris (syn. rapa) and identified 10 genes in addition to the four previously identified (SLG(9), SRK(9), SAE1, and SLL2) in this haplotype. This gene density (1 gene/5.4 kb) suggests that the S locus is embedded in a gene-rich region of the genome. The average G + C content in this region is 32.6%. An En/Spm-type transposon-like element was found downstream of SLG(9). Among the genes we identified that had not previously been found to be linked to the S locus were genes encoding a small cysteine-rich protein, a J-domain protein, and an antisilencing protein (ASF1) homologue. The small cysteine-rich protein was similar to a pollen coat protein, named PCP-A1, which had previously been shown to bind SLG. PMID:10471721

  20. [Genetic Variability and Structure of SNP Haplotypes in the DMPK Gene in Yakuts and Other Ethnic Groups of Northern Eurasia in Relation to Myotonic Dystrophy].

    PubMed

    Swarovskaya, M G; Stepanova, S K; Marussin, A V; Sukhomyasova, A L; Maximova, N R; Stepanov, V A

    2015-06-01

    The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs10415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H(e) = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F(ST) = 0.79%), which was related to the high subdivision of the northern Eurasian population (F(ST) = 11.83%), was observed. PMID:26310035

  1. Y chromosome haplotype diversity in Mongolic-speaking populations and gene conversion at the duplicated STR DYS385a,b in haplogroup C3-M407.

    PubMed

    Malyarchuk, Boris A; Derenko, Miroslava; Denisova, Galina; Woźniak, Marcin; Rogalla, Urszula; Dambueva, Irina; Grzybowski, Tomasz

    2016-06-01

    Y chromosome microsatellite (Y-STR) diversity has been studied in different Mongolic-speaking populations from South Siberia, Mongolia, North-East China and East Europe. The results obtained indicate that the Mongolic-speaking populations clustered into two groups, with one group including populations from eastern part of South Siberia and Central Asia (the Buryats, Barghuts and Khamnigans) and the other group including populations from western part of Central Asia and East Europe (the Mongols and Kalmyks). High frequency of haplogroup C3-M407 (>50%) is present in the Buryats, Barghuts and Khamnigans, whereas in the Mongols and Kalmyks its frequency is much lower. In addition, two allelic combinations in DYS385a,b loci of C3-M407 haplotypes have been observed: the combination 11,18 (as well as 11,17 and 11,19) is frequent in different Mongolic-speaking populations, but the 11,11 branch is present mainly in the Kalmyks and Mongols. Results of locus-specific sequencing suggest that the action of gene conversion is a more likely explanation for origin of homoallelic 11,11 combination. Moreover, analysis of median networks of Y-STR haplotypes demonstrates that at least two gene conversion events can be revealed-one of them has probably occurred among the Mongols, and the other event occurred in the Barghuts. These two events give an average gene conversion rate range of 0.24-7.1 × 10(-3) per generation. PMID:26911356

  2. Beta-globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon.

    PubMed

    Inati, A; Taher, A; Bou Alawi, W; Koussa, S; Kaspar, H; Shbaklo, H; Zalloua, P A

    2003-02-01

    Sickle cell disease (SCD) is an inherited autosomal recessive disorder of the beta-globin chain. Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of the clinical and hematological manifestations is extremely variable. This study examined for the first time in Lebanon the correlation between the clinical manifestation of SCD and the beta-globin gene haplotypes. The haplotypes of 50 patients diagnosed with SCD were determined using polymerase chain reaction amplification of fragments containing nine polymorphic restriction sites around and within the epsilon-Ggamma-Agamma-psibeta-delta-beta-globin gene complex. Most reported haplotypes were found in our population with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels into three groups (Group A: HbF < 5%, Group B: HbF between 5 and 15%, and Group C: HbF > 15%), surprisingly, the highest levels of HbF were associated with the most severe clinical cases. Our findings suggest that fetal hemoglobin levels are important but not the only parameters that affect the severity of the disease. In addition, the high levels of HbF in patients with CAR haplotypes did not seem to ameliorate the severity of symptoms, suggesting that genetic factors other than haplotypes are the major determinants of increased HbF levels in Lebanon.

  3. HLA class II gene associations in African American Type 1 diabetes reveal a protective HLA-DRB1*03 haplotype

    PubMed Central

    Howson, J M M; Roy, M S; Zeitels, L; Stevens, H; Todd, J A

    2013-01-01

    Aims Owing to strong linkage disequilibrium between markers, pinpointing disease associations within genetic regions is difficult in European ancestral populations, most notably the very strong association of the HLA-DRB1*03-DQA1*05:01-DQB1*02:01 haplotype with Type 1 diabetes risk, which is assumed to be because of a combination of HLA-DRB1 and HLA-DQB1. In contrast, populations of African ancestry have greater haplotype diversity, offering the possibility of narrowing down regions and strengthening support for a particular gene in a region being causal. We aimed to study the human leukocyte antigen (HLA) region in African American Type 1 diabetes. Methods Two hundred and twenty-seven African American patients with Type 1 diabetes and 471 African American control subjects were tested for association at the HLA class II genes, HLA-DRB1, HLA-DQA1, HLA-DQB1 and 5147 single nucleotide polymorphisms across the major histocompatibility complex region using logistic regression models. Population admixture was accounted for with principal components analysis. Results Single nucleotide polymorphism marker associations were explained by the HLA associations, with the major peak over the class II loci. The HLA association overall was extremely strong, as expected for Type 1 diabetes, even in African Americans in whom diabetes diagnosis is heterogeneous. In addition, there were unique features: the HLA-DRB1*03 haplotype was split into HLA-DRB1*03:01, which confers greatest susceptibility in these samples (odds ratio 3.17, 95% CI 1.72–5.83) and HLA-DRB1*03:02, an allele rarely observed in Europeans, which confers the greatest protection in these African American samples (odds ratio 0.22, 95% CI 0.09–0.55). Conclusions The unique diversity of the African HLA region we have uncovered supports a specific and major role for HLA-DRB1 in HLA-DRB1*03 haplotype-associated Type 1 diabetes risk. PMID:23398374

  4. Haplotyping the human leukocyte antigen system from single chromosomes

    PubMed Central

    Murphy, Nicholas M.; Burton, Matthew; Powell, David R.; Rossello, Fernando J.; Cooper, Don; Chopra, Abha; Hsieh, Ming Je; Sayer, David C.; Gordon, Lavinia; Pertile, Mark D; Tait, Brian D.; Irving, Helen R.; Pouton, Colin W.

    2016-01-01

    We describe a method for determining the parental HLA haplotypes of a single individual without recourse to conventional segregation genetics. Blood samples were cultured to identify and sort chromosome 6 by bivariate flow cytometry. Single chromosome 6 amplification products were confirmed with a single nucleotide polymorphism (SNP) array and verified by deep sequencing to enable assignment of both alleles at the HLA loci, defining the two haplotypes. This study exemplifies a rapid and efficient method of haplotyping that can be applied to any chromosome pair, or indeed all chromosome pairs, using a single sorting operation. The method represents a cost-effective approach to complete phasing of SNPs, which will facilitate a deeper understanding of the links between SNPs, gene regulation and protein function. PMID:27461731

  5. Prion gene haplotypes of U.S. cattle

    PubMed Central

    Clawson, Michael L; Heaton, Michael P; Keele, John W; Smith, Timothy PL; Harhay, Gregory P; Laegreid, William W

    2006-01-01

    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. PMID:17092337

  6. Functional VEGF haplotypes affect the susceptibility to hypertension.

    PubMed

    Sandrim, V C; Luizon, M R; Izidoro-Toledo, T C; Coelho, E B; Moreno, H; Tanus-Santos, J E

    2013-01-01

    We examined whether vascular endothelial growth factor (VEGF) polymorphisms (C-2578A, G-1154A and G-634C) are associated with hypertension, response to antihypertensive therapy and nitric oxide (NO) formation. Substudy 1 compared the distribution of VEGF genotypes and haplotypes in 178 patients with arterial hypertension (100 whites and 78 blacks) and 186 healthy controls (115 whites and 71 blacks). Substudy 2 compared the distribution of VEGF markers in 82 patients with controlled hypertension, 89 patients with resistant hypertension and 101 normotensive (NT) patients. In substudy 3, plasma nitrite/nitrate (NOx) levels were determined (chemiluminescence assay) in 64 NT subjects and 48 hypertensive (HTN) subjects, and the distribution of VEGF markers was compared in subjects having low NOx with subjects having high NOx. Although the substudy 1 showed no differences in genotypes or allele distributions for the three VEGF polymorphisms between NT and HTN subjects, the 'C-A-G' haplotype was more common in white NT subjects than in the white HTN subjects, and the 'C-A-C' haplotype was more frequent in black and white HTN subjects than in black and white NT subjects. The substudy 2 showed similar results, with no differences between responsive and resistant HTN subjects. The substudy 3 showed that the 'C-A-G' haplotype, which had a protective effect against hypertension, was significantly more common in subjects with higher NOx concentrations than in subjects with lower NOx concentrations. VEGF haplotypes are associated with hypertension, and the haplotype associated with normotension was more common in subjects with increased NO formation, possibly offering a mechanistic clue for our findings. PMID:22189703

  7. Statistical performance of cladistic strategies for haplotype grouping in pharmacogenetics.

    PubMed

    Lunceford, Jared K; Liu, Nancy

    2008-12-10

    Haplotypes comprising multiple single nucleotide polymorphisms (SNPs) are popular covariates for capturing the key genetic variation present over a region of interest in the DNA sequence. Although haplotypes can provide a clearer assessment of genetic variation in a region than their component SNPs considered individually, the multi-allelic nature of haplotypes increases the complexity of the statistical models intended to discover association with outcomes of interest. Cladistic methods cluster haplotypes according to the estimates of their genealogical closeness and have been proposed recently as strategies for reducing model complexity and increasing power. Two examples are methods based on a haplotype nesting algorithm described by Templeton et al. (Genetics 1987; 117:343-351) and hierarchical clustering of haplotypes as described by Durrant et al. (Am. J. Hum. Genet. 2004; 75:35-43). In the context of assessing the pharmacogenetic effects of candidate genes, for which high-density SNP data have been gathered, we have conducted a simulation-based case study of the testing and estimation properties of two strategies based on Templeton's algorithm (TA), one being that described by Seltman et al. (Am. J. Hum. Genet. 2001; 68:1250-1263; Genet. Epidemiol. 2003; 25:48-58), as well as the method of Durrant et al. using data from a diabetes clinical trial. Even after adjusting for multiplicity, improvements in power can be realized using cladistic approaches with treatment group sizes in the range expected for standard trials, although these gains may be sensitive to the cladistic structure used. Differences in the relative performance of the cladistic approaches examined were observed with the clustering approach of Durrant et al. showing statistical properties superior to the methods based on TA.

  8. High Frequency Haplotypes are Expected Events, not Historical Figures.

    PubMed

    Guillot, Elsa G; Cox, Murray P

    2015-01-01

    Cultural transmission of reproductive success states that successful men have more children and pass this raised fecundity to their offspring. Balaresque and colleagues found high frequency haplotypes in a Central Asian Y chromosome dataset, which they attribute to cultural transmission of reproductive success by prominent historical men, including Genghis Khan. Using coalescent simulation, we show that these high frequency haplotypes are consistent with a neutral model, where they commonly appear simply by chance. Hence, explanations invoking cultural transmission of reproductive success are statistically unnecessary.

  9. High Frequency Haplotypes are Expected Events, not Historical Figures

    PubMed Central

    Guillot, Elsa G.; Cox, Murray P.

    2016-01-01

    Cultural transmission of reproductive success states that successful men have more children and pass this raised fecundity to their offspring. Balaresque and colleagues found high frequency haplotypes in a Central Asian Y chromosome dataset, which they attribute to cultural transmission of reproductive success by prominent historical men, including Genghis Khan. Using coalescent simulation, we show that these high frequency haplotypes are consistent with a neutral model, where they commonly appear simply by chance. Hence, explanations invoking cultural transmission of reproductive success are statistically unnecessary. PMID:26834987

  10. Changes of pore systems and infiltration analysis in two degraded soils after rock fragment addition

    NASA Astrophysics Data System (ADS)

    Gargiulo, Laura; Coppola, Antonio; De Mascellis, Roberto; Basile, Angelo; Mele, Giacomo; Terribile, Fabio

    2015-04-01

    Many soils in arid and semi-arid environments contain high amounts of rock fragments as a result of both natural soil forming processes and human activities. The amount, dimension and shape of rock fragment strongly influence soil structure development and therefore many soil processes (e.g. infiltration, water storage, solute transport, etc.). The aim of this work was to test the effects on both infiltration process and soil pore formation following an addition of rock fragments. The test was performed on two different soils: a clayey soil (Alfisol) and a clay loamy soil (Entisol) showing both a natural compact structure and water stagnation problems in field. Three concentrations of 4-8mm rock fragments (15%, 25% and 35%) were added to air-dried soils and the repacked samples have been subject to nine wet/dry cycles in order to induce soil structure formation and its stabilization. The process of infiltration was monitored at -12 cm of pressure heads imposed at the soil surface and kept constant for a certain time by a tension infiltrometer. Moreover, k(h) was determined imposing -9, -6,-3 and -1 cm at soil surface and applying a steady-state solution. After the hydrological measurements the soil samples were resin-impregnated and images of vertical sections of the samples, acquired at 20µm resolution, were analyzed in order to quantify the pore size distribution. This latter was calculated using the "successive opening" approach. The Entisol samples showed similar infiltration curves I(t) among the 4 treatments, with higher percentage of stones (i.e. 25 and 35%) showing a faster rising in the early-time (< 2 min) infiltration; the Alfisol samples are spread, showing a higher variability: limiting the analysis to the first three, despite they show a similar shape, the higher the stones content the lower the cumulated infiltration. The behavior of the 35% sample diverges from the others: it shows a fast rising step at the very early time (< 2 min) followed by a

  11. Analysis of Time to Event Outcomes in Randomized Controlled Trials by Generalized Additive Models

    PubMed Central

    Argyropoulos, Christos; Unruh, Mark L.

    2015-01-01

    Background Randomized Controlled Trials almost invariably utilize the hazard ratio calculated with a Cox proportional hazard model as a treatment efficacy measure. Despite the widespread adoption of HRs, these provide a limited understanding of the treatment effect and may even provide a biased estimate when the assumption of proportional hazards in the Cox model is not verified by the trial data. Additional treatment effect measures on the survival probability or the time scale may be used to supplement HRs but a framework for the simultaneous generation of these measures is lacking. Methods By splitting follow-up time at the nodes of a Gauss Lobatto numerical quadrature rule, techniques for Poisson Generalized Additive Models (PGAM) can be adopted for flexible hazard modeling. Straightforward simulation post-estimation transforms PGAM estimates for the log hazard into estimates of the survival function. These in turn were used to calculate relative and absolute risks or even differences in restricted mean survival time between treatment arms. We illustrate our approach with extensive simulations and in two trials: IPASS (in which the proportionality of hazards was violated) and HEMO a long duration study conducted under evolving standards of care on a heterogeneous patient population. Findings PGAM can generate estimates of the survival function and the hazard ratio that are essentially identical to those obtained by Kaplan Meier curve analysis and the Cox model. PGAMs can simultaneously provide multiple measures of treatment efficacy after a single data pass. Furthermore, supported unadjusted (overall treatment effect) but also subgroup and adjusted analyses, while incorporating multiple time scales and accounting for non-proportional hazards in survival data. Conclusions By augmenting the HR conventionally reported, PGAMs have the potential to support the inferential goals of multiple stakeholders involved in the evaluation and appraisal of clinical trial

  12. Comparative proteomic analysis of drug sodium iron chlorophyllin addition to Hep 3B cell line.

    PubMed

    Zhang, Jun; Wang, Wenhai; Yang, Fengying; Zhou, Xinwen; Jin, Hong; Yang, Peng-yuan

    2012-09-21

    The human hepatoma 3B cell line was chosen as an experimental model for in vitro test of drug screening. The drugs included chlorophyllin and its derivatives such as fluo-chlorophyllin, sodium copper chlorophyllin, and sodium iron chlorophyllin. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) method was used in this study to obtain the primary screening results. The results showed that sodium iron chlorophyllin had the best LC(50) value. Proteomic analysis was then performed for further investigation of the effect of sodium iron chlorophyllin addition to the Hep 3B cell line. The proteins identified from a total protein extract of Hep 3B before and after the drug addition were compared by two-dimensional-gel-electrophoresis. Then 32 three-fold differentially expressed proteins were successfully identified by MALDI-TOF-TOF-MS. There are 29 unique proteins among those identified proteins. These proteins include proliferating cell nuclear antigen (PCNA), T-complex protein, heterogeneous nuclear protein, nucleophosmin, heat shock protein A5 (HspA5) and peroxiredoxin. HspA5 is one of the proteins which are involved in protecting cancer cells against stress-induced apoptosis in cultured cells, protecting them against apoptosis through various mechanisms. Peroxiredoxin has anti-oxidant function and is related to cell proliferation, and signal transduction. It can protect the oxidation of other proteins. Peroxiredoxin has a close relationship with cancer and can eventually become a disease biomarker. This might help to develop a novel treatment method for carcinoma cancer.

  13. Methane flux in non-wetland soils in response to nitrogen addition: a meta-analysis.

    PubMed

    Aronson, E L; Helliker, B R

    2010-11-01

    The controls on methane (CH4) flux into and out of soils are not well understood. Environmental variables including temperature, precipitation, and nitrogen (N) status can have strong effects on the magnitude and direction (e.g., uptake vs. release) of CH4 flux. To better understand the interactions between CH4-cycling microorganisms and N in the non-wetland soil system, a meta-analysis was performed on published literature comparing CH4 flux in N amended and matched control plots. An appropriate study index was developed for this purpose. It was found that smaller amounts of N tended to stimulate CH4 uptake while larger amounts tended to inhibit uptake by the soil. When all other variables were accounted for, the switch occurred at 100 kg N x ha(-1) x yr(-1). Managed land and land with a longer duration of fertilization showed greater inhibition of CH4 uptake with added N. These results support the hypotheses that large amounts of available N can inhibit methanotrophy, but also that methanotrophs in upland soils can be N limited in their consumption of CH4 from the atmosphere. There were interactions between other variables and N addition on the CH4 flux response: lower temperature and, to a lesser extent, higher precipitation magnified the inhibition of CH4 uptake due to N addition. Several mechanisms that may cause these trends are discussed, but none could be conclusively supported with this approach. Further controlled and in situ study should be undertaken to isolate the correct mechanism(s) responsible and to model upland CH4 flux. PMID:21141185

  14. A comparative analysis of British and Taiwanese students' conceptual and procedural knowledge of fraction addition

    NASA Astrophysics Data System (ADS)

    Li, Hui-Chuan

    2014-10-01

    This study examines students' procedural and conceptual achievement in fraction addition in England and Taiwan. A total of 1209 participants (561 British students and 648 Taiwanese students) at ages 12 and 13 were recruited from England and Taiwan to take part in the study. A quantitative design by means of a self-designed written test is adopted as central to the methodological considerations. The test has two major parts: the concept part and the skill part. The former is concerned with students' conceptual knowledge of fraction addition and the latter is interested in students' procedural competence when adding fractions. There were statistically significant differences both in concept and skill parts between the British and Taiwanese groups with the latter having a higher score. The analysis of the students' responses to the skill section indicates that the superiority of Taiwanese students' procedural achievements over those of their British peers is because most of the former are able to apply algorithms to adding fractions far more successfully than the latter. Earlier, Hart [1] reported that around 30% of the British students in their study used an erroneous strategy (adding tops and bottoms, for example, 2/3 + 1/7 = 3/10) while adding fractions. This study also finds that nearly the same percentage of the British group remained using this erroneous strategy to add fractions as Hart found in 1981. The study also provides evidence to show that students' understanding of fractions is confused and incomplete, even those who are successfully able to perform operations. More research is needed to be done to help students make sense of the operations and eventually attain computational competence with meaningful grounding in the domain of fractions.

  15. Genetic polymorphisms and haplotypes of TRAIL gene correlate with NSCLC susceptibility in a group of Chinese patients.

    PubMed

    Luo, Jun; Xiong, Jinmeng; Wu, Jianghua; Ye, Xujun

    2015-01-01

    The association between genetic polymorphisms and haplotypes of TNF-related apoptosis-inducing ligand (TRAIL) and the NSCLC development was investigated in 592 Chinese patients and the prevalence of G1525A, G1588A, and C1595T gene polymorphisms compared between the NSCLC patients and control group in this study. It was found that the frequencies of variant allele A and genotype GA+AA of G1525A were significantly lower and those of variant alleles A and T of G1588A and C1595T significantly higher in the NSCLC patients compared with those in control. The frequencies of variant allele T and genotype CT+TT of C1595T were significantly higher in stage III and IV than in stage I and II of the patients. Moreover, the frequencies of variant allele A and genotype GA+AA of G1525A were significantly higher in stage III and IV than in stage I and II of the patients. In addition, TRAIL gene variants G1525A/G1588A/C1595T were found to be in complete linkage disequilibrium in all patients. Compared with the healthy people, the frequency of AAT haplotype was significantly lower whereas that of GAT haplotype significantly higher in NSCLC patients. The results indicated that the genetic polymorphisms and haplotypes of TRAIL gene correlated significantly with the NSCLC susceptibility in the group of Chinese patients. PMID:26629137

  16. Pediatric surgical capacity and demand: analysis reveals a modest gap in capacity and additional efficiency opportunities.

    PubMed

    Fixler, Tamas; Menaker, Rena J; Blair, Geoffrey K; Wright, James G

    2011-01-01

    The Canadian Paediatric Surgical Wait Times Project conducted an analysis of the alignment between capacity (supply) and demand for pediatric surgery at nine participating hospitals in five provinces. Demand for surgery was modelled using wait list data by assigning patients into monthly buckets of demand ("demand windows") based on the date on which a decision was made to proceed with their surgery plus their surgical wait time access target. Demand was then related to available capacity for various key resources (e.g., operating room availability, intensive care unit [ICU] and in-patient beds). The results indicate a small and not insurmountable gap of 8.5-11% in pediatric surgical capacity at these hospitals. A further capacity issue at many hospitals was ICU occupancy. In addition, an examination of several key performance indicators related to the management of peri-operative resources indicated that opportunities exist for deploying existing resources more efficiently, such as increasing on-time starts and reducing cancellation rates for elective surgery.

  17. Loophole-free Bell test using electron spins in diamond: second experiment and additional analysis

    NASA Astrophysics Data System (ADS)

    Hensen, B.; Kalb, N.; Blok, M. S.; Dréau, A. E.; Reiserer, A.; Vermeulen, R. F. L.; Schouten, R. N.; Markham, M.; Twitchen, D. J.; Goodenough, K.; Elkouss, D.; Wehner, S.; Taminiau, T. H.; Hanson, R.

    2016-08-01

    The recently reported violation of a Bell inequality using entangled electronic spins in diamonds (Hensen et al., Nature 526, 682–686) provided the first loophole-free evidence against local-realist theories of nature. Here we report on data from a second Bell experiment using the same experimental setup with minor modifications. We find a violation of the CHSH-Bell inequality of 2.35 ± 0.18, in agreement with the first run, yielding an overall value of S = 2.38 ± 0.14. We calculate the resulting P-values of the second experiment and of the combined Bell tests. We provide an additional analysis of the distribution of settings choices recorded during the two tests, finding that the observed distributions are consistent with uniform settings for both tests. Finally, we analytically study the effect of particular models of random number generator (RNG) imperfection on our hypothesis test. We find that the winning probability per trial in the CHSH game can be bounded knowing only the mean of the RNG bias. This implies that our experimental result is robust for any model underlying the estimated average RNG bias, for random bits produced up to 690 ns too early by the random number generator.

  18. Loophole-free Bell test using electron spins in diamond: second experiment and additional analysis

    PubMed Central

    Hensen, B.; Kalb, N.; Blok, M. S.; Dréau, A. E.; Reiserer, A.; Vermeulen, R. F. L.; Schouten, R. N.; Markham, M.; Twitchen, D. J.; Goodenough, K.; Elkouss, D.; Wehner, S.; Taminiau, T. H.; Hanson, R.

    2016-01-01

    The recently reported violation of a Bell inequality using entangled electronic spins in diamonds (Hensen et al., Nature 526, 682–686) provided the first loophole-free evidence against local-realist theories of nature. Here we report on data from a second Bell experiment using the same experimental setup with minor modifications. We find a violation of the CHSH-Bell inequality of 2.35 ± 0.18, in agreement with the first run, yielding an overall value of S = 2.38 ± 0.14. We calculate the resulting P-values of the second experiment and of the combined Bell tests. We provide an additional analysis of the distribution of settings choices recorded during the two tests, finding that the observed distributions are consistent with uniform settings for both tests. Finally, we analytically study the effect of particular models of random number generator (RNG) imperfection on our hypothesis test. We find that the winning probability per trial in the CHSH game can be bounded knowing only the mean of the RNG bias. This implies that our experimental result is robust for any model underlying the estimated average RNG bias, for random bits produced up to 690 ns too early by the random number generator. PMID:27509823

  19. Characterization and analysis of surface notches on Ti-alloy plates fabricated by additive manufacturing techniques

    NASA Astrophysics Data System (ADS)

    Chan, Kwai S.

    2015-12-01

    Rectangular plates of Ti-6Al-4V with extra low interstitial (ELI) were fabricated by layer-by-layer deposition techniques that included electron beam melting (EBM) and laser beam melting (LBM). The surface conditions of these plates were characterized using x-ray micro-computed tomography. The depth and radius of surface notch-like features on the LBM and EBM plates were measured from sectional images of individual virtual slices of the rectangular plates. The stress concentration factors of individual surface notches were computed and analyzed statistically to determine the appropriate distributions for the notch depth, notch radius, and stress concentration factor. These results were correlated with the fatigue life of the Ti-6Al-4V ELI alloys from an earlier investigation. A surface notch analysis was performed to assess the debit in the fatigue strength due to the surface notches. The assessment revealed that the fatigue lives of the additively manufactured plates with rough surface topographies and notch-like features are dominated by the fatigue crack growth of large cracks for both the LBM and EBM materials. The fatigue strength reduction due to the surface notches can be as large as 60%-75%. It is concluded that for better fatigue performance, the surface notches on EBM and LBM materials need to be removed by machining and the surface roughness be improved to a surface finish of about 1 μm.

  20. Loophole-free Bell test using electron spins in diamond: second experiment and additional analysis.

    PubMed

    Hensen, B; Kalb, N; Blok, M S; Dréau, A E; Reiserer, A; Vermeulen, R F L; Schouten, R N; Markham, M; Twitchen, D J; Goodenough, K; Elkouss, D; Wehner, S; Taminiau, T H; Hanson, R

    2016-01-01

    The recently reported violation of a Bell inequality using entangled electronic spins in diamonds (Hensen et al., Nature 526, 682-686) provided the first loophole-free evidence against local-realist theories of nature. Here we report on data from a second Bell experiment using the same experimental setup with minor modifications. We find a violation of the CHSH-Bell inequality of 2.35 ± 0.18, in agreement with the first run, yielding an overall value of S = 2.38 ± 0.14. We calculate the resulting P-values of the second experiment and of the combined Bell tests. We provide an additional analysis of the distribution of settings choices recorded during the two tests, finding that the observed distributions are consistent with uniform settings for both tests. Finally, we analytically study the effect of particular models of random number generator (RNG) imperfection on our hypothesis test. We find that the winning probability per trial in the CHSH game can be bounded knowing only the mean of the RNG bias. This implies that our experimental result is robust for any model underlying the estimated average RNG bias, for random bits produced up to 690 ns too early by the random number generator. PMID:27509823

  1. Soil nitrous oxide emissions following crop residue addition: a meta-analysis.

    PubMed

    Chen, Huaihai; Li, Xuechao; Hu, Feng; Shi, Wei

    2013-10-01

    Annual production of crop residues has reached nearly 4 billion metric tons globally. Retention of this large amount of residues on agricultural land can be beneficial to soil C sequestration. Such potential impacts, however, may be offset if residue retention substantially increases soil emissions of N(2)O, a potent greenhouse gas and ozone depletion substance. Residue effects on soil N(2)O emissions have gained considerable attention since early 1990s; yet, it is still a great challenge to predict the magnitude and direction of soil N(2)O emissions following residue amendment. Here, we used a meta-analysis to assess residue impacts on soil N(2)O emissions in relation to soil and residue attributes, i.e., soil pH, soil texture, soil water content, residue C and N input, and residue C : N ratio. Residue effects were negatively associated with C : N ratios, but generally residue amendment could not reduce soil N(2)O emissions, even for C : N ratios well above ca. 30, the threshold for net N immobilization. Residue effects were also comparable to, if not greater than, those of synthetic N fertilizers. In addition, residue effects on soil N(2)O emissions were positively related to the amounts of residue C input as well as residue effects on soil CO(2) respiration. Furthermore, most significant and stimulatory effects occurred at 60-90% soil water-filled pore space and soil pH 7.1-7.8. Stimulatory effects were also present for all soil textures except sand or clay content ≤10%. However, inhibitory effects were found for soils with >90% water-filled pore space. Altogether, our meta-analysis suggests that crop residues played roles beyond N supply for N(2)O production. Perhaps, by stimulating microbial respiration, crop residues enhanced oxygen depletion and therefore promoted anaerobic conditions for denitrification and N(2)O production. Our meta-analysis highlights the necessity to connect the quantity and quality of crop residues with soil properties for predicting

  2. Single nucleotide polymorphisms and haplotypes associated with feed efficiency in beef cattle

    PubMed Central

    2013-01-01

    Background General, breed- and diet-dependent associations between feed efficiency in beef cattle and single nucleotide polymorphisms (SNPs) or haplotypes were identified on a population of 1321 steers using a 50 K SNP panel. Genomic associations with traditional two-step indicators of feed efficiency – residual feed intake (RFI), residual average daily gain (RADG), and residual intake gain (RIG) – were compared to associations with two complementary one-step indicators of feed efficiency: efficiency of intake (EI) and efficiency of gain (EG). Associations uncovered in a training data set were evaluated on independent validation data set. A multi-SNP model was developed to predict feed efficiency. Functional analysis of genes harboring SNPs significantly associated with feed efficiency and network visualization aided in the interpretation of the results. Results For the five feed efficiency indicators, the numbers of general, breed-dependent, and diet-dependent associations with SNPs (P-value < 0.0001) were 31, 40, and 25, and with haplotypes were six, ten, and nine, respectively. Of these, 20 SNP and six haplotype associations overlapped between RFI and EI, and five SNP and one haplotype associations overlapped between RADG and EG. This result confirms the complementary value of the one and two-step indicators. The multi-SNP models included 89 SNPs and offered a precise prediction of the five feed efficiency indicators. The associations of 17 SNPs and 7 haplotypes with feed efficiency were confirmed on the validation data set. Nine clusters of Gene Ontology and KEGG pathway categories (mean P-value < 0.001) including, 9nucleotide binding; ion transport, phosphorous metabolic process, and the MAPK signaling pathway were overrepresented among the genes harboring the SNPs associated with feed efficiency. Conclusions The general SNP associations suggest that a single panel of genomic variants can be used regardless of breed and diet. The breed- and diet

  3. Interleukin-1 haplotype and periodontal disease progression following therapy.

    PubMed

    Ehmke, B; Kress, W; Karch, H; Grimm, T; Klaiber, B; Flemmig, T F

    1999-12-01

    The purpose of this study was to assess the prognostic value of the IL-1 haplotype on the progression of periodontal disease following therapy. 48 adult patients with untreated periodontitis harboring Actinobacillus actinomycetemcomitans and/or Porphyromonas gingivalis were randomly assigned to receive full-mouth scaling alone (control) or in combination with systemic metronidazole plus amoxicillin and supragingival irrigation with chlorhexidine digluconate (test). All patients received supportive periodontal therapy at 3 to 6 months intervals. In 33 patients, lymphocyte DNA was analyzed for polymorphism in the IL-1A gene at position -889 and IL-1B gene at position +3953. Overall, 16 of 33 patients (7 of 17 test and 9 of 16 control) carried the IL-1 haplotype. 2 years following initial periodontal therapy, no differences in the survival rates of sites or teeth not exhibiting probing attachment loss of 2 mm or more compared to baseline, were found between patients who tested positive (85% sites, 53% teeth) and patients who tested negative (89% sites, 56% teeth) for the IL-1 haplotype. The results indicated that the IL-1 haplotype may be of limited value for the prognosis of periodontal disease progression following non-surgical periodontal therapy.

  4. Better ILP-Based Approaches to Haplotype Assembly.

    PubMed

    Chen, Zhi-Zhong; Deng, Fei; Shen, Chao; Wang, Yiji; Wang, Lusheng

    2016-07-01

    Haplotype assembly is to directly construct the haplotypes of an individual from sequence fragments (reads) of the individual. Although a number of programs have been designed for computing optimal or heuristic solutions to the haplotype assembly problem, computing an optimal solution may take days or even months while computing a heuristic solution usually requires a trade-off between speed and accuracy. This article refines a previously known integer linear programming-based (ILP-based) approach to the haplotype assembly problem in twofolds. First, the read-matrices of some datasets (such as NA12878) come with a quality for each base in the reads. We here propose to utilize the qualities in the ILP-based approach. Secondly, we propose to use the ILP-based approach to improve the output of any heuristic program for the problem. Experiments with both real and simulated datasets show that the qualities of read-matrices help us find more accurate solutions without significant loss of speed. Moreover, our experimental results show that the proposed hybrid approach improves the output of ReFHap (the current leading heuristic) significantly (say, by almost 25% of the QAN50 score) without significant loss of speed, and can even find optimal solutions in much shorter time than the original ILP-based approach. Our program is available upon request to the authors. PMID:27347882

  5. Nomenclature of mitochondrial DNA haplotypes for Oncorhynchus mykiss

    USGS Publications Warehouse

    Graziano, Sara L.; Brown, K.H.; Nielsen, Jennifer L.

    2005-01-01

    Congruence of genetic data is critical for comparative and collaborative studies on natural fish populations. A comprehensive list of reported mitochrondrial DNA haplotypes for Oncorhynchus mykiss generated using the S-Phe/P2 primer set is presen