Sample records for snp frequency haplotype

  1. Malaria haplotype frequency estimation.

    PubMed

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

    2013-09-20

    We present a Bayesian approach for estimating the relative frequencies of multi-single nucleotide polymorphism (SNP) haplotypes in populations of the malaria parasite Plasmodium falciparum by using microarray SNP data from human blood samples. Each sample comes from a malaria patient and contains one or several parasite clones that may genetically differ. Samples containing multiple parasite clones with different genetic markers pose a special challenge. The situation is comparable with a polyploid organism. The data from each blood sample indicates whether the parasites in the blood carry a mutant or a wildtype allele at various selected genomic positions. If both mutant and wildtype alleles are detected at a given position in a multiply infected sample, the data indicates the presence of both alleles, but the ratio is unknown. Thus, the data only partially reveals which specific combinations of genetic markers (i.e. haplotypes across the examined SNPs) occur in distinct parasite clones. In addition, SNP data may contain errors at non-negligible rates. We use a multinomial mixture model with partially missing observations to represent this data and a Markov chain Monte Carlo method to estimate the haplotype frequencies in a population. Our approach addresses both challenges, multiple infections and data errors. PMID:23609602

  2. Global haplotype partitioning for maximal associated SNP pairs

    PubMed Central

    Katanforoush, Ali; Sadeghi, Mehdi; Pezeshk, Hamid; Elahi, Elahe

    2009-01-01

    Background Global partitioning based on pairwise associations of SNPs has not previously been used to define haplotype blocks within genomes. Here, we define an association index based on LD between SNP pairs. We use the Fisher's exact test to assess the statistical significance of the LD estimator. By this test, each SNP pair is characterized as associated, independent, or not-statistically-significant. We set limits on the maximum acceptable proportion of independent pairs within all blocks and search for the partitioning with maximal proportion of associated SNP pairs. Essentially, this model is reduced to a constrained optimization problem, the solution of which is obtained by iterating a dynamic programming algorithm. Results In comparison with other methods, our algorithm reports blocks of larger average size. Nevertheless, the haplotype diversity within the blocks is captured by a small number of tagSNPs. Resampling HapMap haplotypes under a block-based model of recombination showed that our algorithm is robust in reproducing the same partitioning for recombinant samples. Our algorithm performed better than previously reported models in a case-control association study aimed at mapping a single locus trait, based on simulation results that were evaluated by a block-based statistical test. Compared to methods of haplotype block partitioning, we performed best on detection of recombination hotspots. Conclusion Our proposed method divides chromosomes into the regions within which allelic associations of SNP pairs are maximized. This approach presents a native design for dimension reduction in genome-wide association studies. Our results show that the pairwise allelic association of SNPs can describe various features of genomic variation, in particular recombination hotspots. PMID:19712447

  3. A Set of Dynamic Programming Algorithms for Haplotype Block Partitioning and Tag SNP Selection via Haplotype

    E-print Network

    Sun, Fengzhu - Sun, Fengzhu

    A Set of Dynamic Programming Algorithms for Haplotype Block Partitioning and Tag SNP Selection via and Computational Biology Program Department of Biological Sciences University of Southern California 1042 West 36th significantly reduce genotyping effort without much loss of power. In this paper, we summarize the dynamic

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

    NASA Astrophysics Data System (ADS)

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

    2009-12-01

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

  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 a Java JAR file. The software can be downloaded from the webpage of the GABI Primary Database at . The application of SATlotyper will provide haplotype information, which can be used in haplotype association mapping studies of polyploid plants. PMID:18667059

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

    PubMed

    Iliadis, Alexandros; Anastassiou, Dimitris; Wang, Xiaodong

    2014-01-01

    Copy number variations (CNVs) are abundant in the human genome. They have been associated with complex traits in genome-wide association studies (GWAS) and expected to continue playing an important role in identifying the etiology of disease phenotypes. As a result of current high throughput whole-genome single-nucleotide polymorphism (SNP) arrays, we currently have datasets that simultaneously have integer copy numbers in CNV regions as well as SNP genotypes. At the same time, haplotypes that have been shown to offer advantages over genotypes in identifying disease traits even though available for SNP genotypes are largely not available for CNV/SNP data due to insufficient computational tools. We introduce a new framework for inferring haplotypes in CNV/SNP data using a sequential Monte Carlo sampling scheme 'Tree-Based Deterministic Sampling CNV' (TDSCNV). We compare our method with polyHap(v2.0), the only currently available software able to perform inference in CNV/SNP genotypes, on datasets of varying number of markers. We have found that both algorithms show similar accuracy but TDSCNV is an order of magnitude faster while scaling linearly with the number of markers and number of individuals and thus could be the method of choice for haplotype inference in such datasets. Our method is implemented in the TDSCNV package which is available for download at http://www.ee.columbia.edu/~anastas/tdscnv. PMID:24868199

  7. Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication

    E-print Network

    Lacy, Bob

    LETTERS Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication,2 . To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide poly- morphisms in dogs and their wild progenitor, the grey wolf. Here we

  8. Global survey of haplotype frequencies and linkage disequilibrium at the RET locus

    E-print Network

    Kidd, Kenneth

    , Roswell Park Cancer Institute, Buffalo, NY, USA; 4 Department of Obstetrics and Gynecology, Faculty populations had from four to eight haplotypes with frequencies exceeding 5%. In general, African, southwest SNP sites was very significant (Pp0.001) for all the non-African populations, but significant

  9. Analysis of Y-chromosomal SNP haplogroups and STR haplotypes in an Algerian population sample

    Microsoft Academic Search

    C. Robino; F. Crobu; C. Di Gaetano; A. Bekada; S. Benhamamouch; N. Cerutti; A. Piazza; S. Inturri; C. Torre

    2008-01-01

    The distribution of Y-chromosomal single nucleotide polymorphism (SNP) haplogroups and short tandem repeat (STR) haplotypes\\u000a was determined in a sample of 102 unrelated men of Arab origin from northwestern Algeria (Oran area). A total of nine different\\u000a haplogroups were identified by a panel of 22 binary markers. The most common haplogroups observed in the Algerian population\\u000a were E3b2 (45.1%) and

  10. Complex SNP-Based Haplotypes in Three Human Helicases: Implications for Cancer Association Studies

    PubMed Central

    Trikka, Dimitra; Fang, Zhe; Renwick, Alex; Jones, Sally H.; Chakraborty, Ranajit; Kimmel, Marek; Nelson, David L.

    2002-01-01

    We have initiated a candidate gene approach to study variation and predisposition to cancer in the four major ethnic groups that constitute the U.S. population (African Americans, Caucasians, Hispanics, and Asians). We resequenced portions of three helicase genes (BLM, WRN, and RECQL) identifying a total of 37 noncoding single nucleotide polymorphisms (SNPs). Haplotype inference predicted 50 haplotypes in BLM, 56 in WRN, and 47 in RECQL in a sample of 600 chromosomes. Approximately 10% of the predicted haplotypes were shared among all ethnic groups. Linkage disequilibrium and recombination effects showed that each locus has taken a diverse evolutionary path. Primate DNA analysis of the same loci revealed one human haplotype per gene shared with the great apes, indicating that the observed diversity occurred since the divergence of humans from the last common ancestor. In BLM, we confirmed the presence of a founder haplotype among Ashkenazi Jews homozygous for the blmAsh mutation. The cosegregating haplotype was seen in all (6/6) samples of Ashkenazi descent, whereas in the general population it has a low frequency (0.02) and was not found in African Americans. In WRN, ethnic samples were studied for their haplotype content and the presence or absence of six previously described coding SNPs (cSNPs). Hispanic individuals carrying two of these cSNPs showed a 60% increase in the frequency of a common haplotype (haplotype No. 28). In the pooled sample, no association was found. Because (1) the majority of the haplotypes are population specific and (2) the patterns of linkage disequilibrium, recombination, and haplotype diversity are markedly different between gene regions, these data show the importance of either ethnically matched controls or within-family-based disease-gene association studies. [The sequence data described in this paper have been submitted to the GenBank data library under accession no. AC006559. Online supplemental material available at http://www.genome.org] PMID:11932247

  11. Application of Homozygosity Haplotype Analysis to Genetic Mapping with High-Density SNP Genotype Data

    PubMed Central

    Jiang, Haiyan; Orr, Andrew; Guernsey, Duane L.; Robitaille, Johane; Asselin, Géraldine; Samuels, Mark E.; Dubé, Marie-Pierre

    2009-01-01

    Background In families segregating a monogenic genetic disorder with a single disease gene introduction, patients share a mutation-carrying chromosomal interval with identity-by-descent (IBD). Such a shared chromosomal interval or haplotype, surrounding the actual pathogenic mutation, is typically detected and defined by multipoint linkage and phased haplotype analysis using microsatellite or SNP genotype data. High-density SNP genotype data presents a computational challenge for conventional genetic analyses. A novel non-parametric method termed Homozygosity Haplotype (HH) was recently proposed for the genome-wide search of the autosomal segments shared among patients using high density SNP genotype data. Methodology/Principal Findings The applicability and the effectiveness of HH in identifying the potential linkage of disease causative gene with high-density SNP genotype data were studied with a series of monogenic disorders ascertained in eastern Canadian populations. The HH approach was validated using the genotypes of patients from a family affected with a rare autosomal dominant disease Schnyder crystalline corneal dystrophy. HH accurately detected the ?1 Mb genomic interval encompassing the causative gene UBIAD1 using the genotypes of only four affected subjects. The successful application of HH to identify the potential linkage for a family with pericentral retinal disorder indicates that HH can be applied to perform family-based association analysis by treating affected and unaffected family members as cases and controls respectively. A new strategy for the genome-wide screening of known causative genes or loci with HH was proposed, as shown the applications to a myoclonus dystonia and a renal failure cohort. Conclusions/Significance Our study of the HH approach demonstrates that HH is very efficient and effective in identifying potential disease linked region. HH has the potential to be used as an efficient alternative approach to sequencing or microsatellite-based fine mapping for screening the known causative genes in genetic disease study. PMID:19399176

  12. Haplotype-based profiling of subtle allelic imbalance with SNP arrays

    PubMed Central

    Vattathil, Selina; Scheet, Paul

    2013-01-01

    Due to limitations of surgical dissection and tumor heterogeneity, tumor samples collected for cancer genomics studies are often heavily diluted with normal tissue or contain subpopulations of cells harboring important aberrations. Methods for profiling tumor-associated allelic imbalance in such scenarios break down at aberrant cell proportions of 10%–15% and below. Here, we present an approach that offers a vast improvement for detection of subtle allelic imbalance, or low proportions of cells harboring aberrant allelic ratio among nonaberrant cells, in unpaired tumor samples using SNP microarrays. We leverage the expected pattern of allele-specific intensity ratios determined by an individual's germline haplotypes, information that has been ignored in existing approaches. We demonstrate our method on real and simulated data from the CRL-2324 breast cancer cell line genotyped on the Illumina 370K array. Assuming a 5 million SNP array, we can detect the presence of aberrant cells in proportions lower than 0.25% in the breast cancer sample, approaching the sensitivity of some minimal residual disease assays. Further, we apply a hidden Markov model to identify copy-neutral LOH (loss of heterozygosity) events as short as 11 Mb in mixtures of only 4% tumor using 370K data. We anticipate our approach will offer a new paradigm for genomic profiling of heterogeneous samples. PMID:23028187

  13. Estimating the frequency of Asian cytochrome B haplotypes in standard European and local Spanish pig breeds

    PubMed Central

    Clop, Alex; Amills, Marcel; Noguera, José Luís; Fernández, Ana; Capote, Juan; Ramón, Maria Misericňrdia; Kelly, Lucía; Kijas, James MH; Andersson, Leif; Sŕnchez, Armand

    2004-01-01

    Mitochondrial DNA has been widely used to perform phylogenetic studies in different animal species. In pigs, genetic variability at the cytochrome B gene and the D-loop region has been used as a tool to dissect the genetic relationships between different breeds and populations. In this work, we analysed four SNP at the cytochrome B gene to infer the Asian (A1 and A2 haplotypes) or European (E1 and E2 haplotypes) origins of several European standard and local pig breeds. We found a mixture of Asian and European haplotypes in the Canarian Black pig (E1, A1 and A2), German Piétrain (E1, A1 and A2), Belgian Piétrain (E1, A1), Large White (E1 and A1) and Landrace (E1 and A1) breeds. In contrast, the Iberian (Guadyerbas, Ervideira, Caldeira, Campanario, Puebla and Torbiscal strains) and the Majorcan Black pig breeds only displayed the E1 haplotype. Our results show that the introgression of Chinese pig breeds affected most of the major European standard breeds, which harbour Asian haplotypes at diverse frequencies (15–56%). In contrast, isolated local Spanish breeds, such as the Iberian and Majorcan Black pig, only display European cytochrome B haplotypes, a feature that evidences that they were not crossed with other Chinese or European commercial populations. These findings illustrate how geographical confinement spared several local Spanish breeds from the extensive introgression event that took place during the 18th and 19th centuries in Europe. PMID:14713412

  14. Linked region detection using high-density SNP genotype data via the minimum recombinant model of pedigree haplotype inference

    PubMed Central

    Wang, Lusheng; Wang, Zhanyong; Yang, Wanling

    2009-01-01

    Background With the rapid development of high-throughput genotyping technologies, efficient methods for identifying linked regions using high-density SNP genotype data have become more and more important. Recently, a deterministic method that works very well on SNP genotyping data has been developed (Lin et al. Bioinformatics 2008, 24(1): 86–93). However, that program can only work on a limited number of family structures. In particular, the results (if any) will be poor when the genotype data for the whole chromosome of one of the parents in a nuclear family is missing. Results We have developed a software package (LIden) for identifying linked regions using high-density SNP genotype data. We focus on handling the case where the genotype data for the whole chromosome of one of the parents in a nuclear family is missing. We use the minimum recombinant model for haplotype inference in pedigrees. Several local optimization algorithms are used to infer the haplotype of each individual and determine the linked regions based on the inferred haplotype data. We have developed a more flexible method to combine nuclear families to further refine (reduce the length of) the linked regions. Conclusion Our new package (LIden) is efficient software for linked region detection using high-density SNP genotype data. LIden can handle some important cases where the existing programs do not work well. In particular, the new package can handle many cases where the genotype data of one of the two parents is missing for the entire chromosome. The running time of the program is O(mn), where m is the number of members in the family and n is the number of SNP sites in the chromosome. LIden is specifically suitable for handling big sized families. This research also demonstrates another practical use of the minimum recombinant model for haplotype inference in pedigrees. The software package can be downloaded at . PMID:19604391

  15. An artificial neural network for estimating haplotype frequencies

    PubMed Central

    Cartier, Kevin C; Baechle, Daniel

    2005-01-01

    The problem of estimating haplotype frequencies from population data has been considered by numerous investigators, resulting in a wide variety of possible algorithmic and statistical solutions. We propose a relatively unique approach that employs an artificial neural network (ANN) to predict the most likely haplotype frequencies from a sample of population genotype data. Through an innovative ANN design for mapping genotype patterns to diplotypes, we have produced a prototype that demonstrates the feasibility of this approach, with provisional results that correlate well with estimates produced by the expectation maximization algorithm for haplotype frequency estimation. Given the computational demands of estimating haplotype frequencies for 20 or more single-nucleotide polymorphisms, the ANN approach is promising because its design fits well with parallel computing architectures. PMID:16451587

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

    PubMed Central

    2012-01-01

    Background Typically, the first phase of a genome wide association study (GWAS) includes genotyping across hundreds of individuals and validation of the most significant SNPs. Allelotyping of pooled genomic DNA is a common approach to reduce the overall cost of the study. Knowledge of haplotype structure can provide additional information to single locus analyses. Several methods have been proposed for estimating haplotype frequencies in a population from pooled DNA data. Results We introduce a technique for haplotype frequency estimation in a population from pooled DNA samples focusing on datasets containing a small number of individuals per pool (2 or 3 individuals) and a large number of markers. We compare our method with the publicly available state-of-the-art algorithms HIPPO and HAPLOPOOL on datasets of varying number of pools and marker sizes. We demonstrate that our algorithm provides improvements in terms of accuracy and computational time over competing methods for large number of markers while demonstrating comparable performance for smaller marker sizes. Our method is implemented in the "Tree-Based Deterministic Sampling Pool" (TDSPool) package which is available for download at http://www.ee.columbia.edu/~anastas/tdspool. Conclusions Using a tree-based determinstic sampling technique we present an algorithm for haplotype frequency estimation from pooled data. Our method demonstrates superior performance in datasets with large number of markers and could be the method of choice for haplotype frequency estimation in such datasets. PMID:23110720

  17. Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11

    Microsoft Academic Search

    T Li; D Ball; J Zhao; R M Murray; X Liu; P C Sham; D A Collier

    2000-01-01

    Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed

  18. The Structure of Haplotype Blocks in the Human Genome

    Microsoft Academic Search

    Stacey B. Gabriel; Stephen F. Schaffner; Huy Nguyen; Jamie M. Moore; Jessica Roy; Brendan Blumenstiel; John Higgins; Matthew DeFelice; Amy Lochner; Maura Faggart; Shau Neen Liu-Cordero; Charles Rotimi; Adebowale Adeyemo; Richard Cooper; Ryk Ward; Eric S. Lander; Mark J. Daly; David Altshuler

    2002-01-01

    Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the

  19. Global patterns of variation in allele and haplotype frequencies and linkage disequilibrium across the CYP2E1 gene

    PubMed Central

    Lee, Mi-Young; Mukherjee, Namita; Pakstis, Andrew J.; Khaliq, Shagufta; Mohyuddin, Aisha; Mehdi, S. Qasim; Speed, William C.; Kidd, Judith R.; Kidd, Kenneth K.

    2009-01-01

    Cytochrome P450 2E1, gene symbol CYP2E1, is one of a family of enzymes with a central role in activating and detoxifying xenobiotics and endogenous compounds. Genetic variation at this gene has been reported in different human populations, and some association studies have reported increased risk for cancers and other diseases. To the best of our knowledge, multi-SNP haplotypes and linkage disequilibrium (LD) have not been systematically studied for CYP2E1 in multiple populations. Haplotypes can greatly increase the power both to identify patterns of genetic variation relevant for gene expression as well as to detect disease-related susceptibility mutations. We present frequency and LD data and analyses for 11 polymorphisms and their haplotypes that we have studied on over 2,600 individuals from 50 human population samples representing the major geographical regions of the world. The diverse patterns of haplotype variation found in the different populations we have studied show that ethnicity may be an important variable helping to explain inconsistencies that have been reported by association studies. More studies clearly are needed of the variants we have studied, especially those in the 5? region, such as the VNTR, as well as studies of additional polymorphisms known for this gene to establish evidence relating any systematic differences in gene expression that exist to the haplotypes at this gene. PMID:18663376

  20. Significant variation in haplotype block structure but conservation in tagSNP patterns among global

    E-print Network

    Kidd, Kenneth

    and understanding human population history.1 ­ 4 Some haplotype studies have suggested that the human genome can on limited population samples has Received 21 July 2006; revised 26 September 2006; accepted 25 October 2006 among global populations Sheng Gu1 , Andrew J Pakstis1 , Hui Li1 , William C Speed1 , Judith R Kidd1

  1. Haplotypes and Informative SNP Selection Algorithms: Don't Block Out Information

    E-print Network

    Bafna, Vineet

    results in unac- ceptably high costs for exhaustive genotyping, and so there is a broad effort are not made or distributed for profit or commercial advantage and that copies bear this notice and the full. INTRODUCTION In anticipation of cost-effective SNP genotyping technol- ogy and the availability of a large

  2. SNP analyses of growth factor genes EGF, TGF{beta}-1, and HGF reveal haplotypic association of EGF with autism

    SciTech Connect

    Toyoda, Takao; Thanseem, Ismail; Kawai, Masayoshi; Sekine, Yoshimoto [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Nakamura, Kazuhiko; Anitha, Ayyappan; Suda, Shiro [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan)]. E-mail: nakamura@hama-med.ac.jp; Yamada, Kazuo [Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama (Japan); Tsujii, Masatsugu [Faculty of Sociology, Chukyo University, Toyota, Aichi (Japan)]|[The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan); Iwayama, Yoshimi; Hattori, Eiji; Toyota, Tomoko; Yoshikawa, Takeo [Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama (Japan); Miyachi, Taishi; Tsuchiya, Kenji; Sugihara, Gen-ichi; Matsuzaki, Hideo [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan); Iwata, Yasuhide; Suzuki, Katsuaki [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan); Mori, Norio [Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192 (Japan)]|[The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Graduate School of Medicine, Osaka University (Japan); Ouchi, Yasuomi [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan)]|[The Positron Medical Center, Hamamatsu Medical Center, Hamamatsu (Japan); Sugiyama, Toshiro [Aichi Children's Health and Medical Center, Obu, Aichi (Japan); Takei, Nori [The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu (Japan)

    2007-09-07

    Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-{beta} (TGF{beta}) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGF{beta}1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGF{beta}1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism.

  3. Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

    PubMed Central

    Campos, Marco; Sun, Wei; Yu, Fuli; Barbalic, Maja; Tang, Weihong; Chambless, Lloyd E.; Wu, Kenneth K.; Ballantyne, Christie; Folsom, Aaron R.; Boerwinkle, Eric

    2011-01-01

    von Willebrand factor (VWF) is an essential component of hemostasis and has been implicated in thrombosis. Multimer size and the amount of circulating VWF are known to impact hemostatic function. We associated 78 VWF single nucleotide polymorphisms (SNPs) and haplotypes constructed from those SNPs with VWF antigen level in 7856 subjects of European descent. Among the nongenomic factors, age and body mass index contributed 4.8% and 1.6% of VWF variation, respectively. The SNP rs514659 (tags O blood type) contributed 15.4% of the variance. Among the VWF SNPs, we identified 18 SNPs that are associated with levels of VWF. The correlative SNPs are either intronic (89%) or silent exonic (11%). Although SNPs examined are distributed throughout the entire VWF gene without apparent cluster, all the positive SNPs are located in a 50-kb region. Exons in this region encode for VWF D2, D?, and D3 domains that are known to regulate VWF multimerization and storage. Mutations in the D3 domain are also associated with von Willebrand disease. Fifteen of these 18 correlative SNPs are in 2 distinct haplotype blocks. In summary, we identified a cluster of intronic VWF SNPs that associate with plasma levels of VWF, individually or additively, in a large cohort of healthy subjects. PMID:21343614

  4. Detection of recombination events, haplotype reconstruction and imputation of sires using half-sib SNP genotypes

    PubMed Central

    2014-01-01

    Background Identifying recombination events and the chromosomal segments that constitute a gamete is useful for a number of applications in genomic analyses. In livestock, genotypic data are commonly available for half-sib families. We propose a straightforward but computationally efficient method to use single nucleotide polymorphism marker genotypes on half-sibs to reconstruct the recombination and segregation events that occurred during meiosis in a sire to form the haplotypes observed in its offspring. These meiosis events determine a block structure in paternal haplotypes of the progeny and this can be used to phase the genotypes of individuals in single half-sib families, to impute haplotypes of the sire if they are not genotyped or to impute the paternal strand of the offspring’s sequence based on sequence data of the sire. Methods The hsphase algorithm exploits information from opposing homozygotes among half-sibs to identify recombination events, and the chromosomal regions from the paternal and maternal strands of the sire (blocks) that were inherited by its progeny. This information is then used to impute the sire’s genotype, which, in turn, is used to phase the half-sib family. Accuracy (defined as R2) and performance of this approach were evaluated by using simulated and real datasets. Phasing results for the half-sibs were benchmarked to other commonly used phasing programs – AlphaPhase, BEAGLE and PedPhase 3. Results Using a simulated dataset with 20 markers per cM, and for a half-sib family size of 4 and 40, the accuracy of block detection, was 0.58 and 0.96, respectively. The accuracy of inferring sire genotypes was 0.75 and 1.00 and the accuracy of phasing was around 0.97, respectively. hsphase was more robust to genotyping errors than PedPhase 3, AlphaPhase and BEAGLE. Computationally, hsphase was much faster than AlphaPhase and BEAGLE. Conclusions In half-sib families of size 8 and above, hsphase can accurately detect block structure of paternal haplotypes, impute genotypes of ungenotyped sires and reconstruct haplotypes in progeny. The method is much faster and more accurate than other widely used population-based phasing programs. A program implementing the method is freely available as an R package (hsphase). PMID:24495596

  5. Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication

    PubMed Central

    vonHoldt, Bridgett M.; Pollinger, John P.; Lohmueller, Kirk E.; Han, Eunjung; Parker, Heidi G.; Quignon, Pascale; Degenhardt, Jeremiah D.; Boyko, Adam R.; Earl, Dent A.; Auton, Adam; Reynolds, Andy; Bryc, Kasia; Brisbin, Abra; Knowles, James C.; Mosher, Dana S.; Spady, Tyrone C.; Elkahloun, Abdel; Geffen, Eli; Pilot, Malgorzata; Jedrzejewski, Wlodzimierz; Greco, Claudia; Randi, Ettore; Bannasch, Danika; Wilton, Alan; Shearman, Jeremy; Musiani, Marco; Cargill, Michelle; Jones, Paul G.; Qian, Zuwei; Huang, Wei; Ding, Zhao-Li; Zhang, Ya-ping; Bustamante, Carlos D.; Ostrander, Elaine A.; Novembre, John; Wayne, Robert K.

    2010-01-01

    Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication1,2. To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data3. Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity. PMID:20237475

  6. Expanding X-chromosomal forensic haplotype frequencies database: Italian population data of four linkage groups.

    PubMed

    Bini, Carla; Riccardi, Laura Natalia; Ceccardi, Stefania; Carano, Francesco; Sarno, Stefania; Luiselli, Donata; Pelotti, Susi

    2015-03-01

    Requests for solving complex kinship casework involving at least one female are increasing and in these circumstances the analysis of X-chromosomal STR markers plays a relevant role. Actually, it is well known the superior statistical power of X-STRs compared to autosomal markers in solving relationship when two sisters or half-sisters are involved and none of parents is available, in maternity testing or in cases involving close relatives as alternative putative fathers. In addition, the possibility to amplify more loci simultaneously and the strategy based on the analysis of four linkage groups to obtain the X-haplotype provide a powerful and validated tool. Nevertheless, haplotypes frequency distribution in different populations is still needed for calculation of probabilities in relationship testing. Published haplotype frequencies from German population data are available, but in different caseworks we found unreported X-haplotypes. To enlarge the forensic X-chromosome database, we present haplotype frequencies and other parameter of forensic interest obtained from 200 anonymous DNA samples of unrelated Italian males for the four linkage groups included in the Investigator Argus X-12 kit. From the comparison of the Italian sample haplotype frequencies with other populations, significant genetic distances were found with Asian and African populations, but not with Europeans. Finally, casework examples of complex kinship analysis are presented. PMID:25435156

  7. Maximum-parsimony haplotype frequencies inference based on a joint constrained sparse representation of pooled DNA

    PubMed Central

    2013-01-01

    Background DNA pooling constitutes a cost effective alternative in genome wide association studies. In DNA pooling, equimolar amounts of DNA from different individuals are mixed into one sample and the frequency of each allele in each position is observed in a single genotype experiment. The identification of haplotype frequencies from pooled data in addition to single locus analysis is of separate interest within these studies as haplotypes could increase statistical power and provide additional insight. Results We developed a method for maximum-parsimony haplotype frequency estimation from pooled DNA data based on the sparse representation of the DNA pools in a dictionary of haplotypes. Extensions to scenarios where data is noisy or even missing are also presented. The resulting method is first applied to simulated data based on the haplotypes and their associated frequencies of the AGT gene. We further evaluate our methodology on datasets consisting of SNPs from the first 7Mb of the HapMap CEU population. Noise and missing data were further introduced in the datasets in order to test the extensions of the proposed method. Both HIPPO and HAPLOPOOL were also applied to these datasets to compare performances. Conclusions We evaluate our methodology on scenarios where pooling is more efficient relative to individual genotyping; that is, in datasets that contain pools with a small number of individuals. We show that in such scenarios our methodology outperforms state-of-the-art methods such as HIPPO and HAPLOPOOL. PMID:24010487

  8. Fish scales and SNP chips: SNP genotyping and allele frequency estimation in individual and pooled DNA from historical samples of Atlantic salmon (Salmo salar)

    PubMed Central

    2013-01-01

    Background DNA extracted from historical samples is an important resource for understanding genetic consequences of anthropogenic influences and long-term environmental change. However, such samples generally yield DNA of a lower amount and quality, and the extent to which DNA degradation affects SNP genotyping success and allele frequency estimation is not well understood. We conducted high density SNP genotyping and allele frequency estimation in both individual DNA samples and pooled DNA samples extracted from dried Atlantic salmon (Salmo salar) scales stored at room temperature for up to 35 years, and assessed genotyping success, repeatability and accuracy of allele frequency estimation using a high density SNP genotyping array. Results In individual DNA samples, genotyping success and repeatability was very high (> 0.973 and?>?0.998, respectively) in samples stored for up to 35 years; both increased with the proportion of DNA of fragment size?>?1000 bp. In pooled DNA samples, allele frequency estimation was highly repeatable (Repeatability?=?0.986) and highly correlated with empirical allele frequency measures (Mean Adjusted R2?=?0.991); allele frequency could be accurately estimated in?>?95% of pooled DNA samples with a reference group of at least 30 individuals. SNPs located in polyploid regions of the genome were more sensitive to DNA degradation: older samples had lower genotyping success at these loci, and a larger reference panel of individuals was required to accurately estimate allele frequencies. Conclusions SNP genotyping was highly successful in degraded DNA samples, paving the way for the use of degraded samples in SNP genotyping projects. DNA pooling provides the potential for large scale population genetic studies with fewer assays, provided enough reference individuals are also genotyped and DNA quality is properly assessed beforehand. We provide recommendations for future studies intending to conduct high-throughput SNP genotyping and allele frequency estimation in historical samples. PMID:23819691

  9. Novel Quantitative Real-Time LCR for the Sensitive Detection of SNP Frequencies in Pooled DNA: Method Development, Evaluation and Application

    Microsoft Academic Search

    Androniki Psifidi; Chrysostomos Dovas; Georgios Banos; Katy C. Kao

    2011-01-01

    BackgroundSingle nucleotide polymorphisms (SNP) have proven to be powerful genetic markers for genetic applications in medicine, life science and agriculture. A variety of methods exist for SNP detection but few can quantify SNP frequencies when the mutated DNA molecules correspond to a small fraction of the wild-type DNA. Furthermore, there is no generally accepted gold standard for SNP quantification, and,

  10. High frequency of intermediate alleles on Huntington disease-associated haplotypes in British Columbia's general population.

    PubMed

    Semaka, Alicia; Kay, Chris; Doty, Crystal N; Collins, Jennifer A; Tam, Natalie; Hayden, Michael R

    2013-12-01

    Intermediate alleles (27-35?CAG, IAs) for Huntington disease (HD) usually do not confer the disease phenotype but are prone to CAG repeat instability. Consequently, offspring are at-risk of inheriting an expanded allele in the HD range (?36?CAG). IAs that expand into a new mutation have been hypothesized to be more susceptible to instability compared to IAs identified on the non-HD side of a family from the general population. Frequency estimates for IAs are limited and have largely been determined using clinical samples of HD or related disorders, which may result in an ascertainment bias. This study aimed to establish the frequency of IAs in a sample of a British Columbia's (B.C.) general population with no known association to HD and examine the haplotype of new mutation and general population IAs. CAG sizing was performed on 1,600 DNA samples from B.C.'s general population. Haplotypes were determined using 22 tagging SNPs across the HTT gene. 5.8% of individuals were found to have an IA, of which 60% were on HD-associated haplotypes. There was no difference in the haplotype distribution of new mutation and general population IAs. These findings suggest that IAs are relatively frequent in the general population and are often found on haplotypes associated with expanded CAG lengths. There is likely no difference in the propensity of new mutation and general population IAs to expand into the disease range given that they are both found on disease-associated haplotypes. These findings have important implications for clinical practice. PMID:24038799

  11. Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX

    Microsoft Academic Search

    Tom R. Gaunt; Santiago Rodríguez; Ian N. M. Day

    2007-01-01

    Background: The frequency of a haplotype comprising one allele at each of two loci can be expressed as a cubic equation (the 'Hill equation'), the solution of which gives that frequency. Most haplotype and linkage disequilibrium analysis programs use iteration-based algorithms which substitute an estimate of haplotype frequency into the equation, producing a new estimate which is repeatedly fed back

  12. Maximum likelihood estimation of frequencies of known haplotypes from pooled sequence data.

    PubMed

    Kessner, Darren; Turner, Thomas L; Novembre, John

    2013-05-01

    DNA samples are often pooled, either by experimental design or because the sample itself is a mixture. For example, when population allele frequencies are of primary interest, individual samples may be pooled together to lower the cost of sequencing. Alternatively, the sample itself may be a mixture of multiple species or strains (e.g., bacterial species comprising a microbiome or pathogen strains in a blood sample). We present an expectation-maximization algorithm for estimating haplotype frequencies in a pooled sample directly from mapped sequence reads, in the case where the possible haplotypes are known. This method is relevant to the analysis of pooled sequencing data from selection experiments, as well as the calculation of proportions of different species within a metagenomics sample. Our method outperforms existing methods based on single-site allele frequencies, as well as simple approaches using sequence read data. We have implemented the method in a freely available open-source software tool. PMID:23364324

  13. The new Y Chromosome Haplotype Reference Database.

    PubMed

    Willuweit, Sascha; Roewer, Lutz

    2015-03-01

    After opening the first version of an internet-accessible worldwide reference database of Y chromosome profiles 14 years ago and six years after the last major relaunch the new YHRD 4.0 repository and website has been rolled-out. By November 2014 about 136k 9-locus haplotypes, among these 84k 17-locus haplotypes, 25k 23-locus haplotypes and 15k Y SNP profiles from 917 sampling locations in 128 countries have been submitted by more than 250 institutes and laboratories. In geographic terms, about 39% of the YHRD samples are from Europe, 32% from Asia, 16% from South America, 6% from North America, 4% from Africa and 2% from Oceania/Australia. Worldwide collaboration is the driving force for the rapid growth of the database and this, in turn, allows the evaluation and implementation of enhanced interpretation tools (variable frequency estimators, LR-based mixture and kinship analysis, Y-SNP-based ancestry assessment). PMID:25529991

  14. HLA-A, -B, -DR haplotype frequencies in the Thai Stem Cell Donor Registry.

    PubMed

    Kupatawintu, P; Pheancharoen, S; Srisuddee, A; Tanaka, H; Tadokoro, K; Nathalang, O

    2010-06-01

    This study aimed to report antigen and haplotype frequencies (HFs) in the Thai Stem Cell Donor Registry (TSCDR). From 16,807 human leukocyte antigen (HLA)-A, -B, and -DR typed donors, 19 HLA-A, 41 HLA-B, and 13 HLA-DR antigens were found. HLA-A43, A80, B78, B82, B83, and DR18 were not observed. A total of 1921 haplotypes were estimated and 245 haplotypes were reliable and their cumulative HF was 75.74%. Similar to previous Thai subpopulation studies, the most common haplotypes were HLA-A33-B58-DR17 (4.54%), A2-B46-DR9 (4.11%), A33-B44-DR7 (2.85%), and A11-B75-DR12 (2.00%). To evaluate the probability in finding matched donors, from April 2002 to August 2008, 793 Thai patients were requested for unrelated stem cell donor searching. The number of patients with HLA-A, -B, -DR split matched donor found were 49%. Only 8% of the patients found matched donor within 1 month. However, high-resolution HLA-A, -B, -DR typing in TSCDR is suggested to accurately estimate HFs and evaluate the probability in finding a matched donor for patients in the future. PMID:20230524

  15. Allele-Level Haplotype Frequencies and Pairwise Linkage Disequilibrium for 14 KIR Loci in 506 European-American Individuals

    PubMed Central

    Vierra-Green, Cynthia; Roe, David; Hou, Lihua; Hurley, Carolyn Katovich; Rajalingam, Raja; Reed, Elaine; Lebedeva, Tatiana; Yu, Neng; Stewart, Mary; Noreen, Harriet; Hollenbach, Jill A.; Guethlein, Lisbeth A.; Wang, Tao; Spellman, Stephen; Maiers, Martin

    2012-01-01

    The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5?KIR2DS3S5 and KIR2DS3S5?KIR2DL1, and telomeric KIR3DL1?KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis. PMID:23139747

  16. Haplotypic Background of a Private Allele at High Frequency in the Americas

    PubMed Central

    Schroeder, Kari B.; Jakobsson, Mattias; Crawford, Michael H.; Schurr, Theodore G.; Boca, Simina M.; Conrad, Donald F.; Tito, Raul Y.; Osipova, Ludmilla P.; Tarskaia, Larissa A.; Zhadanov, Sergey I.; Wall, Jeffrey D.; Pritchard, Jonathan K.; Malhi, Ripan S.; Smith, David G.; Rosenberg, Noah A.

    2009-01-01

    Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 single nucleotide polymorphisms across ?500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the “American Modal Haplotype” (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared with other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared with that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all modern Native Americans and Western Beringians trace a large portion of their ancestry to a single founding population that may have been isolated from other Asian populations prior to expanding into the Americas. PMID:19221006

  17. Analysis of concordance of different haplotype block partitioning algorithms

    PubMed Central

    Indap, Amit R; Marth, Gabor T; Struble, Craig A; Tonellato, Peter; Olivier, Michael

    2005-01-01

    Background Different classes of haplotype block algorithms exist and the ideal dataset to assess their performance would be to comprehensively re-sequence a large genomic region in a large population. Such data sets are expensive to collect. Alternatively, we performed coalescent simulations to generate haplotypes with a high marker density and compared block partitioning results from diversity based, LD based, and information theoretic algorithms under different values of SNP density and allele frequency. Results We simulated 1000 haplotypes using the standard coalescent for three world populations – European, African American, and East Asian – and applied three classes of block partitioning algorithms – diversity based, LD based, and information theoretic. We assessed algorithm differences in number, size, and coverage of blocks inferred under different conditions of SNP density, allele frequency, and sample size. Each algorithm inferred blocks differing in number, size, and coverage under different density and allele frequency conditions. Different partitions had few if any matching block boundaries. However they still overlapped and a high percentage of total chromosomal region was common to all methods. This percentage was generally higher with a higher density of SNPs and when rarer markers were included. Conclusion A gold standard definition of a haplotype block is difficult to achieve, but collecting haplotypes covered with a high density of SNPs, partitioning them with a variety of block algorithms, and identifying regions common to all methods may be the best way to identify genomic regions that harbor SNP variants that cause disease. PMID:16356172

  18. Determination of HLA-A, -C, -B, -DRB1 allele and haplotype frequency in Japanese population based on family study.

    PubMed

    Ikeda, N; Kojima, H; Nishikawa, M; Hayashi, K; Futagami, T; Tsujino, T; Kusunoki, Y; Fujii, N; Suegami, S; Miyazaki, Y; Middleton, D; Tanaka, H; Saji, H

    2015-04-01

    The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B-DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies. PMID:25789826

  19. Rainfall-driven sex-ratio genes in African buffalo suggested by correlations between Y-chromosomal haplotype frequencies and foetal sex ratio

    Microsoft Academic Search

    Pim van Hooft; Herbert HT Prins; Wayne M Getz; Anna E Jolles; Sipke E van Wieren; Barend J Greyling; Paul D van Helden; Armanda DS Bastos

    2010-01-01

    BACKGROUND: The Y-chromosomal diversity in the African buffalo (Syncerus caffer) population of Kruger National Park (KNP) is characterized by rainfall-driven haplotype frequency shifts between year cohorts. Stable Y-chromosomal polymorphism is difficult to reconcile with haplotype frequency variations without assuming frequency-dependent selection or specific interactions in the population dynamics of X- and Y-chromosomal genes, since otherwise the fittest haplotype would inevitably

  20. Announcement of Population Data Allele frequencies for 70 autosomal SNP loci with

    E-print Network

    Interstate Blood Bank, Inc. (Memphis, TN) and Millennium Biotech, Inc. (Ft. Lauderdale, FL). All samples were. SNP markers The 70 autosomal SNP markers are listed in Table 1 (see also http://www.cstl.nist.gov/biotech

  1. Frequencies of two functionally significant SNPs and their haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in six ethnic groups of Pakistani population

    PubMed Central

    Rajput, Tausif Ahmed; Naveed, Abdul Khaliq; Khan, Shakir; Farooqi, Zia-Ur-Rehman

    2014-01-01

    Objective(s): Organic anion transporter polypeptide 1B1 (OATP1B1) encoded by solute carrier organic transporter 1B1 (SLCO1B1) gene; a transporter involved in the uptake of drugs and endogenous compounds is present in hepatocyte sinusoidal membrane. Aim of this study was to investigate the frequencies of functionally significant SNPs (388A>G and 521T>C) and their haplotypes in 6 ethnic groups of Pakistani population through the development of rapid and efficient Tetra amplification refractory mutation system (T. ARMS) genotyping assay. Materials and Methods: Frequencies of alleles, genotype, and haplotypes of two functionally significant Single nucleotide polymorphism in 180 healthy Pakistani subjects and distributions in six ethnic groups by using a single step T. ARMS genotyping assay. Results: The allelic frequency for 388A>G SNP was 50% in total Pakistani population with Single nucleotide polymorphism distributions of 9.7%, 15.1%, 19.4%, 16.1%, 18.3%, and 21.5% in Punjabi, Sindhi, Balouchi, Pathan, Kashmiri and Hazara/Baltistan groups respectively; and for 521T>C SNP it was 23.9% in total Pakistani population with distributions of 11.1%, 8.9%, 15.6%, 11.1%, 31.1% and 22.2% in Punjabi, Sindhi, Balouchi, Pathan, Kashmiri, and Hazara/Baltistan groups. Both functionally significant SNPs occurred in four major haplotypes with a frequency of 35.5% for 388A/521T (*1A), 40.5% for 388G/521T (*1B), 14.4% for 388A/521C (*5), and 9.4% for 388G/521C (*15) with varying distributions among six ethnic groups. Conclusion: The 388A>G and 521T>C genotypes and corresponding haplotypes are present at varying frequencies in various ethnic groups of Pakistani population. Pharmacokinetic and pharmacodynamic profiling is needed to assess and characterize the effects of these haplotypes in our population. PMID:25140206

  2. Constraints on haplotype structure and variable gene frequencies suggest a functional hierarchy within cattle MHC class I.

    PubMed

    Codner, Gemma F; Birch, James; Hammond, John A; Ellis, Shirley A

    2012-06-01

    Six major histocompatibility complex (MHC) classical class I genes have been identified in cattle, and up to three of these are expressed in variable combinations on different haplotypes. The origin and functional significance of this genetic complexity is unknown. However, an improved assembly of the cattle genome, an expanded database of full-length cDNA sequences and high-resolution frequency data concerning expressed class I genes in an economically important cattle breed combine to provide a new opportunity to study the significance of cattle MHC class I diversity. Analysis of these new data supports assignment of alleles to six discrete genes and further shows that all these classical genes share a common ancestor with a single non-classical gene, NC1. While haplotype structure is variable, with thirteen gene configurations identified, there are nevertheless clear constraints relating to both the number and combination of genes. Haplotypes expressing two classical genes are most frequently observed, and the classical class I gene 2 is almost invariably present. The frequency data support the dominance of gene 2, showing that close to 100 % of individuals carry at least one copy. This indicates a hierarchy in the functional importance of particular genes and haplotype structures. Haplotype frequency in cattle populations is therefore likely to impact on differential disease susceptibilities. This knowledge will be important for development of informed breeding strategies aimed at increasing the ability of cattle to survive in the face of future unpredictable pathogen exposure. PMID:22454046

  3. Heuristics for haplotype frequency estimation with a large number of analyzed loci

    NASA Astrophysics Data System (ADS)

    Nowotka, Micha?; Nowak, Robert

    Determining haplotypes with laboratory methods is an expensive and time-consuming activity therefore unsuit- able for the analysis of genetic data coming from a large number of tested individuals. Many existing algorithms for phasing genotypes operate on very impractical runtime and take into account only certain types of polymor- phisms, often without providing graphical user interface. The heuristic algorithm for estimating haplotype frequency developed in this work was examined in terms of time complexity, the speed of execution and the accuracy of results. Consequently, a Rich Internet Application that implements described algorithm has been created and its performance and accuracy to a known set of test data is analyzed. Eventually, a discussion on the architecture and the applications usability in bioinformatics applications is presented. Proposed algorithm can be used to improve the complexity of any algorithm that solves the problem of genotype phasing, which has a worse time complexity and is convergent. The algorithm is easy to scale and can achieve the desired ratio of calculations accuracy to execution time. Implemented application meets all requirements for the programs to solve problems in biology i.e. high performance, accessibility, scalability and usability.

  4. Allele frequencies of a SNP and a 27-bp deletion that are the determinant of earwax type in the ABCC11 gene

    Microsoft Academic Search

    Takashi Kitano; Isao Yuasa; Kentaro Yamazaki; Nori Nakayashiki; Aya Miyoshi; Kyung Sook Park; Kazuo Umetsu

    2008-01-01

    Allele frequencies for a SNP (rs17822931) and a 27-bp deletion that are the determinant of earwax type in the ABCC11 gene were investigated in seven Japanese, one Korean, and one German populations. The SNP will be useful as one of ancestry information markers, because it showed marked difference in frequencies between Asian and European populations.

  5. Detecting local haplotype sharing and haplotype association.

    PubMed

    Xu, Hanli; Guan, Yongtao

    2014-07-01

    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 sharing between individuals at each marker. A statistical model was developed to link the local haplotype sharing and phenotypes to test for association. We devised a novel method to fit the LD model, reducing the complexity from putatively quadratic to linear (in the number of ancestral haplotypes). Therefore, the LD model can be fitted to all study samples simultaneously, and, consequently, our method is applicable to big data sets. Compared to existing haplotype association methods, our method integrated out phase uncertainty, avoided arbitrariness in specifying haplotypes, and had the same number of tests as the single-SNP analysis. We applied our method to data from the Wellcome Trust Case Control Consortium and discovered eight novel associations between seven gene regions and five disease phenotypes. Among these, GRIK4, which encodes a protein that belongs to the glutamate-gated ionic channel family, is strongly associated with both coronary artery disease and rheumatoid arthritis. A software package implementing methods described in this article is freely available at http://www.haplotype.org. PMID:24812308

  6. Detecting Local Haplotype Sharing and Haplotype Association

    PubMed Central

    Xu, Hanli; Guan, Yongtao

    2014-01-01

    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 sharing between individuals at each marker. A statistical model was developed to link the local haplotype sharing and phenotypes to test for association. We devised a novel method to fit the LD model, reducing the complexity from putatively quadratic to linear (in the number of ancestral haplotypes). Therefore, the LD model can be fitted to all study samples simultaneously, and, consequently, our method is applicable to big data sets. Compared to existing haplotype association methods, our method integrated out phase uncertainty, avoided arbitrariness in specifying haplotypes, and had the same number of tests as the single-SNP analysis. We applied our method to data from the Wellcome Trust Case Control Consortium and discovered eight novel associations between seven gene regions and five disease phenotypes. Among these, GRIK4, which encodes a protein that belongs to the glutamate-gated ionic channel family, is strongly associated with both coronary artery disease and rheumatoid arthritis. A software package implementing methods described in this article is freely available at http://www.haplotype.org. PMID:24812308

  7. SNP discovery and allele frequency estimation by deep sequencing of reduced representation libraries

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genome projects routinely produce draft sequences for species from diverse evolutionary clades, but generally do not create single nucleotide polymorphism (SNP) resources. We present an approach for de novo SNP discovery based on short-read sequencing of reduced representation libraries (RRL) to ge...

  8. Inference on Haplotype Effects in Case-Control Studies Using Unphased Genotype Data

    PubMed Central

    Epstein, Michael P.; Satten, Glen A.

    2003-01-01

    A variety of statistical methods exist for detecting haplotype-disease association through use of genetic data from a case-control study. Since such data often consist of unphased genotypes (resulting in haplotype ambiguity), such statistical methods typically apply the expectation-maximization (EM) algorithm for inference. However, the majority of these methods fail to perform inference on the effect of particular haplotypes or haplotype features on disease risk. Since such inference is valuable, we develop a retrospective likelihood for estimating and testing the effects of specific features of single-nucleotide polymorphism (SNP)-based haplotypes on disease risk using unphased genotype data from a case-control study. Our proposed method has a flexible structure that allows, among other choices, modeling of multiplicative, dominant, and recessive effects of specific haplotype features on disease risk. In addition, our method relaxes the requirement of Hardy-Weinberg equilibrium of haplotype frequencies in case subjects, which is typically required of EM-based haplotype methods. Also, our method easily accommodates missing SNP information. Finally, our method allows for asymptotic, permutation-based, or bootstrap inference. We apply our method to case-control SNP genotype data from the Finland–United States Investigation of Non-Insulin-Dependent Diabetes Mellitus (FUSION) Genetics study and identify two haplotypes that appear to be significantly associated with type 2 diabetes. Using the FUSION data, we assess the accuracy of asymptotic P values by comparing them with P values obtained from a permutation procedure. We also assess the accuracy of asymptotic confidence intervals for relative-risk parameters for haplotype effects, by a simulation study based on the FUSION data. PMID:14631556

  9. ?-Calpain, calpastatin, and growth hormone receptor genetic effects on preweaning performance, carcass quality traits, and residual variance of tenderness in Angus cattle selected to increase minor haplotype and allele frequencies.

    PubMed

    Tait, R G; Shackelford, S D; Wheeler, T L; King, D A; Casas, E; Thallman, R M; Smith, T P L; Bennett, G L

    2014-02-01

    Genetic marker effects and interactions are estimated with poor precision when minor marker allele frequencies are low. An Angus population was subjected to marker assisted selection for multiple years to increase divergent haplotype and minor marker allele frequencies to 1) estimate effect size and mode of inheritance for previously reported SNP on targeted beef carcass quality traits; 2) estimate effects of previously reported SNP on nontarget performance traits; and 3) evaluate tenderness SNP specific residual variance models compared to a single residual variance model for tenderness. Divergent haplotypes within µ-calpain (CAPN1), and SNP within calpastatin (CAST) and growth hormone receptor (GHR) were successfully selected to increase their frequencies. Traits evaluated were birth BW, weaning BW, final BW, fat thickness, LM area, USDA marbling score, yield grade, slice shear force (SSF), and visible and near infrared predicted slice shear force. Both CAPN1 and CAST exhibited additive (P < 0.001) modes of inheritance for SSF and neither exhibited dominance (P ? 0.19). Furthermore, the interaction between CAPN1 and CAST for SSF was not significant (P = 0.55). Estimated additive effects of CAPN1 (1.049 kg) and CAST (1.257 kg) on SSF were large in this study. Animals homozygous for tender alleles at both CAPN1 and CAST would have 4.61 kg lower SSF (38.6% of the mean) than animals homozygous tough for both markers. There was also an effect of CAST on yield grade (P < 0.02). The tender CAST allele was associated with more red meat yield and less trimmable fat. There were no significant effects (P ? 0.23) for GHR on any of the traits evaluated in this study. Furthermore, CAST specific residual variance models were found to fit significantly better (P < 0.001) than single residual variance models for SSF, with the tougher genotypes having larger residual variance. Thus, the risk of a tough steak from the undesired CAST genotype is increased through both an increase in mean and an increase in variation. This work confirms the importance of CAPN1 and CAST for tenderness in beef, provides a new effect of CAST on beef tenderness, and questions the utility of GHR as a selection marker for beef quality. PMID:24398843

  10. Genetic Variation within the Mx Gene of Commercially Selected Chicken Lines Reveals Multiple Haplotypes, Recombination and a Protein under Selection Pressure

    PubMed Central

    Fulton, Janet E.; Arango, Jesus; Ali, Rizwana A.; Bohorquez, Elaine B.; Lund, Ashlee R.; Ashwell, Chris M.; Settar, Petek; O'Sullivan, Neil P.; Koci, Matthew D.

    2014-01-01

    The Mx protein is one of the best-characterized interferon-stimulated antiviral mediators. Mx homologs have been identified in most vertebrates examined; however, their location within the cell, their level of activity, and the viruses they inhibit vary widely. Recent studies have demonstrated multiple Mx alleles in chickens and some reports have suggested a specific variant (S631N) within exon 14 confers antiviral activity. In the current study, the complete genome of nine elite egg-layer type lines were sequenced and multiple variants of the Mx gene identified. Within the coding region and upstream putative promoter region 36 SNP variants were identified, producing a total of 12 unique haplotypes. Each elite line contained from one to four haplotypes, with many of these haplotypes being found in only one line. Observation of changes in haplotype frequency over generations, as well as recombination, suggested some unknown selection pressure on the Mx gene. Trait association analysis with either individual SNP or haplotypes showed a significant effect of Mx haplotype on several egg production related traits, and on mortality following Marek's disease virus challenge in some lines. Examination of the location of the various SNP within the protein suggests synonymous SNP tend to be found within structural or enzymatic regions of the protein, while non-synonymous SNP are located in less well defined regions. The putative resistance variant N631 was found in five of the 12 haplotypes with an overall frequency of 47% across the nine lines. Two Mx recombinants were identified within the elite populations, indicating that novel variation can arise and be maintained within intensively selected lines. Collectively, these results suggest the conflicting reports in the literature describing the impact of the different SNP on chicken Mx function may be due to the varying context of haplotypes present in the populations studied. PMID:25244433

  11. A tagging SNP in ALOX5AP and risk of stroke: a haplotype-based analysis among eastern Chinese Han population

    Microsoft Academic Search

    Hao Sun; Hao Wu; Jing Zhang; Jun Wang; Ying Lu; Haixia Ding; Hang Xiao; Jinsong Zhang

    A genome-wide approach found significant association of two at-risk haplotypes (HapA, HapB) in the ALOX5AP gene with myocardial infarction and stroke. To date, it is still controversial whether ALOX5AP gene polymorphisms are risk factors for stroke. The aim of the present study is to investigate the association between the\\u000a ALOX5AP gene polymorphism and the risk for stroke in Eastern Chinese

  12. Low frequency haplotypes of E-selectin polymorphisms G2692A and C1901T give increased protection from coronary artery disease

    PubMed Central

    Gor?cy, Jaros?aw; Gor?cy, Iwona; Kaczmarczyk, Mariusz; Parczewski, Mi?osz; Brykczy?ski, Miros?aw; Clark, Jeremy; Safranow, Krzysztof; Ciechanowicz, Andrzej

    2011-01-01

    Summary Background E-selectin polymorphisms are an independent atherosclerosis and coronary artery disease (CAD) risk factor. This study aimed to investigate the link between the C1901T and G2692A E-selectin tagging SNPs and their haplotypes and the extent of coronary artery disease in Polish patients. Material/Methods For this study 321 patients were recruited CAD extent by coronary angiography and E selectin gene variant were investigated using HapMap, PCR/RFLP, multivariate logistic regression and haplotype analysis. Results Frequency distributions of the C1901T and G2692A polymorphisms were significantly different in CAD patients as compared to control subjects (p=0.037 and p=0.025, respectively). The C1901T polymorphism was found to be an independent genetic predictor of risk of CAD (OR=3.01) in a multivariate model adjusted for classic, environmental risk factors. The A-C and G-T haplotypes showed the strongest significant associations with CAD. The A-C haplotype proved to be significantly more common in controls (haplotype frequency 9.2%) than in CAD (5.7%, p=0.048); the G-T haplotype was not found among control subjects (0.0%) but was found in CAD (1.3%, p=0.0099). Conclusions Associations between the C1901T and G2692A E-selectin polymorphisms and CAD in the Polish population were found. Investigated variants correlated with the risk of coronary artery disease development but not with the extent of coronary artery vascular changes. In the haplotype analysis, 2 haplotypes influenced CAD – the A-C haplotype (7%) proved to exert a protective effect against CAD, while the effect of the less frequent G-T haplotype (1%) was associated with significant increase in CAD risk. PMID:21629188

  13. Infection Frequency of Hepatitis C Virus and IL28B Haplotypes in Papua New Guinea, Fiji, and Kiribati

    PubMed Central

    Harrison, G. L. Abby; Pryor, Jan; Malani, Joji; Supuri, Mathias; Masta, Andrew; Teriboriki, Burentau; Toatu, Tebuka; Penny, David; Allain, Jean-Pierre; Barnes, Eleanor; Pybus, Oliver G.; Klenerman, Paul

    2013-01-01

    It has been estimated that there are more than 60 million Hepatitis C virus (HCV) carriers in the World Health Organisation's Western Pacific region (WHO-WPR), where liver cancer is among the top three causes of cancer death. WHO and the US Centres for Disease Control and Prevention report the prevalence of HCV in the South Pacific islands (countries within the WHO-WPR) to be high (5–10% and >2% respectively). However, since HCV is not tested for in many of these countries, there is sparse data available to support this assertion. We screened ?2000 apparently healthy individuals from Papua New Guinea, Fiji and Kiribati and found a sero-prevalence of 2.0%, 0.1% and 0%, respectively. All sero-positive samples tested negative for HCV RNA. Curious as to why all the sero-positive individuals were negative for HCV-RNA, we also screened them for the HCV protective IL28B SNP markers rs12979860 and rs8099917. All antibody-positive participants bar one had HCV protective haplotypes. Our results suggest that HCV is present in these Pacific island countries, albeit at a prevalence lower than previous estimates. As none of our participants had undergone antiviral treatment, and therefore must have cleared infection naturally, we hypothesise that genotypes 1 and/or 4 are circulating in South Pacific Island people and that these peoples are genetically predisposed to be more likely to spontaneous resolve HCV infection than to become chronic carriers. PMID:23976941

  14. Genome-Wide SNP Detection, Validation, and Development of an 8K SNP Array for Apple

    PubMed Central

    Chagné, David; Crowhurst, Ross N.; Troggio, Michela; Davey, Mark W.; Gilmore, Barbara; Lawley, Cindy; Vanderzande, Stijn; Hellens, Roger P.; Kumar, Satish; Cestaro, Alessandro; Velasco, Riccardo; Main, Dorrie; Rees, Jasper D.; Iezzoni, Amy; Mockler, Todd; Wilhelm, Larry; Van de Weg, Eric; Gardiner, Susan E.; Bassil, Nahla; Peace, Cameron

    2012-01-01

    As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide evaluation of allelic variation in apple (Malus×domestica) breeding germplasm. For genome-wide SNP discovery, 27 apple cultivars were chosen to represent worldwide breeding germplasm and re-sequenced at low coverage with the Illumina Genome Analyzer II. Following alignment of these sequences to the whole genome sequence of ‘Golden Delicious’, SNPs were identified using SoapSNP. A total of 2,113,120 SNPs were detected, corresponding to one SNP to every 288 bp of the genome. The Illumina GoldenGate® assay was then used to validate a subset of 144 SNPs with a range of characteristics, using a set of 160 apple accessions. This validation assay enabled fine-tuning of the final subset of SNPs for the Illumina Infinium® II system. The set of stringent filtering criteria developed allowed choice of a set of SNPs that not only exhibited an even distribution across the apple genome and a range of minor allele frequencies to ensure utility across germplasm, but also were located in putative exonic regions to maximize genotyping success rate. A total of 7867 apple SNPs was established for the IRSC apple 8K SNP array v1, of which 5554 were polymorphic after evaluation in segregating families and a germplasm collection. This publicly available genomics resource will provide an unprecedented resolution of SNP haplotypes, which will enable marker-locus-trait association discovery, description of the genetic architecture of quantitative traits, investigation of genetic variation (neutral and functional), and genomic selection in apple. PMID:22363718

  15. HLA gene and haplotype frequencies in Russians, Bashkirs and Tatars, living in the Chelyabinsk Region (Russian South Urals).

    PubMed

    Suslova, T A; Burmistrova, A L; Chernova, M S; Khromova, E B; Lupar, E I; Timofeeva, S V; Devald, I V; Vavilov, M N; Darke, C

    2012-10-01

    We have characterized the HLA-A, -B, -DRB1, -DQA1 and -DQB1 profiles of three major ethnic groups living in Chelyabinsk Region of Russian South Urals, viz., Russians (n = 207), Bashkirs (n = 146) and Tatars (n = 135). First field level typing was performed by PCR using sequence-specific primers. Estimates included carriage and gene frequencies, linkage disequilibrium and its significance and related values. Population comparisons were made between the allele family frequencies of the three populations and between these populations and 20 others using a dendrogram. Chelyabinsk Region Russians demonstrate all the features typical of a Caucasoid population, but also have some peculiarities. Together with Tatars, Russians have high frequencies of allele families and haplotypes characteristic of Finno-Ugric populations. This presupposes a Finno-Ugric impact on Russian and Tatar ethnogenesis. However, this was not apparent in Bashkirs, the first of the three populations to live in this territory, and implies admixture with populations of a Finno-Ugric origin with precursors of Russians and Tatars before they came to the South Urals. The Bashkirs appear close to Mongoloids in allele and haplotype distribution. However, Bashkirs cannot be labelled either as typical Mongoloids or as Caucasoids. Thus, Bashkirs possess some alleles and haplotypes frequent in Mongoloids, which supports the Turkic impact on Bashkir ethnogenesis, but also possess the AH 8.1 haplotype, which could evidence an ancient Caucasoid population that took part in their ethnic formation or of recent admixture with adjacent populations (Russians and Tatars). Bashkirs showed no features of populations with a substantial Finno-Ugric component, for example Chuvashes or Russian Saami. This disputes the commonly held belief of a Finno-Ugric origin for Bashkirs. Tatars appeared close to many European populations. However, they possessed some characteristics of Asiatic populations possibly reflecting a Mongoloid influence on Tatar ethnogenesis. Some aspects of HLA in Tatars appeared close to Chuvashes and Bulgarians, thus supporting the view that Tatars may be descendents of ancient Bulgars. PMID:22520580

  16. Haplotyping Methods for Pedigrees

    PubMed Central

    Gao, Guimin; Allison, David B.; Hoeschele, Ina

    2009-01-01

    Haplotypes provide valuable information in the study of diseases, complex traits, population histories, and evolutionary genetics. With the dramatic increase in the number of available single nucleotide polymorphism (SNP) markers, haplotype inference (haplotyping) using observed genotype data has become an important component of genetic studies in general and of statistical gene mapping in particular. Existing haplotyping methods include (1) population-based methods, (2) methods for pooled DNA samples, and (3) methods for family and pedigree data. The methods and computer programs for population data and pooled DNA samples were reviewed recently in the literature. As several authors noted, family and pedigree datasets are abundant and have unique advantages. In the past twenty years, many haplotyping methods for family and pedigree data have been developed. Therefore, in this contribution we review haplotyping methods and the corresponding computer programs suitable for family and pedigree data and discuss their applications and limitations. We explore the connections among these methods, and describe the challenges that remain to be addressed. PMID:19172084

  17. Am. J. Hum. Genet. 74:495510, 2004 Incorporating Genotyping Uncertainty in Haplotype Inference

    E-print Network

    Qin, Zhaohui Steve

    the accuracy of haplotype inference and the statistical power of haplotype-based association analyses used in linkage disequilibrium (LD) mapping for complex traits (Risch 2000). Because association tests based on haplo- types may provide greater statistical power than SNP-by- SNP analysis, haplotype

  18. Haplotyping Problem, A Clustering Approach

    NASA Astrophysics Data System (ADS)

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

    2007-09-01

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

  19. Novel Quantitative Real-Time LCR for the Sensitive Detection of SNP Frequencies in Pooled DNA: Method Development, Evaluation and Application

    PubMed Central

    Psifidi, Androniki; Dovas, Chrysostomos; Banos, Georgios

    2011-01-01

    Background Single nucleotide polymorphisms (SNP) have proven to be powerful genetic markers for genetic applications in medicine, life science and agriculture. A variety of methods exist for SNP detection but few can quantify SNP frequencies when the mutated DNA molecules correspond to a small fraction of the wild-type DNA. Furthermore, there is no generally accepted gold standard for SNP quantification, and, in general, currently applied methods give inconsistent results in selected cohorts. In the present study we sought to develop a novel method for accurate detection and quantification of SNP in DNA pooled samples. Methods The development and evaluation of a novel Ligase Chain Reaction (LCR) protocol that uses a DNA-specific fluorescent dye to allow quantitative real-time analysis is described. Different reaction components and thermocycling parameters affecting the efficiency and specificity of LCR were examined. Several protocols, including gap-LCR modifications, were evaluated using plasmid standard and genomic DNA pools. A protocol of choice was identified and applied for the quantification of a polymorphism at codon 136 of the ovine PRNP gene that is associated with susceptibility to a transmissible spongiform encephalopathy in sheep. Conclusions The real-time LCR protocol developed in the present study showed high sensitivity, accuracy, reproducibility and a wide dynamic range of SNP quantification in different DNA pools. The limits of detection and quantification of SNP frequencies were 0.085% and 0.35%, respectively. Significance The proposed real-time LCR protocol is applicable when sensitive detection and accurate quantification of low copy number mutations in DNA pools is needed. Examples include oncogenes and tumour suppressor genes, infectious diseases, pathogenic bacteria, fungal species, viral mutants, drug resistance resulting from point mutations, and genetically modified organisms in food. PMID:21283808

  20. [Gene and haplotype frequencies for the loci HLA-A, B and DRB1 in 11755 north Chinese Han bone marrow registry donors].

    PubMed

    Wu, Qiang-Ju; Liu, Meng-Li; Qi, Jun; Liu, Sheng; Zhang, Yan; Wei, Xiao-Qian

    2007-04-01

    The study was aimed to investigate the human leukocyte antigen (HLA)-A, B, DRB1 alleles and haplotype frequencies and the characteristics of linkage disequilibrium in north Chinese Han bone marrow donors. HLA phenotype data of 11 755 north Chinese Han bone marrow donors were identified by PCR-SSP and PCR-SSO. HLA-A, B, DRB1 allele and haplotype frequencies were calculated by computer software named Arleguin which was based on Expectation-Maximization (EM) algorithms. The results showed that the population of 11755 unrelated-donors was tested by Hardy-Weinberg equilibrium, and 18,42 and 15 specificities of HLA alleles were identified on the HLA-A, B, DRB1 locus respectively, including HLA-A25, B42, B53, B73 and DR3 which were rarely reported in Han population. HLA-A36, A43, A80, B78, B82 and DR18 were not detected in this study. The most frequent alleles with a frequency of over 0.05 were HLA-A*02, A*11, A*24, A*33, A*30, A*01, A*03, A*13, B62, B*51, B*46, B60, B61, B*35, B*44, DRB1*15, DRB1*09, DRB1*04, DRB1*07, DRB1*12, DRB1*11, DRB1*14, DRB1*08, DRB1*13. There were a total of 2 026 kinds of HLA-A-B-DR haplotypes (with a frequency of over 10(-6)) to be obtained. The each frequency of 26 kinds of three-locus haplotypes including HLA-A30-B13-DR7, A2-B46-DR9, A33-B58-DR17 etc was higher than 0.005. A30-B13-DR7 was the most frequent haplotype in north Chinese Han population. There were a total of 538 kinds of haplotypes for HLA-A-B, 227 kinds for A-DR and 522 kinds for B-DR to be obtained, and there were 409, 195, 423 kinds of haplotypes respectively with a frequency higher than 10 - 6. There were 28 kinds of HLA-A-B haplotypes including A30-B13, A2-B46, A33-B58 etc, 26 kinds of HLA-A-DR haplotypes including A2-DR9, A2-DR15, A30-DR7 etc, and 24 kinds of HLA-B-DR haplotypes including B13-DR7, B46-DR9, B13-DR12 etc with a frequency higher than 0.01. 296 (72%) kinds of HLA-A-B, 130 (67%) kinds of A-DR and 308 (73%) kinds of B-DR haplotypes were statistical linkage disequilibrium. HLA-A30-B13, A33-B58, A1-B37, A30-DR7, A33-DR13, A1-DR10, B37-DR10, B8-DR17, B13-DR7, B58-DR17 were significant positive linkage disequilibrium. It is concluded that this HLA-A, B, DRB1 gene and haplotype frequencies and linkage disequilibrium data with the largest sample size up to now is unique in north Chinese Han population. The study will be helpful to find matched donors for patients and establish the important foundation for further studying of transplantation immunity, HLA-related diseases and population genetics of this area. PMID:17493347

  1. Male dominance rarely skews the frequency distribution of Y chromosome haplotypes in human populations

    PubMed Central

    Lansing, J. Stephen; Watkins, Joseph C.; Hallmark, Brian; Cox, Murray P.; Karafet, Tatiana M.; Sudoyo, Herawati; Hammer, Michael F.

    2008-01-01

    A central tenet of evolutionary social science holds that behaviors, such as those associated with social dominance, produce fitness effects that are subject to cultural selection. However, evidence for such selection is inconclusive because it is based on short-term statistical associations between behavior and fertility. Here, we show that the evolutionary effects of dominance at the population level can be detected using noncoding regions of DNA. Highly variable polymorphisms on the nonrecombining portion of the Y chromosome can be used to trace lines of descent from a common male ancestor. Thus, it is possible to test for the persistence of differential fertility among patrilines. We examine haplotype distributions defined by 12 short tandem repeats in a sample of 1269 men from 41 Indonesian communities and test for departures from neutral mutation-drift equilibrium based on the Ewens sampling formula. Our tests reject the neutral model in only 5 communities. Analysis and simulations show that we have sufficient power to detect such departures under varying demographic conditions, including founder effects, bottlenecks, and migration, and at varying levels of social dominance. We conclude that patrilines seldom are dominant for more than a few generations, and thus traits or behaviors that are strictly paternally inherited are unlikely to be under strong cultural selection. PMID:18703660

  2. Haplotypes at ATM Identify Coding-Sequence Variation and Indicate a Region of Extensive Linkage Disequilibrium

    PubMed Central

    Bonnen, Penelope E.; Story, Michael D.; Ashorn, Cheryl L.; Buchholz, Thomas A.; Weil, Michael M.; Nelson, David L.

    2000-01-01

    Genetic variation in the human population may lead to functional variants of genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having frequencies ?.10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease. PMID:11078475

  3. Discovery of high frequencies of the Gly-Ile haplotype of TLR4 in Indian populations requires reformulation of the evolutionary model of its maintenance.

    PubMed

    Mukherjee, Souvik; Ganguli, Debdutta; Majumder, Partha P

    2013-10-01

    The Out-of-Africa migration of modern humans has led to the evolution of immunity genes in general, particularly those related to direct host-pathogen interactions. The Toll-like receptor 4 (TLR4) is one such cell-surface pattern recognition receptor that has been associated with susceptibility and resistance to Gram-negative infections. In this report, we have studied the genetic variation in the TLR4 gene across pre- and post-agricultural populations in India. Two non-synonymous SNPs at the loci Asp299Gly and Thr399Ile are genotyped in 266 individuals from these populations. Previous studies have shown that specific alleles at these two loci are associated with inflammatory response and also claimed the complete absence of the Gly-Ile (double-mutated) haplotype in populations from Asia and America due to some evolutionary disadvantage owing to septic shock. Contrary to such claims, our study reports for the first time, high (10%) to moderate (3-6%) frequencies of the Gly-Ile haplotype in one non-tribal and two tribal populations of India respectively. The presence of this haplotype in ancient tribal populations of India indicates the possibility of its important role in pathogen recognition or susceptibility to infections. Therefore, natural selection, not merely genetic drift, may have played an important role in shaping the frequency distribution of haplotypes at these two loci in TLR4. For a more global perspective, we have also estimated the frequency of this haplotype in all the 14 continental populations included in the 1000 Genomes Project. Our study provides direct evidence for the reformulation of existing models of evolutionary maintenance of these polymorphisms in the TLR4 gene. PMID:23892373

  4. Haplotype Structure

    Microsoft Academic Search

    Yu Zhang; Tianhua Niu

    This chapter consists of three parts. In the first part, we provide definitions for important terms and concepts used in studies\\u000a of population haplotype structures. In the second part, we introduce the user to valuable publicly available genotype\\/haplotype\\u000a databases, such as databases generated by the International HapMap Project. In addition, we provide concise guides to the\\u000a user on how to

  5. Single Nucleotide Polymorphisms and Haplotypes in Native American Populations

    E-print Network

    Kidd, Kenneth

    Single Nucleotide Polymorphisms and Haplotypes in Native American Populations Judith R. Kidd,1 of California, San Diego, CA 92093 KEY WORDS Native Americans; SNP; haplotype; structure; PCA ABSTRACT Autosomal of and relationships among modern Native American populations. At the same time that autosomal markers can be highly

  6. Diversity of Extended HLA-DRB1 Haplotypes in the Finnish Population

    PubMed Central

    Wennerström, Annika; Vlachopoulou, Efthymia; Lahtela, L. Elisa; Paakkanen, Riitta; Eronen, Katja T.; Seppänen, Mikko; Lokki, Marja-Liisa

    2013-01-01

    The Major Histocompatibility Complex (MHC, 6p21) codes for traditional HLA and other host response related genes. The polymorphic HLA-DRB1 gene in MHC Class II has been associated with several complex diseases. In this study we focus on MHC haplotype structures in the Finnish population. We explore the variability of extended HLA-DRB1 haplotypes in relation to the other traditional HLA genes and a selected group of MHC class III genes. A total of 150 healthy Finnish individuals were included in the study. Subjects were genotyped for HLA alleles (HLA-A, -B, -DRB1, -DQB1, and -DPB1). The polymorphism of TNF, LTA, C4, BTNL2 and HLA-DRA genes was studied with 74 SNPs (single nucleotide polymorphism). The C4A and C4B gene copy numbers and a 2-bp silencing insertion at exon 29 in C4A gene were analysed with quantitative genomic realtime-PCR. The allele frequencies for each locus were calculated and haplotypes were constructed using both the traditional HLA alleles and SNP blocks. The most frequent Finnish A?B?DR -haplotype, uncommon in elsewhere in Europe, was A*03?B*35?DRB1*01?01. The second most common haplotype was a common European ancestral haplotype AH 8.1 (A*01?B*08?DRB1*03?01). Extended haplotypes containing HLA-B, TNF block, C4 and HLA-DPB1 strongly increased the number of HLA-DRB1 haplotypes showing variability in the extended HLA-DRB1 haplotype structures. On the contrary, BTNL2 block and HLA-DQB1 were more conserved showing linkage with the HLA-DRB1 alleles. We show that the use of HLA-DRB1 haplotypes rather than single HLA-DRB1 alleles is advantageous when studying the polymorphisms and LD patters of the MHC region. For disease association studies the HLA-DRB1 haplotypes with various MHC markers allows us to cluster haplotypes with functionally important gene variants such as C4 deficiency and cytokines TNF and LTA, and provides hypotheses for further assessment. Our study corroborates the importance of studying population-specific MHC haplotypes. PMID:24278156

  7. Polymorphism of human leukocyte antigen-A, -B, and -DRB1 in a Moroccan population from Casablanca: study of the allelic and the haplotypic frequencies.

    PubMed

    Kabbaj, Maria; Oudghiri, Mounia; Naya, Abdellah; Naamane, Hamid; Bennani, Siham

    2011-01-01

    We have studied the distribution of HLA-A, -B and DRB1 alleles and haplotypes by sequence specific oligonucleotide amplification in a sample of 125 unrelated healthy Moroccan individuals from Casablanca in Morocco. The city of Casablanca is known of its big ethnic diversity, especially Arabs and Berbers. The most frequent alleles found were: HLA-A*02 (18.4%), -A*01 (11.2%), -A*03 (10.8%), -B*51 (8.06%),-B*44 (7.66%), -B*08 (6.85%), -DRB1*04 (15.98%), DRB1*03 and DRB1*07 (13.92%) and -DRB1*01 (10%). High frequency for five two-locus haplotypes was observed for A*03-B*51 (5%), A*02-DRB1*03 (5.5%), A*02-DRB1*04 and A*01-DRB1*04 (5%) and B*35-DRB1*04 (4%). No predominant haplotype was observed for HLA A-B-DRB1. Our results confirm and extend the current knowledge about genetic pattern of the Moroccan of Casablanca. This study will serve as a reference for further anthropological studies, as well as studies of HLA and disease associations in the Moroccan population. PMID:21659045

  8. Association of TERC and OBFC1 Haplotypes with Mean Leukocyte Telomere Length and Risk for Coronary Heart Disease

    PubMed Central

    Maubaret, Cécilia G.; Salpea, Klelia D.; Romanoski, Casey E.; Folkersen, Lasse; Cooper, Jackie A.; Stephanou, Coralea; Wah Li, Ka; Palmen, Jutta; Hamsten, Anders; Neil, Andrew; Stephens, Jeffrey W.; Lusis, Aldons J.; Eriksson, Per; Talmud, Philippa J.; Humphries, Steve E.

    2013-01-01

    Objective To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology. Methods Four SNPs at three loci BICD1 (rs2630578 G?C), 18q12.2 (rs2162440 G?T), and OBFC1 (rs10786775 C?G, rs11591710 A?C) were genotyped in four studies comprised of 2353 subjects out of which 1148 had CHD and 566 T2D. Three SNPs (rs12696304 C?G, rs10936601G>T and rs16847897 G?C) at the TERC locus were genotyped in these four studies, in addition to an offspring study of 765 healthy students. For all samples, LTL had been measured using a real-time PCR-based method. Results Only one SNP was associated with a significant effect on LTL, with the minor allele G of OBFC1 rs10786775 SNP being associated with longer LTL (?=0.029, P=0.04). No SNPs were significantly associated with CHD or T2D. For OBFC1 the haplotype carrying both rare alleles (rs10786775G and rs11591710C, haplotype frequency 0.089) was associated with lower CHD prevalence (OR: 0.77; 95% CI: 0.61–0.97; P= 0.03). The TERC haplotype GTC (rs12696304G, rs10936601T and rs16847897C, haplotype frequency 0.210) was associated with lower risk for both CHD (OR: 0.86; 95% CI: 0.75-0.99; P=0.04) and T2D (OR: 0.74; 95% CI: 0.61–0.91; P= 0.004), with no effect on LTL. Only the last association remained after adjusting for multiple testing. Conclusion Of reported associations, only that between the OBFC1 rs10786775 SNP and LTL was confirmed, although our study has a limited power to detect modest effects. A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. Further work is required to confirm these results and explore the mechanisms of these effects. PMID:24349443

  9. Haplotype frequencies of 17 Y-chromosomal short tandem repeat loci from the Cukurova region of Turkey

    PubMed Central

    Serin, Ayse; Canan, Husniye; Alper, Behnan; Sertdemir, Yasar

    2011-01-01

    Aim To investigate the distribution of 17 Y-short tandem repeat (STR) loci in the population of the Cukurova region of Turkey. Methods In the period between 2009 and 2010, we investigated the distribution of 17 Y-STRs in a sample of 249 unrelated healthy men from the Cukurova region of Turkey. Genomic DNA was extracted with InstaGene matrix and Y-STRs were determined using the AmpFISTR Yfiler PCR amplification kit. Gene and haplotype diversity values were estimated using the Arlequin software. To compare our data to other populations, population pairwise genetic distances and associated probability values were calculated using the Y Chromosome Haplotype Reference Database Web site software. Results At 17 Y-STR loci we detected 148 alleles. The lowest gene diversity in this region was 0.51 for DYS391 and the highest 0.95 for DYS385a/b. Haplotype diversity was 0.9997?±?0.0004. We compared our data with haplotype data of other Turkish populations and no significant differences were found, except with Ankara population (?st?=?0.025, P?=?0.018). Comparisons were also made with the neighboring populations using analysis of molecular variance of the Y-STR loci genetic structure and our population was nearest to Lenkoran-Azerbaijani (?st?=?0.012, P?=?0.068) and Iranian Ahvaz population (?st?=?0.007, P?=?0.173), followed by Greek (?st?=?0.026, P?=?0.000) and Russian (?st?=?0.048, P?=?0.000) population. Other countries like Portugal, Spain, Italy, Egypt, Israel (Palestinian Authority Area), and Taiwan showed a high genetic distance from our population. Conclusion Our study showed that Y-STR polymorphisms were a powerful discrimination tool for routine forensic applications and could be used in genealogical investigations. PMID:22180269

  10. µ-Calpain, calpastatin, and growth hormone receptor genetic effects on preweaning performance, carcass quality traits, and residual variance of tenderness in Angus cattle selected to increase minor haplotype ... frequencies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic marker effects and interactions are estimated with poor precision when minor marker allele frequencies are low. An Angus population was subjected to marker assisted selection for multiple years to increase divergent haplotype and minor marker allele frequencies to 1) estimate effect size an...

  11. TUMOR HAPLOTYPE ASSEMBLY ALGORITHMS FOR CANCER GENOMICS

    PubMed Central

    AGUIAR, DEREK; WONG, WENDY S.W.; ISTRAIL, SORIN

    2014-01-01

    The growing availability of inexpensive high-throughput sequence data is enabling researchers to sequence tumor populations within a single individual at high coverage. But, cancer genome sequence evolution and mutational phenomena like driver mutations and gene fusions are difficult to investigate without first reconstructing tumor haplotype sequences. Haplotype assembly of single individual tumor populations is an exceedingly difficult task complicated by tumor haplotype heterogeneity, tumor or normal cell sequence contamination, polyploidy, and complex patterns of variation. While computational and experimental haplotype phasing of diploid genomes has seen much progress in recent years, haplotype assembly in cancer genomes remains uncharted territory. In this work, we describe HapCompass-Tumor a computational modeling and algorithmic framework for haplotype assembly of copy number variable cancer genomes containing haplotypes at different frequencies and complex variation. We extend our polyploid haplotype assembly model and present novel algorithms for (1) complex variations, including copy number changes, as varying numbers of disjoint paths in an associated graph, (2) variable haplotype frequencies and contamination, and (3) computation of tumor haplotypes using simple cycles of the compass graph which constrain the space of haplotype assembly solutions. The model and algorithm are implemented in the software package HapCompass-Tumor which is available for download from http://www.brown.edu/Research/Istrail_Lab/. PMID:24297529

  12. Variation analysis and gene annotation of eight MHC haplotypes: The MHC Haplotype Project

    PubMed Central

    Horton, Roger; Gibson, Richard; Coggill, Penny; Miretti, Marcos; Allcock, Richard J.; Almeida, Jeff; Forbes, Simon; Gilbert, James G. R.; Halls, Karen; Harrow, Jennifer L.; Hart, Elizabeth; Howe, Kevin; Jackson, David K.; Palmer, Sophie; Roberts, Anne N.; Sims, Sarah; Stewart, C. Andrew; Traherne, James A.; Trevanion, Steve; Wilming, Laurens; Rogers, Jane; de Jong, Pieter J.; Elliott, John F.; Sawcer, Stephen; Todd, John A.; Trowsdale, John

    2008-01-01

    The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine. PMID:18193213

  13. 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

  14. Tag SNP selection using particle swarm optimization.

    PubMed

    Chuang, Li-Yeh; Yang, Cheng-San; Ho, Chang-Hsuan; Yang, Cheng-Hong

    2010-01-01

    Single nucleotide polymorphisms (SNPs) are the most abundant form of genetic variations amongst species. With the genome-wide SNP discovery, many genome-wide association studies are likely to identify multiple genetic variants that are associated with complex diseases. However, genotyping all existing SNPs for a large number of samples is still challenging even though SNP arrays have been developed to facilitate the task. Therefore, it is essential to select only informative SNPs representing the original SNP distributions in the genome (tag SNP selection) for genome-wide association studies. These SNPs are usually chosen from haplotypes and called haplotype tag SNPs (htSNPs). Accordingly, the scale and cost of genotyping are expected to be largely reduced. We introduce binary particle swarm optimization (BPSO) with local search capability to improve the prediction accuracy of STAMPA. The proposed method does not rely on block partitioning of the genomic region, and consistently identified tag SNPs with higher prediction accuracy than either STAMPA or SVM/STSA. We compared the prediction accuracy and time complexity of BPSO to STAMPA and an SVM-based (SVM/STSA) method using publicly available data sets. For STAMPA and SVM/STSA, BPSO effective improved prediction accuracy for smaller and larger scale data sets. These results demonstrate that the BPSO method selects tag SNP with higher accuracy no matter the scale of data sets is used. PMID:20039435

  15. A haplotype inference method based on sparsely connected multi-body ising model

    NASA Astrophysics Data System (ADS)

    Kato, Masashi; Gao, Qian Ji; Chigira, Hiroshi; Shindo, Hiroyuki; Inoue, Masato

    2010-06-01

    Statistical haplotype inference is an indispensable technique in the field of medical science. The method usually has two steps: inference of haplotype frequencies and inference of diplotype for each subject. The first step can be done by using the expectation-maximization (EM) algorithm, but it incurs an unreasonably large calculation cost when the number of single-nucleotide polymorphism (SNP) loci of concern is large. In this article, we describe an approximate probabilistic model of haplotype frequencies. The model is constructed by using several distributions of nearby local SNPs. This approximation seems good because SNPs are generally more strongly correlated when they are close to one another on a chromosome. To implement this approach, we use a log linear model, the Walsh-Hadamard transform, and a combinatorial optimization method. Artificial data suggested that the overall haplotype inference of our method is good if there are nine or more local consecutive SNPs. Some minor problems should be dealt with before this method can be applied to real data.

  16. Allele and haplotype frequencies for HLA class II (DQA1 and DQB1) loci in patients with celiac disease from Spain.

    PubMed

    Vidales, M Concepción; Zubillaga, Paul; Zubillaga, Itziar; Alfonso-Sánchez, Miguel A

    2004-04-01

    Celiac disease (CD) is a complex and multifactorial disease, defined as a malabsorptive disorder of the small intestine resulting from ingestion of gluten. Genetic susceptibility to CD has been associated with human leukocyte antigen (HLA)-DQ2 heterodimer, encoded by the DQA1*0501 and DQB1*02 genes. However, HLA risk factors do not explain the whole genetic predisposition: not all DQ2-encoding haplotypes confer equal susceptibility to CD. The aim of the present work was to confirm the aforementioned findings in a southern European population. With this purpose, 136 unrelated children diagnosed with CD were typed at the DNA level for HLA-DQA1 and -DQB1 loci. Patients are currently attended at the Donostia Hospital (province of Guipúzcoa, Spain). HLA class II typing was performed by polymerase chain reaction-sequence specific primer procedures. Conspicuous frequencies of the alleles associated with susceptibility to CD were observed (DQA1*0501: 0.592, DQB1*0201: 0.471). Accordingly, the haplotypes DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0202 revealed a strong linkage disequilibrium (18.84% and 18.75%, respectively) when compared with the Spanish general population. Of the total sample, 93.4% (127 individuals) were carriers of DQ2 heterodimer, either in homozygosis or in heterozygosis. This percentage coincides with figures reported in previous studies, implying the effect of other genes in the development of CD. PMID:15120190

  17. Haplotype analysis of sucrose synthase gene family in three Saccharum species

    PubMed Central

    2013-01-01

    Background Sugarcane is an economically important crop contributing about 80% and 40% to the world sugar and ethanol production, respectively. The complicated genetics consequential to its complex polyploid genome, however, have impeded efforts to improve sugar yield and related important agronomic traits. Modern sugarcane cultivars are complex hybrids derived mainly from crosses among its progenitor species, S. officinarum and S. spontanuem, and to a lesser degree, S. robustom. Atypical of higher plants, sugarcane stores its photoassimilates as sucrose rather than as starch in its parenchymous stalk cells. In the sugar biosynthesis pathway, sucrose synthase (SuSy, UDP-glucose: D-fructose 2-a-D-glucosyltransferase, EC 2.4.1.13) is a key enzyme in the regulation of sucrose accumulation and partitioning by catalyzing the reversible conversion of sucrose and UDP into UDP-glucose and fructose. However, little is known about the sugarcane SuSy gene family members and hence no definitive studies have been reported regarding allelic diversity of SuSy gene families in Saccharum species. Results We identified and characterized a total of five sucrose synthase genes in the three sugarcane progenitor species through gene annotation and PCR haplotype analysis by analyzing 70 to 119 PCR fragments amplified from intron-containing target regions. We detected all but one (i.e. ScSuSy5) of ScSuSy transcripts in five tissue types of three Saccharum species. The average SNP frequency was one SNP per 108 bp, 81 bp, and 72 bp in S. officinarum, S. robustom, and S. spontanuem respectively. The average shared SNP is 15 between S. officinarum and S. robustom, 7 between S. officinarum and S. spontanuem , and 11 between S. robustom and S. spontanuem. We identified 27, 35, and 32 haplotypes from the five ScSuSy genes in S. officinarum, S. robustom, and S. spontanuem respectively. Also, 12, 11, and 9 protein sequences were translated from the haplotypes in S. officinarum, S. robustom, S. spontanuem, respectively. Phylogenetic analysis showed three separate clusters composed of SbSuSy1 and SbSuSy2, SbSuSy3 and SbSuSy5, and SbSuSy4. Conclusions The five members of the SuSy gene family evolved before the divergence of the genera in the tribe Andropogoneae at least 12 MYA. Each ScSuSy gene showed at least one non-synonymous substitution in SNP haplotypes. The SNP frequency is the lowest in S. officinarum, intermediate in S. robustum, and the highest in S. spontaneum, which may reflect the timing of the two rounds of whole genome duplication in these octoploids. The higher rate of shared SNP frequency between S. officinarum and S. robustum than between S. officinarum and in S. spontaneum confirmed that the speciation event separating S. officinarum and S. robustum occurred after their common ancestor diverged from S. spontaneum. The SNP and haplotype frequencies in three Saccharum species provide fundamental information for designing strategies to sequence these autopolyploid genomes. PMID:23663250

  18. 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. PMID:25772133

  19. The effects of contig length and depth on the estimation of SNP frequencies, and the relative abundance of SNPs in protein-coding and non-coding transcripts of tiger salamanders (Ambystoma tigrinum)

    PubMed Central

    2012-01-01

    Background Next-generation sequencing methods have contributed to rapid progress in the fields of genomics and population genetics. Using this high-throughput and cost-effective technology, a number of studies have estimated single nucleotide polymorphism (SNP) frequency by calculating the mean number of SNPs per unit sequence length (e.g., mean SNPs/kb). However, both read length and contig depth are highly variable and thus raise doubt about simple methods of SNP frequency estimation. Results We used 454 pyrosequencing to identify 2,980 putative SNPs in the eastern tiger salamander (Ambystoma tigrinum tigrinum) transcriptome, then constructed analytical models to estimate SNP frequency. The model which considered only contig length (i.e., the method employed in most published papers) was evaluated with very poor likelihood. Our most robust model considered read depth as well as contig length, and was 7.5?×?1055 times more likely than the length-only model. Using this novel modeling approach, we estimated SNP frequency in protein-coding (mRNA) and non-coding transcripts (e.g., small RNAs). We found little difference in SNP frequency in the contigs, but we found a trend of a higher frequency of SNPs in long contigs representing non-coding transcripts relative to protein-coding transcripts. These results support the hypothesis that long non-coding transcripts are less conserved than long protein-coding transcripts. Conclusions A modeling approach (i.e., using multiple model construction and model selection approaches) can be a powerful tool for identifying selection on specific functional sequence groups by comparing the frequency and distribution of polymorphisms. PMID:22716167

  20. Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis

    PubMed Central

    Luukkonen, Aino; Teramo, Kari; Puttonen, Hilkka; Ojaniemi, Marja; Varilo, Teppo; Chaudhari, Bimal P.; Plunkett, Jevon; Murray, Jeffrey C.; McCarroll, Steven A.; Muglia, Louis J.; Palotie, Aarno; Hallman, Mikko

    2011-01-01

    Preterm birth is the major cause of neonatal death and serious morbidity. Most preterm births are due to spontaneous onset of labor without a known cause or effective prevention. Both maternal and fetal genomes influence the predisposition to spontaneous preterm birth (SPTB), but the susceptibility loci remain to be defined. We utilized a combination of unique population structures, family-based linkage analysis, and subsequent case-control association to identify a susceptibility haplotype for SPTB. Clinically well-characterized SPTB families from northern Finland, a subisolate founded by a relatively small founder population that has subsequently experienced a number of bottlenecks, were selected for the initial discovery sample. Genome-wide linkage analysis using a high-density single-nucleotide polymorphism (SNP) array in seven large northern Finnish non-consanginous families identified a locus on 15q26.3 (HLOD 4.68). This region contains the IGF1R gene, which encodes the type 1 insulin-like growth factor receptor IGF-1R. Haplotype segregation analysis revealed that a 55 kb 12-SNP core segment within the IGF1R gene was shared identical-by-state (IBS) in five families. A follow-up case-control study in an independent sample representing the more general Finnish population showed an association of a 6-SNP IGF1R haplotype with SPTB in the fetuses, providing further evidence for IGF1R as a SPTB predisposition gene (frequency in cases versus controls 0.11 versus 0.05, P?=?0.001, odds ratio 2.3). This study demonstrates the identification of a predisposing, low-frequency haplotype in a multifactorial trait using a well-characterized population and a combination of family and case-control designs. Our findings support the identification of the novel susceptibility gene IGF1R for predisposition by the fetal genome to being born preterm. PMID:21304894

  1. Lactase Haplotype Diversity in the Old World

    PubMed Central

    Hollox, Edward J.; Poulter, Mark; Zvarik, Marek; Ferak, Vladimir; Krause, Amanda; Jenkins, Trefor; Saha, Nilmani; Kozlov, Andrew I.; Swallow, Dallas M.

    2001-01-01

    Lactase persistence, the genetic trait in which intestinal lactase activity persists at childhood levels into adulthood, varies in frequency in different human populations, being most frequent in northern Europeans and certain African and Arabian nomadic tribes, who have a history of drinking fresh milk. Selection is likely to have played an important role in establishing these different frequencies since the development of agricultural pastoralism ?9,000 years ago. We have previously shown that the element responsible for the lactase persistence/nonpersistence polymorphism in humans is cis-acting to the lactase gene and that lactase persistence is associated, in Europeans, with the most common 70-kb lactase haplotype, A. We report here a study of the 11-site haplotype in 1,338 chromosomes from 11 populations that differ in lactase persistence frequency. Our data show that haplotype diversity was generated both by point mutations and recombinations. The four globally common haplotypes (A, B, C, and U) are not closely related and have different distributions; the A haplotype is at high frequencies only in northern Europeans, where lactase persistence is common; and the U haplotype is virtually absent from Indo-European populations. Much more diversity is seen in sub-Saharan Africans than in non-Africans, consistent with an “Out of Africa” model for peopling of the Old World. Analysis of recent recombinant haplotypes by allele-specific PCR, along with deduction of the root haplotype from chimpanzee sequence, allowed construction of a haplotype network that assisted in evaluation of the relative roles of drift and selection in establishing the haplotype frequencies in the different populations. We suggest that genetic drift was important in shaping the general pattern of non-African haplotype diversity, with recent directional selection in northern Europeans for the haplotype associated with lactase persistence. PMID:11095994

  2. Efficient haplotyping for families

    E-print Network

    Williams, Amy Lynne, Ph.D. Massachusetts Institute of Technology

    2010-01-01

    Hapi is a novel dynamic programming algorithm for haplotyping nuclear families that outperforms contemporary family-based haplotyping algorithms. Haplotypes are useful for mapping and identifying genes which cause and ...

  3. Snapshots of Selection: Changes in SNP Allele Frequencies during Phenotypic, Marker-Assisted, and Genomewide Selection in Maize

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Changes in allele frequencies underlie improvements in mean performance for quantitative traits. Limited published information is available on how genomewide marker-allele frequencies change during phenotypic and marker-based selection for multiple traits in applied breeding programs. Here we descri...

  4. Direct molecular haplotyping by melting curve analysis of hybridization probes: beta 2-adrenergic receptor haplotypes as an example

    PubMed Central

    Pont-Kingdon, Genevieve; Lyon, Elaine

    2005-01-01

    Direct determination of the association of multiple genetic polymorphisms, or haplotyping, in individual samples is challenging because of chromosome diploidy. Here, we describe the ability of hybridization probes, commonly used as genotyping tools, to establish single nucleotide polymorphism (SNP) haplotypes in a single step. Three haplotypes found in the beta 2-adrenergic receptor (?2AR) gene and characterized by three different SNPs combinations are presented as examples. Each combination of SNPs has a unique stability, recorded by its melting temperature, even when intervening sequences from the template must loop out during probe hybridization. In the course of this study, two haplotypes in ?2AR not described previously were discovered. This approach provides a tool for molecular haplotyping that should prove useful in clinical molecular genetics diagnostics and pharmacogenetic research where methods for direct haplotyping are needed. PMID:15937194

  5. 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. PMID:20733241

  6. Correlation of Chitinase 3-Like 1 Single Nucleotide Polymorphisms and Haplotypes with Uterine Cervical Cancer in Taiwanese Women

    PubMed Central

    Lin, Yue-Shan; Liu, Yu-Fan; Chou, Ying-Erh; Yang, Shun-Fa; Chien, Ming-Hsien; Wu, Chih-Hsien; Chou, Chi-Hung; Cheng, Chao-Wen; Wang, Po-Hui

    2014-01-01

    Background This study aimed to investigate the relationships of chitinase 3-like 1 (CHI3L1) single nucleotide polymorphisms (SNPs) and haplotypes with the development of uterine cervical cancer in Taiwanese women. The SNPs frequencies and haplotypes were also correlated with the clinicopathologic variables of cervical cancer, cancer recurrence, and patient survival. Methodology and Principal Findings Ninety-nine patients with invasive cancer and 61 with pre-cancerous lesions of the uterine cervix were compared to 310 healthy control subjects. Three SNPs rs6691378 (?1371, G/A), rs10399805 (?247, G/A) and rs4950928 (?131, C/G) in the promoter region, and one SNP rs880633 (+2950, T/C) in exon 5 were analyzed by real time polymerase chain reaction and genotyping. The results showed that the mutant homozygous genotype AA of CHI3L1 SNP rs6691378 and AA of rs10399805, and haplotypes AACC and AACT increased the risk of developing pre-cancerous lesions and invasive cancer. The patients with these risk haplotypes had higher than stage I tumors, larger tumors, and vaginal invasion. In logistic regression model, they also tended to have poor survival event [p?=?0.078; odds ratio (OR): 2.99, 95% confidence interval (CI): 0.89–10.08] and a higher probability of recurrence event (p?=?0.081; OR: 3.07, 95% CI: 0.87–10.81). There was a significant association between the CHI3L1 risk haplotypes and probability of recurrence (p?=?0.002; hazard ratio: 6.21, 95% CI: 1.90–20.41), and a marginal association between the risk haplotypes and overall survival (p?=?0.051; hazard ratio: 3.76, 95% CI: 0.99–14.29) in the patients with SCC, using Cox proportional hazard model. Conclusion The CHI3L1 SNPs rs6691378 and rs10399805 and CHI3L1 haplotypes all correlated with the development of cervical pre-cancerous lesions and invasive cancer. The cervical cancer patients with the CHI3L1 haplotypes AACC or AACT had poor clinicopathologic characteristics and poor recurrence and survival events. These risk haplotypes were associated with higher recurrence, especially in the patients with SCC. PMID:25203433

  7. MDM2 promoter SNP285 and SNP309; phylogeny and impact on cancer risk

    PubMed Central

    Knappskog, Stian; Lřnning, Per E.

    2011-01-01

    MDM2 plays a key role to physiological processes like growth arrest, senescence and apoptosis. It binds to and inhibits key proteins like p53 and the RB protein, and MDM2 amplification as well as protein overexpression without amplification is seen in many solid tumors. An MDM2 promoter polymorphism (SNP309T>G) has been found associated with enhanced Sp1 transcription factor binding and elevated MDM2 transcription. While 309G has been found associated with elevated cancer risk and young age at diagnosis of different cancers, results in Caucasians have been at variance. Recently, we reported a second polymorphism (SNP285G>C) located on the 309G allele. The 285C/309G haplotype accounts for about 12% of all 309G alleles among Norwegians, Dutch and British habitants. Assessing Sp1 binding to the MDM2 promoter using surface plasmon resonance technology, we found SNP309G to enhance Sp1 binding by 22% while SNP285C reduced Sp1 binding by 51%. SNP285C reduced the risk of breast cancer and ovarian cancer among 309TG/309GG carriers by 21 and 26%, respectively, but in particular the risk of ovarian cancer among 309TG heterozygotes (reduction by 37%). The fact that the 285C/309G haplotype accounted for only 1.9% of all 309G alleles among Finns and was absent in Chinese indicate 285C to be a young polymorphism. PMID:21436469

  8. WinHAP: an efficient haplotype phasing algorithm based on scalable sliding windows.

    PubMed

    Xu, Yun; Cheng, Wenhua; Nie, Pengyu; Zhou, Fengfeng

    2012-01-01

    Haplotype phasing represents an essential step in studying the association of genomic polymorphisms with complex genetic diseases, and in determining targets for drug designing. In recent years, huge amounts of genotype data are produced from the rapidly evolving high-throughput sequencing technologies, and the data volume challenges the community with more efficient haplotype phasing algorithms, in the senses of both running time and overall accuracy. 2SNP is one of the fastest haplotype phasing algorithms with comparable low error rates with the other algorithms. The most time-consuming step of 2SNP is the construction of a maximum spanning tree (MST) among all the heterozygous SNP pairs. We simplified this step by replacing the MST with the initial haplotypes of adjacent heterozygous SNP pairs. The multi-SNP haplotypes were estimated within a sliding window along the chromosomes. The comparative studies on four different-scale genotype datasets suggest that our algorithm WinHAP outperforms 2SNP and most of the other haplotype phasing algorithms in terms of both running speeds and overall accuracies. To facilitate the WinHAP's application in more practical biological datasets, we released the software for free at: http://staff.ustc.edu.cn/~xuyun/winhap/index.htm. PMID:22905221

  9. Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women.

    PubMed

    Meirhaeghe, Aline; Cottel, Dominique; Amouyel, Philippe; Dallongeville, Jean

    2005-10-01

    We assessed the association of four polymorphisms (promoter P3 -681C>G, P2 -689C>T, Pro12Ala, and 1431C>T) in peroxisome proliferator-activated receptor gamma (PPARgamma) with the metabolic syndrome risk in a large, French population study (n = 1,155). In this sample, 279 men and women presented with metabolic syndrome according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. When taken individually, none of the polymorphisms was significantly associated with the metabolic syndrome. Haplotype analyses, in contrast, revealed a significant enrichment of the GTGC haplotype frequency (corresponding to the P3 -681C>G, P2 -689C>T, Pro12Ala (C/G), and 1431C>T polymorphisms in this order) among those with metabolic syndrome compared with control subjects. Compared with the most common CCCC haplotype, the adjusted odds ratio (OR) (95% CI) of the metabolic syndrome for bearers of the GTGC haplotype was 2.37 (1.42-3.95; P = 0.002), 1.92 (1.00-3.72; P = 0.05), and 2.47 (1.09-5.62; P = 0.045) in the whole sample of men and women, respectively. Similar results were obtained when using another haplotype (GCCC, GTGT, CCCT, or GCCT) as a reference. Furthermore, when the GTGC haplotype frequency was tested alone (i.e., versus the frequency of the five other haplotypes together), the OR (95% CI) of the metabolic syndrome was 2.30 (1.05-5.00; P = 0.022). These data show that only the frequency of the GTGC haplotype was different between subjects with and without metabolic syndrome. Further analyses stratified on the 1431C>T single nucleotide polymorphism (SNP) indicated that the rare alleles of the P2 -689C>T and Pro12Ala SNPs were associated with an increased risk of the metabolic syndrome when combined to the 1431CC genotype. In conclusion, a specific haplotype of PPARgamma polymorphisms is associated with an increased risk of the metabolic syndrome in a French general population. PMID:16186413

  10. Use of Haplotypes to Estimate Mendelian Sampling Effects and Selection Limits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Limits to selection and Mendelian sampling 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 1,455 Brown Swiss, 40,351 Holstein, and 4,064 Jersey bulls and cows using th...

  11. Genotype Error Detection using Hidden Markov Models of Haplotype Diversity

    E-print Network

    Mandoiu, Ion

    Genotype Error Detection using Hidden Markov Models of Haplotype Diversity Justin Kennedy, Ion,bogdan}@engr.uconn.edu Abstract. The presence of genotyping errors can invalidate statistical tests for linkage and disease a simple likelihood ratio approach for detecting errors in trio genotype data. Un- der this approach, a SNP

  12. Genotype Error Detection using Hidden Markov Models of Haplotype Diversity

    E-print Network

    Mandoiu, Ion

    Genotype Error Detection using Hidden Markov Models of Haplotype Diversity Justin Kennedy Ion Mandoiu Bogdan Pa¸saniuc July 5, 2008 Abstract The presence of genotyping errors can invalidate genotype data. Under this approach, a SNP genotype is flagged as a potential error if the likelihood

  13. Model-based Inference of Haplotype Block Variation Gideon Greenspan

    E-print Network

    Friedman, Nir

    the parameters of this model can be learned from haplotypes and/or unphased genotype data. Using real-world SNP data, we demonstrate that our approach can be used to resolve genotypes into their constituent or distributed for profit or commercial advantage and that copies bear this notice and the full citation

  14. Estimation of the 6-digit level allele and haplotype frequencies of HLA-A, -B, and -C in Koreans using ambiguity-solving DNA typing.

    PubMed

    Jun, J-H; Hwang, K; Kim, S-K; Oh, H-B; Cho, M-C; Lee, K-J

    2014-09-01

    Because Korean society is fast becoming multi-ethnic, the determination of ambiguous human leukocyte antigen (HLA) types using HLA allele frequencies is becoming less applicable. In this study, we focused on the development of new technical methods to directly resolve the ambiguities arising from HLA genotyping. One hundred and fifty unrelated healthy Korean adults were included in this study. All alleles from each HLA locus were first divided into 2-4 groups, with each group amplified in a single PCR tube (multi-group-specific amplification, MGSA). To resolve phase ambiguities, some allele groups were also amplified separately in small group-specific amplification (SGSA) tubes. In order to then resolve incomplete sequence ambiguities, primers for MGSA and SGSA were initially designed to cover additional exons. If needed, a heterozygous ambiguity resolving primer (HARP) or sequence specific primer (SSP) was also used. When MGSA and SGSA methods were applied, the rate of phase ambiguity was greatly reduced to an average of 6% (1.3% in HLA-A, 15.7% in -B, and 2.0% in -C). Additional HARP and SSP methods could resolve all the phase ambiguities. Using our proposed method, we also detected three alleles that have not been previously reported in Korea, C*04:82, C*07:18, and C*08:22, and report 6-digit level HLA allele and haplotype frequencies among Koreans. In conclusion, the use of MGSA/SGSA for the initial amplification step is a cost-effective method facilitating timely and accurate reporting, given the continuing increase in the ethnic diversity of the Korean population. The MGSA described here can be applicable to various populations and thus could be shared by the majority of HLA typing laboratories. However, efforts to solve HLA ambiguity should continue, because SGSA, HARPs and SSPs would be specific to a particular population. PMID:24851935

  15. 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. PMID:25173511

  16. High SNP density in the blacklegged tick, Ixodes scapularis, the principal vector of Lyme disease spirochetes.

    PubMed

    Van Zee, Janice; Black, William C; Levin, Michael; Goddard, Jerome; Smith, Joshua; Piesman, Joseph

    2013-02-01

    Single-nucleotide polymorphisms (SNPs) are the most widespread type of sequence variation in genomes. SNP density and distribution varies among different organisms and genes. Here, we report the first estimates of SNP distribution and density in the genome of the blacklegged tick (Ixodes scapularis), an important vector of the pathogens causing Lyme disease, human granulocytic anaplasmosis and human babesiosis in North America. We sampled 10 individuals from each of 4 collections from New Jersey, Virginia, Georgia, and Mississippi and analyzed the sequences of 9 nuclear genes and the mitochondrial 16S gene. SNPs are extremely abundant (one SNP per every 14 bases). This is the second highest density so far reported in any eukaryotic organism. Population genetic analyses based either on haplotype frequencies or the 372 SNPs in these 9 genes showed that the 40 ticks formed 3 genetic groups. In agreement with earlier population genetic studies, northern ticks from New Jersey and Virginia formed a homogeneous group with low genetic diversity, whereas southern ticks from Georgia and Mississippi consisted of 2 separate groups, each with high genetic diversity. PMID:23219364

  17. The effect of haplotype variation in the bovine PAX6 gene.

    PubMed

    Huang, Yong-Zhen; Jing, Yong-Jie; Wei, Tian-Bao; Lan, Xian-Yong; Lei, Chu-Zhao; Zhang, Chun-Lei; Chen, Hong

    2013-12-01

    The transcription factor paired box 6 gene (PAX6) plays a key role during the early development of various organs. In this study, three single nucleotide polymorphisms (SNPs) have been identified in the introns 2, 8 and 11 of the bovine PAX6 gene. 8 haplotypes and 13 diplotypes were revealed and the linkage disequilibrium (LD) was assessed in 817 cows representing four main cattle breeds from China (Nanyang, NY; Qinchuan, QC; Jiaxian, JX; Chinese Holstein, CH). The LD analysis revealed that the additional three SNPs were not in strong LD, the wild haplotype (Hap 1: CTT) and mutant haplotype (Hap 8: TCC) have a frequency of 9.36, 35.61, 18.32, 57.15 % and 15.60, 14.19, 0.83, 0 % in the four cattle populations. The statistical analyses indicated that the SNP2 and 3 are associated with the body weight at birth, 6 and 12 months in NY and JX cattle population (P < 0.01 or P < 0.05); and significant association was detected between 19 (NY) or 13 (JX) diplotype (combined genotypes) and body weight at different ages (birth, 6 and 12 months). Our results provide evidence that some polymorphisms in PAX6 are associated with growth traits at some ages, and may be used as candidates for marker-assisted selection in beef cattle breeding program. PMID:24072657

  18. Haplotype phasing: Existing methods and new developments

    PubMed Central

    Browning, Sharon R.; Browning, Brian L.

    2011-01-01

    Determination of haplotype phase is increasingly important as we enter the era of large-scale sequencing because many of its applications, such as imputing low frequency variants and characterizing the relationship between genetic variation and disease susceptibility, are particularly relevant to sequence data. Haplotype phase can be generated through laboratory-based experimental methods, or it can be estimated with computational approaches. We assess the haplotype phasing methods that are available, with particular focus on statistical methods, and discuss practical aspects of their application. We also describe recent developments that may transform this field, particularly the use of identity-by-descent for computational phasing. PMID:21921926

  19. HLA class-I and class-II allele frequencies and two-locus haplotypes in Melanesians of Vanuatu and New Caledonia.

    PubMed

    Maitland, K; Bunce, M; Harding, R M; Barnardo, M C N M; Clegg, J B; Welsh, K; Bowden, D K; Williams, T N

    2004-12-01

    HLA class-I and class-II allele frequencies and two-locus haplotypes were examined in 367 unrelated Melanesians living on the islands of Vanuatu and New Caledonia. Diversity at all HLA class-I and class-II loci was relatively limited. In class-I loci, three HLA-A allelic groups (HLA-A*24, HLA-A*34 and HLA-A*11), seven HLA-B alleles or allelic groups (HLA-B*1506, HLA-B*5602, HLA-B*13, HLA-B*5601, HLA-B*4001, HLA-B*4002 and HLA-B*2704) and four HLA-C alleles or allelic groups (HLA-Cw*04, HLA-Cw*01, HLA-Cw*0702 and HLA-Cw*15) constituted more than 90% of the alleles observed. In the class-II loci, four HLA-DRB1 alleles (HLA-DRB1*15, HLA-DRB1*11, HLA-DRB1*04 and HLA-DRB1*16), three HLA-DRB3-5 alleles (HLA-DRB3*02, HLA-DRB4*01 and HLA-DRB5*01/02) and five HLA-DQB1 alleles (HLA-DQB1*0301, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*0601 and HLA-DQB1*0602) constituted over 93, 97 and 98% of the alleles observed, respectively. Homozygosity showed significant departures from expected levels for neutrality based on allele frequency (i.e. excess diversity) at the HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB3/5 loci on some islands. The locus with the strongest departure from neutrality was HLA-DQB1, homozygosity being significantly lower than expected on all islands except New Caledonia. No consistent pattern was demonstrated for any HLA locus in relation to malaria endemicity. PMID:15546341

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

    PubMed Central

    Schierup, Mikkel H; Mailund, Thomas; Li, Heng; Wang, Jun; Tjřnneland, Anne; Vogel, Ulla; Bolund, Lars; Nexř, Bjřrn A

    2009-01-01

    Background A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers. Methods We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk. Results We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the Fst value) closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping. Conclusion The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations. PMID:19257887

  1. Excavating Y-chromosome haplotype strata in Anatolia.

    PubMed

    Cinnio?lu, Cengiz; King, Roy; Kivisild, Toomas; Kalfo?lu, Ersi; Atasoy, Sevil; Cavalleri, Gianpiero L; Lillie, Anita S; Roseman, Charles C; Lin, Alice A; Prince, Kristina; Oefner, Peter J; Shen, Peidong; Semino, Ornella; Cavalli-Sforza, L Luca; Underhill, Peter A

    2004-01-01

    Analysis of 89 biallelic polymorphisms in 523 Turkish Y chromosomes revealed 52 distinct haplotypes with considerable haplogroup substructure, as exemplified by their respective levels of accumulated diversity at ten short tandem repeat (STR) loci. The major components (haplogroups E3b, G, J, I, L, N, K2, and R1; 94.1%) are shared with European and neighboring Near Eastern populations and contrast with only a minor share of haplogroups related to Central Asian (C, Q and O; 3.4%), Indian (H, R2; 1.5%) and African (A, E3*, E3a; 1%) affinity. The expansion times for 20 haplogroup assemblages was estimated from associated STR diversity. This comprehensive characterization of Y-chromosome heritage addresses many multifaceted aspects of Anatolian prehistory, including: (1) the most frequent haplogroup, J, splits into two sub-clades, one of which (J2) shows decreasing variances with increasing latitude, compatible with a northward expansion; (2) haplogroups G1 and L show affinities with south Caucasus populations in their geographic distribution as well as STR motifs; (3) frequency of haplogroup I, which originated in Europe, declines with increasing longitude, indicating gene flow arriving from Europe; (4) conversely, haplogroup G2 radiates towards Europe; (5) haplogroup E3b3 displays a latitudinal correlation with decreasing frequency northward; (6) haplogroup R1b3 emanates from Turkey towards Southeast Europe and Caucasia and; (7) high resolution SNP analysis provides evidence of a detectable yet weak signal (<9%) of recent paternal gene flow from Central Asia. The variety of Turkish haplotypes is witness to Turkey being both an important source and recipient of gene flow. PMID:14586639

  2. Genome Patterns of Selection and Introgression of Haplotypes in Natural Populations of the House Mouse (Mus musculus)

    PubMed Central

    Staubach, Fabian; Lorenc, Anna; Messer, Philipp W.; Tang, Kun; Petrov, Dmitri A.; Tautz, Diethard

    2012-01-01

    General parameters of selection, such as the frequency and strength of positive selection in natural populations or the role of introgression, are still insufficiently understood. The house mouse (Mus musculus) is a particularly well-suited model system to approach such questions, since it has a defined history of splits into subspecies and populations and since extensive genome information is available. We have used high-density single-nucleotide polymorphism (SNP) typing arrays to assess genomic patterns of positive selection and introgression of alleles in two natural populations of each of the subspecies M. m. domesticus and M. m. musculus. Applying different statistical procedures, we find a large number of regions subject to apparent selective sweeps, indicating frequent positive selection on rare alleles or novel mutations. Genes in the regions include well-studied imprinted loci (e.g. Plagl1/Zac1), homologues of human genes involved in adaptations (e.g. alpha-amylase genes) or in genetic diseases (e.g. Huntingtin and Parkin). Haplotype matching between the two subspecies reveals a large number of haplotypes that show patterns of introgression from specific populations of the respective other subspecies, with at least 10% of the genome being affected by partial or full introgression. Using neutral simulations for comparison, we find that the size and the fraction of introgressed haplotypes are not compatible with a pure migration or incomplete lineage sorting model. Hence, it appears that introgressed haplotypes can rise in frequency due to positive selection and thus can contribute to the adaptive genomic landscape of natural populations. Our data support the notion that natural genomes are subject to complex adaptive processes, including the introgression of haplotypes from other differentiated populations or species at a larger scale than previously assumed for animals. This implies that some of the admixture found in inbred strains of mice may also have a natural origin. PMID:22956910

  3. Haplotypic Background of a Private Allele at High Frequency in the Americas Kari B. Schroeder,* Mattias Jakobsson, Michael H. Crawford, Theodore G. Schurr,k Simina

    E-print Network

    Jakobsson, Mattias

    Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily with other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native been isolated from other Asian populations prior to expanding into the Americas. Introduction Despite

  4. SNP Haplotypes: Unveiling the Truth of Past Relationships

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Over the last ten years, molecular markers have been widely accepted as a breeding tool for crop improvement. Currently, microsatellite markers are being used in rice to select for several simply inherited traits like components of cooking quality and a number of major genes linked to resistance to ...

  5. Adiponectin gene ADIPOQ SNP associations with serum adiponectin in two female populations and effects of SNPs on promoter activity.

    PubMed

    Kyriakou, Theodosios; Collins, Laura J; Spencer-Jones, Nicola J; Malcolm, Claire; Wang, Xiaoling; Snieder, Harold; Swaminathan, Ramasamyiyer; Burling, Keith A; Hart, Deborah J; Spector, Tim D; O'Dell, Sandra D

    2008-01-01

    Adiponectin is an insulin sensitiser in muscle and liver, and low serum levels characterise obesity and insulin resistance. Eight tagging single nucleotide polymorphisms (tSNPs) in the ADIPOQ gene and promoter were selected, and association with serum adiponectin was tested, in two independent samples of Caucasian women: the Chingford Study (n = 808, mean age 62.8 +/- 5.9 years) and Twins UK (n = 2,718, mean age 47.4 +/- 12.6 years). In the Chingford cohort, -11391 G/A, -10066 G/A (rs182052), -7734 C/A (rs16861209), +276 G/T (rs1501299) and +3228 C/T (rs1063537) were significantly associated with fasting serum adiponectin (Ps = 1.00 x 10(-4) to 1.40 x 10(-2)). Associations with all except +3228 C/T were replicated in the Twins UK cohort (Ps = 3.19 x 10(-9) to 6.00 x 10(-3)). In Chingford subjects, the 12 most common 8-SNP haplotypes (frequency 1.90%) explained 2.85% (p = 5.00 x 10(-2)) and in Twins UK subjects, the four most common 5-SNP haplotypes (frequency > 5.00%) explained 1.66% of the variance (p = 5.83 x 10(-7)). To investigate effects of -11391 G/A (rs17300539) and -11377 C/G (rs266729) on promoter activity, 1.2 kb of the ADIPOQ promoter region was cloned in a luciferase reporter plasmid, and the four haplotypes were transfected in differentiated 3T3-L1 adipocytes. No significant allelic effects on promoter activity were found. PMID:18523726

  6. Y-SNPs haplotype diversity in four Chinese cattle breeds.

    PubMed

    Zhang, Runfeng; Cheng, Ming; Li, Xiaofeng; Chen, Fuying; Zheng, Jing; Wang, Xiaofei; Meng, Quanke

    2013-01-01

    To investigate the genetic diversity of Chinese cattle, 96 male samples of 4 Chinese native cattle breeds were investigated using 5 single nucleotide polymorphisms specific to the bovine Y chromosome. Two previously described haplotypes (taurine Y2 and indicine Y3) were detected in 74 and 22 animals, respectively. The haplotype frequencies varied amongst the four native breeds. The taurine Y2 haplotype dominated in the Qinchuan, Dabieshan, and Yunba breeds. However, the indicine Y3 haplotype occurred in high frequency in the Enshi breed. Among the four native breeds, Yunba had the highest haplotype diversity (0.4330 ± 0.0750), followed by Qinchuan (0.2899 ± 0.1028) and Enshi (0.2222 ± 0.1662), Dabieshan was the least differentiated (0.1079 ± 0.0680). Compared with some foreign cattle breeds, the low level of haplotype diversity was detected in our breeds (0.2633 ± 0.1030). PMID:23947665

  7. Variantes del ADNmt en isleńos del lago Titicaca: máxima frecuencia del haplotipo B1 y evidencia de efecto fundador Variants of mtDNA among islanders of the lake Titicaca: highest frequency of haplotype B1 and evidence of founder effect

    Microsoft Academic Search

    José Sandoval; Bedsabé Delgado; Luis Rivas; Bertha Bonilla; Daniel Nugent; Ricardo Fujita

    2004-01-01

    We analyzed mitochondrial DNA haplotypes from 144 samples of islanders of the Taquile and Amantani (Quechua speakers) and Los Uros and Anapia (Aymara speakers) of the Lake Titicaca, Peru. We have found the highest frequency of B1 mtDNA haplotype ever reported: 100% in Taquile (n= 57); 88,6% in Amantani (n= 35); 87,5% in Anapia (n= 24) and 75% in Los

  8. Visualizing SNP statistics in the context of linkage disequilibrium using LD-Plus

    PubMed Central

    Bush, William S.; Dudek, Scott M.; Ritchie, Marylyn D.

    2010-01-01

    Summary: Often in human genetic analysis, multiple tables of single nucleotide polymorphism (SNP) statistics are shown alongside a Haploview style correlation plot. Readers are then asked to make inferences that incorporate knowledge across these multiple sets of results. To better facilitate a collective understanding of all available data, we developed a Ruby-based web application, LD-Plus, to generate figures that simultaneously display physical location of SNPs, binary SNP attributes (such as coding/non-coding or presence on genotyping platforms), common haplotypes and their frequencies and continuously scaled values (such as Fst, minor allele frequency, genotyping efficiency or P-values), all in the context of the D? and r2 linkage disequilibrium structures. Combining these results into one comprehensive figure reduces dereferencing between figures and tables, and can provide unique insights into genetic features that are not clearly seen when results are partitioned across multiple figures and tables. Availability: LD-Plus is freely available for non-commercial research institutions. For full details see http://chgr.mc.vanderbilt.edu/ritchielab/ldplus. Contact: ritchie@chgr.mc.vanderbilt.edu PMID:20130027

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

    PubMed Central

    2013-01-01

    Background Genomic prediction uses two sources of information: linkage disequilibrium between markers and quantitative trait loci, and additive genetic relationships between individuals. One way to increase the accuracy of genomic prediction is to capture more linkage disequilibrium by regression on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. Methods A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (?) of the haplotype covariates had zero effect, i.e. a Bayesian mixture method. Results About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some cases, decreased the bias of prediction. With the Bayesian method, accuracy of prediction was less sensitive to parameter ? when fitting haplotypes compared to fitting markers. Conclusions Use of haplotypes based on genealogy can slightly increase the accuracy of genomic prediction. Improved methods to cluster the haplotypes constructed from local genealogy could lead to additional gains in accuracy. PMID:23496971

  10. Allele and haplotype frequencies for HLA class II (DQA1 and DQB1) loci in patients with celiac disease from Spain

    Microsoft Academic Search

    M. Concepción Vidales; Paul Zubillaga; Itziar Zubillaga; Miguel A Alfonso-Sánchez

    2004-01-01

    Celiac disease (CD) is a complex and multifactorial disease, defined as a malabsorptive disorder of the small intestine resulting from ingestion of gluten. Genetic susceptibility to CD has been associated with human leukocyte antigen (HLA)-DQ2 heterodimer, encoded by the DQA1*0501 and DQB1*02 genes. However, HLA risk factors do not explain the whole genetic predisposition: not all DQ2-encoding haplotypes confer equal

  11. Haplotype diversity in the equine myostatin gene with focus on variants associated with race distance propensity and muscle fiber type proportions.

    PubMed

    Petersen, Jessica L; Valberg, Stephanie J; Mickelson, James R; McCue, Molly E

    2014-12-01

    Two variants in the equine myostatin gene (MSTN), including a T/C SNP in the first intron and a 227-bp SINE insertion in the promoter, are associated with muscle fiber type proportions in the Quarter Horse (QH) and with the prediction of race distance propensity in the Thoroughbred (TB). Genotypes from these loci, along with 18 additional variants surrounding MSTN, were examined in 301 horses of 14 breeds to evaluate haplotype relationships and diversity. The C allele of intron 1 was found in 12 of 14 breeds at a frequency of 0.27; the SINE was observed in five breeds, but common in only the TB and QH (0.73 and 0.48 respectively). Haplotype data suggest the SINE insertion is contemporary to and arose upon a haplotype containing the intron 1 C allele. Gluteal muscle biopsies of TBs showed a significant association of the intron 1 C allele and SINE with a higher proportion of Type 2B and lower proportion of Type 1 fibers. However, in the Belgian horse, in which the SINE is not present, the intron 1 SNP was not associated with fiber type proportions, and evaluation of fiber type proportions across the Belgian, TB and QH breeds shows the significant effect of breed on fiber type proportions is negated when evaluating horses without the SINE variant. These data suggest the SINE, rather than the intron 1 SNP, is driving the observed muscle fiber type characteristics and is the variant targeted by selection for short-distance racing. PMID:25160752

  12. Analysis of DAZL SNP260 and SNP386 in infertile Chinese males using multi-analyte suspension array.

    PubMed

    Zhu, Yijian; Ma, Mingfu; Wan, Ling; Zhang, Danyan; Zhao, Letian; Wei, Li; Li, Lianbing

    2014-12-01

    The aim of the present study was to investigate the association between two single nucleotide polymorphisms (SNPs) and infertility in Chinese males using multi-analyte suspension array (MASA). A total of 196 male patients with azoospermia or severe oligospermia (sperm density <5x106/ml, non?obstructed) who had a normal karyotype and no azoospermia factor microdeletions were recruited, along with 40 healthy, fertile males as controls. Two SNPs of the deleted in azoospermia-like (DAZL) gene, SNP260 and SNP386, were genotyped by allele?specific primer extension (ASPE) combined with MASA technology. The SNP260A>G and SNP386A>G mutations were found in the males with infertility. The SNP260, but not the SNP386, mutation was detectable in the control group. The mutation rates in the controls and patients were 2.5 and 3.06% for SNP260, and 0 and 2.04% for SNP386, respectively. A ?2 analysis did not identify any significant differences in the frequency of either mutation between the fertile and infertile males. In conclusion, the combination of ASPE and MASA methods for SNP genotyping was high?throughput, accurate and cost?efficient. The method was applied to detect SNP polymorphisms in the DAZL gene; and neither the A260G nor the A386G polymorphism of DAZL appeared to be involved in male infertility in the Chinese population. PMID:25323654

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

    PubMed Central

    Song, Chun Meng; Yeo, Boon Huat; Tantoso, Erwin; Yang, Yuchen; Lim, Yun Ping; Li, Kuo-Bin; Rajagopal, Gunaretnam

    2006-01-01

    Background The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. Results To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. Conclusion The iHAP resource, available at , provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies. PMID:17137522

  14. An effective haplotype assembly algorithm based on hypergraph partitioning.

    PubMed

    Chen, Xiao; Peng, Qinke; Han, Libin; Zhong, Tao; Xu, Tao

    2014-10-01

    The haplotype assembly problem has been proven to be complex. Heuristic algorithms are the main methods that are used to solve the problem. These algorithms perform well when the SNP fragments are error-free, but they are less accurate when the error rate increases. The complex relationships caused by fragment errors present a major barrier to assembling accurate haplotypes. Therefore, modeling the complex relationships is the key to solve the problem. In this study, we model the haplotype assembly problem using hypergraph partitioning formulations and propose a novel method termed HGHap (Hypergraph-based Haplotype assembly method). HGHap approaches the haplotype assembly problem in two phases. In the first phase, a hypergraph is constructed in which each vertex corresponds to a fragment and vertices are multiply connected to form hyperedges. In the second phase, a hypergraph partitioning algorithm is employed to obtain two groups of fragments to construct the haplotypes. The hyperedges capture higher-order relationships among fragments that facilitate the subsequent partitioning. Our results demonstrate that the method performs better than other methods in most cases, especially in cases with a high error rate. PMID:24954019

  15. Single Nucleotide Polymorphism (SNP)-Strings: An Alternative Method for Assessing Genetic Associations

    PubMed Central

    Goodin, Douglas S.; Khankhanian, Pouya

    2014-01-01

    Background Genome-wide association studies (GWAS) identify disease-associations for single-nucleotide-polymorphisms (SNPs) from scattered genomic-locations. However, SNPs frequently reside on several different SNP-haplotypes, only some of which may be disease-associated. This circumstance lowers the observed odds-ratio for disease-association. Methodology/Principal Findings Here we develop a method to identify the two SNP-haplotypes, which combine to produce each person’s SNP-genotype over specified chromosomal segments. Two multiple sclerosis (MS)-associated genetic regions were modeled; DRB1 (a Class II molecule of the major histocompatibility complex) and MMEL1 (an endopeptidase that degrades both neuropeptides and ?-amyloid). For each locus, we considered sets of eleven adjacent SNPs, surrounding the putative disease-associated gene and spanning ?200 kb of DNA. The SNP-information was converted into an ordered-set of eleven-numbers (subject-vectors) based on whether a person had zero, one, or two copies of particular SNP-variant at each sequential SNP-location. SNP-strings were defined as those ordered-combinations of eleven-numbers (0 or 1), representing a haplotype, two of which combined to form the observed subject-vector. Subject-vectors were resolved using probabilistic methods. In both regions, only a small number of SNP-strings were present. We compared our method to the SHAPEIT-2 phasing-algorithm. When the SNP-information spanning 200 kb was used, SHAPEIT-2 was inaccurate. When the SHAPEIT-2 window was increased to 2,000 kb, the concordance between the two methods, in both of these eleven-SNP regions, was over 99%, suggesting that, in these regions, both methods were quite accurate. Nevertheless, correspondence was not uniformly high over the entire DNA-span but, rather, was characterized by alternating peaks and valleys of concordance. Moreover, in the valleys of poor-correspondence, SHAPEIT-2 was also inconsistent with itself, suggesting that the SNP-string method is more accurate across the entire region. Conclusions/Significance Accurate haplotype identification will enhance the detection of genetic-associations. The SNP-string method provides a simple means to accomplish this and can be extended to cover larger genomic regions, thereby improving a GWAS’s power, even for those published previously. PMID:24727690

  16. Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon.

    PubMed

    Gansmo, Liv B; Knappskog, Stian; Romundstad, Pĺl; Hveem, Kristian; Vatten, Lars; Lřnning, Per E

    2015-07-01

    MDM2 is a key regulator of the p53 tumor suppressor protein and is overexpressed in many human cancers. Two single nucleotide polymorphisms (SNPs) located in the MDM2 intronic promoter (P2) have been found to exert biological function. The G-allele of SNP309T>G; rs2279744 increases MDM2 transcription and has been linked to increased cancer risk. In contrast, the less frequent SNP285G>C; rs117039649, which is in complete linkage disequilibrium with SNP309 (generating a SNP285C/309G variant haplotype), has been related to reduced MDM2 transcription and to reduced risk of breast, endometrial and ovarian cancer. In this large population-based case-control study, we genotyped SNP309 and SNP285 in 10,830 individuals, including cases with cancer of the breast (n=1,717), colon (n=1,532), lung (n=1,331) and prostate (n=2,501), as well as 3,749 non-cancer controls. We found a slightly reduced risk for lung cancer among individuals harboring the SNP309TG/GG genotypes compared to the SNP309TT genotype (OR= 0.86; CI?=?0.67-0.98), but this association was restricted to women (OR?=?0.77; CI?=?0.63-0.95) and was not present among men (OR?=?0.91; CI?=?0.77-1.08). Consistent with previous findings, we found a reduced risk for breast cancer among individuals carrying the SNP285GC/309GG genotype versus the SNP285GG/309GG genotype (OR?=?0.55; CI?=?0.33-0.93). In conclusion, our data support the hypothesis that the effects of both SNP285 and SNP309 status are tissue dependent. PMID:25431177

  17. The impact of using related individuals for haplotype reconstruction in population studies

    E-print Network

    Williams, Chris

    that a preliminary estimate of the haplotype frequency distribution can be valuable in large population studiesThe impact of using related individuals for haplotype reconstruction in population studies Michael highlighted the dangers of using haplotypes reconstructed directly from population data for a fine

  18. Multi-locus stepwise regression: a haplotype-based algorithm for finding genetic associations applied to atopic dermatitis

    PubMed Central

    2012-01-01

    Background Genome-wide association studies (GWAS) provide an increasing number of single nucleotide polymorphisms (SNPs) associated with diseases. Our aim is to exploit those closely spaced SNPs in candidate regions for a deeper analysis of association beyond single SNP analysis, combining the classical stepwise regression approach with haplotype analysis to identify risk haplotypes for complex diseases. Methods Our proposed multi-locus stepwise regression starts with an evaluation of all pair-wise SNP combinations and then extends each SNP combination stepwise by one SNP from the region, carrying out haplotype regression in each step. The best associated haplotype patterns are kept for the next step and must be corrected for multiple testing at the end. These haplotypes should also be replicated in an independent data set. We applied the method to a region of 259 SNPs from the epidermal differentiation complex (EDC) on chromosome 1q21 of a German GWAS using a case control set (1,914 individuals) and to 268 families with at least two affected children as replication. Results A 4-SNP haplotype pattern with high statistical significance in the case control set (p = 4.13 × 10-7 after Bonferroni correction) could be identified which remained significant in the family set after Bonferroni correction (p = 0.0398). Further analysis revealed that this pattern reflects mainly the effect of the well-known FLG gene; however, a FLG-independent haplotype in case control set (OR = 1.71, 95% CI: 1.32-2.23, p = 5.6 × 10-5) and family set (OR = 1.68, 95% CI: 1.18-2.38, p = 2.19 × 10-3) could be found in addition. Conclusion Our approach is a useful tool for finding allele combinations associated with diseases beyond single SNP analysis in chromosomal candidate regions. PMID:22284537

  19. Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity

    PubMed Central

    Wang, Danxin; Poi, Ming J.; Sun, Xiaochun; Gaedigk, Andrea; Leeder, J. Steven; Sadee, Wolfgang

    2014-01-01

    Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically used drugs. Genetic polymorphisms cause substantial variation in CYP2D6 activity and serve as biomarkers guiding drug therapy. However, genotype–phenotype relationships remain ambiguous except for poor metabolizers carrying null alleles, suggesting the presence of yet unknown genetic variants. Searching for regulatory CYP2D6 polymorphisms, we find that a SNP defining the CYP2D6*2 allele, rs16947 [R296C, 17–60% minor allele frequency (MAF)], previously thought to convey normal activity, alters exon 6 splicing, thereby reducing CYP2D6 expression at least 2-fold. In addition, two completely linked SNPs (rs5758550/rs133333, MAF 13–42%) increase CYP2D6 transcription more than 2-fold, located in a distant downstream enhancer region (>100 kb) that interacts with the CYP2D6 promoter. In high linkage disequilibrium (LD) with each other, rs16947 and the enhancer SNPs form haplotypes that affect CYP2D6 enzyme activity in vivo. In a pediatric cohort of 164 individuals, rs16947 alone (minor haplotype frequency 28%) was associated with reduced CYP2D6 metabolic activity (measured as dextromethorphan/metabolite ratios), whereas rs5758550/rs133333 alone (frequency 3%) resulted in increased CYP2D6 activity, while haplotypes containing both rs16947 and rs5758550/rs133333 were similar to the wild-type. Other alleles used in biomarker panels carrying these variants such as CYP2D6*41 require re-evaluation of independent effects on CYP2D6 activity. The occurrence of two regulatory variants of high frequency and in high LD, residing on a long haplotype, highlights the importance of gene architecture, likely shaped by evolutionary selection pressures, in determining activity of encoded proteins. PMID:23985325

  20. Development of Vibrio spp. infection resistance related SNP markers using multiplex SNaPshot genotyping method in the clam Meretrix meretrix.

    PubMed

    Nie, Qing; Yue, Xin; Liu, Baozhong

    2015-04-01

    The clam Meretrix meretrix is a commercially important mollusc species in the coastal areas of South and Southeast Asia. In the present study, large-scale SNPs were genotyped by the Multiplex SNaPshot genotyping method among the stocks of M. meretrix with different Vibrio spp. infection resistance profile. Firstly, the AUTOSNP software was applied to mine SNPs from M. meretrix transcriptome, and 323 SNP loci (including 120 indels) located on 64 contigs were selected based on Uniprot-GO associations. Then, 38 polymorphic SNP loci located on 15 contigs were genotyped successfully in the clam stocks with different resistance to Vibrio parahaemolyticus infection (11-R and 11-S groups). Pearson's Chi-square test was applied to compare the allele and genotype frequency distributions of the SNPs between the different stocks, and seven SNP markers located on three contigs were found to be associated with V. parahaemolyticus infection resistance trait. Haplotype-association analysis showed that six haplotypes had significantly different frequency distributions in 11-S and 11-R (P < 0.05). With selective genotyping between 09-R and 09-C populations, which had different resistance to Vibrio harveyi infection, four out of the seven selected SNPs had significantly different distributions (P < 0.05) and therefore they were considered to be associated with Vibrio spp. infection resistance. Sequence alignments and annotations indicated that the contigs containing the associated SNPs had high similarity to the immune related genes. All these results would be useful for the future marker-assisted selection of M. meretrix strains with high Vibrio spp. infection resistance. PMID:25655323

  1. Socioaffective Neuroscience & Psychology (SNP)

    E-print Network

    Paris-Sud XI, Université de

    Socioaffective Neuroscience & Psychology (SNP) I t is an exciting challenge for us to launch a new interdisciplinary journal, Socioaffective Neuroscience & Psychology. We believe the journal will appeal to a wide within cogni- tive neuroscience and psychology have started to emerge: (1) affective neurosciences

  2. Application of a posteriori granddaughter and modified granddaughter designs to determine Holstein haplotype effects

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A posteriori and modified granddaughter designs were applied to determine haplotype effects for Holstein bulls and cows with BovineSNP50 genotypes. The a posteriori granddaughter design was applied to 52 sire families, each with '100 genotyped sons with genetic evaluations based on progeny tests. Fo...

  3. g you The direct determination of haplotypes from extended regions of genomic DNA

    PubMed Central

    2010-01-01

    Background One of the major obstacles to the exploitation of genetic variation in human medicine, veterinary medicine, and animal breeding is the difficulty in defining haplotypes in unrelated individuals. Results We have developed a Multiplex Double Amplification Refractory Mutation System combined with Solid Phase PCR on Fluorescently labelled beads. The process is inherently amenable to automation. It provides a high degree of internal Quality Control, as each PCR product is represented in duplicate on the bead array, and each SNP is tested against multiple partners. This technique can resolve very complex genotypes into their constituent haplotypes; it defined all the alleles at 60 SNP in exon 2 of the ovine DRB1 MHC locus in a sample of 109 rams. These 60 SNP formed 33 DRB1 exon 2 alleles; two of which had not been previously identified; although both of them have been independently confirmed. Conclusion This technique has the same resolution as allele specific sequencing. Sequencing has the advantage of identifying novel polymorphic sites but where all SNP sites have been identified this novel procedure can resolve all alleles and haplotypes and identify novel combinations of polymorphisms. This method is similar in price to direct sequencing and provides a low cost system for direct haplotyping of extended DNA sequences. PMID:20370899

  4. ATM haplotypes and breast cancer risk in Jewish high-risk women , G Kimmel2

    E-print Network

    Shamir, Ron

    ATM haplotypes and breast cancer risk in Jewish high-risk women M Koren1 , G Kimmel2 , E Ben-Asher3 a role in conferring breast cancer risk, the contribution of ATM gene mutations to breast cancer is still was performed on 66 women with breast cancer and 76 asymptomatic. One SNP (rs228589) was significantly more

  5. Haplotype Inference in General Pedigrees Using the Cluster Variation Method

    PubMed Central

    Albers, Cornelis A.; Heskes, Tom; Kappen, Hilbert J.

    2007-01-01

    We present CVMHAPLO, a probabilistic method for haplotyping in general pedigrees with many markers. CVMHAPLO reconstructs the haplotypes by assigning in every iteration a fixed number of the ordered genotypes with the highest marginal probability, conditioned on the marker data and ordered genotypes assigned in previous iterations. CVMHAPLO makes use of the cluster variation method (CVM) to efficiently estimate the marginal probabilities. We focused on single-nucleotide polymorphism (SNP) markers in the evaluation of our approach. In simulated data sets where exact computation was feasible, we found that the accuracy of CVMHAPLO was high and similar to that of maximum-likelihood methods. In simulated data sets where exact computation of the maximum-likelihood haplotype configuration was not feasible, the accuracy of CVMHAPLO was similar to that of state of the art Markov chain Monte Carlo (MCMC) maximum-likelihood approximations when all ordered genotypes were assigned and higher when only a subset of the ordered genotypes was assigned. CVMHAPLO was faster than the MCMC approach and provided more detailed information about the uncertainty in the inferred haplotypes. We conclude that CVMHAPLO is a practical tool for the inference of haplotypes in large complex pedigrees. PMID:17660564

  6. Imputation of Microsatellite Alleles from Dense SNP Genotypes for Parental Verification

    PubMed Central

    McClure, Matthew; Sonstegard, Tad; Wiggans, George; Van Tassell, Curtis P

    2012-01-01

    Microsatellite (MS) markers have recently been used for parental verification and are still the international standard despite higher cost, error rate, and turnaround time compared with Single Nucleotide Polymorphisms (SNP)-based assays. Despite domestic and international interest from producers and research communities, no viable means currently exist to verify parentage for an individual unless all familial connections were analyzed using the same DNA marker type (MS or SNP). A simple and cost-effective method was devised to impute MS alleles from SNP haplotypes within breeds. For some MS, imputation results may allow inference across breeds. A total of 347 dairy cattle representing four dairy breeds (Brown Swiss, Guernsey, Holstein, and Jersey) were used to generate reference haplotypes. This approach has been verified (>98% accurate) for imputing the International Society of Animal Genetics recommended panel of 12 MS for cattle parentage verification across a validation set of 1,307 dairy animals. Implementation of this method will allow producers and breed associations to transition to SNP-based parentage verification utilizing MS genotypes from historical data on parents where SNP genotypes are missing. This approach may be applicable to additional cattle breeds and other species that wish to migrate from MS- to SNP-based parental verification. PMID:22912645

  7. Haplotypes versus genotypes on pedigrees

    PubMed Central

    2011-01-01

    Background Genome sequencing will soon produce haplotype data for individuals. For pedigrees of related individuals, sequencing appears to be an attractive alternative to genotyping. However, methods for pedigree analysis with haplotype data have not yet been developed, and the computational complexity of such problems has been an open question. Furthermore, it is not clear in which scenarios haplotype data would provide better estimates than genotype data for quantities such as recombination rates. Results To answer these questions, a reduction is given from genotype problem instances to haplotype problem instances, and it is shown that solving the haplotype problem yields the solution to the genotype problem, up to constant factors or coefficients. The pedigree analysis problems we will consider are the likelihood, maximum probability haplotype, and minimum recombination haplotype problems. Conclusions Two algorithms are introduced: an exponential-time hidden Markov model (HMM) for haplotype data where some individuals are untyped, and a linear-time algorithm for pedigrees having haplotype data for all individuals. Recombination estimates from the general haplotype HMM algorithm are compared to recombination estimates produced by a genotype HMM. Having haplotype data on all individuals produces better estimates. However, having several untyped individuals can drastically reduce the utility of haplotype data. PMID:21504603

  8. A system for exact and approximate genetic linkage analysis of SNP data in large pedigrees

    PubMed Central

    Silberstein, Mark; Weissbrod, Omer; Otten, Lars; Tzemach, Anna; Anisenia, Andrei; Shtark, Oren; Tuberg, Dvir; Galfrin, Eddie; Gannon, Irena; Shalata, Adel; Borochowitz, Zvi U.; Dechter, Rina; Thompson, Elizabeth; Geiger, Dan

    2013-01-01

    Motivation: The use of dense single nucleotide polymorphism (SNP) data in genetic linkage analysis of large pedigrees is impeded by significant technical, methodological and computational challenges. Here we describe Superlink-Online SNP, a new powerful online system that streamlines the linkage analysis of SNP data. It features a fully integrated flexible processing workflow comprising both well-known and novel data analysis tools, including SNP clustering, erroneous data filtering, exact and approximate LOD calculations and maximum-likelihood haplotyping. The system draws its power from thousands of CPUs, performing data analysis tasks orders of magnitude faster than a single computer. By providing an intuitive interface to sophisticated state-of-the-art analysis tools coupled with high computing capacity, Superlink-Online SNP helps geneticists unleash the potential of SNP data for detecting disease genes. Results: Computations performed by Superlink-Online SNP are automatically parallelized using novel paradigms, and executed on unlimited number of private or public CPUs. One novel service is large-scale approximate Markov Chain–Monte Carlo (MCMC) analysis. The accuracy of the results is reliably estimated by running the same computation on multiple CPUs and evaluating the Gelman–Rubin Score to set aside unreliable results. Another service within the workflow is a novel parallelized exact algorithm for inferring maximum-likelihood haplotyping. The reported system enables genetic analyses that were previously infeasible. We demonstrate the system capabilities through a study of a large complex pedigree affected with metabolic syndrome. Availability: Superlink-Online SNP is freely available for researchers at http://cbl-hap.cs.technion.ac.il/superlink-snp. The system source code can also be downloaded from the system website. Contact: omerw@cs.technion.ac.il Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23162081

  9. Probability Theory-based SNP Association Study Method for Identifying Susceptibility Loci and Genetic Disease Models in Human Case-Control Data

    PubMed Central

    Yuan, Xiguo; Zhang, Junying; Wang, Yue

    2010-01-01

    One of the most challenging points in studying human common complex diseases is to search for both strong and weak susceptibility single-nucleotide polymorphisms (SNPs) and identify forms of genetic disease models. Currently, a number of methods have been proposed for this purpose. Many of them have not been validated through applications into various genome datasets, so their abilities are not clear in real practice. In this paper, we present a novel SNP association study method based on probability theory, called ProbSNP. The method firstly detects SNPs by evaluating their joint probabilities in combining with disease status and selects those with the lowest joint probabilities as susceptibility ones, and then identifies some forms of genetic disease models through testing multiple-locus interactions among the selected SNPs. The joint probabilities of combined SNPs are estimated by establishing Gaussian distribution probability density functions, in which the related parameters (i.e., mean value and standard deviation) are evaluated based on allele and haplotype frequencies. Finally, we test and validate the method using various genome datasets. We find that ProbSNP has shown remarkable success in the applications to both simulated genome data and real genome-wide data. PMID:20840904

  10. Finding Haplotype Tagging SNPs by Use of Principal Components Analysis

    PubMed Central

    Lin, Zhen; Altman, Russ B.

    2004-01-01

    The immense volume and rapid growth of human genomic data, especially single nucleotide polymorphisms (SNPs), present special challenges for both biomedical researchers and automatic algorithms. One such challenge is to select an optimal subset of SNPs, commonly referred as “haplotype tagging SNPs” (htSNPs), to capture most of the haplotype diversity of each haplotype block or gene-specific region. This information-reduction process facilitates cost-effective genotyping and, subsequently, genotype-phenotype association studies. It also has implications for assessing the risk of identifying research subjects on the basis of SNP information deposited in public domain databases. We have investigated methods for selecting htSNPs by use of principal components analysis (PCA). These methods first identify eigenSNPs and then map them to actual SNPs. We evaluated two mapping strategies, greedy discard and varimax rotation, by assessing the ability of the selected htSNPs to reconstruct genotypes of non-htSNPs. We also compared these methods with two other htSNP finders, one of which is PCA based. We applied these methods to three experimental data sets and found that the PCA-based methods tend to select the smallest set of htSNPs to achieve a 90% reconstruction precision. PMID:15389393

  11. Genotype frequencies of VKORC1 and CYP2C9 in Native and Mestizo populations from Mexico, potential impact for coumarin dosing.

    PubMed

    Villegas-Torres, Beatriz; Sánchez-Girón, Francisco; Jaramillo-Villafuerte, Karla; Soberón, Xavier; Gonzalez-Covarrubias, Vanessa

    2015-03-10

    The collection of pharmacogenetic variants in Mexican populations remains incomplete, thus, we aimed to characterize the genotype frequency of 11 SNP on CYP2C9 and VKORC1 in more than one-thousand individuals, and to explore their potential impact on coumarin dosing. In natives, genotype frequencies indicate that over 92% would reflect an extensive metabolism. For Mestizo populations, the proportion of CYP2C9 extensive (79%), intermediate (20.0%) and poor metabolizers (1.0%) was significantly different from that of natives, and varied among the different states of Mexico. Genotype frequencies of 7 SNP on VKORC1, were more homogenously distributed among natives and Mestizos. VKORC1 haplotype analysis revealed that most natives can be grouped into haplotypes H1 or H7-H8, while Mestizos showed a wider frequency distribution for other haplotypes. Our observations confirm previous reports on the genotype distribution of major CYP2C9 alleles, and contribute to the collection of genotype frequencies on relevant VKORC1 variants. PMID:25560189

  12. HLA Type Inference via Haplotypes Identical by Descent

    NASA Astrophysics Data System (ADS)

    Setty, Manu N.; Gusev, Alexander; Pe'Er, Itsik

    The Human Leukocyte Antigen (HLA) genes play a major role in adaptive immune response and are used to differentiate self antigens from non self ones. HLA genes are hyper variable with nearly every locus harboring over a dozen alleles. This variation plays an important role in susceptibility to multiple autoimmune diseases and needs to be matched on for organ transplantation. Unfortunately, HLA typing by serological methods is time consuming and expensive compared to high throughput Single Nucleotide Polymorphism (SNP) data. We present a new computational method to infer per-locus HLA types using shared segments Identical By Descent (IBD), inferred from SNP genotype data. IBD information is modeled as graph where shared haplotypes are explored among clusters of individuals with known and unknown HLA types to identify the latter. We analyze performance of the method in a previously typed subset of the HapMap population, achieving accuracy of 96% in HLA-A, 94% in HLA-B, 95% in HLA-C, 77% in HLA-DR1, 93% in HLA-DQA1 and 90% in HLA-DQB1 genes. We compare our method to a tag SNP based approach and demonstrate higher sensitivity and specificity. Our method demonstrates the power of using shared haplotype segments for large-scale imputation at the HLA locus.

  13. 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

  14. Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

    Microsoft Academic Search

    Lidija Turkovic; Lyle C Gurrin; Melanie Bahlo; Gillian S Dite; Melissa C Southey; John L Hopper

    2010-01-01

    BACKGROUND: BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of

  15. Online resources for SNP analysis

    Microsoft Academic Search

    Christopher Phillips

    2007-01-01

    The major online single nucleotide polymorphism (SNP) databases freely available as research tools for genetic analysis are\\u000a explained, reviewed, and compared. An outline is given of the search strategies that can be used with the most extensive current\\u000a SNP databases: National Centre for Biotechnology Information (NCBI) dbSNP and HapMap to help the use secure the most appropriate\\u000a data for the

  16. 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 this association is not sub-phenotype-specific. PMID:23372721

  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. PMID:23885196

  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. High-resolution haplotype block structure in the cattle genome

    PubMed Central

    Villa-Angulo, Rafael; Matukumalli, Lakshmi K; Gill, Clare A; Choi, Jungwoo; Van Tassell, Curtis P; Grefenstette, John J

    2009-01-01

    Background The Bovine HapMap Consortium has generated assay panels to genotype ~30,000 single nucleotide polymorphisms (SNPs) from 501 animals sampled from 19 worldwide taurine and indicine breeds, plus two outgroup species (Anoa and Water Buffalo). Within the larger set of SNPs we targeted 101 high density regions spanning up to 7.6 Mb with an average density of approximately one SNP per 4 kb, and characterized the linkage disequilibrium (LD) and haplotype block structure within individual breeds and groups of breeds in relation to their geographic origin and use. Results From the 101 targeted high-density regions on bovine chromosomes 6, 14, and 25, between 57 and 95% of the SNPs were informative in the individual breeds. The regions of high LD extend up to ~100 kb and the size of haplotype blocks ranges between 30 bases and 75 kb (10.3 kb average). On the scale from 1–100 kb the extent of LD and haplotype block structure in cattle has high similarity to humans. The estimation of effective population sizes over the previous 10,000 generations conforms to two main events in cattle history: the initiation of cattle domestication (~12,000 years ago), and the intensification of population isolation and current population bottleneck that breeds have experienced worldwide within the last ~700 years. Haplotype block density correlation, block boundary discordances, and haplotype sharing analyses were consistent in revealing unexpected similarities between some beef and dairy breeds, making them non-differentiable. Clustering techniques permitted grouping of breeds into different clades given their similarities and dissimilarities in genetic structure. Conclusion This work presents the first high-resolution analysis of haplotype block structure in worldwide cattle samples. Several novel results were obtained. First, cattle and human share a high similarity in LD and haplotype block structure on the scale of 1–100 kb. Second, unexpected similarities in haplotype block structure between dairy and beef breeds make them non-differentiable. Finally, our findings suggest that ~30,000 uniformly distributed SNPs would be necessary to construct a complete genome LD map in Bos taurus breeds, and ~580,000 SNPs would be necessary to characterize the haplotype block structure across the complete cattle genome. PMID:19393054

  20. Generating SNP barcode to evaluate SNP-SNP interaction of disease by particle swarm optimization.

    PubMed

    Chang, Hsueh-Wei; Yang, Cheng-Hong; Ho, Chang-Hsuan; Wen, Cheng-Hao; Chuang, Li-Yeh

    2009-02-01

    Genome-wide association analysis involved many single-nucleotide polymorphisms (SNPs) data is challenging mathematically and computationally. Hence, we propose the odds ratio-based discrete binary particle swarm optimization (OR-DBPSO) method that uses the OR as a new quantitative measure of disease risk among many SNP combinations with genotypes called "SNP barcode". DBPSO are applied to generate SNP barcode, which computes the maximal difference of occurrence between the case and control groups, to predict disease susceptibility such as osteoporosis. Different SNP barcode patterns may occur several times in either low or high bone mineral density (BMD) groups. Our results showed that a DBPSO can effectively identify a specific SNP barcode with an optimized fitness value. SNP barcodes with a low fitness value will naturally be discarded from the population. A representative SNP barcode with a variable number of SNPs is processed to OR analysis to determine the maximum difference between the low and high BMD groups in statistics manner. Therefore, this paper introduces a powerful procedure to analyze disease-associated SNP-SNP interaction in genome-wide genes. PMID:18789770

  1. Haplotype Analysis Improved Evidence for Candidate Genes for Intramuscular Fat Percentage from a Genome Wide Association Study of Cattle

    PubMed Central

    Barendse, William

    2011-01-01

    In genome wide association studies (GWAS), haplotype analyses of SNP data are neglected in favour of single point analysis of associations. In a recent GWAS, we found that none of the known candidate genes for intramuscular fat (IMF) had been identified. In this study, data from the GWAS for these candidate genes were re-analysed as haplotypes. First, we confirmed that the methodology would find evidence for association between haplotypes in candidate genes of the calpain-calpastatin complex and musculus longissimus lumborum peak force (LLPF), because these genes had been confirmed through single point analysis in the GWAS. Then, for intramuscular fat percent (IMF), we found significant partial haplotype substitution effects for the genes ADIPOQ and CXCR4, as well as suggestive associations to the genes CEBPA, FASN, and CAPN1. Haplotypes for these genes explained 80% more of the phenotypic variance compared to the best single SNP. For some genes the analyses suggested that there was more than one causative mutation in some genes, or confirmed that some causative mutations are limited to particular subgroups of a species. Fitting the SNPs and their interactions simultaneously explained a similar amount of the phenotypic variance compared to haplotype analyses. Haplotype analysis is a neglected part of the suite of tools used to analyse GWAS data, would be a useful method to extract more information from these data sets, and may contribute to reducing the missing heritability problem. PMID:22216329

  2. Power and Sample Size Calculations for Genetic Case\\/Control Studies Using Gene-Centric SNP Maps: Application to Human Chromosomes 6, 21, and 22 in Three Populations

    Microsoft Academic Search

    Francisco M. De La Vega; Derek Gordon; Xiaoping Su; Charles Scafe; Hadar Isaac; Dennis A. Gilbert; Eugene G. Spier

    2005-01-01

    Power and sample size calculations are critical parts of any research design for genetic association. We present a method that utilizes haplotype frequency information and average marker-marker linkage disequilibrium on SNPs typed in and around all genes on a chromosome. The test statistic used is the classic likelihood ratio test applied to haplotypes in case\\/control populations. Haplotype frequencies are computed

  3. Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

    PubMed Central

    Kimchi-Sarfaty, Chava; Marple, Andrew H; Shinar, Shiri; Kimchi, Avraham M.; Scavo, David; Roma, M. Isabella; Kim, In-Wha; Jones, Adam; Arora, Mili; Gribar, John; Gurwitz, David; Gottesman, Michael M

    2007-01-01

    Introduction The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related. Methods In this study, 95 individuals representative of the entire ethnic make-up of the United States were compared to 101 individuals from an Ashkenazi Jewish population. These individuals were analyzed by genomic sequencing and PCR-RFLP to calculate their genotype frequencies. Results Twenty-five SNPs were located in the exons of the ABCB1 gene. All of the polymorphisms identified were in parts of the ABCB1 gene product predicted to be intracellular, and 16 appear to be novel as compared to those listed by NCBI. Frequencies of the 1236C>T and 2677G>T/A/C SNPs were similar for the American and Ashkenazi populations (64.2% and 60.4% respectively for 1236C>T – ?2 is 0.30 p?1; 55.8% and 64.4% for 2677G>T/A/C ?2 is 1.49 p?1), but were different for 3435C>T (24.2% for the American population and 69.3% for the Ashkenazi population ?2 is 39.927 p<0.001). The 1236T/2677T/3435T haplotype occurred in 23.6% (SE 0.013) of the Ashkenazi population. Conclusion The SNP at location 3435C>T plays a significant role in the ABCB1 gene. The haplotype and genotype analysis from these data may be used as a basis for studies on the relationship between ABCB1 genotypes and drug efficacy, drug toxicity, disease susceptibility or other phenotypes. PMID:17187507

  4. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.

    PubMed

    Albers, Cornelis A; Paul, Dirk S; Schulze, Harald; Freson, Kathleen; Stephens, Jonathan C; Smethurst, Peter A; Jolley, Jennifer D; Cvejic, Ana; Kostadima, Myrto; Bertone, Paul; Breuning, Martijn H; Debili, Najet; Deloukas, Panos; Favier, Rémi; Fiedler, Janine; Hobbs, Catherine M; Huang, Ni; Hurles, Matthew E; Kiddle, Graham; Krapels, Ingrid; Nurden, Paquita; Ruivenkamp, Claudia A L; Sambrook, Jennifer G; Smith, Kenneth; Stemple, Derek L; Strauss, Gabriele; Thys, Chantal; van Geet, Chris; Newbury-Ecob, Ruth; Ouwehand, Willem H; Ghevaert, Cedric

    2012-04-01

    The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome. PMID:22366785

  5. A High Density SNP Array for the Domestic Horse and Extant Perissodactyla: Utility for Association Mapping, Genetic Diversity, and Phylogeny Studies

    PubMed Central

    McCue, Molly E.; Bannasch, Danika L.; Petersen, Jessica L.; Gurr, Jessica; Bailey, Ernie; Binns, Matthew M.; Distl, Ottmar; Guérin, Gérard; Hasegawa, Telhisa; Hill, Emmeline W.; Leeb, Tosso; Lindgren, Gabriella; Penedo, M. Cecilia T.; Rřed, Knut H.; Ryder, Oliver A.; Swinburne, June E.; Tozaki, Teruaki; Valberg, Stephanie J.; Vaudin, Mark; Lindblad-Toh, Kerstin

    2012-01-01

    An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of ?43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50–100 kb and reached background levels within 1–2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the Mongolian and Quarter Horse. Multidimensional scaling (MDS) analyses demonstrated the tight grouping of individuals within most breeds, close proximity of related breeds, and less tight grouping in admixed breeds. The close relationship between the Przewalski's Horse and the domestic horse was demonstrated by pair-wise genetic distance and MDS. Genotyping of other Perissodactyla (zebras, asses, tapirs, and rhinoceros) was variably successful, with call rates and the number of polymorphic loci varying across taxa. Parsimony analysis placed the modern horse as sister taxa to Equus przewalski. The utility of the SNP array in genome-wide association was confirmed by mapping the known recessive chestnut coat color locus (MC1R) and defining a conserved haplotype of ?750 kb across all breeds. These results demonstrate the high quality of this SNP genotyping resource, its usefulness in diverse genome analyses of the horse, and potential use in related species. PMID:22253606

  6. 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

  7. 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, Tőnu; 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

  8. [Study on HLA haplotypes in Jiangsu-Zhejiang-Shanghai Han population].

    PubMed

    Feng, Ming-Liang; Ji, Yun; Lu, Qiong; Yang, Jian-Hao; Xie, Jun-Hua; Ji, Yue-Hua; Zhang, Gong-Liang; Yang, Ying

    2003-06-01

    This study is to investigate HLA haplotypes in Jiangsu-Zhejiang-Shanghai Han population based on 166 families by serological and molecular biological HLA typing methods and to analyze the distribution characteristic of HLA haplotypes. The results showed that allele frequencies of more than 10% for HLA antigens were A2, A11, A24, B13, B46, B60, DRB1 *04, DRB1 *08, DRB1* 09, DRB1 * 12 and DRB1 * 15. In the analysis of HLA haplotypes, 128 kinds of A-B haplotypes and 182 kinds of B-DRB1 haplotypes were found, comprising 19.28% (128/664) and 27.41%(182/664) of total theoretical haplotypes, respectively. 18 kinds of A-B haplotypes and 23 kinds of B-DRB1 haplotypes occurred at frequencies of more than 0.5% (linkage disequilibrium value, delta > 0) .351 kinds of A-B-DRB1 haplotypes were found, comprising 52.86% (351/664) of total theoretical haplotypes, and 8 kinds of A-B-DRB1 haplotypes occurred at frequencies of more than 0.5% (delta > 0). The common A-B-DRB1 haplotypes were A30-B13-DRB1 * 07(4.22%), A2-B46-DRB1 * 09(3.77%), A33-B58-DRB1 * 17(3.01%), A33-B58-DRB1 * 13.1 (1.81%) and A11-B75-DRB1 * 12(1.51%). The HLA haplotype distribution of Jiangsu-Zhejiang-Shanghai Han population has its own genetic characteristics, so it suggests this population is between southern and northern Han population. The HLA polymorphism of Chinese Han population is more abundant in East Asian populations. PMID:12939805

  9. Y-SNP L1034: limited genetic link between Mansi and Hungarian-speaking populations.

    PubMed

    Fehér, T; Németh, E; Vándor, A; Kornienko, I V; Csáji, L K; Pamjav, H

    2015-02-01

    Genetic studies noted that the Hungarian Y-chromosomal gene pool significantly differs from other Uralic-speaking populations. Hungarians show very limited or no presence of haplogroup N-Tat, which is frequent among other Uralic-speaking populations. We proposed that some genetic links need to be observed between the linguistically related Hungarian and Mansi populations.This is the first attempt to divide haplogroup N-Tat into subhaplogroups by testing new downstream SNP markers L708 and L1034. Sixty Northern Mansi samples were collected in Western Siberia and genotyped for Y-chromosomal haplotypes and haplogroups. We found 14 Mansi and 92 N-Tat samples from 7 populations. Comparative results showed that all N-Tat samples carried the N-L708 mutation. Some Hungarian, Sekler, and Uzbek samples were L1034 SNP positive, while all Mongolians, Buryats, Khanty, Finnish, and Roma samples yielded a negative result for this marker. Based on the above, L1034 marker seems to be a subgroup of N-Tat, which is typical for Mansi and Hungarian-speaking ethnic groups so far. Based on our time to most recent common ancestor data, the L1034 marker arose 2,500 years before present. The overall frequency of the L1034 is very low among the analyzed populations, thus it does not necessarily mean that proto-Hungarians and Mansi descend from common ancestors. It does provide, however, a limited genetic link supporting language contact. Both Hungarians and Mansi have much more complex genetic population history than the traditional tree-based linguistic model would suggest. PMID:25258186

  10. RNA-Seq Identifies SNP Markers for Growth Traits in Rainbow Trout

    PubMed Central

    Salem, Mohamed; Vallejo, Roger L.; Leeds, Timothy D.; Palti, Yniv; Liu, Sixin; Sabbagh, Annas; Rexroad, Caird E.; Yao, Jianbo

    2012-01-01

    Fast growth is an important and highly desired trait, which affects the profitability of food animal production, with feed costs accounting for the largest proportion of production costs. Traditional phenotype-based selection is typically used to select for growth traits; however, genetic improvement is slow over generations. Single nucleotide polymorphisms (SNPs) explain 90% of the genetic differences between individuals; therefore, they are most suitable for genetic evaluation and strategies that employ molecular genetics for selective breeding. SNPs found within or near a coding sequence are of particular interest because they are more likely to alter the biological function of a protein. We aimed to use SNPs to identify markers and genes associated with genetic variation in growth. RNA-Seq whole-transcriptome analysis of pooled cDNA samples from a population of rainbow trout selected for improved growth versus unselected genetic cohorts (10 fish from 1 full-sib family each) identified SNP markers associated with growth-rate. The allelic imbalances (the ratio between the allele frequencies of the fast growing sample and that of the slow growing sample) were considered at scores >5.0 as an amplification and <0.2 as loss of heterozygosity. A subset of SNPs (n?=?54) were validated and evaluated for association with growth traits in 778 individuals of a three-generation parent/offspring panel representing 40 families. Twenty-two SNP markers and one mitochondrial haplotype were significantly associated with growth traits. Polymorphism of 48 of the markers was confirmed in other commercially important aquaculture stocks. Many markers were clustered into genes of metabolic energy production pathways and are suitable candidates for genetic selection. The study demonstrates that RNA-Seq at low sequence coverage of divergent populations is a fast and effective means of identifying SNPs, with allelic imbalances between phenotypes. This technique is suitable for marker development in non-model species lacking complete and well-annotated genome reference sequences. PMID:22574143

  11. HLA haplotypes associated with hemochromatosis mutations in the Spanish population

    PubMed Central

    Pacho, Arantza; Mancebo, Esther; del Rey, Manuel J; Castro, Maria J; Oliver, Desamparados; García-Berciano, Miguel; González, Luis; Morales, Pablo

    2004-01-01

    Background The present study is an analysis of the frequencies of HLA-A and -B antigens and HLA haplotypes in two groups of individuals homozygous for the two main HFE mutations (C282Y and H63D) and a group heterozygous for the S65C mutation. Methods The study population includes: 1123 healthy individuals, 100 homozygous for the C282Y mutation, 138 homozygous for the H63D mutation and 17 heterozygous for the S65C mutation. HFE and HLA alleles were detected using DNA-based and microlymphocytotoxicity techniques respectively. Results An expected significant association between C282Y and the HLA-A3/B7 haplotype was found, but other HLA haplotypes carrying the -A3 antigen were found: HLA-A3/B62 and HLA-A3/B44. Also, a significant association between H63D mutation and HLA-A29/B44 haplotype was found, and again other HLA haplotypes carrying the HLA-A29 antigen were also found: HLA-A29/B14 and HLA-A29/B62. In addition, the S65C mutation seems to be associated with a HLA haplotype carrying the HLA-A26 antigen. Conclusion These findings clearly suggest that HLA-A3/B7 and HLA-A29/B44 are the ancestral haplotypes from which the C282Y and H63D mutations originated, respectively. The frequencies of these mutations in different populations, their geographical distribution, and the degree of the statistical association to the ancestral haplotypes, suggest that the H63D mutation must have occurred earlier than the C282Y mutation. PMID:15498100

  12. PicSNP: A Catalog of Non-Synonymous SNP

    NSDL National Science Digital Library

    Chang, Hangil.

    1969-12-31

    Maintained by Hangil Chang at the University of Tokyo, PicSNP "is a catalog of non-synonymous Single Nucleotide Polymorphism (SNP) in the human genome." Recently updated, the database allows users to select SNPs by gene name, function of affected genes, biological process relevant to affected genes, or cellular component that contain affected genes. The site does not include much instruction on how to use the database, meaning it is most suitable for users who are familiar with the subject.

  13. Genome-wide haplotype changes produced by artificial selection during modern rice breeding in Japan.

    PubMed

    Yonemaru, Jun-ichi; Yamamoto, Toshio; Ebana, Kaworu; Yamamoto, Eiji; Nagasaki, Hideki; Shibaya, Taeko; Yano, Masahiro

    2012-01-01

    During the last 90 years, the breeding of rice has delivered cultivars with improved agronomic and economic characteristics. Crossing of different lines and successive artificial selection of progeny based on their phenotypes have changed the chromosomal constitution of the ancestors of modern rice; however, the nature of these changes is unclear. The recent accumulation of data for genome-wide single-nucleotide polymorphisms (SNPs) in rice has allowed us to investigate the change in haplotype structure and composition. To assess the impact of these changes during modern breeding, we studied 177 Japanese rice accessions, which were categorized into three groups: landraces, improved cultivars developed from 1931 to 1974 (the early breeding phase), and improved cultivars developed from 1975 to 2005 (the late breeding phase). Phylogenetic tree and structure analysis indicated genetic differentiation between non-irrigated (upland) and irrigated (lowland) rice groups as well as genetic structuring within the irrigated rice group that corresponded to the existence of three subgroups. Pedigree analysis revealed that a limited number of landraces and cultivars was used for breeding at the beginning of the period of systematic breeding and that 11 landraces accounted for 70% of the ancestors of the modern improved cultivars. The values for linkage disequilibrium estimated from SNP alleles and the haplotype diversity determined from consecutive alleles in five-SNP windows indicated that haplotype blocks became less diverse over time as a result of the breeding process. A decrease in haplotype diversity, caused by a reduced number of polymorphisms in the haplotype blocks, was observed in several chromosomal regions. However, our results also indicate that new haplotype polymorphisms have been generated across the genome during the breeding process. These findings will facilitate our understanding of the association between particular haplotypes and desirable phenotypes in modern Japanese rice cultivars. PMID:22427922

  14. PanSNPdb: the Pan-Asian SNP genotyping database.

    PubMed

    Ngamphiw, Chumpol; Assawamakin, Anunchai; Xu, Shuhua; Shaw, Philip J; Yang, Jin Ok; Ghang, Ho; Bhak, Jong; Liu, Edison; Tongsima, Sissades

    2011-01-01

    The HUGO Pan-Asian SNP consortium conducted the largest survey to date of human genetic diversity among Asians by sampling 1,719 unrelated individuals among 71 populations from China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand. We have constructed a database (PanSNPdb), which contains these data and various new analyses of them. PanSNPdb is a research resource in the analysis of the population structure of Asian peoples, including linkage disequilibrium patterns, haplotype distributions, and copy number variations. Furthermore, PanSNPdb provides an interactive comparison with other SNP and CNV databases, including HapMap3, JSNP, dbSNP and DGV and thus provides a comprehensive resource of human genetic diversity. The information is accessible via a widely accepted graphical interface used in many genetic variation databases. Unrestricted access to PanSNPdb and any associated files is available at: http://www4a.biotec.or.th/PASNP. PMID:21731755

  15. 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?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?SNP associations suggest that a single panel of genomic variants can be used regardless of breed and diet. The breed- and diet-dependent associations between SNPs and feed efficiency suggest that further refinement of variant panels require the consideration of the breed and management practices. The unique genomic variants associated with the one- and two-step indicators suggest that both types of indicators offer complementary description of feed efficiency that can be exploited for genome-enabled selection purposes. PMID:24066663

  16. Confirmation of Linkage to and Localization of Familial Colon Cancer Risk Haplotype on Chromosome 9q22

    PubMed Central

    Gray-McGuire, Courtney; Guda, Kishore; Adrianto, Indra; Lin, Chee Paul; Natale, Leanna; Potter, John D.; Newcomb, Polly; Poole, Elizabeth M.; Ulrich, Cornelia M.; Lindor, Noralane; Goode, Ellen L.; Fridley, Brooke L.; Jenkins, Robert; Marchand, Loic Le; Casey, Graham; Haile, Robert; Hopper, John; Jenkins, Mark; Young, Joanne; Buchanan, Daniel; Gallinger, Steve; Adams, Mark; Lewis, Susan; Willis, Joseph; Elston, Robert; Markowitz, Sanford D.; Wiesner, Georgia L.

    2010-01-01

    Colorectal cancer is the second leading cause of cancer mortality in adult Americans and is caused by both genetic and environmental risk factors. We have replicated our originally reported linkage signal at 9q22-31 by fine mapping an independent collection of colon cancer families. Then, using a custom array of single nucleotide polymorphisms (SNPs) densely spaced across the candidate region, we performed both single-SNP and moving-window association analyses to identify a colon neoplasia risk haplotype. We isolated the association effect to a five SNP haplotype centered around 98.15 megabases (Mb) on chromosome 9q. This haplotype is in strong linkage disequilibrium with the haplotype block containing HABP4 and may be a surrogate for the effect of this CD30 Ki-1 antigen. It is also in close proximity to the GALNT12, which has been recently shown to be altered in colon tumors. Finally, we used a predictive modeling algorithm to demonstrate the contribution of this risk haplotype and surrounding candidate genes in distinguishing between colon cancer cases and healthy controls. The ability to replicate this finding, the strength of the haplotype association (OR=3.68) and the accuracy of our prediction model (~60%) all strongly support the presence of a locus for familial colon cancer on chromosome 9q. PMID:20551049

  17. 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

  18. LOXL1 Promoter Haplotypes Are Associated with Exfoliation Syndrome in a U.S. Caucasian Population

    PubMed Central

    Fan, Bao Jian; Pasquale, Louis R.; Rhee, Douglas; Li, Tiansen; Haines, Jonathan L.

    2011-01-01

    Purpose. LOXL1 is a major genetic risk factor for exfoliation syndrome (ES) and exfoliation glaucoma (EG). Recent evidence documenting reversal of risk alleles for the disease-associated missense variants R141L and G153D suggests that these variants are not causative and that they may be proxies for other unknown functional LOXL1 variants. The purpose of this study was to investigate the disease association of LOXL1 variants spanning the gene region, including the 5? and 3? regulatory regions, in a U.S. Caucasian case–control sample. Methods. Twenty-five LOXL1 single-nucleotide polymorphisms (SNPs), distributed throughout the gene, were genotyped in 196 Caucasian patients with ES/EG and 201 matched controls. Genotype data were analyzed for single SNP associations, SNP interactions, and haplotype associations. Results. Promoter region haplotypes that included the risk alleles for rs12914489, a SNP located in the distal promoter region and independently associated with ES, and rs16958477, a SNP previously shown to affect gene transcription, were associated with increased disease risk (P = 0.0008; odds ratio [OR], 2.34; 95% confidence interval [CI], 1.42–3.85) and with protective effects (P = 2.3 × 10?6; OR, 0.38; 95% CI, 0.25–0.57). Haplotypes containing rs12914489 and rs16958477 risk and protective alleles also significantly influenced the disease risk associated with missense alleles R141L and G153D. Conclusions. LOXL1 promoter haplotypes were identified that are significantly associated with ES/EG in a U.S. Caucasian population. These results suggest that promoter region SNPs can influence LOXL1 gene expression, potentially causing a reduction of enzyme activity that may predispose to disease. PMID:21212179

  19. Introgression of a rare haplotype from Southeastern Africa to breed California blackeyes with larger seeds

    PubMed Central

    Lucas, Mitchell R.; Huynh, Bao-Lam; Roberts, Philip A.; Close, Timothy J.

    2015-01-01

    Seed size distinguishes most crops from their wild relatives and is an important quality trait for the grain legume cowpea. In order to breed cowpea varieties with larger seeds we introgressed a rare haplotype associated with large seeds at the Css-1 locus from an African buff seed type cultivar, IT82E-18 (18.5 g/100 seeds), into a blackeye seed type cultivar, CB27 (22 g/100 seed). Four recombinant inbred lines derived from these two parents were chosen for marker-assisted breeding based on SNP genotyping with a goal of stacking large seed haplotypes into a CB27 background. Foreground and background selection were performed during two cycles of backcrossing based on genome-wide SNP markers. The average seed size of introgression lines homozygous for haplotypes associated with large seeds was 28.7g/100 seed and 24.8 g/100 seed for cycles 1 and 2, respectively. One cycle 1 introgression line with desirable seed quality was selfed for two generations to make families with very large seeds (28–35 g/100 seeds). Field-based performance trials helped identify breeding lines that not only have large seeds but are also desirable in terms of yield, maturity, and plant architecture when compared to industry standards. A principal component analysis was used to explore the relationships between the parents relative to a core set of landraces and improved varieties based on high-density SNP data. The geographic distribution of haplotypes at the Css-1 locus suggest the haplotype associated with large seeds is unique to accessions collected from Southeastern Africa. Therefore this quantitative trait locus has a strong potential to develop larger seeded varieties for other growing regions which is demonstrated in this work using a California pedigree. PMID:25852699

  20. Introgression of a rare haplotype from Southeastern Africa to breed California blackeyes with larger seeds.

    PubMed

    Lucas, Mitchell R; Huynh, Bao-Lam; Roberts, Philip A; Close, Timothy J

    2015-01-01

    Seed size distinguishes most crops from their wild relatives and is an important quality trait for the grain legume cowpea. In order to breed cowpea varieties with larger seeds we introgressed a rare haplotype associated with large seeds at the Css-1 locus from an African buff seed type cultivar, IT82E-18 (18.5 g/100 seeds), into a blackeye seed type cultivar, CB27 (22 g/100 seed). Four recombinant inbred lines derived from these two parents were chosen for marker-assisted breeding based on SNP genotyping with a goal of stacking large seed haplotypes into a CB27 background. Foreground and background selection were performed during two cycles of backcrossing based on genome-wide SNP markers. The average seed size of introgression lines homozygous for haplotypes associated with large seeds was 28.7g/100 seed and 24.8 g/100 seed for cycles 1 and 2, respectively. One cycle 1 introgression line with desirable seed quality was selfed for two generations to make families with very large seeds (28-35 g/100 seeds). Field-based performance trials helped identify breeding lines that not only have large seeds but are also desirable in terms of yield, maturity, and plant architecture when compared to industry standards. A principal component analysis was used to explore the relationships between the parents relative to a core set of landraces and improved varieties based on high-density SNP data. The geographic distribution of haplotypes at the Css-1 locus suggest the haplotype associated with large seeds is unique to accessions collected from Southeastern Africa. Therefore this quantitative trait locus has a strong potential to develop larger seeded varieties for other growing regions which is demonstrated in this work using a California pedigree. PMID:25852699

  1. Linkage disequilibrium and haplotype block structure in a composite beef cattle breed

    PubMed Central

    2014-01-01

    Background The development of linkage disequilibrium (LD) maps and the characterization of haplotype block structure at the population level are useful parameters for guiding genome wide association (GWA) studies, and for understanding the nature of non-linear association between phenotypes and genes. The elucidation of haplotype block structure can reduce the information of several single nucleotide polymorphisms (SNP) into the information of a haplotype block, reducing the number of SNPs in a coherent way for consideration in GWA and genomic selection studies. Results The maximum average LD, measured by r2 varied between 0.33 to 0.40 at a distance of < 2.5 kb, and the minimum average values of r2 varied between 0.05 to 0.07 at distances ranging from 400 to 500 kb, clearly showing that the average r2 reduced with the increase in SNP pair distances. The persistence of LD phase showed higher values at shorter genomic distances, decreasing with the increase in physical distance, varying from 0.96 at a distance of < 2.5 kb to 0.66 at a distance from 400 to 500 kb. A total of 78% of all SNPs were clustered into haplotype blocks, covering 1,57 Mb of the total autosomal genome size. Conclusions This study presented the first high density linkage disequilibrium map and haplotype block structure for a composite beef cattle population, and indicates that the high density SNP panel over 700 k can be used for genomic selection implementation and GWA studies for Canchim beef cattle. PMID:25573652

  2. Sickle Cell Disease in a Brazilian Population from Sao Paulo: A Study of the ?s Haplotypes

    Microsoft Academic Search

    M. S. Goncalves; J. F. Nechtman; M. S. Figueiredo; J. Kerbauy; V. R. Armda; M. F. Sonati; S. O. T. Saad; F. F. Costa; T. A. Stoming

    1994-01-01

    In this study we have determined the frequency of ?s haplotypes in a Brazilian sickle cell disease population from Sao Paulo, Brazil, by analyzing sequence variations in the immediate 5’ flanking and second intervening sequence (IVSII) regions of the ? globin genes. This association between sequence differences and ?s haplotype backgrounds was determined by screening genomic DNA samples using dot

  3. Mapping Haplotype-haplotype Interactions with Adaptive LASSO

    PubMed Central

    2010-01-01

    Background The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs) have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it presents daunting challenges in statistical modeling and testing of the interaction effects, largely due to the complicated higher order epistatic complexity. Results In this article, we propose a new strategy in modeling haplotype-haplotype interactions under the penalized logistic regression framework with adaptive L1-penalty. We consider interactions of sequence variants between haplotype blocks. The adaptive L1-penalty allows simultaneous effect estimation and variable selection in a single model. We propose a new parameter estimation method which estimates and selects parameters by the modified Gauss-Seidel method nested within the EM algorithm. Simulation studies show that it has low false positive rate and reasonable power in detecting haplotype interactions. The method is applied to test haplotype interactions involved in mother and offspring genome in a small for gestational age (SGA) neonates data set, and significant interactions between different genomes are detected. Conclusions As demonstrated by the simulation studies and real data analysis, the approach developed provides an efficient tool for the modeling and testing of haplotype interactions. The implementation of the method in R codes can be freely downloaded from http://www.stt.msu.edu/~cui/software.html. PMID:20799953

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

    PubMed

    Daiger, S P; Reed, L; Huang, S S; Zeng, Y T; Wang, T; Lo, W H; Okano, Y; Hase, Y; Fukuda, Y; Oura, T

    1989-08-01

    DNA polymorphisms at the phenylalanine hydroxylase (PAH) locus have proved highly effective in linkage diagnosis of phenylketonuria (PKU) in Caucasian families. More than 10 RFLP sites have been reported within the PAH structural locus in Caucasians. With information from affected and unaffected offspring in PKU families it is often possible to reconstruct complete RFLP haplotypes in parents and to use these haplotypes to follow the segregation of PKU within families and to determine the distribution of PKU chromosomes within populations. To establish the utility of these RFLPs in characterizing Asian families with PKU, we typed eight DNA sites in 21 Chinese families and 12 Japanese families with classical PKU. The eight RFLPs were chosen for their informativeness in Caucasians. From these families we reconstructed a total of 91 complete PAH haplotypes, 44 from non-PKU chromosomes and 47 from PKU-bearing chromosomes. Although all eight marker sites are polymorphic in both Chinese and Japanese, there is much less haplotypic variation in Asians than in Caucasians. In particular, one haplotype alone, haplotype 4, accounts for more than 77% of non-PKU chromosomes and for more than 80% of PKU-bearing chromosomes. Haplotype 4 is also relatively common in Caucasians. The next most common Asian haplotype is 10 times less frequent than haplotype 4. By contrast, in many Caucasian populations the sum of the frequencies of the five most common haplotypes is still less than 80%, and several of the most common haplotypes are equally frequent. Even though the extent of haplotypic variation in Asians is severely limited, the few haplotypes that are found often differ at a number of RFLP sites.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2569272

  5. Haplo2Ped: a tool using haplotypes as markers for linkage analysis

    PubMed Central

    2011-01-01

    Background Generally, SNPs are abundant in the genome; however, they display low power in linkage analysis because of their limited heterozygosity. Haplotype markers, on the other hand, which are composed of many SNPs, greatly increase heterozygosity and have superiority in linkage statistics. Results Here we developed Haplo2Ped to automatically transform SNP data into haplotype markers and then to compute the logarithm (base 10) of odds (LOD) scores of regional haplotypes that are homozygous within the disease co-segregation haploid group. The results are reported as a hypertext file and a 3D figure to help users to obtain the candidate linkage regions. The hypertext file contains parameters of the disease linked regions, candidate genes, and their links to public databases. The 3D figure clearly displays the linkage signals in each chromosome. We tested Haplo2Ped in a simulated SNP dataset and also applied it to data from a real study. It successfully and accurately located the causative genomic regions. Comparison of Haplo2Ped with other existing software for linkage analysis further indicated the high effectiveness of this software. Conclusions Haplo2Ped uses haplotype fragments as mapping markers in whole genome linkage analysis. The advantages of Haplo2Ped over other existing software include straightforward output files, increased accuracy and superior ability to deal with pedigrees showing incomplete penetrance. Haplo2Ped is freely available at: http://bighapmap.big.ac.cn/software.html. PMID:21854652

  6. AN IL-6 HAPLOTYPE ON HUMAN CHROMOSOME 7P21 CONFERS RISK FOR IMPAIRED RENAL FUNCTION IN TYPE 2 DIABETES

    PubMed Central

    Ng, Daniel P.K.; Nurbaya, Siti; Ye, Sandra; Krolewski, Andrzej S.

    2009-01-01

    Human chromosome 7p21 potentially harbors a major gene for end-stage renal disease (ESRD) and variation in glomerular filtration rate. The pro-inflammatory IL-6 is a prime positional candidate gene since chronic inflammation has been implicated in diabetic nephropathy. To test this hypothesis, single SNP and haplotype analyses were performed using a case-control study design with 295 cases and 174 normoalbuminuric controls. Cases were subcategorized into those with proteinuria (n=138) or chronic renal failure (CRF)/ESRD (n=157). Tagging SNPs (rs2069827, rs1800795 (-174G>CSNP), rs2069837, rs2069840, rs2069861) were chosen based on linkage disequilibrium patterns and genotyped along with rs1800796 (-634G>C SNP). Single SNP analyses suggested that the rs1800795 may be associated with risk of CRF/ESRD (P=0.028) but this was not significant after Bonferroni correction. While haplotype analyses revealed no association with the presence of proteinuria, there was significant evidence for such an association with CRF/ESRD. Strikingly, there was an excess of the G-G-G-A-G-C haplotype among cases with CRF/ESRD (25.5%) compared to controls (15.4%) (P=0.0016). This association remained statistically significant even after correction for multiple testing (Bonferroni corrected P-value = 0.0224). In conclusion, our study has yielded first evidence for an IL-6 haplotype that confers risk for impaired renal function in type 2 diabetes. PMID:18496509

  7. High-resolution haplotype structure in the human genome

    Microsoft Academic Search

    John D. Rioux; Stephen F. Schaffner; Thomas J. Hudson; Mark J. Daly; Eric S. Lander

    2001-01-01

    Linkage disequilibrium (LD) analysis is traditionally based on individual genetic markers and often yields an erratic, non- monotonic picture, because the power to detect allelic associa- tions depends on specific properties of each marker, such as frequency and population history. Ideally, LD analysis should be based directly on the underlying haplotype structure of the human genome, but this structure has

  8. Haplotype association analysis of combining unrelated case-control and triads with consideration of population stratification.

    PubMed

    Wen, Shu-Hui; Tsai, Miao-Yu

    2014-01-01

    Combining data when data are collected under different study designs, such as family trios and unrelated case-control samples, gains more power and is cost-effective than analyzing each data separately. However, a potential concern is population stratification (PS) among unrelated case-control samples and analyses integrating data should address this confounding effect. In this paper, we develop a simpler method, haplotype generalized linear model (HGLM), that tests and estimates haplotype effects on disease risk and allows for modification against PS for combining data. We proposed to combine information across aggregations of haplotype weighted-counts estimated from population case-control data and trio data separately, and to perform subsequent GLM analysis. Furthermore, we present a framework of analysis of variance based on haplotype weighted-counts for detecting whether it is appropriate to combine two data sources, as well as the modified HGLM with clustering methods for addressing PS. We evaluate the statistical properties in terms of the accuracy, false positive rate (FPR) and empirical power using simulated data with regard to various disease risks, sample sizes, multi-SNP haplotypes and the presence of PS. Our simulation results indicate that HGLM performs comparably well with the likelihood-based haplotype association analysis, particularly when the haplotype effects are moderate, but may not perform well when dealing with lengthy haplotypes for small sample sizes. In the presence of PS, the modified HGLM remains valid and has satisfactory nominal level and small bias. Overall, HGLM appears to be successful in combining data and is simple to implement in standard statistical software. PMID:24860592

  9. A Novel Haplotype-Sharing Approach for Genome-Wide Case-Control Association Studies Implicates the Calpastatin Gene in Parkinson’s Disease

    PubMed Central

    Allen, Andrew S.; Satten, Glen A.

    2014-01-01

    The large number of markers considered in a genome-wide association study (GWAS) has resulted in a simplification of analyses conducted. Most studies are analyzed one marker at a time using simple tests like the trend test. Methods that account for the special features of genetic association studies, yet remain computationally feasible for genome-wide analysis, are desirable as they may lead to increased power to detect associations. Haplotype sharing attempts to translate between population genetics and genetic epidemiology. Near a recent mutation that increases disease risk, haplotypes of case participants should be more similar to each other than haplotypes of control participants; conversely, the opposite pattern may be found near a recent mutation that lowers disease risk. We give computationally simple association tests based on haplotype sharing that can be easily applied to GWASs while allowing use of fast (but not likelihood-based) haplotyping algorithms and properly accounting for the uncertainty introduced by using inferred haplotypes. We also give haplotype-sharing analyses that adjust for population stratification. Applying our methods to a GWAS of Parkinson’s disease, we find a genome-wide significant signal in the CAST gene that is not found by single-SNP methods. Further, a missing-data artifact that causes a spurious single-SNP association on chromosome 9 does not impact our test. PMID:19365859

  10. Plastid DNA sequencing and nuclear SNP genotyping help resolve the puzzle of central American Platanus

    PubMed Central

    De Castro, Olga; Di Maio, Antonietta; Lozada García, José Armando; Piacenti, Danilo; Vázquez-Torres, Mario; De Luca, Paolo

    2013-01-01

    Background and Aims Recent research on the history of Platanus reveals that hybridization phenomena occurred in the central American species. This study has two goals: to help resolve the evolutive puzzle of central American Platanus, and to test the potential of real-time polymerase chain reaction (PCR) for detecting ancient hybridization. Methods Sequencing of a uniparental plastid DNA marker [psbA-trnH(GUG) intergenic spacer] and qualitative and quantitative single nucleotide polymorphism (SNP) genotyping of biparental nuclear ribosomal DNA (nrDNA) markers [LEAFY intron 2 (LFY-i2) and internal transcribed spacer 2 (ITS2)] were used. Key Results Based on the SNP genotyping results, several Platanus accessions show the presence of hybridization/introgression, including some accessions of P. rzedowskii and of P. mexicana var. interior and one of P. mexicana var. mexicana from Oaxaca (= P. oaxacana). Based on haplotype analyses of the psbA-trnH spacer, five haplotypes were detected. The most common of these is present in taxa belonging to P. orientalis, P. racemosa sensu lato, some accessions of P. occidentalis sensu stricto (s.s.) from Texas, P. occidentalis var. palmeri, P. mexicana s.s. and P. rzedowskii. This is highly relevant to genetic relationships with the haplotypes present in P. occidentalis s.s. and P. mexicana var. interior. Conclusions Hybridization and introgression events between lineages ancestral to modern central and eastern North American Platanus species occurred. Plastid haplotypes and qualitative and quantitative SNP genotyping provide information critical for understanding the complex history of Mexican Platanus. Compared with the usual molecular techniques of sub-cloning, sequencing and genotyping, real-time PCR assay is a quick and sensitive technique for analysing complex evolutionary patterns. PMID:23798602

  11. SNP-PHAGE - High throughput SNP discovery pipeline

    Microsoft Academic Search

    Lakshmi K. Matukumalli; John J. Grefenstette; David L. Hyten; Ik-young Choi; Perry B. Cregan; Curtis P. Van Tassell

    2006-01-01

    Background: Single nucleotide polymorphisms (SNPs) as defined here are single base sequence changes or short insertion\\/deletions between or within individuals of a given species. As a result of their abundance and the availability of high throughput analysis technologies SNP markers have begun to replace other traditional markers such as restriction fragment length polymorphisms (RFLPs), amplified fragment length polymorphisms (AFLPs) and

  12. Bovine exome sequence analysis and targeted SNP genotyping of recessive fertility defects HH2, HH3, and BH1 reveals causative mutation in SMC2 for HH3

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The recent discovery of bovine haplotypes with negative effects on fertility in the Holstein, Jersey, and Brown Swiss breeds has allowed producers to identify carrier animals using current commercial single nucleotide polymorphism (SNP) genotyping assays. This study was devised to identify the caus...

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

    PubMed Central

    Daiger, Stephen P.; Chakraborty, Ranajit; Reed, Lori; Fekete, György; Schuler, Dezso; Berenssi, György; Nasz, Istvan; Brdi?ka, Radim; Kamarýt, Jaromir; Pijá?ková, Anna; Moore, Sharon; Sullivan, Susan; Woo, Savio L. C.

    1989-01-01

    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.” There are statistically significant differences between European populations in the frequencies of non-PKU chromosomal haplotypes (P = .025) and PKU chromosomal haplotypes (P < < .001). Haplotype frequencies of the PKU and non-PKU chromosomes also differ significantly (P < < .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. Within these European populations a parent carrying a PKU mutation has an average probability of greater than 86% of being heterozygous–and hence informative for linkage–at one or more PAH RFLP sites. Thus these RFLP alleles and haplotypes provide an effective tool for linkage diagnosis of disease and carrier status in PKU families. PMID:2569271

  14. Role of the H1 haplotype of microtubule-associated protein tau (MAPT) gene in Greek patients with Parkinson's disease

    PubMed Central

    Refenes, Nikolaos; Bolbrinker, Juliane; Tagaris, Georgios; Orlacchio, Antonio; Drakoulis, Nikolaos; Kreutz, Reinhold

    2009-01-01

    Background The extended tau haplotype (H1) that covers the entire human microtubule-associated protein tau (MAPT) gene has been implicated in Parkinson's disease (PD). Nevertheless, controversial results, such as two studies in Greek populations with opposite effects, have been reported. Therefore, we set out to determine whether the H1 haplotype and additional single nucleotide polymorphisms (SNPs) included in H1 are associated with PD in a sample of Greek patients. Methods We analysed MAPT haplotypes in cohorts of 122 patients and 123 controls of Greek origin, respectively. SNP genotyping was performed with Taqman assays and genotyping results were confirmed by sequencing. Results The presence of the H1 haplotype was significantly associated with PD (odds ratio for H1H1 vs. H1H2 and H2H2: 1.566; 95% CI: 1.137–2.157; P = 0.006) and remained so after adjustment for sex. Further analysis of H1 sub-haplotypes with three single nucleotide polymorphisms (rs242562, rs2435207 and rs3785883) demonstrated no significant association with PD. Conclusion Our data support the overall genetic role of MAPT and the H1 haplotype for PD susceptibility in Greek patients. However, the previously supported association of H1 sub-haplotypes with PD could not be confirmed in our study. PMID:19558713

  15. Polymorphic DNA haplotypes at the phenlalanine hydroxylase (PAH) locus in Asian families with phenylketonuria (PKU)

    PubMed Central

    Daiger, Stephen P.; Reed, Lori; Huang, Shu-Shen; Zeng, Yi-Tao; Wang, Tao; Lo, Wilson H. Y.; Okano, Yoshiyuki; Hase, Yutaka; Fukuda, Y.; Oura, Toshiaki; Tada, Keiya; Woo, Savio L. C.

    1989-01-01

    DNA polymorphisms at the phenylalanine hydroxylase (PAH) locus have proved highly efiective in linkage diagnosis of phenylketonuria (PKU) in Caucasian families. More than 10 RFLP sites have been reported within the PAH structural locus in Caucasians. With information from affected and unaffected offspring in PKU families it is often possible to reconstruct complete RFLP haplotypes in parents and to use these haplotypes to follow the segregation of PKU within families and to determine the distribution of PKU chromosomes within populations. To establish the utility of these RFLPs in charaterizing Asian families with PKU, we typed eight DNA sites in 21 Chinese families and 12 Japanese families with classical PKU. The eight RFLPs were chosen for their informativeness in Caucasians. From these families we reconstructed a total of 91 complete PAH haplotypes, 44 from non-PKU chromosomes and 47 from PKU-bearing chromosomes. Although all eight marker sites are polymorphic in both Chinese and Japanese, there is much less haplotypic variation in Asians than in Caucasians. In particular, one haplotype alone, haplotype 4, accounts for more than 77% of non-PKU chromosomes and for more than 80% of PKU-bearing chromosomes. Haplotype 4 is also relatively common in Caucasians. The next most common Asian haplotype is 10 times less frequent than haplotype 4. By contrast, in many Caucasian populations the sum of the frequencies of the five most common haplotypes is still less than 80%, and several of the most common haplotypes are equally frequent. Even though the extent of haplotypic variation in Asians is severely limited, the few haplotypes that are found often differ at a number of RFLP sites. This accounts for the observation that haplotypes show little variation in Chinese and Japanese but that the individual RFLP sites are all polymorphic in both populations. It appears that these RFLPs predate the separation of Asians and Caucasians but that the haplotypic variation has either decreased or increased in one or the other racial group since then. Although the PAH RFLPs and haplotypes will not be as useful in Asian families with PKU as in Caucasian families with PKU, at least 36% of Asian carriers of PKU are heterozygous–and hence informative–at one or more RFLP sites. PMID:2569272

  16. Haplotype Structure, LD Blocks, and Uneven Recombination Within the LRP5 Gene

    PubMed Central

    Twells, Rebecca C.J.; Mein, Charles A.; Phillips, Michael S.; Hess, J. Fred; Veijola, Riitta; Gilbey, Matthew; Bright, Matthew; Metzker, Michael; Lie, Benedicte A.; Kingsnorth, Amanda; Gregory, Edward; Nakagawa, Yusuke; Snook, Hywel; Wang, William Y.S.; Masters, Jennifer; Johnson, Gillian; Eaves, Iain; Howson, Joanna M.M.; Clayton, David; Cordell, Heather J.; Nutland, Sarah; Rance, Helen; Carr, Philippa; Todd, John A.

    2003-01-01

    Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in “LD blocks,” interspersed by apparent “hot spots” of recombination. Previously, we cloned and physically characterized the low-density lipoprotein-receptor-related protein 5 (LRP5) gene. Here, we have extensively analysed both LRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms. Analysis revealed high levels of recombination across LRP5, including a hot-spot region from intron 1 to intron 7 of LRP5, where there are 109 recombinants/Mb (4882 meioses), in contrast to flanking regions of 14.6 recombinants/Mb. This region of high recombination could be delineated into three to four hot spots, one within a 601-bp interval. For LRP5, three haplotype blocks were identified, flanked by the hot spots. Each LD block comprised over 80% common haplotypes, concurring with a previous study of 14 genes that showed that common haplotypes account for at least 80% of all haplotypes. The identification of hot spots in between these LD blocks provides additional evidence that LD blocks are separated by areas of higher recombination. [Supplementary material: primers are available from our Web site: http://www-gene.cimr.cam.ac.uk/todd/human_data.shtml.] PMID:12727905

  17. Haplotypes versus Genotypes on Pedigrees B. Kirkpatrick

    E-print Network

    Kirkpatrick, Bonnie

    Haplotypes versus Genotypes on Pedigrees B. Kirkpatrick Jan 7, 2010 Abstract Genome sequencing to be an attractive alternative to genotyping. However, methods for pedigree analysis with haplotype data have not yet. Furthermore, it is not clear in which scenarios haplotype data would provide better estimates than genotype

  18. 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...

  19. Extended Major Histocompatibility Complex Haplotypes

    E-print Network

    Alper, Chester A.

    diabetic and normal chro- mosomes in the study families. We demonstrated that all of the previouslyExtended Major Histocompatibility Complex Haplotypes in Type I Diabetes Mellitus Donald Raum studied major histocom- patibility complex markers in Caucasian patients with type I diabetes mellitus

  20. 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 citrus genotypes were detected, and compared to estimate the heterozygosity of each genome. All the SNP oligo sequences were aligned with the Clementine citrus genome to determine their distribution and uniqueness and for in silico validation, in addition to SNaPshot and sequencing validation of selected SNPs. PMID:24175923

  1. Beta2 Adrenergic Receptor (ADR?2) Haplotype Pair (2/4) Is Associated with Severe Asthma

    PubMed Central

    Chung, Li Ping; Baltic, Svetlana; Ferreira, Manuel; Temple, Suzanna; Waterer, Grant; Thompson, Philip J.

    2014-01-01

    Background ?2 adrenergic receptor (ADR?2) polymorphisms including ADR?2+46G>A have been reported to cause adverse outcomes in mild asthmatics. The extent to which ADR?2 polymorphisms and in particular their haplotypes contribute to severe asthma is unknown. Objective To determine the association of ADR?2 polymorphisms and haplotypes with asthma severity. Methods Caucasians (n?=?2979) were genotyped for 11 ADR?2 polymorphisms. The cohort (mean age 39.6, 60% female) included 2296 non-asthmatics, 386 mild asthmatics, 172 moderate asthmatics and 125 severe asthmatics. Haplotype frequency and haplotype pair for each subject was determined using the PHASE algorithm. Results The three asthmatic cohorts were comparable in age and gender but were distinguishable from each other in terms of symptoms, spirometry, medication use and health care utilisation (p <0.001). None of the polymorphisms showed a genotypic or allelic association with asthma diagnosis or severity. Nine haplotypes were identified and no association was found with asthma diagnosis or severity per se. Haplotype pair 2/4 was associated with asthma severity (Trend Test, OR 1.42, p?=?0.0008) but not with asthma per se. Prevalence of haplotype pair 2/2 appeared to decrease with asthma severity (Trend Test, OR 0.78, p?=?0.067). Two new haplotypes were identified, occurring exclusively in asthmatics at a frequency of ? 1%. In addition, a positive association between carriage of ADR?2 +523*C and increased risk of atopy was discovered. Conclusions ADR?2 haplotype pair 2/4 is associated with severe asthma and is consistent with findings of poor bronchodilator response in mild asthmatics who are also haplotype 2/4. PMID:24691493

  2. Detecting disease-predisposing variants: The haplotype method

    SciTech Connect

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

    1997-03-01

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

  3. Interactions between SNP Alleles at Multiple Loci Contribute to Skin Color Differences between Caucasoid and Mongoloid Subjects

    PubMed Central

    Anno, Sumiko; Abe, Takashi; Yamamoto, Takushi

    2008-01-01

    This study aimed to identify single nucleotide polymorphism (SNP) alleles at multiple loci associated with racial differences in skin color using SNP genotyping. A total of 122 Caucasians in Toledo, Ohio and 100 Mongoloids in Japan were genotyped for 20 SNPs in 7 candidate genes, encoding the Agouti signaling protein (ASIP), tyrosinase-related protein 1 (TYRP1), tyrosinase (TYR), melanocortin 1 receptor (MC1R), oculocutaneous albinism II (OCA2), microphthalmia-associated transcription factor (MITF), and myosin VA (MYO5A). Data were used to analyze associations between the 20 SNP alleles using linkage disequilibrium (LD). Combinations of SNP alleles were jointly tested under LD for associations with racial groups by performing a ?2 test for independence. Results showed that SNP alleles at multiple loci can be considered the haplotype that contributes to significant differences between the two population groups and suggest a high probability of LD. Confirmation of these findings requires further study with other ethnic groups to analyze the associations between SNP alleles at multiple loci and skin color variation among races. PMID:18392143

  4. Selection at Work in Self-Incompatible Arabidopsis lyrata. II. Spatial Distribution of S Haplotypes in Iceland

    Microsoft Academic Search

    Mikkel H. Schierup; Jesper S. Bechsgaard; Freddy B. Christiansen

    2008-01-01

    We survey the distribution of haplotypes at the self-incompatibility (SI) locus of Arabidopsis lyrata (Brassicaceae) at 12 locations spread over the species' natural distribution in Iceland. Previous investigations of the system have identified 34 functionally different S haplotypes maintained by frequency-dependent selection and arranged them into four classes of dominance in their phenotypic expression. On the basis of this model

  5. Haplotype Diversity in Four Genes (CLCNKA, CLCNKB, BSND, NEDD4L) Involved in Renal Salt Reabsorption

    PubMed Central

    Sile, Saba; Velez, Digna R.; Gillani, Niloufar B.; Alexander, Charles R.; George, Alfred L.; Williams, Scott M.

    2007-01-01

    Objective Differences exist among various populations with regards to hypertension prevalence, severity, progression and response to therapy. Such differences may be due to genetic or environmental factors. We characterized the genetic variation and haplotype diversity of four hypertension candidate genes (CLCNKA, CLCNKB, BSND, NEDD4L) in four different ethnic groups (Caucasian Americans, African-Americans, Han Chinese, and Mexican-Americans). Methods We genotyped 42 single nucleotide polymorphisms across the four genes in equal numbers of each ethnically defined population, then tested for linkage disequilibrium, computed allelic and haplotype frequencies, and compared data across the different ethnic groups. Results We identified significant genotype and allele frequency differences among ethnic groups. The strongest differences were observed between African-American and Mexican-Americans and between Caucasian and Mexican-Americans. In addition, haplotype blocks were defined for BSND, CLCNKA_B and NEDD4L in the four populations examined. Completely mismatched (‘yin yang’) haplotypes were also observed. We found that the number of inferred halpotypes varied gene to gene and in some instances between the populations for a given gene indicating substantial haplotype diversity. The haplotype diversity among the various ethnic populations observed in our study was greater than that reported in Perlegen database. Conclusions Haplotype diversity in hypertension candidate genes has important implications for designing and evaluating candidate gene or genome-wide blood pressure association studies that consider these genes. PMID:17652939

  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. Bovine Exome Sequence Analysis and Targeted SNP Genotyping of Recessive Fertility Defects BH1, HH2, and HH3 Reveal a Putative Causative Mutation in SMC2 for HH3

    PubMed Central

    McClure, Matthew C.; Bickhart, Derek; Null, Dan; VanRaden, Paul; Xu, Lingyang; Wiggans, George; Liu, George; Schroeder, Steve; Glasscock, Jarret; Armstrong, Jon; Cole, John B.; Van Tassell, Curtis P.; Sonstegard, Tad S.

    2014-01-01

    The recent discovery of bovine haplotypes with negative effects on fertility in the Brown Swiss, Holstein, and Jersey breeds has allowed producers to identify carrier animals using commercial single nucleotide polymorphism (SNP) genotyping assays. This study was devised to identify the causative mutations underlying defective bovine embryo development contained within three of these haplotypes (Brown Swiss haplotype 1 and Holstein haplotypes 2 and 3) by combining exome capture with next generation sequencing. Of the 68,476,640 sequence variations (SV) identified, only 1,311 genome-wide SNP were concordant with the haplotype status of 21 sequenced carriers. Validation genotyping of 36 candidate SNP identified only 1 variant that was concordant to Holstein haplotype 3 (HH3), while no variants located within the refined intervals for HH2 or BH1 were concordant. The variant strictly associated with HH3 is a non-synonymous SNP (T/C) within exon 24 of the Structural Maintenance of Chromosomes 2 (SMC2) on Chromosome 8 at position 95,410,507 (UMD3.1). This polymorphism changes amino acid 1135 from phenylalanine to serine and causes a non-neutral, non-tolerated, and evolutionarily unlikely substitution within the NTPase domain of the encoded protein. Because only exome capture sequencing was used, we could not rule out the possibility that the true causative mutation for HH3 might lie in a non-exonic genomic location. Given the essential role of SMC2 in DNA repair, chromosome condensation and segregation during cell division, our findings strongly support the non-synonymous SNP (T/C) in SMC2 as the likely causative mutation. The absence of concordant variations for HH2 or BH1 suggests either the underlying causative mutations lie within a non-exomic region or in exome regions not covered by the capture array. PMID:24667746

  8. A Genomic Portrait of Haplotype Diversity and Signatures of Selection in Indigenous Southern African Populations

    PubMed Central

    Chimusa, Emile R.; Meintjies, Ayton; Tchanga, Milaine; Mulder, Nicola; Seioghe, Cathal; Soodyall, Himla; Ramesar, Rajkumar

    2015-01-01

    We report a study of genome-wide, dense SNP (?900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region. PMID:25811879

  9. A genomic portrait of haplotype diversity and signatures of selection in indigenous southern african populations.

    PubMed

    Chimusa, Emile R; Meintjies, Ayton; Tchanga, Milaine; Mulder, Nicola; Seioghe, Cathal; Soodyall, Himla; Ramesar, Rajkumar

    2015-02-01

    We report a study of genome-wide, dense SNP (?900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region. PMID:25811879

  10. Population genetic analysis of ascertained SNP data

    PubMed Central

    2004-01-01

    The large single nucleotide polymorphism (SNP) typing projects have provided an invaluable data resource for human population geneticists. Almost all of the available SNP loci, however, have been identified through a SNP discovery protocol that will influence the allelic distributions in the sampled loci. Standard methods for population genetic analysis based on the available SNP data will, therefore, be biased. This paper discusses the effect of this ascertainment bias on allelic distributions and on methods for quantifying linkage disequilibrium and estimating demographic parameters. Several recently developed methods for correcting for the ascertainment bias will also be discussed. PMID:15588481

  11. Haplotype and Linkage Disequilibrium Architecture for Human Cancer-Associated Genes

    PubMed Central

    Bonnen, Penelope E.; Wang, Peggy J.; Kimmel, Marek; Chakraborty, Ranajit; Nelson, David L.

    2002-01-01

    To facilitate association-based linkage studies we have studied the linkage disequilibrium (LD) and haplotype architecture around five genes of interest for cancer risk: ATM, BRCA1, BRCA2, RAD51, and TP53. Single nucleotide polymorphisms (SNPs) were identified and used to construct haplotypes that span 93–200 kb per locus with an average SNP density of 12 kb. These markers were genotyped in four ethnically defined populations that contained 48 each of African Americans, Asian Americans, Hispanic Americans, and European Americans. Haplotypes were inferred using an expectation maximization (EM) algorithm, and the data were analyzed using D‘, R2, Fisher’s exact P-values, and the four-gamete test for recombination. LD levels varied widely between loci from continuously high LD across 200 kb to a virtual absence of LD across a similar length of genome. LD structure also varied at each gene and between populations studied. This variation indicates that the success of linkage-based studies will require a precise description of LD at each locus and in each population to be studied. One striking consistency between genes was that at each locus a modest number of haplotypes present in each population accounted for a high fraction of the total number of chromosomes. We conclude that each locus has its own genomic profile with regard to LD, and despite this there is the widespread trend of relatively low haplotype diversity. As a result, a low marker density should be adequate to identify haplotypes that represent the common variation at a locus, thereby decreasing costs and increasing efficacy of association studies. [Supplemental material is available online at http://www.genome.org.] PMID:12466288

  12. 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

  13. 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

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

    PubMed

    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

  15. High-Throughput SNP Genotyping

    PubMed Central

    Gibson, Neil

    2002-01-01

    Whole genome approaches using single nucleotide polymorphism (SNP) markers have the potential to transform complex disease genetics and expedite pharmacogenetics research. This has led to a requirement for high-throughput SNP genotyping platforms. Development of a successful high-throughput genotyping platform depends on coupling reliable assay chemistry with an appropriate detection system to maximise efficiency with respect to accuracy, speed and cost. Current technology platforms are able to deliver throughputs in excess of 100 000 genotypes per day, with an accuracy of >99%, at a cost of 20–30 cents per genotype. In order to meet the demands of the coming years, however, genotyping platforms need to deliver throughputs in the order of one million genotypes per day at a cost of only a few cents per genotype. In addition, DNA template requirements must be minimised such that hundreds of thousands of SNPs can be interrogated using a relatively small amount of genomic DNA. As such, it is predicted that the next generation of high-throughput genotyping platforms will exploit large-scale multiplex reactions and solid phase assay detection systems. PMID:18628885

  16. Haplotype associations with quantitative traits in the presence of complex multilocus and heterogeneous effects

    PubMed Central

    Shibata, Kyoko; Diatchenko, Luda; Zaykin, Dmitri V.

    2009-01-01

    In genetic mapping of complex traits, scored haplotypes are likely to represent only a subset of all causal polymorphisms. At the extreme of this scenario, observed polymorphisms are not themselves functional, and only linked to causal ones via linkage disequilibrium (LD). We will demonstrate that due to such incomplete knowledge regarding the underlying genetic mechanism, the variance of a trait may become different between the scored haplotypes. Thus, unequal variances between haplotypes may be indicative of additional functional polymorphisms affecting the trait. Methods accounting for such haplotype-specific variance may also provide an increased power to detect complex associations. We suggest ways to estimate and test these haplotypic variance contrasts, and incorporate them into the haplotypic tests for association. We further extend this approach to data with unknown gametic phase via likelihood-based simultaneous estimation of haplotypic effects and their frequencies. We find our approach to provide additional power, especially under the following types of models: (a) where scored and unobserved variants are epistatically interacting with each other; and (b) under heterogeneity models, where multiple unobserved mutations are linked to nonfunctional observed polymorphisms via LD. An illustrative example of usefulness of the method is discussed, utilizing analysis of multilocus effects within the catechol-O-methyl transferase (COMT) gene. PMID:18636529

  17. Application of a posteriori granddaughter and modified granddaughter designs to determine Holstein haplotype effects.

    PubMed

    Weller, J I; VanRaden, P M; Wiggans, G R

    2013-08-01

    A posteriori and modified granddaughter designs were applied to determine haplotype effects for Holstein bulls and cows with BovineSNP50 [~50,000 single nucleotide polymorphisms (SNP); Illumina Inc., San Diego, CA] genotypes. The a posteriori granddaughter design was applied to 52 sire families, each with ?100 genotyped sons with genetic evaluations based on progeny tests. For 33 traits (milk, fat, and protein yields; fat and protein percentages; somatic cell score; productive life; daughter pregnancy rate; heifer and cow conception rates; service-sire and daughter calving ease; service-sire and daughter stillbirth; 18 conformation traits; and net merit), the analysis was applied to the autosomal segment with the SNP with the greatest effect in the genomic evaluation of each trait. All traits except 2 had a within-family haplotype effect. The same design was applied with the genetic evaluations of sons corrected for SNP effects associated with chromosomes besides the one under analysis. The number of within-family contrasts was 166 without adjustment and 211 with adjustment. Of the 52 bulls analyzed, 36 had BovineHD (high density; Illumina Inc.) genotypes that were used to test for concordance between sire quantitative trait loci and SNP genotypes; complete concordance was not obtained for any effects. Of the 31 traits with effects from the a posteriori granddaughter design, 21 were analyzed with the modified granddaughter design. Only sires with a contrast for the a posteriori granddaughter design and ?200 granddaughters with a record usable for genetic evaluation were included. Calving traits could not be analyzed because individual cow evaluations were not computed. Eight traits had within-family haplotype effects. With respect to milk and fat yields and fat percentage, the results on Bos taurus autosome (BTA) 14 corresponded to the hypothesis that a missense mutation in the diacylglycerol O-acyltransferase 1 (DGAT1) gene is the main causative mutation, although other polymorphisms in that gene also modify fat yield and percentage. The positive allele for protein concentration was less frequent, which indicated that selection on that locus could be effective. Although the results can be used to determine causative polymorphisms for most of the analyzed traits, complete DNA sequencing of most of the analyzed sires probably will be required. PMID:23746582

  18. Rapid haplotype inference for nuclear families

    PubMed Central

    2010-01-01

    Hapi is a new dynamic programming algorithm that ignores uninformative states and state transitions in order to efficiently compute minimum-recombinant and maximum likelihood haplotypes. When applied to a dataset containing 103 families, Hapi performs 3.8 and 320 times faster than state-of-the-art algorithms. Because Hapi infers both minimum-recombinant and maximum likelihood haplotypes and applies to related individuals, the haplotypes it infers are highly accurate over extended genomic distances. PMID:21034477

  19. Developing a multiplex mtSNP assay for forensic application in Han Chinese based on mtDNA phylogeny and hot spot.

    PubMed

    Ren, Zheng; Luo, Haibo; Song, Feng; Wei, Wei; Yang, Yuyou; Zhai, Xiandun; Chen, Xiaogang; Hou, Yiping

    2015-02-01

    We designed one multiplex assay with a reduced number of SNPs from whole mitochondrial genome as a screening approach for forensic purposes and developed a multiplex SNaPshot assay with 26 mitochondrial SNPs (mtSNPs). This assay included 16 target mtSNPs that defined the main haplogroups in Chinese population and ten hot-spot mtSNPs found by pyrosequencing. To validate our multiplex mtSNP assay, we not only analyzed a Chinese Han population sample, but also sequenced the complete control region of same set of individuals. Fifty-one haplotypes were observed in 204 individuals using our multiplex mtSNP assay and the haplotype diversity was estimated to be 0.9626. Our multiplex mtSNP assay could also distinguish some individuals sharing the same control region sequences. The same mtSNP profiles were obtained from the bloodstain, hair shaft, and salivary swab from same individuals. A good profile could be obtained with 50 pg of DNA. It was evident that our multiplex mtSNP assay not only improved the discrimination power, but also allowed allocating mitochondrial DNA profiles to particular haplogroups not clearly defined with the control region alone. We highlight the importance of the balance of target mtSNPs for haplogroup assignment and hot-spot mtSNPs for increasing discrimination power. PMID:25382174

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

    PubMed Central

    Abdel-Rahman, Sherif Z.

    2014-01-01

    The O 6-methylguanine-DNA methyltransferase gene (MGMT) encodes the direct reversal DNA repair protein that removes alkyl adducts from the O 6 position of guanine. Several single-nucleotide polymorphisms (SNPs) exist in the MGMT promoter/enhancer (P/E) region. However, the haplotype structure encompassing these SNPs and their functional/biological significance are currently unknown. We hypothesized that MGMT P/E haplotypes, rather than individual SNPs, alter MGMT transcription and can thus alter human sensitivity to alkylating agents. To identify the haplotype structure encompassing the MGMT P/E region SNPs, we sequenced 104 DNA samples from healthy individuals and inferred the haplotypes using the data generated. We identified eight SNPs in this region, namely T7C (rs180989103), T135G (rs1711646), G290A (rs61859810), C485A (rs1625649), C575A (rs113813075), G666A (rs34180180), C777A (rs34138162) and C1099T (rs16906252). Phylogenetics and Sequence Evolution analysis predicted 21 potential haplotypes that encompass these SNPs ranging in frequencies from 0.000048 to 0.39. Of these, 10 were identified in our study population as 20 paired haplotype combinations. To determine the functional significance of these haplotypes, luciferase reporter constructs representing these haplotypes were transfected into glioblastoma cells and their effect on MGMT promoter activity was determined. Compared with the most common (reference) haplotype 1, seven haplotypes significantly upregulated MGMT promoter activity (18–119% increase; P < 0.05), six significantly downregulated MGMT promoter activity (29–97% decrease; P < 0.05) and one haplotype had no effect. Mechanistic studies conducted support the conclusion that MGMT P/E haplotypes, rather than individual SNPs, differentially regulate MGMT transcription and could thus play a significant role in human sensitivity to environmental and therapeutic alkylating agents. PMID:24163400

  1. Efficient Algorithms for SNP Genotype Data Analysis using Hidden Markov Models of Haplotype Diversity

    E-print Network

    Mandoiu, Ion

    of genes associated with complex human diseases. Currently, such studies involve genotyping thousands inference that effectively ex- ploits Linkage Disequilibrium (LD) information. Experiments on simulated ad the best current methods for closely related ancestral pop- ulations. Finally, we introduce a hierarchical

  2. A New SNP Haplotype associated with blue disease resistance gene in cotton (Gossypium hirsutum L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Resistance to cotton blue disease (CBD) was evaluated in 364 F2.3 families of 3 populations derived from resistant variety ‘Delta Opal’. The CBD resistance in ‘Delta Opal’ was controlled by one single dominant gene designated Cbd. Two simple sequence repeat (SSR) markers were identified as linked t...

  3. A new SNP haplotype associated with blue disease resistance gene in cotton ( Gossypium hirsutum L.)

    Microsoft Academic Search

    David D. Fang; Jinhua Xiao; Paulo C. Canci; Roy G. Cantrell

    2010-01-01

    Resistance to cotton blue disease (CBD) was evaluated in 364 F2.3 families of three populations derived from resistant variety ‘Delta Opal’. The CBD resistance in ‘Delta Opal’ was controlled\\u000a by one single dominant gene designated Cbd. Two simple sequence repeat (SSR) markers were identified as linked to Cbd by bulked segregant analysis. Cbd resides at the telomere region of chromosome

  4. Y chromosome probe p49a detects complex PvuII haplotypes and many new TaqI haplotypes in southern African populations.

    PubMed Central

    Spurdle, A; Jenkins, T

    1992-01-01

    Y-specific 49a/TaqI haplotypes were determined for 831 individuals drawn from 21 different southern African populations. A total of 31 new haplotypes were observed, some of which contained new alleles or allelic variants. Duplication, in addition to CpG mutation, is implicated in the generation of certain allelic variants. Cluster analysis of genetic distances between the populations, calculated using the 49a/TaqI haplotype frequencies, revealed a basic split between African and non-African populations. Hybrid groups cluster with the caucasoid groups, indicating that male gene flow has occurred from the latter into the former. Clustering of the negroid and Khoisan groups is not what might have been expected from the known linguistic affinities. It is suggested that the 49a/TaqI haplotype analysis of these populations is not sufficiently sensitive to distinguish between many of the populations. The Y-specific 49a/PvuII polymorphism was studied in 127 individuals from southern African populations, and 17 polymorphic fragments ranging in size from 3.6 kb to greater than 48 kb were identified. A total of 53 PvuII haplotypes were observed, corresponding to only 30 TaqI haplotypes. There appears to be poor correlation between the two polymorphisms. Images Figure 2 Figure 4 PMID:1729883

  5. MDM2 Promoter SNP344T>A (rs1196333) Status Does Not Affect Cancer Risk

    PubMed Central

    Knappskog, Stian; Gansmo, Liv B.; Romundstad, Pĺl; Bjřrnslett, Merete; Trovik, Jone; Sommerfelt-Pettersen, Jan; Lřkkevik, Erik; Tollenaar, Rob A. E. M.; Seynaeve, Caroline; Devilee, Peter; Salvesen, Helga B.; Dřrum, Anne; Hveem, Kristian; Vatten, Lars; Lřnning, Per E.

    2012-01-01

    The MDM2 proto-oncogene plays a key role in central cellular processes like growth control and apoptosis, and the gene locus is frequently amplified in sarcomas. Two polymorphisms located in the MDM2 promoter P2 have been shown to affect cancer risk. One of these polymorphisms (SNP309T>G; rs2279744) facilitates Sp1 transcription factor binding to the promoter and is associated with increased cancer risk. In contrast, SNP285G>C (rs117039649), located 24 bp upstream of rs2279744, and in complete linkage disequilibrium with the SNP309G allele, reduces Sp1 recruitment and lowers cancer risk. Thus, fine tuning of MDM2 expression has proven to be of significant importance with respect to tumorigenesis. We assessed the potential functional effects of a third MDM2 promoter P2 polymorphism (SNP344T>A; rs1196333) located on the SNP309T allele. While in silico analyses indicated SNP344A to modulate TFAP2A, SPIB and AP1 transcription factor binding, we found no effect of SNP344 status on MDM2 expression levels. Assessing the frequency of SNP344A in healthy Caucasians (n?=?2,954) and patients suffering from ovarian (n?=?1,927), breast (n?=?1,271), endometrial (n?=?895) or prostatic cancer (n?=?641), we detected no significant difference in the distribution of this polymorphism between any of these cancer forms and healthy controls (6.1% in healthy controls, and 4.9%, 5.0%, 5.4% and 7.2% in the cancer groups, respectively). In conclusion, our findings provide no evidence indicating that SNP344A may affect MDM2 transcription or cancer risk. PMID:22558411

  6. Haplotype analysis in Huntington desease provides insights into mechanisms of CAG repeat expansion

    SciTech Connect

    Andrew, S.E.; Goldberg, Y.P.; Squitieri, F. [Univ. of British Columbia, Vancouver (Canada)] [and others

    1994-09-01

    Huntington disease (HD) is one of 7 disorders now known to be caused by expansion of a trinucleotide repeat. The HD mutation is a polymorphic trinucleotide (CAG) repeat in the 5{prime} region of a novel gene that expands beyond the normal range of 10-35 repeats in persons destined to develop the disease. Haplotype analysis of other dynamic mutation disorders such as myotonic dystrophy and Fragil X have suggested that a rare ancestral expansion event on a normal chromosome is followed by subsequent expansion events, resulting in a pool of chromosomes in the premutation range, which is inherently unstable and prone to further multiple expansion events leading to disease range chromosomes. Haplotype analysis of 67 HD and 84 control chromosomes using 5 polymorphic markers, both intragenic and 5{prime} to the disease mutation, demonstrate that multiple haplotypes underlie HD. However, 94% of the chromosomes can be grouped under two major haplotypes. These two haplotypes are also present in the normal population. A third major haplotype is seen on 38% of normal chromosomes but rarely on HD chromosomes (6%). CAG lengths on the normal chromosomes with the two haplotypes seen in the HD population are higher than those seen on the normal chromosomes with the haplotype rarely seen on HD chromosomes. Furthermore, in populations with a diminished frequency of HD, CAG length on normal chromosomes is significantly less than other populations with higher prevalence rates for HD. These data suggest that CAG length on normal chromosomes may be a significant factor contributing to repeat instability that eventually leads to chromosomes with CAG repeat lengths in the HD range. Haplotypes on the HD chromosomes are identical to those normal chromosomes which have CAG lengths in the high range of normal, suggesting that further expansions of this pool of chromosomes leads to chromosomes with CAG repeat sizes within the disease range, consistent with a multistep model.

  7. A New Method for Haplotype Inference Including Full-Sib Information

    PubMed Central

    Ding, Xiang Dong; Simianer, Henner; Zhang, Qin

    2007-01-01

    Recent literature has suggested that haplotype inference through close relatives, especially from nuclear families, can be an alternative strategy in determining linkage phase and estimating haplotype frequencies. In the case of no possibility to obtain genotypes for parents, and only full-sib information being used, a new approach is suggested to infer phase and to reconstruct haplotypes. We present a maximum-likelihood method via an expectation-maximization algorithm, called FSHAP, using only full-sib information when parent information is not available. FSHAP can deal with families with an arbitrary number of children, and missing parents or missing genotypes can be handled as well. In a simulation study we compare FSHAP with another existing expectation-maximization (EM)-based approach (FAMHAP), the conditioning approach implemented in FBAT and GENEHUNTER, which is only pedigree based and assumes linkage equilibrium. In most situations, FSHAP has the smallest discrepancy of haplotype frequency estimation and the lowest error rate in haplotype reconstruction, only in some cases FAMHAP yields comparable results. GENEHUNTER produces the largest discrepancy, and FBAT produces the highest error rate in offspring in most situations. Among the methods compared, FSHAP has the highest accuracy in reconstructing the diplotypes of the unavailable parents. Potential limitations of the method, e.g., in analyzing very large haplotypes, are indicated and possible solutions are discussed. PMID:17947415

  8. Sequence, Haplotype, and Association Analysis of ADR?2 in a Multiethnic Asthma Case-Control Study

    PubMed Central

    Hawkins, Gregory A.; Tantisira, Kelan; Meyers, Deborah A.; Ampleford, Elizabeth J.; Moore, Wendy C.; Klanderman, Barbara; Liggett, Stephen B.; Peters, Stephen P.; Weiss, Scott T.; Bleecker, Eugene R.

    2006-01-01

    Rationale: The comprehensive evaluation of gene variation, haplotype structure, and linkage disequilibrium is important in understanding the function of ?2-adrenergic receptor gene (ADR?2) on disease susceptibility, pulmonary function, and therapeutic responses in different ethnic groups with asthma. Objectives: To identify ADR?2 polymorphisms and haplotype structure in white and African American subjects and to test for genotype and haplotype association with asthma phenotypes. Methods: A 5.3-kb region of ADR?2 was resequenced in 669 individuals from 429 whites and 240 African Americans. A total of 12 polymorphisms, representing an optimal haplotype tagging set, were genotyped in whites (338 patients and 326 control subjects) and African Americans (222 patients and 299 control subjects). Results: A total of 49 polymorphisms were identified, 21 of which are novel; 31 polymorphisms (frequency > 0.03) were used to identify 24 haplotypes (frequency > 0.01) and assess linkage disequilibrium. Association with ratio (FEV1/FVC)2 for single-nucleotide polymorphism +79 (p < 0.05) was observed in African Americans. Significant haplotype association for (FEV1/FVC)2 was also observed in African Americans. Conclusions: There are additional genetic variants besides +46 (Gly16Arg) that are important in determining asthma phenotypes. These data suggest that the length of a poly-C repeat (+1269) in the 3? untranslated region of ADR?2 may influence lung function, and may be important in delineating variation in ?-agonist responses, especially in African Americans. PMID:16931635

  9. Vitamin D Receptor Gene Polymorphisms and Haplotypes in Hungarian Patients with Idiopathic Inflammatory Myopathy

    PubMed Central

    Griger, Zoltán; Dankó, Katalin

    2015-01-01

    Idiopathic inflammatory myopathies are autoimmune diseases characterized by symmetrical proximal muscle weakness. Our aim was to identify a correlation between VDR polymorphisms or haplotypes and myositis. We studied VDR-BsmI, VDR-ApaI, VDR-TaqI, and VDR-FokI polymorphisms and haplotypes in 89 Hungarian poly-/dermatomyositis patients (69 females) and 93 controls (52 females). We did not obtain any significant differences for VDR-FokI, BsmI, ApaI, and TaqI genotypes and allele frequencies between patients with myositis and healthy individuals. There was no association of VDR polymorphisms with clinical manifestations and laboratory profiles in myositis patients. Men with myositis had a significantly different distribution of BB, Bb, and bb genotypes than female patients, control male individuals, and the entire control group. Distribution of TT, Tt, and tt genotypes was significantly different in males than in females in patient group. According to four-marker haplotype prevalence, frequencies of sixteen possible haplotypes showed significant differences between patient and control groups. The three most frequent haplotypes in patients were the fbAt, FBaT, and fbAT. Our findings may reveal that there is a significant association: Bb and Tt genotypes can be associated with myositis in the Hungarian population we studied. We underline the importance of our result in the estimated prevalence of four-marker haplotypes. PMID:25649962

  10. Local mitochondrial DNA haplotype databases needed for domestic dog populations that have experienced founder effect.

    PubMed

    Spadaro, Amanda; Ream, Kelsey; Braham, Caitlyn; Webb, Kristen M

    2015-03-01

    Biological material from pets is often collected as evidence from crime scenes. Due to sample type and quality, mitochondrial DNA (mtDNA) is frequently evaluated to identify the potential contributor. MtDNA has a lower discriminatory power than nuclear DNA with multiple individuals in a population potentially carrying the same mtDNA sequence, or haplotype. The frequency distribution of mtDNA haplotypes in a population must be known in order to determine the evidentiary value of a match between crime scene evidence and the potential contributor of the biological material. This is especially important in geographic areas that include remote and/or isolated populations where founder effect may have lead to a decrease in genetic diversity and a non-random distribution of haplotypes relative to the population at large. Here we compared the haplotype diversity in dogs from the noncontiguous states of Alaska and Hawaii relative to the contiguous United States (US). We report a greater proportion of dogs carrying an A haplotype in Alaska relative to any other US population. Significant variation in the distribution of haplotype frequencies was discovered when comparing the haplotype diversity of dogs in Hawaii to that of the continental US. Each of these regions exhibits reduced genetic diversity relative to the contiguous US, likely due to founder effect. We recommend that specific databases be created to accurately represent the mitochondrial haplotype diversity in these remote areas. Furthermore, our work demonstrates the importance of local surveys for populations that may have experienced found effect. PMID:25612881

  11. Haplotyping for Disease Association: A Combinatorial Approach

    E-print Network

    Ravi, R.

    Rizzi Abstract--We consider a combinatorial problem derived from haplotyping a population with respect and diseased, and the corresponding sets of genotypes, we want to infer "bad" and "good" haplotypes to account for these genotypes and for the disease. Assume, for example, that the disease is recessive. Then, the resolving

  12. Maximum Likelihood Haplotyping for General Pedigrees

    Microsoft Academic Search

    Ma’ayan Fishelson; Nickolay Dovgolevsky; Dan Geiger

    2005-01-01

    Haplotype data is valuable in mapping disease-susceptibility genes in the study of Mendelian and complex diseases. We present algorithms for inferring a most likely haplotype configuration for general pedigrees, implemented in the newest version of the genetic linkage analysis system SUPERLINK. In SUPERLINK, genetic linkage analysis problems are represented internally using Bayesian networks. The use of Bayesian networks enables efficient

  13. Most parsimonious haplotype allele sharing determination

    PubMed Central

    Cai, Zhipeng; Sabaa, Hadi; Wang, Yining; Goebel, Randy; Wang, Zhiquan; Xu, Jiaofen; Stothard, Paul; Lin, Guohui

    2009-01-01

    Background The "common disease – common variant" hypothesis and genome-wide association studies have achieved numerous successes in the last three years, particularly in genetic mapping in human diseases. Nevertheless, the power of the association study methods are still low, in particular on quantitative traits, and the description of the full allelic spectrum is deemed still far from reach. Given increasing density of single nucleotide polymorphisms available and suggested by the block-like structure of the human genome, a popular and prosperous strategy is to use haplotypes to try to capture the correlation structure of SNPs in regions of little recombination. The key to the success of this strategy is thus the ability to unambiguously determine the haplotype allele sharing status among the members. The association studies based on haplotype sharing status would have significantly reduced degrees of freedom and be able to capture the combined effects of tightly linked causal variants. Results For pedigree genotype datasets of medium density of SNPs, we present two methods for haplotype allele sharing status determination among the pedigree members. Extensive simulation study showed that both methods performed nearly perfectly on breakpoint discovery, mutation haplotype allele discovery, and shared chromosomal region discovery. Conclusion For pedigree genotype datasets, the haplotype allele sharing status among the members can be deterministically, efficiently, and accurately determined, even for very small pedigrees. Given their excellent performance, the presented haplotype allele sharing status determination programs can be useful in many downstream applications including haplotype based association studies. PMID:19379528

  14. 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. PMID:21872942

  15. Haplotype Analyses of DNA Repair Gene Polymorphisms and Their Role in Ulcerative Colitis

    PubMed Central

    Bardia, Avinash; Tiwari, Santosh K.; Vishwakarma, Sandeep K.; Habeeb, Md. Aejaz; Nallari, Pratibha; Sultana, Shaik A.; Pasha, Shaik A.; Reddy, Yugandhar P.; Khan, Aleem A.

    2014-01-01

    Ulcerative colitis (UC) is a major clinical form of inflammatory bowel disease. UC is characterized by mucosal inflammation limited to the colon, always involving the rectum and a variable extent of the more proximal colon in a continuous manner. Genetic variations in DNA repair genes may influence the extent of repair functions, DNA damage, and thus the manifestations of UC. This study thus evaluated the role of polymorphisms of the genes involved in DNA repair mechanisms. A total of 171 patients and 213 controls were included. Genotyping was carried out by ARMS PCR and PCR-RFLP analyses for RAD51, XRCC3 and hMSH2 gene polymorphisms. Allelic and genotypic frequencies were computed in both control & patient groups and data was analyzed using appropriate statistical tests. The frequency of ‘A’ allele of hMSH2 in the UC group caused statistically significant increased risk for UC compared to controls (OR 1.64, 95% CI 1.16–2.31, p?=?0.004). Similarly, the CT genotype of XRCC3 gene was predominant in the UC group and increased the risk for UC by 1.75 fold compared to controls (OR 1.75, 95% CI 1.15–2.67, p?=?0.03), further confirming the risk of ‘T’ allele in UC. The GC genotype frequency of RAD51 gene was significantly increased (p?=?0.02) in the UC group (50.3%) compared to controls (38%). The GC genotype significantly increased the risk for UC compared to GG genotype by 1.73 fold (OR 1.73, 95% CI 1.14–2.62, p?=?0.02) confirming the strong association of ‘C’ allele with UC. Among the controls, the SNP loci combination of hMSH2:XRCC3 were in perfect linkage. The GTC and ACC haplotypes were found to be predominant in UC than controls with a 2.28 and 2.93 fold significant increase risk of UC. PMID:25247297

  16. Suicidal behavior and haplotypes of the dopamine receptor gene (DRD2) and ANKK1 gene polymorphisms in patients with alcohol dependence--preliminary report.

    PubMed

    Jasiewicz, Andrzej; Samochowiec, Agnieszka; Samochowiec, Jerzy; Ma?ecka, Iwona; Suchanecka, Aleksandra; Grzywacz, Anna

    2014-01-01

    Suicide is a significant public health issue and a major cause of death throughout the world. According to WHO it accounts for almost 2% of deaths worldwide. The etiology of suicidal behavior is complex but the results of many studies suggest that genetic determinants are of significant importance. In our study,--we have analyzed selected SNPs polymorphisms in the DRD2 and ANKK1 genes in patients with alcohol dependence syndrome (169 Caucasian subjects) including a subgroup of individuals (n = 61) who have experienced at least one suicide attempt. The aim of the study was to verify if various haplotypes of selected genes, comprising Taq1A, Taq1B, and Taq1D single nucleotide polymorphisms (SNP), play any role in the development of alcohol dependence and suicidal behavior. The control group comprised 157 unrelated individuals matched for ethnicity, gender,- and age and included no individuals with mental disorders. All subjects were recruited in the North West region of Poland. The study showed that alcohol dependent subjects with a history of at least one suicidal attempt were characterized by a significantly higher frequency of the T-G-A2 haplotype when compared to individuals in whom alcohol dependence was not associated with suicidal behavior (p = 0.006). It appears that studies based on identifying correlation between SNPs is the future for research on genetic risk factors that contribute to the development of alcohol addiction and other associated disorders. To sum up, there is a necessity to perform further research to explain dependencies between the dopaminergic system, alcohol use disorders and suicidal behavior. PMID:25415204

  17. Suicidal Behavior and Haplotypes of the Dopamine Receptor Gene (DRD2) and ANKK1 Gene Polymorphisms in Patients with Alcohol Dependence – Preliminary Report

    PubMed Central

    Jasiewicz, Andrzej; Samochowiec, Agnieszka; Samochowiec, Jerzy; Ma?ecka, Iwona; Suchanecka, Aleksandra; Grzywacz, Anna

    2014-01-01

    Suicide is a significant public health issue and a major cause of death throughout the world. According to WHO it accounts for almost 2% of deaths worldwide. The etiology of suicidal behavior is complex but the results of many studies suggest that genetic determinants are of significant importance. In our study,- we have analyzed selected SNPs polymorphisms in the DRD2 and ANKK1 genes in patients with alcohol dependence syndrome (169 Caucasian subjects) including a subgroup of individuals (n?=?61) who have experienced at least one suicide attempt. The aim of the study was to verify if various haplotypes of selected genes, comprising Taq1A, Taq1B, and Taq1D single nucleotide polymorphisms (SNP), play any role in the development of alcohol dependence and suicidal behavior. The control group comprised 157 unrelated individuals matched for ethnicity, gender,- and age and included no individuals with mental disorders. All subjects were recruited in the North West region of Poland. The study showed that alcohol dependent subjects with a history of at least one suicidal attempt were characterized by a significantly higher frequency of the T-G-A2 haplotype when compared to individuals in whom alcohol dependence was not associated with suicidal behavior (p?=?0.006). It appears that studies based on identifying correlation between SNPs is the future for research on genetic risk factors that contribute to the development of alcohol addiction and other associated disorders. To sum up, there is a necessity to perform further research to explain dependencies between the dopaminergic system, alcohol use disorders and suicidal behavior. PMID:25415204

  18. Haplotype analysis of genomic polymorphisms in and around the myotonic dystrophy locus in diverse populations of India.

    PubMed

    Basu, P; Majumder, P P; Roychoudhury, S; Bhattacharyya, N P

    2001-04-01

    The frequencies of haplotypes based upon the (CTG)n repeat and three other biallelic markers in and around the myotonic dystrophy (DM) locus were estimated in 13 ethnically, linguistically and geographically diverse sub-populations of India. The range of CTG repeats in caste populations was 5-31, while in tribal populations the range was shorter (5-23). Extensive variation in frequencies of large (CTG)n alleles (> or =18 repeats) was found in Indian populations. The implications of this finding on DM epidemiology are discussed. Haplotype diversity was found to be very high in most populations. The majority of the Indian DM patients carried a haplotype that is commonly found among DM patients globally; this is the most common haplotype in the class of large (> or =18 repeats) CTG alleles. However, one haplotype was found to be present in particularly high frequency in Indian populations; this haplotype was also found among Indian DM patients. This haplotype may be a characteristic of Indian and possibly of other East Asian populations. PMID:11379877

  19. SNP Set Association Analysis for Genome-Wide Association Studies

    PubMed Central

    Cai, Min; Dai, Hui; Qiu, Yongyong; Zhao, Yang; Zhang, Ruyang; Chu, Minjie; Dai, Juncheng; Hu, Zhibin; Shen, Hongbing; Chen, Feng

    2013-01-01

    Genome-wide association study (GWAS) is a promising approach for identifying common genetic variants of the diseases on the basis of millions of single nucleotide polymorphisms (SNPs). In order to avoid low power caused by overmuch correction for multiple comparisons in single locus association study, some methods have been proposed by grouping SNPs together into a SNP set based on genomic features, then testing the joint effect of the SNP set. We compare the performances of principal component analysis (PCA), supervised principal component analysis (SPCA), kernel principal component analysis (KPCA), and sliced inverse regression (SIR). Simulated SNP sets are generated under scenarios of 0, 1 and ?2 causal SNPs model. Our simulation results show that all of these methods can control the type I error at the nominal significance level. SPCA is always more powerful than the other methods at different settings of linkage disequilibrium structures and minor allele frequency of the simulated datasets. We also apply these four methods to a real GWAS of non-small cell lung cancer (NSCLC) in Han Chinese population PMID:23658731

  20. A procedure for the detection of linkage with high density SNP arrays in a large pedigree with colorectal cancer

    PubMed Central

    Middeldorp, Anneke; Jagmohan-Changur, Shantie; Helmer, Quinta; van der Klift, Heleen M; Tops, Carli MJ; Vasen, Hans FA; Devilee, Peter; Morreau, Hans; Houwing-Duistermaat, Jeanine J; Wijnen, Juul T; van Wezel, Tom

    2007-01-01

    Background The apparent dominant model of colorectal cancer (CRC) inheritance in several large families, without mutations in known CRC susceptibility genes, suggests the presence of so far unidentified genes with strong or moderate effect on the development of CRC. Linkage analysis could lead to identification of susceptibility genes in such families. In comparison to classical linkage analysis with multi-allelic markers, single nucleotide polymorphism (SNP) arrays have increased information content and can be processed with higher throughput. Therefore, SNP arrays can be excellent tools for linkage analysis. However, the vast number of SNPs on the SNP arrays, combined with large informative pedigrees (e.g. >35–40 bits), presents us with a computational complexity that is challenging for existing statistical packages or even exceeds their capacity. We therefore setup a procedure for linkage analysis in large pedigrees and validated the method by genotyping using SNP arrays of a colorectal cancer family with a known MLH1 germ line mutation. Methods Quality control of the genotype data was performed in Alohomora, Mega2 and SimWalk2, with removal of uninformative SNPs, Mendelian inconsistencies and Mendelian consistent errors, respectively. Linkage disequilibrium was measured by SNPLINK and Merlin. Parametric linkage analysis using two flanking markers was performed using MENDEL. For multipoint parametric linkage analysis and haplotype analysis, SimWalk2 was used. Results On chromosome 3, in the MLH1-region, a LOD score of 1.9 was found by parametric linkage analysis using two flanking markers. On chromosome 11 a small region with LOD 1.1 was also detected. Upon linkage disequilibrium removal, multipoint linkage analysis yielded a LOD score of 2.1 in the MLH1 region, whereas the LOD score dropped to negative values in the region on chromosome 11. Subsequent haplotype analysis in the MLH1 region perfectly matched the mutation status of the family members. Conclusion We developed a workflow for linkage analysis in large families using high-density SNP arrays and validated this workflow in a family with colorectal cancer. Linkage disequilibrium has to be removed when using SNP arrays, because it can falsely inflate the LOD score. Haplotype analysis is adequate and can predict the carrier status of the family members. PMID:17222328

  1. Extensive interbreed, but minimal intrabreed, variation of DLA class II alleles and haplotypes in dogs.

    PubMed

    Kennedy, Lorna J; Barnes, A; Happ, G M; Quinnell, R J; Bennett, D; Angles, J M; Day, M J; Carmichael, N; Innes, J F; Isherwood, D; Carter, S D; Thomson, W; Ollier, W E R

    2002-03-01

    The DLA class II genes in the dog major histocompatibility complex are highly polymorphic. To date, 52 DLA-DRB1, 16 DLA-DQA1 and 41 DLA-DQB1 allelic sequences have been assigned. The aim of this study was to examine the intrabreed and interbreed variation of DLA allele and haplotype frequencies in dogs, and to ascertain whether conserved DLA class II haplotypes occur within and between different breeds. One thousand and 25 DNA samples from over 80 different breeds were DLA class II genotyped, the number of dogs per breed ranging from 1 to 61. DNA sequence based typing and sequence specific oligonucleotide probing were used to characterize dogs for their DLA-DRB1, DQA1 and DQB1 alleles. The high frequency of DLA class II homozygous animals (35%), allowed the assignment of many haplotypes despite the absence of family data. Four new DLA alleles were identified during the course of this study. Analysis of the data revealed considerable interbreed variation, not only in allele frequency, but also in the numbers of alleles found per breed. There was also considerable variation in the number of breeds in which particular alleles were found. These interbreed variations were found in all three DLA class II loci tested, and also applied to the three-locus haplotypes identified. Within this data set, 58 different DLA-DRB1/DQA1/DQB1 three-locus haplotypes were identified, which were all found in at least two different animals. Some of the haplotypes appeared to be characteristic of certain breeds. The high interbreed, and relatively low intrabreed, variation of MHC alleles and haplotypes found in this study could provide an explanation for reports of interbreed variation of immune responses to vaccines, viruses and other infections. PMID:12074709

  2. SNP genotyping by DNA photoligation: application to SNP detection of genes from food crops

    NASA Astrophysics Data System (ADS)

    Yoshimura, Yoshinaga; Ohtake, Tomoko; Okada, Hajime; Ami, Takehiro; Tsukaguchi, Tadashi; Fujimoto, Kenzo

    2009-06-01

    We describe a simple and inexpensive single-nucleotide polymorphism (SNP) typing method, using DNA photoligation with 5-carboxyvinyl-2'-deoxyuridine and two fluorophores. This SNP-typing method facilitates qualitative determination of genes from indica and japonica rice, and showed a high degree of single nucleotide specificity up to 10 000. This method can be used in the SNP typing of actual genomic DNA samples from food crops.

  3. Efficient mining of haplotype patterns for linkage disequilibrium mapping.

    PubMed

    Lin, Li; Wong, Limsoon; Leong, Tze-Yun; Lai, Poh San

    2010-12-01

    Effective identification of disease-causing gene locations can have significant impact on patient management decisions that will ultimately increase survival rates and improve the overall quality of health care. Linkage disequilibrium mapping is the process of finding disease gene locations through comparisons of haplotype frequencies between disease chromosomes and normal chromosomes. This work presents a new method for linkage disequilibrium mapping. The main advantage of the proposed algorithm, called LinkageTracker, is its consistency in producing good predictive accuracy under different conditions, including extreme conditions where the occurrence of disease samples with the mutation of interest is very low and there is presence of error or noise. We compared our method with some leading methods in linkage disequilibrium mapping such as HapMiner, Blade, GeneRecon, and Haplotype Pattern Mining (HPM). Experimental results show that for a substantial class of problems, our method has good predictive accuracy while taking reasonably short processing time. Furthermore, LinkageTracker does not require any population ancestry information about the disease and the genealogy of the haplotypes. Therefore, it is useful for linkage disequilibrium mapping when the users do not have such information about their datasets. PMID:21155024

  4. Efficient Inference of Haplotypes From Genotypes on a Large Animal Pedigree

    PubMed Central

    Baruch, Eyal; Weller, Joel Ira; Cohen-Zinder, Miri; Ron, Micha; Seroussi, Eyal

    2006-01-01

    We present a simple algorithm for reconstruction of haplotypes from a sample of multilocus genotypes. The algorithm is aimed specifically for analysis of very large pedigrees for small chromosomal segments, where recombination frequency within the chromosomal segment can be assumed to be zero. The algorithm was tested both on simulated pedigrees of 155 individuals in a family structure of three generations and on real data of 1149 animals from the Israeli Holstein dairy cattle population, including 406 bulls with genotypes, but no females with genotypes. The rate of haplotype resolution for the simulated data was >91% with a standard deviation of 2%. With 20% missing data, the rate of haplotype resolution was 67.5% with a standard deviation of 1.3%. In both cases all recovered haplotypes were correct. In the real data, allele origin was resolved for 22% of the heterozygous genotypes, even though 70% of the genotypes were missing. Haplotypes were resolved for 36% of the males. Computing time was insignificant for both data sets. Despite the intricacy of large-scale real pedigree genotypes, the proposed algorithm provides a practical rule-based solution for resolving haplotypes for small chromosomal segments in commercial animal populations. PMID:16361242

  5. Unusual Haplotypic Structure of IL8, a Susceptibility Locus for a Common Respiratory Virus

    PubMed Central

    Hull, Jeremy; Ackerman, Hans; Isles, Kate; Usen, Stanley; Pinder, Margaret; Thomson, Anne; Kwiatkowski, Dominic

    2001-01-01

    Interleukin-8 (IL8) is believed to play a role in the pathogenesis of bronchiolitis, a common viral disease of infancy, and a recent U.K. family study identified an association between this disease and the IL8?251A allele. In the present study we report data, from a different set of families, which replicate this finding; combined analysis of 194 nuclear families through use of the transmission/disequilibrium test gives P=.001. To explore the underlying genetic cause, we identified nine single-nucleotide polymorphisms (SNPs) in a 7.6-kb segment spanning the IL8 gene and its promoter region and used six of these SNPs to define the haplotypic structure of the IL8 locus. The IL8?251A allele resides on two haplotypes, only one of which is associated with disease, suggesting that this may not be the functional allele. Europeans show an unusual haplotype genealogy that is dominated by two common haplotypes differing at multiple sites, whereas Africans have much greater haplotypic diversity. These marked haplotype-frequency differences give an FST of .25, and, in the European sample, both Tajima’s D statistic (D=2.58,P=.007) and the Hudson/Kreitman/Aguade test (?2=4.9,P=.03) reject neutral equilibrium, suggesting that selective pressure may have acted on this locus. PMID:11431705

  6. Low Diversity of T Haplotypes in the Eastern Form of the House Mouse, Mus Musculus L

    PubMed Central

    Ruvinsky, A.; Polyakov, A.; Agulnik, A.; Tichy, H.; Figueroa, F.; Klein, J.

    1991-01-01

    In previous studies, 13 different recessive embryonic lethal genes have been associated with t haplotypes in the wild mice of the species Mus domesticus. In this communication we have analyzed five populations of Mus musculus for the presence and identity of t haplotypes. The populations occupy geographically distant regions in the Soviet Union: Altai Mountains, western and eastern Siberia, Azerbaijan and Turkmenistan. No t haplotypes were found in mice from eastern Siberia. In the remaining four populations, t haplotypes occurred with frequencies ranging from 0.07 to 0.21. All the t haplotypes extracted from these populations and analyzed by the genetic complementation test were shown to carry the same lethal gene tcl-w73. In one population (that of western Siberia), another lethal gene (tcl-w5) was found to be present on the same chromosome as tcl-w73. This situation is in striking contrast to that found in the populations of the western form of the house mouse, M. domesticus. In the latter species, tcl-w73 has not been found at all and the different populations are characterized by the presence of several different lethal genes. The low diversity of t haplotypes in M. musculus is consistent with lower genetic variability of other traits and indicates a different origin and speciation mode compared to M. domesticus. Serological typing for H-2 antigenic determinants suggests that most, if not all, of the newly described t haplotypes might have arisen by recombination of t(w73) from M. musculus with t haplotypes from M. domesticus either in the hybrid zone between the two species or in regions where the two species mixed accidentally. PMID:2016041

  7. DASH: A Method for Identical-by-Descent Haplotype Mapping Uncovers Association with Recent Variation

    PubMed Central

    Gusev, Alexander; Kenny, Eimear E.; Lowe, Jennifer K.; Salit, Jaqueline; Saxena, Richa; Kathiresan, Sekar; Altshuler, David M.; Friedman, Jeffrey M.; Breslow, Jan L.; Pe'er, Itsik

    2011-01-01

    Rare variants affecting phenotype pose a unique challenge for human genetics. Although genome-wide association studies have successfully detected many common causal variants, they are underpowered in identifying disease variants that are too rare or population-specific to be imputed from a general reference panel and thus are poorly represented on commercial SNP arrays. We set out to overcome these challenges and detect association between disease and rare alleles using SNP arrays by relying on long stretches of genomic sharing that are identical by descent. We have developed an algorithm, DASH, which builds upon pairwise identical-by-descent shared segments to infer clusters of individuals likely to be sharing a single haplotype. DASH constructs a graph with nodes representing individuals and links on the basis of such segments spanning a locus and uses an iterative minimum cut algorithm to identify densely connected components. We have applied DASH to simulated data and diverse GWAS data sets by constructing haplotype clusters and testing them for association. In simulations we show this approach to be significantly more powerful than single-marker testing in an isolated population that is from Kosrae, Federated States of Micronesia and has abundant IBD, and we provide orthogonal information for rare, recent variants in the outbred Wellcome Trust Case-Control Consortium (WTCCC) data. In both cohorts, we identified a number of haplotype associations, five such loci in the WTCCC data and ten in the isolated, that were conditionally significant beyond any individual nearby markers. We have replicated one of these loci in an independent European cohort and identified putative structural changes in low-pass whole-genome sequence of the cluster carriers. PMID:21620352

  8. High-Density SNP Mapping of the HLA Region Identifies Multiple Independent Susceptibility Loci Associated with Selective IgA Deficiency

    PubMed Central

    Ferreira, Ricardo C.; Pan-Hammarström, Qiang; Graham, Robert R.; Fontán, Gumersindo; Lee, Annette T.; Ortmann, Ward; Wang, Ning; Urcelay, Elena; Fernández-Arquero, Miguel; Núńez, Concepción; Jorgensen, Gudmundur; Ludviksson, Björn R.; Koskinen, Sinikka; Haimila, Katri; Padyukov, Leonid; Gregersen, Peter K.

    2012-01-01

    Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1?600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P?=?7.69×10?57; OR?=?2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P?=?5.86×10?17; OR?=?4.28) and the DRB1*1501 (combined P?=?2.24×10?35; OR?=?0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis. PMID:22291608

  9. 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 (? = -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 effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression. PMID:25324900

  10. A DRD2 and ANKK1 haplotype is associated with nicotine dependence.

    PubMed

    Voisey, Joanne; Swagell, Christopher Dean; Hughes, Ian Paul; van Daal, Angela; Noble, Ernest Pascal; Lawford, Bruce Robert; Young, Ross McDonald; Morris, Charles Phillip

    2012-04-30

    To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the DRD2 C957T, -141delC and ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The -141delC SNP did not show any association but both the C957T and TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/TaqI A1 haplotype was more than 3.5 times as likely to be associated with nicotine dependence compared with the 957T/TaqI A1 haplotype (P=0.003). Analysis of the combined genotypes of both SNPs revealed that individuals who were homozygous for the 957C-allele (CC) and had either one or two copies of the TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (P=0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the DRD2 C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence. PMID:22382052

  11. Ribosomal DNA haplotype distribution of Bursaphelenchus xylophilus in Kyushu and Okinawa islands, Japan

    PubMed Central

    Nose, Mine; Miyahara, Fumihiko; Ohira, Mineko; Matsunaga, Koji; Tobase, Masashi; Koyama, Takao; Yoshimoto, Kikuo

    2009-01-01

    Ribosomal DNA region sequences (partial 18S, 28S and complete ITS1, 5.8S, and ITS2) of the pinewood nematode (Bursaphelenchus xylophilus) were obtained from DNA extracted directly from wood pieces collected from wilted pine trees throughout the Kyushu and Okinawa islands, Japan. Either a 2569bp or 2573bp sequence was obtained from 88 of 143 samples. Together with the 45 rDNA sequences of pinewood nematode isolates previously reported, there were eight single nucleotide polymorphisms and two indels of two bases. Based on these mutations, nine haplotypes were estimated. The haplotype frequencies differed among regions in Kyushu island (northwest, northeast and center, southeast, and southwest), and the distribution was consistent with the invasion and spreading routes of the pinewood nematode previously estimated from past records of pine wilt and wood importation. There was no significant difference in haplotype frequencies among the collection sites on Okinawa island. PMID:22736814

  12. Estimation of Pairwise Identity by Descent From Dense Genetic Marker Data in a Population Sample of Haplotypes

    PubMed Central

    Browning, Sharon R.

    2008-01-01

    I present a new approach for calculating probabilities of identity by descent for pairs of haplotypes. The approach is based on a joint hidden Markov model for haplotype frequencies and identity by descent (IBD). This model allows for linkage disequilibrium, and the method can be applied to very dense marker data. The method has high power for detecting IBD tracts of genetic length of 1 cM, with the use of sufficiently dense markers. This enables detection of pairwise IBD between haplotypes from individuals whose most recent common ancestor lived up to 50 generations ago. PMID:18430938

  13. Development of SNP markers for genes of the phenylpropanoid pathway and their association to kernel and malting traits in barley

    PubMed Central

    2013-01-01

    Background Flavonoids are an important class of secondary compounds in angiosperms. Next to certain biological functions in plants, they play a role in the brewing process and have an effect on taste, color and aroma of beer. The aim of this study was to reveal the haplotype diversity of candidate genes involved in the phenylpropanoid biosynthesis pathway in cultivated barley varieties (Hordeum vulgare L.) and to determine associations to kernel and malting quality parameters. Results Five genes encoding phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H), chalcone synthase (CHS), flavanone 3-hydroxylase (F3H) and dihydroflavonol reductase (DFR) of the phenylpropanoid biosynthesis pathway were partially resequenced in 16 diverse barley reference genotypes. Their localization in the barley genome, their genetic structure, and their genetic variation e.g. single nucleotide polymorphism (SNP) and Insertion/Deletion (InDel) patterns were revealed. In total, 130 SNPs and seven InDels were detected. Of these, 21 polymorphisms were converted into high-throughput pyrosequencing markers. The resulting SNP and haplotype patterns were used to calculate associations with kernel and malting quality parameters. Conclusions SNP patterns were found to be highly variable for the investigated genes. The developed high-throughput markers are applicable for assessing the genetic variability and for the determination of haplotype patterns in a set of barley accessions. The candidate genes PAL, C4H and F3H were shown to be associated to several malting properties like glassiness (PAL), viscosity (C4H) or to final attenuation (F3H). PMID:24088365

  14. Rapid haplotype inference for nuclear families

    E-print Network

    Williams, Amy L.

    Hapi is a new dynamic programming algorithm that ignores uninformative states and state transitions in order to efficiently compute minimum-recombinant and maximum likelihood haplotypes. When applied to a dataset containing ...

  15. A Haplotype Framework for Cystic Fibrosis Mutations in Iran

    PubMed Central

    Elahi, Elahe; Khodadad, Ahmad; Kupershmidt, Ilya; Ghasemi, Fereshteh; Alinasab, Babak; Naghizadeh, Ramin; Eason, Robert G.; Amini, Mahshid; Esmaili, Mehran; Esmaeili Dooki, Mohammad R.; Sanati, Mohammad H.; Davis, Ronald W.; Ronaghi, Mostafa; Thorstenson, Yvonne R.

    2006-01-01

    This is the first comprehensive profile of cystic fibrosis transmembrane conductance regulator (CFTR) mutations and their corresponding haplotypes in the Iranian population. All of the 27 CFTR exons of 60 unrelated Iranian CF patients were sequenced to identify disease-causing mutations. Eleven core haplotypes of CFTR were identified by genotyping six high-frequency simple nucleotide polymorphisms. The carrier frequency of 2.5 in 100 (1 in 40) was estimated from the frequency of heterozygous patients and suggests that contrary to popular belief, cystic fibrosis may be a common, under-diagnosed disease in Iran. A heterogeneous mutation spectrum was observed at the CFTR locus in 60 cystic fibrosis (CF) patients from Iran. Twenty putative disease-causing mutations were identified on 64 (53%) of the 120 chromosomes. The five most common Iranian mutations together represented 37% of the expected mutated alleles. The most frequent mutation, ?F508 (p.F508del), represented only 16% of the expected mutated alleles. The next most frequent mutations were c.1677del2 (p.515fs) at 7.5%, c.4041C>G (p.N1303K) at 5.6%, c.2183AA>G (p.684fs) at 5%, and c.3661A>T (p.K1177X) at 2.5%. Three of the five most frequent Iranian mutations are not included in a commonly used panel of CF mutations, underscoring the importance of identifying geographic-specific mutations in this population. PMID:16436643

  16. Genome-wide SNP detection, validation, and development of an 8K SNP array for apple

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide...

  17. SNPMeta: SNP annotation and SNP metadata collection without a reference genome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The increase in availability of resequencing data is greatly accelerating SNP discovery and has facilitated the development of SNP genotyping assays. This, in turn, is increasing interest in annotation of individual SNPs. Currently, these data are only available through curation, or comparison to a ...

  18. Relaxing haplotype block models for association testing.

    PubMed

    Castellana, Natalie; Dhamdhere, Kedar; Sridhar, Srinath; Schwartz, Russell

    2006-01-01

    The arrival of publicly available genome-wide variation data is creating new opportunities for reconciling model-based methods for associating genotypes and phenotypes with the complexities of real genome data. Such data is particularly valuable for testing the utility of models of conserved haplotype structure to association studies. While there is much interest in "haplotype block" models that assume population-wide regions of low diversity, there is also evidence that such models eliminate correlations potentially useful to association studies. We investigate the value of relaxing the rigidity of block models by developing an association testing method using the previously developed "haplotype motif" model, which retains the notion of representing haploid sequences as concatenations of conserved haplotypes but abandons the assumption of population-wide block boundaries. We compare the effectiveness of motif, block, and single-variant models at finding association with simulated phenotypes using real and simulated data. We conclude that the benefits of haplotype models in any form are modest, but that haplotype models in general and block-free models in particular are useful in picking up correlations near the boundaries of the detectable level. PMID:17094260

  19. 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

  20. History and origin of beta-thalassemia in Turkey: sequence haplotype diversity of beta-globin genes.

    PubMed

    Tadmouri, G O; Garguier, N; Demont, J; Perrin, P; Ba?ak, A N

    2001-10-01

    In the present study we report the sequence haplotypes associated with 22 beta-globin gene mutations present in Turkey. Nine nucleotide polymorphisms and an (AT)xTy motif located at the 5' end of the beta-globin gene form the sequence haplotypes that were investigated in 204 unrelated beta-thalassemia and wild-type chromosomes from Turkey. Twelve sequence haplotypes were observed in the chromosomes analyzed and haplotypic heterogeneity was found in the wild-type beta-globin genes. Samples from the Black Sea region demonstrated a remarkable level of haplotypic heterogeneity in contrast to the homogeneity present in Central Anatolian samples. Of the 22 beta-globin mutations analyzed, 18 were related with single sequence haplotypes. This simple association led to the attempt to determine the origin of these mutations by comparing their frequencies in Turkey with those in other countries and/or the world distribution of the haplotypes carrying them. However, the presence of several exceptions for the "one haplotype/one mutation" rule showed that the beta-globin gene cluster is far from static. Each of the IVS-I-110 (G-->A), Cd 39 (C-->T), IVS-I-6 (T-->C), and -30 (T-->A) beta-globin mutations was associated with a minimum of two sequence haplotypes. This fact is best explained by the likelihood of strong recombination mechanisms taking place, rather than by assuming multiple origins for each of these alleles. According to our results, malarial selection for the oldest beta-thalassemia allele in Anatolia (i.e., IVS-I-110 G-->A) may have occurred between 6500 and 2000 B.C. From that date on, most of the common beta-thalassemia mutations in Turkey were established, and by the 13th century A.D. most of them were brought to frequencies close to those observed at present. PMID:11758688

  1. Differences in Meiotic Recombination Rates in Childhood Acute Lymphoblastic Leukemia at an MHC Class II Hotspot Close to Disease Associated Haplotypes

    PubMed Central

    Thompson, Pamela; Urayama, Kevin; Zheng, Jie; Yang, Peng; Ford, Matt; Buffler, Patricia; Chokkalingam, Anand; Lightfoot, Tracy; Taylor, Malcolm

    2014-01-01

    Childhood Acute Lymphoblastic Leukemia (ALL) is a malignant lymphoid disease of which B-cell precursor- (BCP) and T-cell- (T) ALL are subtypes. The role of alleles encoded by major histocompatibility loci (MHC) have been examined in a number of previous studies and results indicating weak, multi-allele associations between the HLA-DPB1 locus and BCP-ALL suggested a role for immunosusceptibility and possibly infection. Two independent SNP association studies of ALL identified loci approximately 37 kb from one another and flanking a strong meiotic recombination hotspot (DNA3), adjacent to HLA-DOA and centromeric of HLA-DPB1. To determine the relationship between this observation and HLA-DPB1 associations, we constructed high density SNP haplotypes of the 316 kb region from HLA-DMB to COL11A2 in childhood ALL and controls using a UK GWAS data subset and the software PHASE. Of four haplotype blocks identified, predicted haplotypes in Block 1 (centromeric of DNA3) differed significantly between BCP-ALL and controls (P?=?0.002) and in Block 4 (including HLA-DPB1) between T-ALL and controls (P?=?0.049). Of specific common (>5%) haplotypes in Block 1, two were less frequent in BCP-ALL, and in Block 4 a single haplotype was more frequent in T-ALL, compared to controls. Unexpectedly, we also observed apparent differences in ancestral meiotic recombination rates at DNA3, with BCP-ALL showing increased and T-ALL decreased levels compared to controls. In silico analysis using LDsplit sotware indicated that recombination rates at DNA3 are influenced by flanking loci, including SNPs identified in childhood ALL association studies. The observed differences in rates of meiotic recombination at this hotspot, and potentially others, may be a characteristic of childhood leukemia and contribute to disease susceptibility, alternatively they may reflect interactions between ALL-associated haplotypes in this region. PMID:24959916

  2. Am. J. Hum. Genet. 66:18821899, 2000 Haplotypes and Linkage Disequilibrium at the Phenylalanine Hydroxylase

    E-print Network

    Kidd, Kenneth

    the opposite ends is significant only in Native American populations and in one African population. This study was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-frequency variation exists between some regions of the world. In European populations, linkage

  3. Comparison of linkage disequilibrium and haplotype diversity on macro- and microchromosomes in chicken

    Microsoft Academic Search

    Hendrik-Jan Megens; Richard PMA Crooijmans; John WM Bastiaansen; Hindrik HD Kerstens; Albart Coster; Ruud Jalving; Addie Vereijken; Pradeepa Silva; William M Muir; Hans H Cheng; Olivier Hanotte; Martien AM Groenen

    2009-01-01

    BACKGROUND: The chicken (Gallus gallus), like most avian species, has a very distinct karyotype consisting of many micro- and a few macrochromosomes. While it is known that recombination frequencies are much higher for micro- as compared to macrochromosomes, there is limited information on differences in linkage disequilibrium (LD) and haplotype diversity between these two classes of chromosomes. In this study,

  4. Modeling of Identity-by-Descent Processes Along a Chromosome Between Haplotypes and Their Genotyped Ancestors

    PubMed Central

    Druet, Tom; Farnir, Frederic Paul

    2011-01-01

    Identity-by-descent probabilities are important for many applications in genetics. Here we propose a method for modeling the transmission of the haplotypes from the closest genotyped relatives along an entire chromosome. The method relies on a hidden Markov model where hidden states correspond to the set of all possible origins of a haplotype within a given pedigree. Initial state probabilities are estimated from average genetic contribution of each origin to the modeled haplotype while transition probabilities are computed from recombination probabilities and pedigree relationships between the modeled haplotype and the various possible origins. The method was tested on three simulated scenarios based on real data sets from dairy cattle, Arabidopsis thaliana, and maize. The mean identity-by-descent probabilities estimated for the truly inherited parental chromosome ranged from 0.94 to 0.98 according to the design and the marker density. The lowest values were observed in regions close to crossing over or where the method was not able to discriminate between several origins due to their similarity. It is shown that the estimated probabilities were correctly calibrated. For marker imputation (or QTL allele prediction for fine mapping or genomic selection), the method was efficient, with 3.75% allelic imputation error rates on a dairy cattle data set with a low marker density map (1 SNP/Mb). The method should prove useful for situations we are facing now in experimental designs and in plant and animal breeding, where founders are genotyped with relatively high markers densities and last generation(s) genotyped with a lower-density panel. PMID:21441215

  5. Cross Haplotype Sharing Statistic: Haplotype length based method for whole genome association testing

    E-print Network

    Zelikovsky, Alexander

    Cross Haplotype Sharing Statistic: Haplotype length based method for whole genome association of Groningen, the Netherlands; b Department of Pathology and Laboratory Medicine, section Medical Biology the method fast enough and hence practically useful even for whole genome screens with marker densities

  6. Efficient haplotype block recognition of very long and dense genetic sequences

    PubMed Central

    2014-01-01

    Background The new sequencing technologies enable to scan very long and dense genetic sequences, obtaining datasets of genetic markers that are an order of magnitude larger than previously available. Such genetic sequences are characterized by common alleles interspersed with multiple rarer alleles. This situation has renewed the interest for the identification of haplotypes carrying the rare risk alleles. However, large scale explorations of the linkage-disequilibrium (LD) pattern to identify haplotype blocks are not easy to perform, because traditional algorithms have at least ?(n2) time and memory complexity. Results We derived three incremental optimizations of the widely used haplotype block recognition algorithm proposed by Gabriel et al. in 2002. Our most efficient solution, called MIG ++, has only ?(n) memory complexity and, on a genome-wide scale, it omits >80% of the calculations, which makes it an order of magnitude faster than the original algorithm. Differently from the existing software, the MIG ++ analyzes the LD between SNPs at any distance, avoiding restrictions on the maximal block length. The haplotype block partition of the entire HapMap II CEPH dataset was obtained in 457 hours. By replacing the standard likelihood-based D? variance estimator with an approximated estimator, the runtime was further improved. While producing a coarser partition, the approximate method allowed to obtain the full-genome haplotype block partition of the entire 1000 Genomes Project CEPH dataset in 44 hours, with no restrictions on allele frequency or long-range correlations. These experiments showed that LD-based haplotype blocks can span more than one million base-pairs in both HapMap II and 1000 Genomes datasets. An application to the North American Rheumatoid Arthritis Consortium (NARAC) dataset shows how the MIG ++ can support genome-wide haplotype association studies. Conclusions The MIG ++ enables to perform LD-based haplotype block recognition on genetic sequences of any length and density. In the new generation sequencing era, this can help identify haplotypes that carry rare variants of interest. The low computational requirements open the possibility to include the haplotype block structure into genome-wide association scans, downstream analyses, and visual interfaces for online genome browsers. PMID:24423111

  7. Phylogeny- and Parsimony-Based Haplotype Inference with Constraints

    NASA Astrophysics Data System (ADS)

    Elberfeld, Michael; Tantau, Till

    Haplotyping, also known as haplotype phase prediction, is the problem of predicting likely haplotypes based on genotype data. One fast computational haplotyping method is based on an evolutionary model where a perfect phylogenetic tree is sought that explains the observed data. In their CPM 2009 paper, Fellows et al. studied an extension of this approach that incorporates prior knowledge in the form of a set of candidate haplotypes from which the right haplotypes must be chosen. While this approach may help to increase the accuracy of haplotyping methods, it was conjectured that the resulting formal problem constrained perfect phylogeny haplotyping might be NP-complete. In the present paper we present a polynomial-time algorithm for it. Our algorithmic ideas also yield new fixed-parameter algorithms for related haplotyping problems based on the maximum parsimony assumption.

  8. HLA in coeliac disease families: a novel test of risk modification by the 'other' haplotype when at least one DQA1*05-DQB1*02 haplotype is carried.

    PubMed

    Louka, A S; Nilsson, S; Olsson, M; Talseth, B; Lie, B A; Ek, J; Gudjónsdóttir, A H; Ascher, H; Sollid, L M

    2002-08-01

    Predisposition to coeliac disease (CD) involves HLA genes. We investigated whether any haplotypes modify risk when carried trans to a known high-risk haplotype, DQA1*05-DQB1*02. Earlier attempts to rank levels of risk contributed by the 'other' haplotype were burdened by use of case-control populations; haplotype frequencies were estimated and homozygosity was only presumed. In contrast, exact haplotypes can be determined and allele transmission can be traced in families. A similar study in narcolepsy reported strata of different degrees of predisposition, attributable to the 'other' haplotype. A gene dosage effect similar to that described for DQB1*02 in CD, has also been reported in narcolepsy. We genotyped 439 simplex/multiplex trios for DQA1 and DQB1. We designed a new statistic to test risk modulation by the trans haplotype, even if the affected offspring was homozygous. We tested for significant deviation in transmission of the 'other' haplotype, i.e., modification of DQA1*05-DQB1*02 risk. We also addressed the proposed difference in risk, between DQA1*05-DQB1*02 homozygotes and DQA1*05-DQB1*02/DQA1*0201-DQB1*02 heterozygotes, reported in Southern Europe. We confirmed a DQB1*02 gene dosage effect. However, no haplotypes were found to modify risk when carried trans to DQA1*05-DQB1*02, except DQA1*05-DQB1*02 and DQA1*0201-DQB1*02 which were already known. We did not find credible evidence for a difference in risk conferred by DQA1*05-DQB1*02 and DQA1*0201-DQB1*02, when carried with DQA1*05-DQB1*02. The new test, which directly inspects haplotype transmissions rather than estimated haplotype frequencies, was used to demonstrate that the 'other' haplotype (except DQA1*05-DQB1*02 and DQA1*0201-DQB1*02) does not modify risk conferred by DQA1*05-DQB1*02. The test is applicable to other diseases. PMID:12392509

  9. Haplotype diversity in "source-sink" dynamics of Escherichia coli urovirulence.

    PubMed

    Chattopadhyay, Sujay; Feldgarden, Michael; Weissman, Scott J; Dykhuizen, Daniel E; van Belle, Gerald; Sokurenko, Evgeni V

    2007-02-01

    FimH, the mannose-specific, type 1 fimbrial adhesin of Escherichia coli, acquires amino acid replacements adaptive in extraintestinal niches (the genitourinary tract) but detrimental in the main habitat (the large intestine). This microevolutionary dynamics is reminiscent of an ecological "source-sink" model of continuous species spread from a stable primary habitat (source) into transient secondary niches (sink), with eventual extinction of the sink-evolved populations. Here, we have adapted two ecological analytical tools-diversity indexes DS and alpha--to compare size and frequency distributions of fimH haplotypes between evolutionarily conserved FimH variants ("source" haplotypes) and FimH variants with adaptive mutations (putative "sink" haplotypes). Both indexes show two- to threefold increased diversity of the sink fimH haplotypes relative to the source haplotypes, a pattern that ran opposite to those seen with nonstructural fimbrial genes (fimC and fimI) and housekeeping loci (adk and fumC) but similar to that seen with another fimbrial adhesin of E. coli, papG-II, also implicated in extraintestinal infections. The increased diversity of the sink pool of adhesin genes is due to the increased richness of the haplotypes (the number of unique haplotypes), rather than their evenness (the extent of similarity in relative abundances). Taken together, this pattern supports a continuous emergence and extinction of the gene alleles adaptive to virulence sink habitats of E. coli, rather than a one-time change in the habitat conditions. Thus, ecological methods of species diversity analysis can be successfully adapted to characterize the emergence of microbial virulence in bacterial pathogens subject to source-sink dynamics. PMID:17177088

  10. Toward accurate high-throughput SNP genotyping in the presence of inherited copy number variation

    PubMed Central

    MacConaill, Laura E; Aldred, Micheala A; Lu, Xincheng; LaFramboise, Thomas

    2007-01-01

    Background The recent discovery of widespread copy number variation in humans has forced a shift away from the assumption of two copies per locus per cell throughout the autosomal genome. In particular, a SNP site can no longer always be accurately assigned one of three genotypes in an individual. In the presence of copy number variability, the individual may theoretically harbor any number of copies of each of the two SNP alleles. Results To address this issue, we have developed a method to infer a "generalized genotype" from raw SNP microarray data. Here we apply our approach to data from 48 individuals and uncover thousands of aberrant SNPs, most in regions that were previously unreported as copy number variants. We show that our allele-specific copy numbers follow Mendelian inheritance patterns that would be obscured in the absence of SNP allele information. The interplay between duplication and point mutation in our data shed light on the relative frequencies of these events in human history, showing that at least some of the duplication events were recurrent. Conclusion This new multi-allelic view of SNPs has a complicated role in disease association studies, and further work will be necessary in order to accurately assess its importance. Software to perform generalized genotyping from SNP array data is freely available online [1]. PMID:17608949

  11. HLA class I and II alleles and haplotypes in ethnic Northeast Thais.

    PubMed

    Romphruk, A V; Romphruk, A; Kongmaroeng, C; Klumkrathok, K; Paupairoj, C; Leelayuwat, C

    2010-06-01

    Allele frequencies (AFs) and haplotypic associations of human leukocyte antigen (HLA) class I and II were investigated in 400 unrelated, healthy, ethnic Northeast Thais. HLA-A, -B, -Cw, -DRB1 and -DQB1 were typed by polymerase chain reaction-sequence specific primer, -sequence specific oligonucleotide probe and -single-strand conformation polymorphism methods. In this population, 17 HLA-A, 26 HLA-B, 15 HLA-Cw, 26 HLA-DRB1 and 13 HLA-DQB1 alleles (or groups of alleles) were found. AFs > 10% included A*11 (23.3%), 24 (18.8%), 0207 (14.4%), 33 (11.5%), 0203 (10.6%); B*4601 (13.9%); Cw*07(01-03) (18.5%), 01 (15.9%), 04 (12.0%), 0304 (10.6%); DRB1*1502 (18.5%), 1202 (13.4%); DQB1*0502 (20.3%), 0501 (16.3%), 0301 (14.1%) and 02 (10.9%). The most common of 2-locus haplotypes included A*0207-B*4601 (9.3%), B*4601-Cw*01 (13.5%), B*5801-DRB1*0301 (5.8%) and DRB1*1502-DQB1*0501 (14.1%). Of the 49 five-locus HLA haplotypes identified, 24 were confirmed in 31 family studies: the most common being; A*33-Cw*0302-B*5801-DRB1*0301-DQB1*02 (4.6%), A*0207-Cw*01-B*4601-DRB1*09-DQB1*0303 (3.4%) and A*33-Cw*07(01-03)-B*44-DRB1*07-DQB1*02 (2.6%). Apparently, the HLA-B*46-carrying haplotype is fragmented in ethnic Northeast Thais, including seven haplotypes with different HLA-A and HLA-DR/DQ combinations. One of these haplotypes (A*11-Cw*01-B*4601-DRB1*1202-DQB1*0502) has not been reported in other Asians. The results indicated that there were marked differences in the distribution of HLA alleles and haplotypes between ethnic Northeast Thais and other ethnic groups in Southeast and East Asia. These results also dictate that future studies of HLA alleles and diseases need precise identification of ethnically and geographically matched controls. The HLA allele and haplotype analyses in this large sample provide baseline information on ethnic Northeast Thais for anthropological studies and for determining HLA allele/haplotype frequencies when searching for HLA-compatible donors for unrelated bone marrow transplantation. PMID:20230525

  12. Exploiting Hardy-Weinberg Equilibrium for Efficient Screening of Single SNP Associations from Case-Control Studies

    Microsoft Academic Search

    Jinbo Chen; Nilanjan Chatterjee

    2007-01-01

    In case-control studies, the assessment of the association between a binary disease outcome and a single nucleotide polymorphism (SNP) is often based on comparing the observed genotype distribution for the cases against that for the controls. In this article, we investigate an alternative analytic strategy in which the observed genotype frequencies of cases are compared against the expected genotype frequencies

  13. Familial Mediterranean fever (FMF) in Moroccan Jews: demonstration of a founder effect by extended haplotype analysis.

    PubMed

    Aksentijevich, I; Pras, E; Gruberg, L; Shen, Y; Holman, K; Helling, S; Prosen, L; Sutherland, G R; Richards, R I; Dean, M

    1993-09-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disease causing attacks of fever and serositis. The FMF gene (designated "MEF") is on 16p, with the gene order 16cen-D16S80-MEF-D16S94-D16S283-D16S291-++ +16pter. Here we report the association of FMF susceptibility with alleles as D16S94, D16S283, and D16S291 among 31 non-Ashkenazi Jewish families (14 Moroccan, 17 non-Moroccan). We observed highly significant associations at D16S283 and D16S291 among the Moroccan families. For the non-Moroccans, only the allelic association at D16S94 approached statistical significance. Haplotype analysis showed that 18/25 Moroccan FMF chromosomes, versus 0/21 noncarrier chromosomes, bore a specific haplotype for D16S94-D16S283-D16S291. Among non-Moroccans this haplotype was present in 6/26 FMF chromosomes versus 1/28 controls. Both groups of families are largely descended from Jews who fled the Spanish Inquisition. The strong haplotype association seen among the Moroccans is most likely a founder effect, given the recent origin and genetic isolation of the Moroccan Jewish community. The lower haplotype frequency among non-Moroccan carriers may reflect differences both in history and in population genetics. PMID:8102507

  14. Molecular analysis of PKU haplotypes in the population of southern Poland.

    PubMed

    Zygulska, M; Eigel, A; Aulehla-Scholz, C; Pietrzyk, J J; Horst, J

    1991-01-01

    Out of a population of 138,598 infants born in southern Poland between 1987 and 1989, and screened for phenylketonuria (PKU), 28 cases were ascertained probands and their parents were isolated and eight polymorphic restriction sites were analyzed within the phenylalanine hydroxylase gene region. Twenty-one different haplotypes (HT) were revealed, five of them representing new categories. The most common haplotypes among those carrying normal alleles were: HT1 (27.3%) and HT4 (11.4%). Within the group of haplotypes with mutant alleles the most frequent was HT2 (56.8%), whereas the frequency of this haplotype in other European populations, such as French, Danish and German, ranged from 12% to 24%. HT3, being the most common in Danish (38%), and relatively frequent in the other western European (13-14%) populations, appeared to be very rare in our sample (2.3%). The mutation of codon 408 (exon 12, C----T, Arg----Trp), which has been described to be tightly linked to HT2, was tested on amplified DNA by dot-blot hybridization. This mutation was found in 25 out of 44 proband chromosomes. In one case it was linked to HT5, in the remaining 24 to HT2. Our results confirm molecular heterogeneity of PKU haplotypes, as well as their significant interpopulation variation. PMID:1671770

  15. Familial Mediterranean Fever (FMF) in Moroccan Jews: Demonstration of a founder effect by extened haplotype analysis

    SciTech Connect

    Aksentijevich, I.; Pras, E.; Helling, S.; Prosen, L.; Kastner, D.L.; Gruberg, L.; Pras, M. (Heller Institute for Medical Research, Tel-Hashomer (Israel))

    1993-09-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disease causing attacks of fever and serositis. The FMF gene (designated MEF') is on 16p, with the gene order 16 cen-D16S80-MEF-D16S94-D16S283-D16S291-16pter. Here the authors report the association of FMF susceptibility with alleles at D16S94, D16S283, and D16S291 among 31 non-Ashkenazi Jewish families 14 Moroccan families. For the non-Moroccans, only the allelic association at D16S94 approached statistical significance. Haplotype analysis showed that 18/25 Moroccan FMF chromosomes, versus 0/21 noncarrier chromosomes, bore a specific haplotype for D16S94-D16S283-D16S291. Among non-Moroccans this haplotype was present in 6/26 FMF chromosomes versus 1/28 controls. Both groups of families are largely descended from Jews who fled the Spanish Inquisition. The strong haplotype association seen among the Moroccans is most likely a founder effect, given the recent origin and genetic isolation of the Moroccan Jewish community. The lowest haplotype frequency among non-Moroccan carriers may reflect differences both in history and in population genetics. 28 refs., 1 fig., 3 tabs.

  16. Haplotypes in the Dystrophin DNA Segment Point to a Mosaic Origin of Modern Human Diversity

    PubMed Central

    Zi?tkiewicz, Ewa; Yotova, Vania; Gehl, Dominik; Wambach, Tina; Arrieta, Isabel; Batzer, Mark; Cole, David E. C.; Hechtman, Peter; Kaplan, Feige; Modiano, David; Moisan, Jean-Paul; Michalski, Roman; Labuda, Damian

    2003-01-01

    Although Africa has played a central role in human evolutionary history, certain studies have suggested that not all contemporary human genetic diversity is of recent African origin. We investigated 35 simple polymorphic sites and one Tn microsatellite in an 8-kb segment of the dystrophin gene. We found 86 haplotypes in 1,343 chromosomes from around the world. Although a classical out-of-Africa topology was observed in trees based on the variant frequencies, the tree of haplotype sequences reveals three lineages accounting for present-day diversity. The proportion of new recombinants and the diversity of the Tn microsatellite were used to estimate the age of haplotype lineages and the time of colonization events. The lineage that underwent the great expansion originated in Africa prior to the Upper Paleolithic (27,000–56,000 years ago). A second group, of structurally distinct haplotypes that occupy a central position on the tree, has never left Africa. The third lineage is represented by the haplotype that lies closest to the root, is virtually absent in Africa, and appears older than the recent out-of-Africa expansion. We propose that this lineage could have left Africa before the expansion (as early as 160,000 years ago) and admixed, outside of Africa, with the expanding lineage. Contemporary human diversity, although dominated by the recently expanded African lineage, thus represents a mosaic of different contributions. PMID:14513410

  17. Modeling Haplotype Block Variation Using Markov Chains

    PubMed Central

    Greenspan, G.; Geiger, D.

    2006-01-01

    Models of background variation in genomic regions form the basis of linkage disequilibrium mapping methods. In this work we analyze a background model that groups SNPs into haplotype blocks and represents the dependencies between blocks by a Markov chain. We develop an error measure to compare the performance of this model against the common model that assumes that blocks are independent. By examining data from the International Haplotype Mapping project, we show how the Markov model over haplotype blocks is most accurate when representing blocks in strong linkage disequilibrium. This contrasts with the independent model, which is rendered less accurate by linkage disequilibrium. We provide a theoretical explanation for this surprising property of the Markov model and relate its behavior to allele diversity. PMID:16361244

  18. Multivariate Association Test Using Haplotype Trend Regression

    PubMed Central

    Pei, Yu-Fang; Zhang, Lei; Liu, Jianfeng; Deng, Hong-Wen

    2009-01-01

    Summary Genetic association analyses with haplotypes may be more powerful than analyses with single markers, under certain conditions. Furthermore, simultaneously considering multiple correlated traits may make use of additional information that would not be considered when analyzing individual traits. In this study, we propose a haplotype based test of association for multivariate quantitative traits in unrelated samples. Specifically, we extend a population based haplotype trend regression (HTR) approach to multivariate scenarios. We mainly focused on bivariate HTR, and the simulation results showed that the proposed method had correct pre-specified type-I error rates. The power of the proposed method was largely influenced by the size and source of correlation between variables, being greatest when correlation of a specific gene was opposite in sign to the residual correlation. PMID:19489754

  19. Detecting Structure of Haplotypes and Local Ancestry

    PubMed Central

    Guan, Yongtao

    2014-01-01

    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 ancestry of admixed individuals. Our method outperforms competing state-of-the-art methods, particularly for regions of small ancestral track lengths. Applying our method to Mexican samples in HapMap3, we found two regions on chromosomes 6 and 8 that show significant departure of local ancestry from the genome-wide average. A software package implementing the methods described in this article is freely available at http://bcm.edu/cnrc/mcmcmc. PMID:24388880

  20. MULTIPLEXING SCHEMES FOR GENERIC SNP GENOTYPING ASSAYS

    E-print Network

    Shamir, Ron

    MULTIPLEXING SCHEMES FOR GENERIC SNP GENOTYPING ASSAYS R. SHARAN International Computer Science yakhini@agilent.com. Abstract A generic genotyping assay utilizes a xed set of reagents, which with a genotyping experiment, it is desirable to design a set of experiments, which maximizes the number of SNPs

  1. MULTIPLEXING SCHEMES FOR GENERIC SNP GENOTYPING ASSAYS

    E-print Network

    Sharan, Roded

    MULTIPLEXING SCHEMES FOR GENERIC SNP GENOTYPING ASSAYS R. SHARAN International Computer Science yakhini@agilent.com. Abstract A generic genotyping assay utilizes a fixed set of reagents, which with a genotyping experiment, it is desirable to design a set of experiments, which maximizes the number of SNPs

  2. BUILDI NG A DEER SNP CHIP

    Microsoft Academic Search

    M. J. Bixley; J. F. Ward; R. Brauning; J. A. Archer; P. J. Fisher

    SUMMARY Advances in genomic sequencing programmes in livestock species such as cattle and sheep have enabled the building and application of large SNP (single nucleotide polymorphism) chips containing more than 50,000 markers. Applications include improved parentage and pedigree assignment as well as more accurate diversity and breed composition analysis. Further, genomewide selection (GWS) has been used to predict performance with

  3. Correcting Coalescent Analyses for Panel-Based SNP Ascertainment

    PubMed Central

    McGill, James R.; Walkup, Elizabeth A.; Kuhner, Mary K.

    2013-01-01

    Single-nucleotide polymorphism (SNP) data are routinely obtained by sequencing a region of interest in a small panel, constructing a chip with probes specific to sites found to vary in the panel, and using the chip to assay subsequent samples. The size of the chip is often reduced by removing low-frequency alleles from the set of SNPs. Using coalescent estimation of the scaled population size parameter, ?, as a test case, we demonstrate the loss of information inherent in this procedure and develop corrections for coalescent analysis of SNPs obtained via a panel. We show that more accurate ?-estimates can be recovered if the panel size is known, but at considerable computational cost as the panel individuals must be explicitly modeled in the analysis. We extend this technique to apply to the case where rare alleles have been omitted from the SNP panel. We find that when appropriate corrections for panel ascertainment and rare-allele omission are used, the biases introduced by ascertainment are largely correctable, but recovered estimates are less accurate than would be obtained with fully sequenced data. This method is then applied to recombinant multiple population data to investigate the effects of recombination and migration on the estimate of ?. PMID:23335334

  4. Haplotypic polymorphisms of the TNFB gene

    Microsoft Academic Search

    Lawrence J. Abraham; Daisy Chin Du; Kamyar Zahedi; Roger L. Dawkins; Alexander S. Whitehead

    1991-01-01

    The NTFB genes from two major histocomptibility complex (MHC) ancestral haplotypes have been compared. The genes carried by the ancestral haplotypes 8.1 (A1,B8,BfS,C4AQ0, C4B1,DR3) and 57.1 (A1,B57, BfS,C4A6,C4B1,DR7) were cloned and sequenced to determine the degree of polymorphism. In this report we show that the r e spective TNF genes are allelic and have unique nucleotide sequences. The data demonstrate

  5. 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. PMID:16341006

  6. Glucose-6-phosphate dehydrogenase deficiency in Portugal: biochemical and mutational profiles, heterogeneity, and haplotype association.

    PubMed

    Rodrigues, Maria-Odete; Freire, Ana Ponces; Martins, Gisela; Pereira, Júlia; Martins, Maria-do-Carmo; Monteiro, Carolino

    2002-01-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. This deficiency in erythrocytes has a prevalence of 0.51 +/- 0.109 in the Caucasoid male population of Portugal. The frequency for deficiency-conferring genes is 0.39% in the Portuguese population. In the herein study populations males from areas of Portugal presenting with the highest prevalence of G6PD deficiency (Castelo Branco, Setúbal, Faro, and Lisbon) as well as similar subjects located in the border Center/North area of the country (Viseu) have been analyzed for biochemical parameters and screened for mutations and haplotype-associated mutations commensurate with G6PD deficiency. Six intragenic restriction fragment length polymorphisms (RFLPs) were studied: exon 5, nt 376 A -->G, FokI; intron 5, nt 611 C--> G, PvuII; intron 8, nt 163 C--> T, BspHI; exon 10, nt 116 G --> A, PstI; exon 11, nt 1311 C--> T, BclI; and intron 11, nt 93 T -->C, NlaIII. New haplotypes were constructed with the inclusion of intron 11, nt 93 T--> C, NlaIII, and only 5 of 64 possible haplotypes were found to show a marked linkage disequilibrium for several RFLPs and also for mutations and specific haplotypes. The control population (n = 168 males) presented the G6PD B variant and corresponded to haplotypes I (- - + + - -), Ia (- - + + - +), and VIIa (- - + + + +), in 91.8, 2.3, and 5.9%, respectively. The PCR and sequencing analysis of extracted DNAs from the deficient G6PD group showed 48.6% (16/33) of individuals with the G6PD A- mutation, corresponding to haplotype VIa (+ + - + - +); 9% (3/33) with the Betica mutation and 18% (6/33) with the Santa Maria mutation, both of them associated with haplotype IVa (+ - - + \\- +); 6.1% (2/33) with the Mediterranean mutation associated with haplotype VIIa; 12.3% (4/33) with the Seattle mutation, 3.0% (1/33) with Gaohe mutation; and a new mutation, 3.0% (1/33), which we designated by G6PD Flores, all of them associated with haplotype I. PMID:12064920

  7. Haplotype combination of polymorphisms in the ADIPOQ gene promoter is associated with growth traits in Qinchuan cattle.

    PubMed

    Zhang, Liangzhi; Li, Mijie; Lai, Xinsheng; Yang, Mingjuan; Xu, Yao; Hua, Liushuai; Lan, Xianyong; Zhang, Chunlei; Chen, Hong

    2013-07-01

    Adiponectin modulates lipid and glucose metabolism in adipose tissues and is also related to bone metabolism. Polymorphisms in the ADIPOQ gene likely have an impact on growth traits in cattle. In this study, we examined the relationship between ADIPOQ polymorphisms and body measurement parameters in Chinese beef cattle. First, we sequenced ADIPOQ and 1.2 kb of DNA upstream of its promoter, and we found 14 polymorphisms. With the luciferase reporter assay, we showed that the two polymorphisms SNP PR_-135 A>G and PR_-68 G>C, which are located in the core region of promoter, influence promoter activity of ADIPOQ. Second, we identified three haplotypes involved in these two polymorphic sites: A (A-135/C-68), B (A-135/G-68), and C (G-135/G-68). Haplotypes B and C are major haplotypes in five Chinese populations of cattle (Qinchuan, Nanyang, Jiaxian, Hazakh, and Chinese Holstein). We studied the effects of these three haplotypes on body measurements, gene expression, and promoter activity, and we found that the genotypes are associated with body measurement parameters in Qinchuan cattle. Individuals with genotype BC (AG/GG) had significantly higher body height and heart girth than others, and this result may be interpreted by the following two observations. The promoter activity with haplotype B (A/G) is significantly higher than those with A (A/C) and C (G/G) in driving reporter gene transcription; the ADIPOQ mRNA level in cattle with genotype BC (AG/GG) is relatively lower than that in cattle with genotype BB (AA/GG). PMID:24099391

  8. QualitySNPng: a user-friendly SNP detection and visualization tool

    PubMed Central

    Nijveen, Harm; van Kaauwen, Martijn; Esselink, Danny G.; Hoegen, Brechtje; Vosman, Ben

    2013-01-01

    QualitySNPng is a new software tool for the detection and interactive visualization of single-nucleotide polymorphisms (SNPs). It uses a haplotype-based strategy to identify reliable SNPs; it is optimized for the analysis of current RNA-seq data; but it can also be used on genomic DNA sequences derived from next-generation sequencing experiments. QualitySNPng does not require a sequenced reference genome and delivers reliable SNPs for di- as well as polyploid species. The tool features a user-friendly interface, multiple filtering options to handle typical sequencing errors, support for SAM and ACE files and interactive visualization. QualitySNPng produces high-quality SNP information that can be used directly in genotyping by sequencing approaches for application in QTL and genome-wide association mapping as well as to populate SNP arrays. The software can be used as a stand-alone application with a graphical user interface or as part of a pipeline system like Galaxy. Versions for Windows, Mac OS X and Linux, as well as the source code, are available from http://www.bioinformatics.nl/QualitySNPng. PMID:23632165

  9. Beta-globin gene haplotypes among cameroonians and review of the global distribution: is there a case for a single sickle mutation origin in Africa?

    PubMed

    Bitoungui, Valentina J Ngo; Pule, Gift D; Hanchard, Neil; Ngogang, Jeanne; Wonkam, Ambroise

    2015-03-01

    Studies of hemoglobin S haplotypes in African subpopulations have potential implications for patient care and our understanding of genetic factors that have shaped the prevalence of sickle cell disease (SCD). We evaluated HBB gene cluster haplotypes in SCD patients from Cameroon, and reviewed the literature for a global distribution. We reviewed medical records to obtain pertinent socio-demographic and clinical features for 610 Cameroonian SCD patients, including hemoglobin electrophoresis and full blood counts. RFLP-PCR was used to determine the HBB gene haplotype on 1082 chromosomes. A systematic review of the current literature was undertaken to catalogue HBB haplotype frequencies in SCD populations around the world. Benin (74%; n=799) and Cameroon (19%; n=207) were the most prevalent haplotypes observed among Cameroonian patients. There was no significant association between HBB haplotypes and clinical life events, anthropometric measures, hematological parameters, or fetal hemoglobin (HbF) levels. The literature review of the global haplotype distributions was consistent with known historical migrations of the people of Africa. Previously reported data from Sudan showed a distinctly unusual pattern; all four classical haplotypes were reported, with an exceptionally high proportion of the Senegal, Cameroon, and atypical haplotypes. We did not observe any significant associations between HBB haplotype and SCD disease course in this cohort. Taken together, the data from Cameroon and from the wider literature suggest that a careful reassessment of African HBB haplotypes may shed further light on the evolutionary dynamics of the sickle allele, which could suggest a single origin of the sickle mutation. PMID:25748438

  10. A dynamic programming algorithm for haplotype block partitioning

    Microsoft Academic Search

    Kui Zhang; Minghua Deng; Ting Chen; Michael S. Waterman; Fengzhu Sun

    2002-01-01

    We develop a dynamic programming algorithm for haplotype block partitioning to minimize the number of representative single nucleotide polymorphisms (SNPs) required to account for most of the common haplotypes in each block. Any measure of haplotype quality can be used in the algorithm and of course the measure should depend on the specific application. The dynamic programming algorithm is applied

  11. Reconstructing Haplotypes from Genotypes in the Presence of Recombination

    E-print Network

    Goldschmidt, Christina

    Reconstructing Haplotypes from Genotypes in the Presence of Recombination HO Pui Shan Supervisors;Abstract This dissertation proposes a method of reconstructing haplotypes from genotypes in the presence of recombination events. Given a set of genotype sequences, our goal is to reconstruct a set of haplotype sequences

  12. Haplotype Inference by Entropy Minimization Ion Mandoiu1

    E-print Network

    Mandoiu, Ion

    haplotyping problem (PHP) is to infer the haplotypes from the genotypes of a large population; see [1, 2, 3 common haplotypes are evenly distributed in large populations. They also proposed a simple greedy entropy of the human population has become the next major target in genomics (http://www.hapmap.org/). The population

  13. Fast and Cheap Genome Wide Haplotype Construction via Optical Mapping

    Microsoft Academic Search

    Thomas S. Anantharaman; Venkatesh Mysore; Bud Mishra

    2005-01-01

    We describe an efficient algorithm to construct genome wide haplotype restriction maps of an individual by aligning single molecule DNA fragments collected with Optical Mapping technology. Using this algorithm and small amount of genomic material, we can construct the parental haplotypes for each diploid chromosome for any individual. Since such haplotype maps reveal the polymorphisms due to single nucleotide differences

  14. Tumor Necrosis Factor (TNF) Microsatellite Haplotypes in Relation to Extended

    E-print Network

    Alper, Chester A.

    ELSEVIER Tumor Necrosis Factor (TNF) Microsatellite Haplotypes in Relation to Extended Haplotypes involved in effector immune function 121 (complement proteins C2, C4, and factor B and tumor From from those of other extended haplotypes. Tumor necrosis factors (TNF) (Y 141 and p IS] are closely

  15. A New Statistical Method for Haplotype Reconstruction from Population Data

    Microsoft Academic Search

    Matthew Stephens; Nicholas J. Smith; Peter Donnelly

    2001-01-01

    Current routine genotyping methods typically do not provide haplotype information, which is essential for many analyses of fine-scale molecular-genetics data. Haplotypes can be obtained, at considerable cost, experimentally or (partially) through genotyping of additional family members. Alternatively, a statistical method can be used to infer phase and to reconstruct haplotypes. We present a new statistical method, applicable to genotype data

  16. Vitis Phylogenomics: Hybridization Intensities from a SNP Array Outperform Genotype Calls

    PubMed Central

    Miller, Allison J.; Matasci, Naim; Schwaninger, Heidi; Aradhya, Mallikarjuna K.; Prins, Bernard; Zhong, Gan-Yuan; Simon, Charles; Buckler, Edward S.; Myles, Sean

    2013-01-01

    Understanding relationships among species is a fundamental goal of evolutionary biology. Single nucleotide polymorphisms (SNPs) identified through next generation sequencing and related technologies enable phylogeny reconstruction by providing unprecedented numbers of characters for analysis. One approach to SNP-based phylogeny reconstruction is to identify SNPs in a subset of individuals, and then to compile SNPs on an array that can be used to genotype additional samples at hundreds or thousands of sites simultaneously. Although powerful and efficient, this method is subject to ascertainment bias because applying variation discovered in a representative subset to a larger sample favors identification of SNPs with high minor allele frequencies and introduces bias against rare alleles. Here, we demonstrate that the use of hybridization intensity data, rather than genotype calls, reduces the effects of ascertainment bias. Whereas traditional SNP calls assess known variants based on diversity housed in the discovery panel, hybridization intensity data survey variation in the broader sample pool, regardless of whether those variants are present in the initial SNP discovery process. We apply SNP genotype and hybridization intensity data derived from the Vitis9kSNP array developed for grape to show the effects of ascertainment bias and to reconstruct evolutionary relationships among Vitis species. We demonstrate that phylogenies constructed using hybridization intensities suffer less from the distorting effects of ascertainment bias, and are thus more accurate than phylogenies based on genotype calls. Moreover, we reconstruct the phylogeny of the genus Vitis using hybridization data, show that North American subgenus Vitis species are monophyletic, and resolve several previously poorly known relationships among North American species. This study builds on earlier work that applied the Vitis9kSNP array to evolutionary questions within Vitis vinifera and has general implications for addressing ascertainment bias in array-enabled phylogeny reconstruction. PMID:24236035

  17. Viability of in-house datamarting approaches for population genetics analysis of SNP genotypes

    PubMed Central

    Amigo, Jorge; Phillips, Christopher; Salas, Antonio; Carracedo, Ángel

    2009-01-01

    Background Databases containing very large amounts of SNP (Single Nucleotide Polymorphism) data are now freely available for researchers interested in medical and/or population genetics applications. While many of these SNP repositories have implemented data retrieval tools for general-purpose mining, these alone cannot cover the broad spectrum of needs of most medical and population genetics studies. Results To address this limitation, we have built in-house customized data marts from the raw data provided by the largest public databases. In particular, for population genetics analysis based on genotypes we have built a set of data processing scripts that deal with raw data coming from the major SNP variation databases (e.g. HapMap, Perlegen), stripping them into single genotypes and then grouping them into populations, then merged with additional complementary descriptive information extracted from dbSNP. This allows not only in-house standardization and normalization of the genotyping data retrieved from different repositories, but also the calculation of statistical indices from simple allele frequency estimates to more elaborate genetic differentiation tests within populations, together with the ability to combine population samples from different databases. Conclusion The present study demonstrates the viability of implementing scripts for handling extensive datasets of SNP genotypes with low computational costs, dealing with certain complex issues that arise from the divergent nature and configuration of the most popular SNP repositories. The information contained in these databases can also be enriched with additional information obtained from other complementary databases, in order to build a dedicated data mart. Updating the data structure is straightforward, as well as permitting easy implementation of new external data and the computation of supplementary statistical indices of interest. PMID:19344481

  18. A hidden Markov model for investigating recent positive selection through haplotype structure.

    PubMed

    Chen, Hua; Hey, Jody; Slatkin, Montgomery

    2015-02-01

    Recent positive selection can increase the frequency of an advantageous mutant rapidly enough that a relatively long ancestral haplotype will be remained intact around it. We present a hidden Markov model (HMM) to identify such haplotype structures. With HMM identified haplotype structures, a population genetic model for the extent of ancestral haplotypes is then adopted for parameter inference of the selection intensity and the allele age. Simulations show that this method can detect selection under a wide range of conditions and has higher power than the existing frequency spectrum-based method. In addition, it provides good estimate of the selection coefficients and allele ages for strong selection. The method analyzes large data sets in a reasonable amount of running time. This method is applied to HapMap III data for a genome scan, and identifies a list of candidate regions putatively under recent positive selection. It is also applied to several genes known to be under recent positive selection, including the LCT, KITLG and TYRP1 genes in Northern Europeans, and OCA2 in East Asians, to estimate their allele ages and selection coefficients. PMID:25446961

  19. ORIGINAL ARTICLE Conserved extended haplotypes discriminate

    E-print Network

    Alper, Chester A.

    with type 1 diabetes mellitus and celiac disease JR Bilbao1,2,9 , B Calvo1,9 , AM Aransay3 , A Martin and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD 2006 Keywords: conserved extended haplotypes; type 1 diabetes mellitus; celiac disease; HLA-DR3; single

  20. Digital genotyping and haplotyping with polymerase colonies

    E-print Network

    Church, George M.

    by cloning or somatic cell fusion. The results indicate that polony genotyping and haplotyping may play in the human population has the potential to greatly improve human health, both by predict- ing susceptibility to disease and guiding choice of therapy. The most common genetic variations in the human population

  1. An Arabidopsis haplotype map takes root

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Laying the foundation for an A. thaliana haplotype map, Clark et al.1 conducted a thorough array resequencing of 20 diverse A. thaliana genomes at single-base resolution. This provided a powerful catalog of genetic diversity, with more than 1 million SNPs and hypervariable regions (50-bp to >10-kb d...

  2. The Evolution of Isochores: Evidence From SNP Frequency Distributions

    Microsoft Academic Search

    Martin J. Lercher; Nick G. C. Smith; Adam Eyre-Walker; Laurence D. Hurst

    2002-01-01

    The large-scale systematic variation in nucleotide composition along mammalian and avian genomes has been a focus of the debate between neutralist and selectionist views of molecular evolution. Here we test whether the compositional variation is due to mutation bias using two new tests, which do not assume compositional equilibrium. In the first test we assume a standard population genetics model,

  3. Generation of SNP datasets for orangutan population genomics using improved reduced-representation sequencing and direct comparisons of SNP calling algorithms

    PubMed Central

    2014-01-01

    Background High-throughput sequencing has opened up exciting possibilities in population and conservation genetics by enabling the assessment of genetic variation at genome-wide scales. One approach to reduce genome complexity, i.e. investigating only parts of the genome, is reduced-representation library (RRL) sequencing. Like similar approaches, RRL sequencing reduces ascertainment bias due to simultaneous discovery and genotyping of single-nucleotide polymorphisms (SNPs) and does not require reference genomes. Yet, generating such datasets remains challenging due to laboratory and bioinformatical issues. In the laboratory, current protocols require improvements with regards to sequencing homologous fragments to reduce the number of missing genotypes. From the bioinformatical perspective, the reliance of most studies on a single SNP caller disregards the possibility that different algorithms may produce disparate SNP datasets. Results We present an improved RRL (iRRL) protocol that maximizes the generation of homologous DNA sequences, thus achieving improved genotyping-by-sequencing efficiency. Our modifications facilitate generation of single-sample libraries, enabling individual genotype assignments instead of pooled-sample analysis. We sequenced ~1% of the orangutan genome with 41-fold median coverage in 31 wild-born individuals from two populations. SNPs and genotypes were called using three different algorithms. We obtained substantially different SNP datasets depending on the SNP caller. Genotype validations revealed that the Unified Genotyper of the Genome Analysis Toolkit and SAMtools performed significantly better than a caller from CLC Genomics Workbench (CLC). Of all conflicting genotype calls, CLC was only correct in 17% of the cases. Furthermore, conflicting genotypes between two algorithms showed a systematic bias in that one caller almost exclusively assigned heterozygotes, while the other one almost exclusively assigned homozygotes. Conclusions Our enhanced iRRL approach greatly facilitates genotyping-by-sequencing and thus direct estimates of allele frequencies. Our direct comparison of three commonly used SNP callers emphasizes the need to question the accuracy of SNP and genotype calling, as we obtained considerably different SNP datasets depending on caller algorithms, sequencing depths and filtering criteria. These differences affected scans for signatures of natural selection, but will also exert undue influences on demographic inferences. This study presents the first effort to generate a population genomic dataset for wild-born orangutans with known population provenance. PMID:24405840

  4. Development and evaluation of the first high-throughput SNP array for common carp (Cyprinus carpio)

    PubMed Central

    2014-01-01

    Background A large number of single nucleotide polymorphisms (SNPs) have been identified in common carp (Cyprinus carpio) but, as yet, no high-throughput genotyping platform is available for this species. C. carpio is an important aquaculture species that accounts for nearly 14% of freshwater aquaculture production worldwide. We have developed an array for C. carpio with 250,000 SNPs and evaluated its performance using samples from various strains of C. carpio. Results The SNPs used on the array were selected from two resources: the transcribed sequences from RNA-seq data of four strains of C. carpio, and the genome re-sequencing data of five strains of C. carpio. The 250,000 SNPs on the resulting array are distributed evenly across the reference C.carpio genome with an average spacing of 6.6 kb. To evaluate the SNP array, 1,072 C. carpio samples were collected and tested. Of the 250,000 SNPs on the array, 185,150 (74.06%) were found to be polymorphic sites. Genotyping accuracy was checked using genotyping data from a group of full-siblings and their parents, and over 99.8% of the qualified SNPs were found to be reliable. Analysis of the linkage disequilibrium on all samples and on three domestic C.carpio strains revealed that the latter had the longer haplotype blocks. We also evaluated our SNP array on 80 samples from eight species related to C. carpio, with from 53,526 to 71,984 polymorphic SNPs. An identity by state analysis divided all the samples into three clusters; most of the C. carpio strains formed the largest cluster. Conclusions The Carp SNP array described here is the first high-throughput genotyping platform for C. carpio. Our evaluation of this array indicates that it will be valuable for farmed carp and for genetic and population biology studies in C. carpio and related species. PMID:24762296

  5. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Im, Kate M.; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y.; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M.; Fredericksen, Zachary; Pankratz, V. Shane; Guiducci, Candace; Crenshaw, Andrew; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Mai, Phuong L.; Greene, Mark H.; Piedmonte, Marion; Rubinstein, Wendy S.; Hogervorst, Frans B.; Rookus, Matti A.; Collée, J. Margriet; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Meijers-Heijboer, Hanne E. J.; Van Roozendaal, Cees E.; Caldes, Trinidad; Perez-Segura, Pedro; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Blecharz, Pawe?; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Barkardottir, Rosa B.; Montagna, Marco; D'Andrea, Emma; Devilee, Peter; Olopade, Olufunmilayo I.; Neuhausen, Susan L.; Peissel, Bernard; Bonanni, Bernardo; Peterlongo, Paolo; Singer, Christian F.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda Ewart; Caligo, Maria Adelaide; Beattie, Mary S.; Chan, Salina; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Phelan, Catherine; Narod, Steven; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary-Beth; Tung, Nadine; Hansen, Thomas v. O.; Osorio, Ana; Benitez, Javier; Durán, Mercedes; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare T.; Frost, Debra; Platte, Radka; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Paterson, Joan; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Laitman, Yael; Meindl, Alfons; Deissler, Helmut; Varon-Mateeva, Raymonda; Preisler-Adams, Sabine; Kast, Karin; Venat-Bouvet, Laurence; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.; Klein, Robert J.; Daly, Mark J.; Friedman, Eitan; Dean, Michael; Clark, Andrew G.; Altshuler, David M.; Antoniou, Antonis C.; Couch, Fergus J.; Offit, Kenneth; Gold, Bert

    2011-01-01

    Abstract Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage dis-equilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews. PMID:21597964

  6. Allele diversity for abiotic stress responsive candidate genes in chickpea reference set using gene based SNP markers.

    PubMed

    Roorkiwal, Manish; Nayak, Spurthi N; Thudi, Mahendar; Upadhyaya, Hari D; Brunel, Dominique; Mournet, Pierre; This, Dominique; Sharma, Prakash C; Varshney, Rajeev K

    2014-01-01

    Chickpea is an important food legume crop for the semi-arid regions, however, its productivity is adversely affected by various biotic and abiotic stresses. Identification of candidate genes associated with abiotic stress response will help breeding efforts aiming to enhance its productivity. With this objective, 10 abiotic stress responsive candidate genes were selected on the basis of prior knowledge of this complex trait. These 10 genes were subjected to allele specific sequencing across a chickpea reference set comprising 300 genotypes including 211 genotypes of chickpea mini core collection. A total of 1.3 Mbp sequence data were generated. Multiple sequence alignment (MSA) revealed 79 SNPs and 41 indels in nine genes while the CAP2 gene was found to be conserved across all the genotypes. Among 10 candidate genes, the maximum number of SNPs (34) was observed in abscisic acid stress and ripening (ASR) gene including 22 transitions, 11 transversions and one tri-allelic SNP. Nucleotide diversity varied from 0.0004 to 0.0029 while polymorphism information content (PIC) values ranged from 0.01 (AKIN gene) to 0.43 (CAP2 promoter). Haplotype analysis revealed that alleles were represented by more than two haplotype blocks, except alleles of the CAP2 and sucrose synthase (SuSy) gene, where only one haplotype was identified. These genes can be used for association analysis and if validated, may be useful for enhancing abiotic stress, including drought tolerance, through molecular breeding. PMID:24926299

  7. 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

  8. 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. PMID:25764907

  9. RadixHap: a radix tree-based heuristic for solving the single individual haplotyping problem.

    PubMed

    Wang, Tai-Chun; Taheri, Javid; Zomaya, Albert Y

    2015-01-01

    Single nucleotide polymorphism studies have recently received significant amount of attention from researchers in many life science disciplines. Previous researches indicated that a series of SNPs from the same chromosome, called haplotype, contains more information than individual SNPs. Hence, discovering ways to reconstruct reliable Single Individual Haplotypes becomes one of the core issues in the whole-genome research nowadays. However, obtaining sequence from current high-throughput sequencing technologies always contain inevitable sequencing errors and/or missing information. The SIH reconstruction problem can be formulated as bi-partitioning the input SNP fragment matrix into paternal and maternal sections to achieve minimum error correction; a problem that is proved to be NP-hard. In this study, we introduce a greedy approach, named RadixHap, to handle data sets with high error rates. The experimental results show that RadixHap can generate highly reliable results in most cases. Furthermore, the algorithm structure of RadixHap is particularly suitable for whole-genome scale data sets. PMID:25667383

  10. Strong association between microsatellites and an HLA-B, DR haplotype (B18-DR3): Implication for microsatellite evolution

    SciTech Connect

    Crouau-Roy, B.; Bouzekri, N.; Clayton, J. [CNRS, Toulouse (France)] [and others] [CNRS, Toulouse (France); and others

    1996-09-01

    The HLA haplotype B18-DR3 has a widespread geographical distribution, but has its greatest frequencies in Southern Europe, probably vestigial of the earliest populations of this region, particularly in the Pays Basque and Sardinia. This haplotype is of medical significance, being that most implicated as a factor of risk in insulin-dependent diabetes mellitus. In this study, the closely linked microsatellite markers (TNFa,b,c) in the region of the tumor necrosis factor (TNF) genes have been used in an attempt to subtype this haplotype in the two populations and/or in healthy and diabetic populations. A total of 79 HLA-B18-DR3 haplotypes were analyzed: 54 in Basques (12 from healthy individuals and 42 from diabetics or their first-degree relatives) and 25 in Sardinians (13 from healthy and 13 from diabetic individuals). The TNF haplotype a1-b5-c2 is completely associated with B18-DR3 in both populations. The homogeneity of the B18-DR3 haplotype in two ethnically pure populations implies stability in evolution, which suggest that the mutation rate of these microsatellite markers must be less than is usually assumed (i.e., {approximately} 5x10{sup {minus}6} per site per generation). Such markers should be powerful tools for studying genetic drift and admixture of populations, but it remains to be established whether this stability is a rule for all microsatellites in HLA haplotypes or whether or whether it is restricted to some microsatellites and/or some HLA haplotypes. The population genetics of those microsatellites associated with HLA B18-DR3 was also studied in a random sample of the Basque population. 44 refs., 3 tabs.

  11. Identification of single nucleotide polymorphisms within the mtDNA genome of the domestic dog to discriminate individuals with common HVI haplotypes.

    PubMed

    Imes, Donna L; Wictum, Elizabeth J; Allard, Marc W; Sacks, Benjamin N

    2012-09-01

    We sequenced the entire ?16 kb canine mitochondrial genome (mtGenome) of 100 unrelated domestic dogs (Canis lupus familiaris) and compared these to 246 published sequences to assess hypervariable region I (HVI) haplotype frequencies. We then used all available sequences to identify informative single nucleotide polymorphisms (SNPs) outside of the control region for use in further resolving mtDNA haplotypes corresponding to common HVI haplotypes. Haplotype frequencies in our data set were highly correlated with previous ones (e.g., F(ST)=0.02, r=0.90), suggesting the total data set reasonably reflected the broader dog population. A total of 128 HVI haplotypes was represented. The 10 most common HVI haplotypes (n=184 dogs) represented 53.3% of the sample. We identified a total 71 SNPs in the mtGenomes (external to the control region) that resolved the 10 most common HVI haplotypes into 63 mtGenome subhaplotypes. The random match probability of the dataset based solely on the HVI sequence was 4%, whereas the random match probability of the mtGenome subhaplotypes was <1%. Thus, the panel of 71 SNPs identified in this study represents a useful forensic tool to further resolve the identity of individual dogs from mitochondrial DNA (mtDNA). PMID:22436122

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

    PubMed

    Haaning Andersen, A D; Lange, M; Lillevang, S T

    2003-04-01

    The human chromosome region 2q33 including the three costimulatory molecules CD28, CTLA-4 and ICOS, has been subject to much attention due to its linkage to a number of autoimmune diseases. The search for the causal relationship of this linkage has revealed several polymorphisms, but no variations in the amino acid sequences, except for one polymorphism in the leader sequence of CTLA-4. In the present study, we examined the ICOS gene of an unrelated group of healthy donors from the Danish population. We were able to report 16 intronic SNP, one intronic G-insert and two repeat regions in intron 4, consistent with the [T]n and the [GT]n regions reported in a Japanese study. Putative haplotypes for the established SNP and repeat polymorphisms have been estimated by computational analysis. Sequencing of approximately 3500 bp of the upstream region of ICOS revealed an additional eight SNP of which two resided in putative NF-kB and Sp1 sites. In accordance with previous studies we detected no variations in the coding regions except for a rare polymorphism that was found in one donor in the last codon of exon 5, which lead to a heterozygous genotype, but no amino acid change. This suggests that regulation of transcription rather than protein structure could be a possible mechanism in the explanation of linkage. PMID:12753665

  13. Unique haplotypes in ant-attended aphids and widespread haplotypes in non-attended aphids

    PubMed Central

    Yao, Izumi; Kanbe, Takashi

    2012-01-01

    Aphid species within the genus Tuberculatus Mordvilko (Hemiptera: Aphididae) exhibit a variety of interactions with ants, ranging from close associations to non-attendance. A previous study indicated that despite wing possession, ant-attended Tuberculatus species exhibited low dispersal rates compared with non-attended species. This study examined if presence or absence of mutualistic interactions and habitat continuity of host plants affected intraspecific genetic diversity and genetic differentiation in mitochondrial DNA cytochrome oxidase I (COI) sequences. Sympatric ant-attended Tuberculatus quercicola (Matsumura) (Hemiptera: Aphididae) and non-attended Tuberculatus paiki Hille Ris Lambers (Hemiptera: Aphididae) were collected from the daimyo oak Quercus dentata Thunberg (Fagales: Fagaceae) in Japan and examined for haplotype variability. Seventeen haplotypes were identified in 568 T. quercicola individuals representing 23 populations and seven haplotypes in 425 T. paiki representing 19 populations. Haplotype diversity, which indicates the mean number of differences between all pairs of haplotypes in the sample, and nucleotide diversity were higher in T. quercicola than T. paiki. Analysis of molecular variance (AMOVA) showed higher genetic differentiation among populations within groups of T. quercicola (39.8%) than T. paiki (22.6%). The effects of attendant ant species on genetic differentiation in T. quercicola were not distinguishable from geographic factors. Despite low dispersal rates, host plant habitat continuity might facilitate widespread dispersal of a T. quercicola haplotype in Hokkaido. These results suggested that following T. quercicola colonization, gene flow among populations was limited, resulting in genetic drift within populations. However, frequent T. paiki dispersal is clearly evident by low genetic differentiation among populations within groups, resulting in lower haplotype diversity. PMID:23139889

  14. Interactions Between SNP Alleles at Multiple Loci and Variation in Skin Pigmentation in 122 Caucasians

    PubMed Central

    Anno, Sumiko; Abe, Takashi; Sairyo, Koichi; Kudo, Susumu; Yamamoto, Takushi; Ogata, Koretsugu; Goel, Vijay K.

    2007-01-01

    This study was undertaken to clarify the molecular basis for human skin color variation and the environmental adaptability to ultraviolet irradiation, with the ultimate goal of predicting the impact of changes in future environments on human health risk. One hundred twenty-two Caucasians living in Toledo, Ohio participated. Back and cheek skin were assayed for melanin as a quantitative trait marker. Buccal cell samples were collected and used for DNA extraction. DNA was used for SNP genotyping using the Masscode™ system, which entails two-step PCR amplification and a platform chemistry which allows cleavable mass spectrometry tags. The results show gene-gene interaction between SNP alleles at multiple loci (not necessarily on the same chromosome) contributes to inter-individual skin color variation while suggesting a high probability of linkage disequilibrium. Confirmation of these findings requires further study with other ethic groups to analyze the associations between SNP alleles at multiple loci and human skin color variation. Our overarching goal is to use remote sensing data to clarify the interaction between atmospheric environments and SNP allelic frequency and investigate human adaptability to ultraviolet irradiation. Such information should greatly assist in the prediction of the health effects of future environmental changes such as ozone depletion and increased ultraviolet exposure. If such health effects are to some extent predictable, it might be possible to prepare for such changes in advance and thus reduce the extent of their impact. PMID:19461972

  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

    SciTech Connect

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

    1991-02-15

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

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

    PubMed Central

    Palha, Teresinha; Gusmăo, Leonor; Ribeiro-Rodrigues, Elzemar; Guerreiro, Joăo 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

  17. The Wilson disease gene: Haplotypes and mutations

    SciTech Connect

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

    1994-09-01

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

  18. Patterns of haplotypes for 92 cystic fibrosis mutations: Variability, association and recurrence

    SciTech Connect

    Morral, N.; Llevadot, R.; Estivill, X. [I.R.O., Barcelona (Spain)] [and others

    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.

  19. Haplotype test reveals departure from neutrality in a segment of the white gene of Drosophila melanogaster

    SciTech Connect

    Kirby, D.A.; Stephan, W. [Univ. of Maryland, College Park, MD (United States)

    1995-12-01

    Restriction map studies previously revealed extensive linkage disequilibria in the transcriptional unit of the white locus in natural Drosophila melanogaster populations. To understand the causes of these disequilibria, we sequenced a 4722-bp region of the white gene from 15 lines of D. melanogaster and 1 line of Drosophila simulans. Statistical tests applied to the entire 4722-bp region do not reject neutrality. In contrast, a test for high-frequency haplotypes ({open_quotes}Haplotype test{close_quotes}) revealed an 834-bp segment, encompassing the 3{prime} end of intron 1 to the 3{prime} end of intron 2, in which the structure of variation deviates significantly from the predictions of a neutral equilibrium model. The variants in this 834-bp segment segregate as single haplotype blocks. We propose that these unusually large haplotype blocks are due to positive selection on polymorphisms within the white gene, including a replacement polymorphism, Arg{yields}Leu, within this segment. 45 refs., 4 figs., 1 tab.

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

    Microsoft Academic Search

    Chun-Mei Shen; Bo-Feng Zhu; Ya-Jun Deng; Shi-Hui Ye; Jiang-Wei Yan; Guang Yang; Hong-Dan Wang; Hai-Xia Qin; Qi-Zhao Huang; Jing-Jing Zhang; Igor Mokrousov

    2010-01-01

    BackgroundPrevious studies indicate that the frequency distributions of HLA alleles and haplotypes vary from one ethnic group to another or between the members of the same ethnic group living in different geographic areas. It is necessary and meaningful to study the high-resolution allelic and haplotypic distributions of HLA loci in different groups.Methodology\\/Principal FindingsHigh-resolution HLA typing for the Uyghur ethnic minority

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

    Microsoft Academic Search

    Maíra Carneiro Proietti; Paula Lara-Ruiz; Júlia Wiener Reisser; Luciano da Silva Pinto; Odir Antonio Dellagostin; Luis Fernando Marins

    2009-01-01

    We analyzed mtDNA control region sequences of green turtles (Chelonia mydas) from Arvoredo Island, a foraging ground in southern Brazil, and identified eight haplotypes. Of these, CM-A8 (64%) and CM-A5 (22%) were dominant, the remainder presenting low frequencies (< 5%). Haplotype (h) and nucleotide () diversities were 0.5570 0.0697 and 0.0021 0.0016, respectively. Exact tests of differentiation and AMOVA ST

  2. Assigning Linkage Haplotypes from Parent and Progeny Genotypes

    PubMed Central

    Nejati-Javaremi, A.; Smith, C.

    1996-01-01

    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 genotypes 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. PMID:8846912

  3. Using cDNA and genomic sequences as tools to develop SNP strategies in cassava ( Manihot esculenta Crantz)

    Microsoft Academic Search

    C. Lopez; B. Piégu; R. Cooke; M. Delseny; J. Tohme; V. Verdier

    2005-01-01

    Single nucleotide polymorphisms (SNP) are the most abundant type of DNA polymorphism found in animal and plant genomes. They provide an important new source of molecular markers that are useful in genetic mapping, map-based positional cloning, quantitative trait locus mapping and the assessment of genetic distances between individuals. Very little is known on the frequency of SNPs in cassava. We

  4. Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26.

    PubMed

    Ravel, C; El Houate, B; Chantot, S; Lourenço, D; Dumaine, A; Rouba, H; Bandyopadahyay, A; Radhakrishna, U; Das, B; Sengupta, S; Mandelbaum, J; Siffroi, J P; McElreavey, K

    2006-10-01

    Recently, mutations in the X-linked ubiquitin protease 26 (USP26) gene have been proposed to be associated with male infertility. In particular a 371insACA, 494T>C and 1423C>T haplotype, which results in a T123-124ins, L165S and H475Y amino acid change respectively, has been reported to be associated with Sertoli cell-only syndrome (SCOS) and an absence of sperm in the ejaculate. Here, we demonstrate that two of these changes actually correspond to the ancestral sequence of the gene and that the USP26 haplotype is present in significant frequencies in sub-Saharan African and South and East Asian populations, including in individuals with known fertility. This indicates that the allele is not associated with infertility. The pattern of frequency distribution of the derived haplotype (371delACA, 494T), which is present at high frequencies in most non-African populations could be interpreted as either a result of migration followed by simple genetic drift or alternatively as positive selection acting on the derived alleles. The latter hypothesis seems likely, because there is evidence of strong positive selection acting on the USP26 gene. PMID:16888075

  5. SNP Discovery in the Transcriptome of White Pacific Shrimp Litopenaeus vannamei by Next Generation Sequencing

    PubMed Central

    Yu, Yang; Wei, Jiankai; Zhang, Xiaojun; Liu, Jingwen; Liu, Chengzhang; Li, Fuhua; Xiang, Jianhai

    2014-01-01

    The application of next generation sequencing technology has greatly facilitated high throughput single nucleotide polymorphism (SNP) discovery and genotyping in genetic research. In the present study, SNPs were discovered based on two transcriptomes of Litopenaeus vannamei (L. vannamei) generated from Illumina sequencing platform HiSeq 2000. One transcriptome of L. vannamei was obtained through sequencing on the RNA from larvae at mysis stage and its reference sequence was de novo assembled. The data from another transcriptome were downloaded from NCBI and the reads of the two transcriptomes were mapped separately to the assembled reference by BWA. SNP calling was performed using SAMtools. A total of 58,717 and 36,277 SNPs with high quality were predicted from the two transcriptomes, respectively. SNP calling was also performed using the reads of two transcriptomes together, and a total of 96,040 SNPs with high quality were predicted. Among these 96,040 SNPs, 5,242 and 29,129 were predicted as non-synonymous and synonymous SNPs respectively. Characterization analysis of the predicted SNPs in L. vannamei showed that the estimated SNP frequency was 0.21% (one SNP per 476 bp) and the estimated ratio for transition to transversion was 2.0. Fifty SNPs were randomly selected for validation by Sanger sequencing after PCR amplification and 76% of SNPs were confirmed, which indicated that the SNPs predicted in this study were reliable. These SNPs will be very useful for genetic study in L. vannamei, especially for the high density linkage map construction and genome-wide association studies. PMID:24498047

  6. Melting Curve SNP (McSNP) Genotyping: a Useful Approach for Diallelic Genotyping in Forensic Science

    Microsoft Academic Search

    Jian Ye; Esteban J. Parra; Donna M. Sosnoski; Kevin Hiester; P. A. Underhill; Mark D. Shriver

    The increasing availability of Single Nucleotide Polymorphisms (SNPs) and Deletion\\/Insertion Polymorphisms (DIPs), as well as the outstanding progress in SNP genotyping tech- nologies, will impact forensics profoundly. We have developed a new method for genotyping SNPs and DIPs, which is based on the determination of melting curve profiles of amplified DNA in solu- tion. We have termed this method Melting

  7. A genome-wide association study of production traits in a commercial population of Large White pigs: evidence of haplotypes affecting meat quality

    PubMed Central

    2014-01-01

    Background Numerous quantitative trait loci (QTL) have been detected in pigs over the past 20 years using microsatellite markers. However, due to the low density of these markers, the accuracy of QTL location has generally been poor. Since 2009, the dense genome coverage provided by the Illumina PorcineSNP60 BeadChip has made it possible to more accurately map QTL using genome-wide association studies (GWAS). Our objective was to perform high-density GWAS in order to identify genomic regions and corresponding haplotypes associated with production traits in a French Large White population of pigs. Methods Animals (385 Large White pigs from 106 sires) were genotyped using the PorcineSNP60 BeadChip and evaluated for 19 traits related to feed intake, growth, carcass composition and meat quality. Of the 64 432 SNPs on the chip, 44 412 were used for GWAS with an animal mixed model that included a regression coefficient for the tested SNPs and a genomic kinship matrix. SNP haplotype effects in QTL regions were then tested for association with phenotypes following phase reconstruction based on the Sscrofa10.2 pig genome assembly. Results Twenty-three QTL regions were identified on autosomes and their effects ranged from 0.25 to 0.75 phenotypic standard deviation units for feed intake and feed efficiency (four QTL), carcass (12 QTL) and meat quality traits (seven QTL). The 10 most significant QTL regions had effects on carcass (chromosomes 7, 10, 16, 17 and 18) and meat quality traits (two regions on chromosome 1 and one region on chromosomes 8, 9 and 13). Thirteen of the 23 QTL regions had not been previously described. A haplotype block of 183 kb on chromosome 1 (six SNPs) was identified and displayed three distinct haplotypes with significant (0.0001?SNP60 BeadChip enabled the detection of 23 QTL regions that affect feed consumption, carcass and meat quality traits in a LW population, of which 13 were novel QTL. The proportionally larger number of QTL found for meat quality traits suggests a specific opportunity for improving these traits in the pig by genomic selection. PMID:24528607

  8. Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

    PubMed Central

    Weickert, C S; Tiwari, Y; Schofield, P R; Mowry, B J; Fullerton, J M

    2012-01-01

    Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type I–IV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (?2=7.815; P=0.05). The average nucleotide diversity (?=10.0 × 10?4) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (?(case)=13.2 × 10?4; ?(control)=10.0 × 10?4). The specific HapICE risk haplotype was associated with increased type III mRNA (F=3.76, P=0.028), which in turn, was correlated with an earlier age of onset (r=?0.343, P=0.038). We found a novel intronic five-SNP haplotype ?730?kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia. PMID:22832904

  9. 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; Previderč, 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 be discriminated by the whole set of 13 RM Y-STRs, which was very close to the theoretically expected estimate of 19.5% given the mutation rates of the markers used. Results obtained from a high-coverage Italian haplotype dataset confirm on the regional scale the exceptional ability of RM Y-STRs to resolve male lineages previously observed globally, and attest the unsurpassed value of RM Y-STRs for male-relative differentiation purposes. PMID:25457630

  10. Coverage and efficiency in current SNP chips.

    PubMed

    Ha, Ngoc-Thuy; Freytag, Saskia; Bickeboeller, Heike

    2014-09-01

    To answer the question as to which commercial high-density SNP chip covers most of the human genome given a fixed budget, we compared the performance of 12 chips of different sizes released by Affymetrix and Illumina for the European, Asian, and African populations. These include Affymetrix' relatively new population-optimized arrays, whose SNP sets are each tailored toward a specific ethnicity. Our evaluation of the chips included the use of two measures, efficiency and cost-benefit ratio, which we developed as supplements to genetic coverage. Unlike coverage, these measures factor in the price of a chip or its substitute size (number of SNPs on chip), allowing comparisons to be drawn between differently priced chips. In this fashion, we identified the Affymetrix population-optimized arrays as offering the most cost-effective coverage for the Asian and African population. For the European population, we established the Illumina Human Omni 2.5-8 as the preferred choice. Interestingly, the Affymetrix chip tailored toward an Eastern Asian subpopulation performed well for all three populations investigated. However, our coverage estimates calculated for all chips proved much lower than those advertised by the producers. All our analyses were based on the 1000 Genome Project as reference population. PMID:24448550

  11. Bayesian modeling of haplotype effects in multiparent populations.

    PubMed

    Zhang, Zhaojun; Wang, Wei; Valdar, William

    2014-09-01

    A general Bayesian model, Diploffect, is described for estimating the effects of founder haplotypes at quantitative trait loci (QTL) detected in multiparental genetic populations; such populations include the Collaborative Cross (CC), Heterogeneous Socks (HS), and many others for which local genetic variation is well described by an underlying, usually probabilistically inferred, haplotype mosaic. Our aim is to provide a framework for coherent estimation of haplotype and diplotype (haplotype pair) effects that takes into account the following: uncertainty in haplotype composition for each individual; uncertainty arising from small sample sizes and infrequently observed haplotype combinations; possible effects of dominance (for noninbred subjects); genetic background; and that provides a means to incorporate data that may be incomplete or has a hierarchical structure. Using the results of a probabilistic haplotype reconstruction as prior information, we obtain posterior distributions at the QTL for both haplotype effects and haplotype composition. Two alternative computational approaches are supplied: a Markov chain Monte Carlo sampler and a procedure based on importance sampling of integrated nested Laplace approximations. Using simulations of QTL in the incipient CC (pre-CC) and Northport HS populations, we compare the accuracy of Diploffect, approximations to it, and more commonly used approaches based on Haley-Knott regression, describing trade-offs between these methods. We also estimate effects for three QTL previously identified in those populations, obtaining posterior intervals that describe how the phenotype might be affected by diplotype substitutions at the modeled locus. PMID:25236455

  12. Bayesian Modeling of Haplotype Effects in Multiparent Populations

    PubMed Central

    Zhang, Zhaojun; Wang, Wei; Valdar, William

    2014-01-01

    A general Bayesian model, Diploffect, is described for estimating the effects of founder haplotypes at quantitative trait loci (QTL) detected in multiparental genetic populations; such populations include the Collaborative Cross (CC), Heterogeneous Socks (HS), and many others for which local genetic variation is well described by an underlying, usually probabilistically inferred, haplotype mosaic. Our aim is to provide a framework for coherent estimation of haplotype and diplotype (haplotype pair) effects that takes into account the following: uncertainty in haplotype composition for each individual; uncertainty arising from small sample sizes and infrequently observed haplotype combinations; possible effects of dominance (for noninbred subjects); genetic background; and that provides a means to incorporate data that may be incomplete or has a hierarchical structure. Using the results of a probabilistic haplotype reconstruction as prior information, we obtain posterior distributions at the QTL for both haplotype effects and haplotype composition. Two alternative computational approaches are supplied: a Markov chain Monte Carlo sampler and a procedure based on importance sampling of integrated nested Laplace approximations. Using simulations of QTL in the incipient CC (pre-CC) and Northport HS populations, we compare the accuracy of Diploffect, approximations to it, and more commonly used approaches based on Haley–Knott regression, describing trade-offs between these methods. We also estimate effects for three QTL previously identified in those populations, obtaining posterior intervals that describe how the phenotype might be affected by diplotype substitutions at the modeled locus. PMID:25236455

  13. Altered transmission of maternal angiotensin II receptor haplotypes in fetal growth restriction.

    PubMed

    Tower, Clare; Chappell, Sally; Acharya, Meera; Crane, Richard; Szolin, Stephanie; Symonds, Lyneth; Chevins, Helen; Kalsheker, Noor; Baker, Philip; Morgan, Linda

    2006-02-01

    Fetal growth restriction (FGR) predisposes to significant short- and long-term health problems. Epidemiological studies have suggested a role for inherited factors in its pathogenesis. The angiotensin II receptor genes, AGTR1 and AGTR2, are candidate genes because they mediate processes that are important for placentation. This study investigated AGTR1 and AGTR2 haplotypes and genotypes in FGR. A total of 107 families (father, mother, and baby) with FGR, and 101 families with normal pregnancies were genotyped at five sites in AGTR1 and six sites across AGTR2. All of the participants were white western Europeans. FGR was identified antenatally by ultrasound scans and confirmed postnatally by correcting the birth weight centile for gestation, infant sex, maternal height, weight, and parity. Fetal genes were investigated using transmission disequilibrium testing (TDT), and a case-control comparison of maternal haplotypes was conducted. FGR was associated with maternal (but not paternal) transmission of the AGTR1 haplotype (GenBank AF245699.1) g.4955T, g.5052T, g.5245C, g.5612A, and haplotype g.4955T, g.5052T, g.5245T, g.5612A. Haplotype g.4955A, g.5052G, g.5245T, g.5612G was undertransmitted (P = 0.002). TDT of the AGTR1 genotype showed undertransmission of maternal AGTR1 genotypes g.4955T>A (odds ratio (OR), 0.34 (95% confidence interval (CI), 0.14-0.86); P = 0.02), g.5052T>G (OR, 0.18 (0.06-0.48); P<0.001), and g.5612A>G (OR, 0.21 (0.08-0.55); P < 0.001) in FGR. There were no differences in maternal haplotype frequencies between normal pregnancy and FGR for AGTR1 or AGTR2 (P > 0.10). This is the first study to show distortion of transmission of maternal AGTR1 haplotypes in FGR, which suggests that this gene plays a role in FGR. In particular, maternal-fetal gene sharing may be an important factor. PMID:16395664

  14. Functional promoter haplotypes of interleukin-18 condition susceptibility to severe malarial anemia and childhood mortality.

    PubMed

    Anyona, Samuel B; Kempaiah, Prakasha; Raballah, Evans; Ouma, Collins; Were, Tom; Davenport, Gregory C; Konah, Stephen N; Vulule, John M; Hittner, James B; Gichuki, Charity W; Ong'echa, John M; Perkins, Douglas J

    2011-12-01

    Severe malarial anemia (SMA) is a leading cause of morbidity and mortality in children residing in regions where Plasmodium falciparum transmission is holoendemic. Although largely unexplored in children with SMA, interleukin-18 (IL-18) is important for regulating innate and acquired immunity in inflammatory and infectious diseases. As such, we selected two functional single-nucleotide polymorphisms (SNPs) in the IL-18 promoter (-137G?C [rs187238] and -607C?A [rs1946518]) whose haplotypes encompass significant genetic variation due to the presence of strong linkage disequilibrium among these variants. The relationship between the genotypes/haplotypes, SMA (hemoglobin [Hb], <5.0 g/dl], and longitudinal clinical outcomes were then investigated in Kenyan children (n = 719). Multivariate logistic regression analyses controlling for age, gender, sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency, HIV-1, and bacteremia revealed that carriage of the -607AA genotype was associated with protection against SMA (odds ratio [OR] = 0.440 [95% confidence interval {CI} = 0.21 to 0.90], P = 0.031) in children with acute infection. In contrast, carriers of the -137G/-607C (GC) haplotype had increased susceptibility to SMA (OR = 2.050 [95% CI = 1.04 to 4.05], P = 0.039). Measurement of IL-18 gene expression in peripheral blood leukocytes demonstrated that elevated IL-18 transcripts were associated with reduced hemoglobin concentrations (? = -0.293, P = 0.010) and that carriers of the "susceptible" GC haplotype had elevated IL-18 transcripts (P = 0.026). Longitudinal investigation of clinical outcomes over a 3-year follow-up period revealed that carriers of the rare CC haplotype (?1% frequency) had 5.76 times higher mortality than noncarriers (P = 0.001). Results presented here demonstrate that IL-18 promoter haplotypes that condition elevated IL-18 gene products during acute infection are associated with increased risk of SMA. Furthermore, carriage of the rare CC haplotype significantly increases the risk of childhood mortality. PMID:21969001

  15. A 34-plex autosomal SNP single base extension assay for ancestry investigations.

    PubMed

    Phillips, C; Fondevila, M; Lareau, Maria Victoria

    2012-01-01

    Ancestry inference based on autosomal markers remains a niche approach in forensic analysis: most laboratories feel more secure with a review of the cumulative STR profile frequencies in a range of relevant populations with the possible additional analysis of mitochondrial and/or Y-chromosome variability. However, a proportion of autosomal single nucleotide polymorphisms (SNPs) show very well-differentiated allele frequencies among global population-groups. Furthermore, such ancestry informative marker SNPs (AIM-SNPs) lend themselves to relatively straightforward typing with short-amplicon PCR and multiplexed single base extension reactions using the same capillary electrophoresis detectors required for the sequencing and STR genotyping of mainstream forensic markers. In this chapter, we describe a 34 AIM-SNP multiplex that is robust enough for the analysis of challenging, often highly degraded DNA typical of much of routine forensic casework. We also outline in detail the in-silico procedures necessary for collecting parental population reference data from the SPSmart SNP databases and performing ancestry inference of single AIM-SNP profiles or large-scale population data using the companion ancestry analysis website of Snipper. Two casework examples are described that show, in both cases, that an inference of likely ancestry using AIM-SNPs helped the identification of highly degraded skeletal material. PMID:22139656

  16. A SNP Haplotype Associated with a gene resistant to Xanthomonas axonopodis pv. malvacearum in Upland Cotton (Gossyium hirsutum L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An F5 population of 285 families with each tracing back to a different F2 plant , derived from a cotton bacterial blight resistant line ‘DeltaOpal’ and a susceptible line ‘DP388’, was artificially inoculated with bacterial blight race 18 (Xanthomonas campestris pv. Malvacearum) to assay their resist...

  17. SNP and Haplotype Analysis of the Tryptophan Hydroxylase 2 Gene in Alcohol-Dependent Patients and Alcohol-Related Suicide

    Microsoft Academic Search

    Peter Zill; Ulrich W Preuss; Gabrielle Koller; Brigitta Bondy; Michael Soyka

    2007-01-01

    Several lines of evidence indicate that disturbances of the central serotonergic system are involved in the pathophysiology of alcohol dependence and suicidal behavior. Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate limiting synthesis of neuronal serotonin. Genetic variations in the TPH2 gene have been associated with

  18. Molecular and genetic analyses of four nonfunctional S haplotype variants derived from a common ancestral S haplotype identified in sour cherry (Prunus cerasus L.).

    PubMed

    Tsukamoto, Tatsuya; Hauck, Nathanael R; Tao, Ryutaro; Jiang, Ning; Iezzoni, Amy F

    2010-02-01

    Tetraploid sour cherry (Prunus cerasus) has an S-RNase-based gametophytic self-incompatibility (GSI) system; however, individuals can be either self-incompatible (SI) or self-compatible (SC). Unlike the situation in the Solanaceae, where self-compatibility accompanying polyploidization is often due to the compatibility of heteroallelic pollen, the genotype-dependent loss of SI in sour cherry is due to the compatibility of pollen containing two nonfunctional S haplotypes. Sour cherry individuals with the S(4)S(6)S(36a)S(36b) genotype are predicted to be SC, as only pollen containing both nonfunctional S(36a) and S(36b) haplotypes would be SC. However, we previously found that individuals of this genotype were SI. Here we describe four nonfunctional S(36) variants. Our molecular analyses identified a mutation that would confer loss of stylar S function for one of the variants, and two alterations that might cause loss of pollen S function for all four variants. Genetic crosses showed that individuals possessing two nonfunctional S(36) haplotypes and two functional S haplotypes have reduced self-fertilization due to a very low frequency of transmission of the one pollen type that would be SC. Our finding that the underlying mechanism limiting successful transmission of genetically compatible gametes does not involve GSI is consistent with our previous genetic model for Prunus in which heteroallelic pollen is incompatible. This provides a unique case in which breakdown of SI does not occur despite the potential to generate SC pollen genotypes. PMID:19917768

  19. Molecular and Genetic Analyses of Four Nonfunctional S Haplotype Variants Derived from a Common Ancestral S Haplotype Identified in Sour Cherry (Prunus cerasus L.)

    PubMed Central

    Tsukamoto, Tatsuya; Hauck, Nathanael R.; Tao, Ryutaro; Jiang, Ning; Iezzoni, Amy F.

    2010-01-01

    Tetraploid sour cherry (Prunus cerasus) has an S-RNase-based gametophytic self-incompatibility (GSI) system; however, individuals can be either self-incompatible (SI) or self-compatible (SC). Unlike the situation in the Solanaceae, where self-compatibility accompanying polyploidization is often due to the compatibility of heteroallelic pollen, the genotype-dependent loss of SI in sour cherry is due to the compatibility of pollen containing two nonfunctional S haplotypes. Sour cherry individuals with the S4S6S36aS36b genotype are predicted to be SC, as only pollen containing both nonfunctional S36a and S36b haplotypes would be SC. However, we previously found that individuals of this genotype were SI. Here we describe four nonfunctional S36 variants. Our molecular analyses identified a mutation that would confer loss of stylar S function for one of the variants, and two alterations that might cause loss of pollen S function for all four variants. Genetic crosses showed that individuals possessing two nonfunctional S36 haplotypes and two functional S haplotypes have reduced self-fertilization due to a very low frequency of transmission of the one pollen type that would be SC. Our finding that the underlying mechanism limiting successful transmission of genetically compatible gametes does not involve GSI is consistent with our previous genetic model for Prunus in which heteroallelic pollen is incompatible. This provides a unique case in which breakdown of SI does not occur despite the potential to generate SC pollen genotypes. PMID:19917768

  20. Single-tube real-time multiple allele-specific PCR for genotyping chicken Mx gene G2032A SNP.

    PubMed

    Ye, X; Zhang, Y; Tan, Z; Li, K

    2010-06-01

    1. A non-synonymous, single nucleotide polymorphism (G to A) at position 2032 (Ser 631 Asn) of the chicken Mx gene has been demonstrated to be related to resistance to antiviral activity. This study developed a new real-time PCR-based allelic discrimination assay for the rapid genotyping of the chicken Mx gene G2032A SNP. The distribution of the Mx gene G2032A SNP genotypes and the allele frequencies of A and G alleles among different chicken breed populations were screened with the use of this method. 2. We combined previously described allele-specific PCR and SYBR Green I-based real-time PCR melting curve analysis with a novel primer design strategy. A pair of outer nested primers was designed to amplify a fragment containing the SNP site, and two 3'-specific, allele-specific primers were combined with the outer primers to amplify SNP-specific fragments. Genotypes were identified based on the characteristic melting temperature of the SNP-specific fragments. 3. Genotyping assignments were successfully performed on samples from 8 chicken breeds, which were analysed by agarose gel electrophoresis of the PCR products and compared with results obtained from the direct sequencing of the outer primer amplicon. Five native breeds from Southern China carried a relatively higher frequency of the resistant A allele than the three commercial chicken lines. 4. This single-tube real-time multiplex allele-specific PCR assay is rapid, reliable, sensitive and easy to perform. It is appropriate for high-throughput sample analysis in large population-based Mx SNP genotyping studies. PMID:20680871

  1. Accelerating genetic improvement with SNP chips and DNA sequencing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The development of high-density single nucleotide polymorphism (SNP) assays is expected to have a profound impact on genetic progress in the U.S. dairy industry. In the 16 months since its initial availability, the Illumina BovineSNP50 BeadChip has been used to genotype nearly 20,000 Holsteins. Thes...

  2. INVESTIGATION An SNP-Based Linkage Map for Zebrafish Reveals

    E-print Network

    Broman, Karl W.

    INVESTIGATION An SNP-Based Linkage Map for Zebrafish Reveals Sex Determination Loci Kevin M in teleost fish. In the common zebrafish model organism, heteromorphic sex chromosomes are not observed-wide linkage study of sex determination in zebrafish using a novel SNP genetic map. We identified loci

  3. Large-Scale SNP Marker Development and Genotyping in Oat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, our goals are to develop genome-wide SNP markers using next generation sequencing technologies and to apply a highly parallel SNP genotyping system developed by Illumina for genetics and breeding applications in oat. The large amount of DNA sequence sources generated from cDNAs and Di...

  4. Single nucleotide polymorphism (SNP) variation of wolves (Canis lupus) in Southeast Alaska and comparison with wolves, dogs, and coyotes in North America.

    PubMed

    Cronin, Matthew A; Cánovas, Angela; Bannasch, Danika L; Oberbauer, Anita M; Medrano, Juan F

    2015-01-01

    There is considerable interest in the genetics of wolves (Canis lupus) because of their close relationship to domestic dogs (C. familiaris) and the need for informed conservation and management. This includes wolf populations in Southeast Alaska for which we determined genotypes of 305 wolves at 173662 single nucleotide polymorphism (SNP) loci. After removal of invariant and linked SNP, 123801 SNP were used to quantify genetic differentiation of wolves in Southeast Alaska and wolves, coyotes (C. latrans), and dogs from other areas in North America. There is differentiation of SNP allele frequencies between the species (wolves, coyotes, and dogs), although differentiation is relatively low between some wolf and coyote populations. There are varying levels of differentiation among populations of wolves, including low differentiation of wolves in interior Alaska, British Columbia, and the northern US Rocky Mountains. There is considerable differentiation of SNP allele frequencies of wolves in Southeast Alaska from wolves in other areas. However, wolves in Southeast Alaska are not a genetically homogeneous group and there are comparable levels of genetic differentiation among areas within Southeast Alaska and between Southeast Alaska and other geographic areas. SNP variation and other genetic data are discussed regarding taxonomy and management. PMID:25429025

  5. 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

  6. Restricted dog leucocyte antigen (DLA) class II haplotypes and genotypes in Beagles

    PubMed Central

    Soutter, Francesca; Kennedy, Lorna J.; Ollier, William E.R.; Solano-Gallego, Laia; Catchpole, Brian

    2015-01-01

    Beagles are commonly used in vaccine trials as part of the regulatory approval process. Genetic restriction within this breed and the impact this might have on vaccine responses are rarely considered. This study was designed to characterise diversity of dog leucocyte antigen (DLA) class II genes in a breeding colony of laboratory Beagles, whose offspring are used in vaccine studies. DLA haplotypes were determined by PCR and sequence-based typing from genomic DNA extracted from blood. Breeding colony Beagles had significantly different DLA haplotype frequencies in comparison with pet Beagles and both groups showed limited DLA diversity. Restricted DLA class II genetic variability within Beagles might result in selective antigen presentation and vaccine responses that are not necessarily representative of those seen in other dog breeds. PMID:25634081

  7. Atomic Force Microscopy for DNA SNP Identification

    NASA Astrophysics Data System (ADS)

    Valbusa, Ugo; Ierardi, Vincenzo

    The knowledge of the effects of single-nucleotide polymorphisms (SNPs) in the human genome greatly contributes to better comprehension of the relation between genetic factors and diseases. Sequence analysis of genomic DNA in different individuals reveals positions where variations that involve individual base substitutions can occur. Single-nucleotide polymorphisms are highly abundant and can have different consequences at phenotypic level. Several attempts were made to apply atomic force microscopy (AFM) to detect and map SNP sites in DNA strands. The most promising approach is the study of DNA mutations producing heteroduplex DNA strands and identifying the mismatches by means of a protein that labels the mismatches. MutS is a protein that is part of a well-known complex of mismatch repair, which initiates the process of repairing when the MutS binds to the mismatched DNA filament. The position of MutS on the DNA filament can be easily recorded by means of AFM imaging.

  8. Y chromosome haplotype diversity of domestic sheep (Ovis aries) in northern Eurasia.

    PubMed

    Zhang, Min; Peng, Wei-Feng; Yang, Guang-Li; Lv, Feng-Hua; Liu, Ming-Jun; Li, Wen-Rong; Liu, Yong-Gang; Li, Jin-Quan; Wang, Feng; Shen, Zhi-Qiang; Zhao, Sheng-Guo; Hehua, Eer; Marzanov, Nurbiy; Murawski, Maziek; Kantanen, Juha; Li, Meng-Hua

    2014-12-01

    Variation in two SNPs and one microsatellite on the Y chromosome was analyzed in a total of 663 rams representing 59 breeds from a large geographic range in northern Eurasia. SNPA-oY1 showed the highest allele frequency (91.55%) across the breeds, whereas SNPG-oY1 was present in only 56 samples. Combined genotypes established seven haplotypes (H4, H5, H6, H7, H8, H12 and H19). H6 dominated in northern Eurasia, and H8 showed the second-highest frequency. H4, which had been earlier reported to be absent in European breeds, was detected in one European breed (Swiniarka), whereas H7, which had been previously identified to be unique to European breeds, was present in two Chinese breeds (Ninglang Black and Large-tailed Han), one Buryatian (Transbaikal Finewool) and two Russian breeds (North Caucasus Mutton-Wool and Kuibyshev). H12, which had been detected only in Turkish breeds, was also found in Chinese breeds in this work. An overall low level of haplotype diversity (median h = 0.1288) was observed across the breeds with relatively higher median values in breeds from the regions neighboring the Near Eastern domestication center of sheep. H6 is the dominant haplotype in northwestern and eastern China, in which the haplotype distribution could be explained by the historical translocations of the H4 and H8 Y chromosomes to China via the Mongol invasions followed by expansions to northwestern and eastern China. Our findings extend previous results of sheep Y chromosomal genetic variability and indicate probably recent paternal gene flows between sheep breeds from distinct major geographic regions. PMID:25204383

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  10. Posterior Scleritis and Its Association with HLA B27 Haplotype

    Microsoft Academic Search

    Arundhati Anshu; Soon Phaik Chee

    2007-01-01

    Background: Posterior scleritis is most commonly idiopathic but is also found in association with systemic disorders like rheumatoid arthritis. HLA B27 spondyloarthropathy manifests itself mainly in the form of anterior uveitis and anterior scleritis. Posterior scleritis has not been previously reported in patients with HLA B27 haplotype. We document the likely association between posterior scleritis and HLA B27 haplotype in

  11. Modeling Informatively Missing Genotypes in Haplotype Nianjun Liu

    E-print Network

    Jin, Jiashun

    Modeling Informatively Missing Genotypes in Haplotype Analysis by Nianjun Liu The University to have missing genotypes in practical genetic studies. The majority of the existing statistical methods, including those on haplotype analysis, assume that genotypes are missing at randomb assumption can induce

  12. Phylogeny-and Parsimony-Based Haplotype Inference with Constraints

    E-print Network

    Lübeck, Universität zu

    biological insights into the haplotype distribution in a population. They either use statistics, pioneered, is the problem of predicting likely hap- lotypes based on genotype data. One fast computational haplotyping are determined, yielding the individual's genotype for the different sites. In order to study phenotypic traits

  13. 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...

  14. An efficient method for multi-locus molecular haplotyping

    Microsoft Academic Search

    Bernard A. Konfortov; Alan T. Bankier; Paul H. Dear

    2006-01-01

    Many methods exist for genotyping—revealing which alleles an individual carries at different genetic loci. A harder problem is haplotyping— determining which alleles lie on each of the two homologous chromosomes in a diploid individual. Conventional approaches to haplotyping require the use of several generations to reconstruct haplo- types within a pedigree, or use statistical methods to estimate the prevalence of

  15. HIV Haplotype Inference Using a Propagating Dirichlet Process Mixture Model

    E-print Network

    Vetter, Thomas

    HIV Haplotype Inference Using a Propagating Dirichlet Process Mixture Model Sandhya Prabhakaran computational technique for the identification of HIV haplotypes. HIV tends to generate many potentially drug-resistant mutants within the HIV-infected patient and being able to identify these different mutants is important

  16. Haploview: analysis and visualization of LD and haplotype maps

    Microsoft Academic Search

    Jeffrey C. Barrett; B. Fry; Julian Maller; Mark Daly

    2005-01-01

    Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine r esearch activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing

  17. 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%). PMID:17879084

  18. A SURVEY ON HAPLOTYPING ALGORITHMS FOR TIGHTLY LINKED MARKERS

    PubMed Central

    JIANG, TAO

    2010-01-01

    Two grand challenges in the postgenomic era are to develop a detailed understanding of heritable variation in the human genome, and to develop robust strategies for identifying the genetic contribution to diseases and drug responses. Haplotypes of single nucleotide polymorphisms (SNPs) have been suggested as an effective representation of human variation, and various haplotype-based association mapping methods for complex traits have been proposed in the literature. However, humans are diploid and, in practice, genotype data instead of haplotype data are collected directly. Therefore, efficient and accurate computational methods for haplotype reconstruction are needed and have recently been investigated intensively, especially for tightly linked markers such as SNPs. This paper reviews statistical and combinatorial haplotyping algorithms using pedigree data, unrelated individuals, or pooled samples. PMID:18324755

  19. 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

  20. Mapping genes for resistance to Verticillium albo-atrum in tetraploid and diploid potato populations using haplotype association tests and genetic linkage analysis.

    PubMed

    Simko, I; Haynes, K G; Ewing, E E; Costanzo, S; Christ, B J; Jones, R W

    2004-06-01

    Verticillium wilt disease of potato is caused predominantly by Verticillium albo-atrum and V. dahliae. StVe1 -a putative QTL for resistance against V. dahliae -was previously mapped to potato chromosome 9. To develop allele-specific, SNP-based markers within the locus, the StVe1 fragment from a set of 30 North American potato cultivars was analyzed. Three distinct and highly diverse haplotypes can be distinguished at the StVe1 locus. These were detected in 97%, 33%, and 10% of the cultivars analyzed. We tested for haplotype association and for genetic linkage between the StVe1 haplotypes and resistance of tetraploid potato to V. albo-atrum. Moreover, field resistance was assessed in diploid populations with known molecular linkage maps in order to identify novel QTLs. Resistance QTLs against V. albo-atrum were detected on four chromosomes (2, 6, 9, and 12) at the diploid level, with one QTL on chromosome 2 contributing over 40% to the total phenotypic variation of the trait. At the tetraploid level, a significant association between the StVe1-839-C haplotype and susceptibility to the disease was detected, suggesting that resistance-related genes directed against V. albo-atrum and V. dahliae are located in the same genomic region of chromosome 9. However, on the basis of the present analysis, we cannot determine whether these genes are closely linked or if a single gene provides resistance against both Verticillium species. To assess the usefulness of the StVe1-839-C haplotype for marker-assisted selection, we subjected the resistance data to Bayesian analysis, and calculated positive (0.65) and negative (0.75) predictive values, and overall predictive accuracy (0.72). Our results indicate that tagging of additional genes for resistance to Verticillium with molecular markers will be required for efficient marker-assisted selection. PMID:15107986

  1. Identity of the mtDNA haplotype(s) of Phytophthora infestans in historical specimens from the Irish potato famine.

    PubMed

    May, Kimberley Jane; Ristaino, Jean Beagle

    2004-05-01

    The mtDNA haplotypes of the plant pathogen Phytophthora infestans present in dried potato and tomato leaves from herbarium specimens collected during the Irish potato famine and later in the 19th and early 20th century were identified. A 100 bp fragment of ribosomal DNA (rDNA) specific for P. infestans was amplified from 90% of the specimens (n = 186), confirming infection by P. infestans. Primers were designed that distinguish the extant mtDNA haplotypes. 86% percent of the herbarium specimens from historic epidemics were infected with the Ia mtDNA haplotype. Two mid-20th century potato leaves from Ecuador (1967) and Bolivia (1944) were infected with the Ib mtDNA haplotype of the pathogen. Both the Ia and IIb haplotypes were found in specimens collected in Nicaragua in the 1950s. The data suggest that the Ia haplotype of P. infestans was responsible for the historic epidemics during the 19th century in the UK, Europe, and the USA. The Ib mtDNA haplotype of the pathogen was dispersed later in the early 20th century from Bolivia and Ecuador. Multiple haplotypes were present outside Mexico in the 1940s-60s, indicating that pathogen diversity was greater than previously believed. PMID:15229999

  2. Determination of allelic expression of SNP rs1880676 in choline acetyltransferase gene in HeLa cells.

    PubMed

    Yang, Zhongli; Lin, Chen; Wang, Shaolin; Seneviratne, Chamindi; Wang, Jundong; Li, Ming D

    2013-10-25

    Recently, we reported that several polymorphisms and haplotypes in the choline acetyltransferase gene (ChAT) are associated with nicotine dependence (ND). Of them, SNP rs1880676 is of particular interest because: (1) it is a non-synonymous variant located in the coding region of an alternatively spliced form of ChAT and (2) it is located in several haplotypes that are significantly associated with ND. The objective of this study was to determine, using an in vitro system, whether the alleles G (coding for aspartic acid) or A (coding for asparagine) of rs1880676 have any allele-specific effect on ChAT expression. We first used site-directed mutagenesis to construct two expression vectors differed in the allelic position of rs1880676 (G/A), which were transfected into HeLa cells. We then measured expression of ChAT associated with each allele. We found significant expression differences for the two alleles, with the G allele being expressed significantly greater than A allele (P<0.01 at both mRNA and protein levels). Further, we validated the ChAT expression of the G allele was significantly higher than that of the A allele by using ELISA assay (P=0.00016). We concluded that rs1880676 is functional and that the allelic variations of this polymorphism are involved in developing ND by altering ChAT expression. PMID:24076142

  3. Determination of allelic expression of SNP rs1880676 in choline acetyltransferase gene in HeLa cells

    PubMed Central

    Yang, Zhongli; Lin, Chen; Wang, Shaolin; Seneviratne, Chamindi; Wang, Jundong; Li, Ming D.

    2013-01-01

    Recently, we reported that several polymorphisms and haplotypes in the choline acetyltransferase gene (ChAT) are associated with nicotine dependence (ND). Of them, SNP rs1880676 is of particular interest because: 1) it is a non-synonymous variant located in the coding region of an alternatively spliced form of ChAT and 2) it is located in several haplotypes that are significantly associated with ND. The objective of this study was to determine, using an in vitro system, whether the alleles G (coding for aspartic acid) or A (coding for asparagine) of rs1880676 have any allele-specific effect on ChAT expression. We first used site-directed mutagenesis to construct two expression vectors differed in the allelic position of rs1880676(G/A), which were transfected into HeLa cells. We then measured expression of ChAT associated with each allele. We found significant expression differences for the two alleles, with the G allele being expressed significantly greater than A allele (P<0.01 at both mRNA and protein levels). Further, we validated the ChAT expression of the G allele was significantly higher than that of the A allele by using ELISA assay (P=0.00016). We concluded that rs1880676 is functional and that the allelic variations of this polymorphism are involved in developing ND by altering ChAT expression. PMID:24076142

  4. Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami.

    PubMed

    Huyghe, Jeroen R; Fransen, Erik; Hannula, Samuli; Van Laer, Lut; Van Eyken, Els; Mäki-Torkko, Elina; Lysholm-Bernacchi, Alana; Aikio, Pekka; Stephan, Dietrich A; Sorri, Martti; Huentelman, Matthew J; Van Camp, Guy

    2010-05-01

    The Saami from Fennoscandia are believed to represent an ancient, genetically isolated population with no evidence of population expansion. Theoretical work has indicated that under this demographic scenario, extensive linkage disequilibrium (LD) is generated by genetic drift. Therefore, it has been suggested that the Saami would be particularly suited for genetic association studies, offering a substantial power advantage and allowing more economic study designs. However, no study has yet assessed this claim. As part of a GWAS for a complex trait, we evaluated the relative power for association studies of common variants in the Finnish Saami. LD patterns in the Saami were very similar to those in the non-African HapMap reference panels. Haplotype diversity was reduced and, on average, levels of LD were higher in the Saami as compared with those in the HapMap panels. However, using a 'hidden' SNP approach we show that this does not translate into a power gain in association studies. Contrary to earlier claims, we show that for a given set of common SNPs, genomic coverage attained in the Saami is similar to that in the non-African HapMap panels. Nevertheless, the reduced haplotype diversity could potentially facilitate gene identification, especially if multiple rare variants play a role in disease etiology. Our results further indicate that the HapMap is a useful resource for genetic studies in the Saami. PMID:19935831

  5. Vitamin D receptor gene polymorphisms and haplotypes (Apa I, Bsm I, Fok I, Taq I) in Turkish psoriasis patients

    PubMed Central

    Acikbas, Ibrahim; Sanl?, Berna; Tepeli, Emre; Ergin, Seniz; Aktan, Sebnem; Bagci, Huseyin

    2012-01-01

    Summary Background Psoriasis is an inflammatory disease characterized by increased squamous cell proliferation and impaired differentiation. Vitamin D, Calcitriol, and its analogues are successfully used for psoriasis therapy. However, it is unknown why some psoriasis patients are resistant to Vitamin D therapy. Vitamin D mediates its activity by a nuclear receptor. It is suggested that polymorphisms and haplotypes in the VDR gene may explain the differences in response to vitamin D therapy. Material/Methods In this study, 102 psoriasis patients and 102 healthy controls were studied for VDR gene polymorphisms. The Fok I, Bsm I, Apa I and Taq I polymorphisms were examined by PCR-RFLP, and 50 subjects received vitamin D therapy to evaluate the association between VDR gene polymorphisms and response to vitamin D therapy. Existence of cutting site is shown by capital letters, and lack was shown by lower case. The haplotypes were analysed by CHAPLIN. Results There was significant difference in allele frequency of T and genotype frequency of Tt between cases and controls (p values 0.038 and 0.04, respectively). The Aa and bb genotypes were significantly higher in early onset than late onset psoriasis (p values 0.008 and 0.04, respectively). The genotypes Ff, ff and TT are significantly different between vitamin D3 therapy responders and non-responders (p values 0.04, 0.0001, 0.009, respectively). To the best of our knowledge, this is the first report showing importance of VDR gene haplotypes in psoriasis, the significance of the Wald and LR (Likelihood Ratio) statistics (p=0,0042) suggest that FfBbAatt is a disease-susceptibility haplotype. Conclusions Haplotype analysis is a recent and commonly used method in genetic association studies. Our results reveal a previously unidentified susceptibility haplotype and indicate that certain haplotypes are important in the resistance to vitamin D3 therapy and the onset of psoriasis. The haplotypes can give valuable data where genotypes unable to do. PMID:23111742

  6. SNP Discovery and Development of a High-Density Genotyping Array for Sunflower

    PubMed Central

    Bachlava, Eleni; Taylor, Christopher A.; Tang, Shunxue; Bowers, John E.; Mandel, Jennifer R.; Burke, John M.; Knapp, Steven J.

    2012-01-01

    Recent advances in next-generation DNA sequencing technologies have made possible the development of high-throughput SNP genotyping platforms that allow for the simultaneous interrogation of thousands of single-nucleotide polymorphisms (SNPs). Such resources have the potential to facilitate the rapid development of high-density genetic maps, and to enable genome-wide association studies as well as molecular breeding approaches in a variety of taxa. Herein, we describe the development of a SNP genotyping resource for use in sunflower (Helianthus annuus L.). This work involved the development of a reference transcriptome assembly for sunflower, the discovery of thousands of high quality SNPs based on the generation and analysis of ca. 6 Gb of transcriptome re-sequencing data derived from multiple genotypes, the selection of 10,640 SNPs for inclusion in the genotyping array, and the use of the resulting array to screen a diverse panel of sunflower accessions as well as related wild species. The results of this work revealed a high frequency of polymorphic SNPs and relatively high level of cross-species transferability. Indeed, greater than 95% of successful SNP assays revealed polymorphism, and more than 90% of these assays could be successfully transferred to related wild species. Analysis of the polymorphism data revealed patterns of genetic differentiation that were largely congruent with the evolutionary history of sunflower, though the large number of markers allowed for finer resolution than has previously been possible. PMID:22238659

  7. High-resolution SNP array analysis of patients with developmental disorder and normal array CGH results

    PubMed Central

    2012-01-01

    Background Diagnostic analysis of patients with developmental disorders has improved over recent years largely due to the use of microarray technology. Array methods that facilitate copy number analysis have enabled the diagnosis of up to 20% more patients with previously normal karyotyping results. A substantial number of patients remain undiagnosed, however. Methods and Results Using the Genome-Wide Human SNP array 6.0, we analyzed 35 patients with a developmental disorder of unknown cause and normal array comparative genomic hybridization (array CGH) results, in order to characterize previously undefined genomic aberrations. We detected no seemingly pathogenic copy number aberrations. Most of the vast amount of data produced by the array was polymorphic and non-informative. Filtering of this data, based on copy number variant (CNV) population frequencies as well as phenotypically relevant genes, enabled pinpointing regions of allelic homozygosity that included candidate genes correlating to the phenotypic features in four patients, but results could not be confirmed. Conclusions In this study, the use of an ultra high-resolution SNP array did not contribute to further diagnose patients with developmental disorders of unknown cause. The statistical power of these results is limited by the small size of the patient cohort, and interpretation of these negative results can only be applied to the patients studied here. We present the results of our study and the recurrence of clustered allelic homozygosity present in this material, as detected by the SNP 6.0 array. PMID:22984989

  8. 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

  9. Epistatic Effects on Abdominal Fat Content in Chickens: Results from a Genome-Wide SNP-SNP Interaction Analysis

    PubMed Central

    Li, Fangge; Hu, Guo; Zhang, Hui; Wang, Shouzhi; Wang, Zhipeng; Li, Hui

    2013-01-01

    We performed a pairwise epistatic interaction test using the chicken 60 K single nucleotide polymorphism (SNP) chip for the 11th generation of the Northeast Agricultural University broiler lines divergently selected for abdominal fat content. A linear mixed model was used to test two dimensions of SNP interactions affecting abdominal fat weight. With a threshold of P<1.2×10?11 by a Bonferroni 5% correction, 52 pairs of SNPs were detected, comprising 45 pairs showing an Additive×Additive and seven pairs showing an Additive×Dominance epistatic effect. The contribution rates of significant epistatic interactive SNPs ranged from 0.62% to 1.54%, with 47 pairs contributing more than 1%. The SNP-SNP network affecting abdominal fat weight constructed using the significant SNP pairs was analyzed, estimated and annotated. On the basis of the network’s features, SNPs Gga_rs14303341 and Gga_rs14988623 at the center of the subnet should be important nodes, and an interaction between GGAZ and GGA8 was suggested. Twenty-two quantitative trait loci, 97 genes (including nine non-coding genes), and 50 pathways were annotated on the epistatic interactive SNP-SNP network. The results of the present study provide insights into the genetic architecture underlying broiler chicken abdominal fat weight. PMID:24339942

  10. SNP Discovery Using Next Generation Transcriptomic Sequencing in Atlantic Herring (Clupea harengus)

    PubMed Central

    Bekkevold, Dorte; Babbucci, Massimiliano; van Houdt, Jeroen; Maes, Gregory E.; Bargelloni, Luca; Nielsen, Rasmus O.; Taylor, Martin I.; Ogden, Rob; Cariani, Alessia; Carvalho, Gary R.; Consortium, FishPopTrace; Panitz, Frank

    2012-01-01

    The introduction of Next Generation Sequencing (NGS) has revolutionised population genetics, providing studies of non-model species with unprecedented genomic coverage, allowing evolutionary biologists to address questions previously far beyond the reach of available resources. Furthermore, the simple mutation model of Single Nucleotide Polymorphisms (SNPs) permits cost-effective high-throughput genotyping in thousands of individuals simultaneously. Genomic resources are scarce for the Atlantic herring (Clupea harengus), a small pelagic species that sustains high revenue fisheries. This paper details the development of 578 SNPs using a combined NGS and high-throughput genotyping approach. Eight individuals covering the species distribution in the eastern Atlantic were bar-coded and multiplexed into a single cDNA library and sequenced using the 454 GS FLX platform. SNP discovery was performed by de novo sequence clustering and contig assembly, followed by the mapping of reads against consensus contig sequences. Selection of candidate SNPs for genotyping was conducted using an in silico approach. SNP validation and genotyping were performed simultaneously using an Illumina 1,536 GoldenGate assay. Although the conversion rate of candidate SNPs in the genotyping assay cannot be predicted in advance, this approach has the potential to maximise cost and time efficiencies by avoiding expensive and time-consuming laboratory stages of SNP validation. Additionally, the in silico approach leads to lower ascertainment bias in the resulting SNP panel as marker selection is based only on the ability to design primers and the predicted presence of intron-exon boundaries. Consequently SNPs with a wider spectrum of minor allele frequencies (MAFs) will be genotyped in the final panel. The genomic resources presented here represent a valuable multi-purpose resource for developing informative marker panels for population discrimination, microarray development and for population genomic studies in the wild. PMID:22879907

  11. High-throughput SNP discovery and genotyping in durum wheat (Triticum durum Desf.).

    PubMed

    Trebbi, Daniele; Maccaferri, Marco; de Heer, Peter; Sřrensen, Anker; Giuliani, Silvia; Salvi, Silvio; Sanguineti, Maria Corinna; Massi, Andrea; van der Vossen, Edwin Andries Gerard; Tuberosa, Roberto

    2011-08-01

    We describe the application of complexity reduction of polymorphic sequences (CRoPS(®)) technology for the discovery of SNP markers in tetraploid durum wheat (Triticum durum Desf.). A next-generation sequencing experiment was carried out on reduced representation libraries obtained from four durum cultivars. SNP validation and minor allele frequency (MAF) estimate were carried out on a panel of 12 cultivars, and the feasibility of genotyping these SNPs in segregating populations was tested using the Illumina Golden Gate (GG) technology. A total of 2,659 SNPs were identified on 1,206 consensus sequences. Among the 768 SNPs that were chosen irrespective of their genomic repetitiveness level and assayed on the Illumina BeadExpress genotyping system, 275 (35.8%) SNPs matched the expected genotypes observed in the SNP discovery phase. MAF data indicated that the overall SNP informativeness was high: a total of 196 (71.3%) SNPs had MAF >0.2, of which 76 (27.6%) showed MAF >0.4. Of these SNPs, 157 were mapped in one of two mapping populations (Meridiano × Claudio and Colosseo × Lloyd) and integrated into a common genetic map. Despite the relatively low genotyping efficiency of the GG assay, the validated CRoPS-derived SNPs showed valuable features for genomics and breeding applications such as a uniform distribution across the wheat genome, a prevailing single-locus codominant nature and a high polymorphism. Here, we report a new set of 275 highly robust genome-wide Triticum SNPs that are readily available for breeding purposes. PMID:21611761

  12. Genome-wide SNP genotyping highlights the role of natural selection in Plasmodium falciparum population divergence

    PubMed Central

    Neafsey, Daniel E; Schaffner, Stephen F; Volkman, Sarah K; Park, Daniel; Montgomery, Philip; Milner, Danny A; Lukens, Amanda; Rosen, David; Daniels, Rachel; Houde, Nathan; Cortese, Joseph F; Tyndall, Erin; Gates, Casey; Stange-Thomann, Nicole; Sarr, Ousmane; Ndiaye, Daouda; Ndir, Omar; Mboup, Soulyemane; Ferreira, Marcelo U; Moraes, Sandra do Lago; Dash, Aditya P; Chitnis, Chetan E; Wiegand, Roger C; Hartl, Daniel L; Birren, Bruce W; Lander, Eric S; Sabeti, Pardis C; Wirth, Dyann F

    2008-01-01

    Background The malaria parasite Plasmodium falciparum exhibits abundant genetic diversity, and this diversity is key to its success as a pathogen. Previous efforts to study genetic diversity in P. falciparum have begun to elucidate the demographic history of the species, as well as patterns of population structure and patterns of linkage disequilibrium within its genome. Such studies will be greatly enhanced by new genomic tools and recent large-scale efforts to map genomic variation. To that end, we have developed a high throughput single nucleotide polymorphism (SNP) genotyping platform for P. falciparum. Results Using an Affymetrix 3,000 SNP assay array, we found roughly half the assays (1,638) yielded high quality, 100% accurate genotyping calls for both major and minor SNP alleles. Genotype data from 76 global isolates confirm significant genetic differentiation among continental populations and varying levels of SNP diversity and linkage disequilibrium according to geographic location and local epidemiological factors. We further discovered that nonsynonymous and silent (synonymous or noncoding) SNPs differ with respect to within-population diversity, inter-population differentiation, and the degree to which allele frequencies are correlated between populations. Conclusions The distinct population profile of nonsynonymous variants indicates that natural selection has a significant influence on genomic diversity in P. falciparum, and that many of these changes may reflect functional variants deserving of follow-up study. Our analysis demonstrates the potential for new high-throughput genotyping technologies to enhance studies of population structure, natural selection, and ultimately enable genome-wide association studies in P. falciparum to find genes underlying key phenotypic traits. PMID:19077304

  13. SNP discovery using Next Generation Transcriptomic Sequencing in Atlantic herring (Clupea harengus).

    PubMed

    Helyar, Sarah J; Limborg, Morten T; Bekkevold, Dorte; Babbucci, Massimiliano; van Houdt, Jeroen; Maes, Gregory E; Bargelloni, Luca; Nielsen, Rasmus O; Taylor, Martin I; Ogden, Rob; Cariani, Alessia; Carvalho, Gary R; Consortium, Fishpoptrace; Panitz, Frank

    2012-01-01

    The introduction of Next Generation Sequencing (NGS) has revolutionised population genetics, providing studies of non-model species with unprecedented genomic coverage, allowing evolutionary biologists to address questions previously far beyond the reach of available resources. Furthermore, the simple mutation model of Single Nucleotide Polymorphisms (SNPs) permits cost-effective high-throughput genotyping in thousands of individuals simultaneously. Genomic resources are scarce for the Atlantic herring (Clupea harengus), a small pelagic species that sustains high revenue fisheries. This paper details the development of 578 SNPs using a combined NGS and high-throughput genotyping approach. Eight individuals covering the species distribution in the eastern Atlantic were bar-coded and multiplexed into a single cDNA library and sequenced using the 454 GS FLX platform. SNP discovery was performed by de novo sequence clustering and contig assembly, followed by the mapping of reads against consensus contig sequences. Selection of candidate SNPs for genotyping was conducted using an in silico approach. SNP validation and genotyping were performed simultaneously using an Illumina 1,536 GoldenGate assay. Although the conversion rate of candidate SNPs in the genotyping assay cannot be predicted in advance, this approach has the potential to maximise cost and time efficiencies by avoiding expensive and time-consuming laboratory stages of SNP validation. Additionally, the in silico approach leads to lower ascertainment bias in the resulting SNP panel as marker selection is based only on the ability to design primers and the predicted presence of intron-exon boundaries. Consequently SNPs with a wider spectrum of minor allele frequencies (MAFs) will be genotyped in the final panel. The genomic resources presented here represent a valuable multi-purpose resource for developing informative marker panels for population discrimination, microarray development and for population genomic studies in the wild. PMID:22879907

  14. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function

    PubMed Central

    Fung, King Leung; Gottesman, Michael M.

    2009-01-01

    The MDR1 (ABCB1) gene encodes a membrane-bound transporter that actively effluxes a wide range of compounds from cells. The overexpression of MDR1 by multidrug-resistant cancer cells is a serious impediment to chemotherapy. MDR1 is expressed in various tissues to protect them from the adverse effect of toxins. The pharmacokinetics of drugs that are also MDR1 substrates also influence disease outcome and treatment efficacy. Although MDR1 is a well conserved gene, there is increasing evidence that its polymorphisms affect substrate specificity. Three single nucleotide polymorphisms (SNPs) occur frequently and have strong linkage, creating a common haplotype at positions 1236C>T (G412G), 2677G>T (A893S) and 3435C>T (I1145I). The frequency of the synonymous 3435C>T polymorphism has been shown to vary significantly according to ethnicity. Existing literature suggests that the haplotype plays a role in response to drugs and disease susceptibility. This review summarizes recent findings on the 3435C>T polymorphism of MDR1 and the haplotype to which it belongs. A possible molecular mechanism of action by ribosome stalling that can change protein structure and function by altering protein folding is discussed. PMID:19285158

  15. Evolutionary analysis identifies an MX2 haplotype associated with natural resistance to HIV-1 infection.

    PubMed

    Sironi, Manuela; Biasin, Mara; Cagliani, Rachele; Gnudi, Federica; Saulle, Irma; Ibba, Salomč; Filippi, Giulia; Yahyaei, Sarah; Tresoldi, Claudia; Riva, Stefania; Trabattoni, Daria; De Gioia, Luca; Lo Caputo, Sergio; Mazzotta, Francesco; Forni, Diego; Pontremoli, Chiara; Pineda, Juan Antonio; Pozzoli, Uberto; Rivero-Juarez, Antonio; Caruz, Antonio; Clerici, Mario

    2014-09-01

    The protein product of the myxovirus resistance 2 (MX2) gene restricts HIV-1 and simian retroviruses. We demonstrate that MX2 evolved adaptively in mammals with distinct sites representing selection targets in distinct branches; selection mainly involved residues in loop 4, previously shown to carry antiviral determinants. Modeling data indicated that positively selected sites form a continuous surface on loop 4, which folds into two antiparallel ?-helices protruding from the stalk domain. A population genetics-phylogenetics approach indicated that the coding region of MX2 mainly evolved under negative selection in the human lineage. Nonetheless, population genetic analyses demonstrated that natural selection operated on MX2 during the recent history of human populations: distinct selective events drove the frequency increase of two haplotypes in the populations of Asian and European ancestry. The Asian haplotype carries a susceptibility allele for melanoma; the European haplotype is tagged by rs2074560, an intronic variant. Analyses performed on three independent European cohorts of HIV-1-exposed seronegative individuals with different geographic origin and distinct exposure route showed that the ancestral (G) allele of rs2074560 protects from HIV-1 infection with a recessive effect (combined P = 1.55 × 10(-4)). The same allele is associated with lower in vitro HIV-1 replication and increases MX2 expression levels in response to IFN-?. Data herein exploit evolutionary information to identify a novel host determinant of HIV-1 infection susceptibility. PMID:24930137

  16. A dynamic programming algorithm for haplotype block partitioning

    PubMed Central

    Zhang, Kui; Deng, Minghua; Chen, Ting; Waterman, Michael S.; Sun, Fengzhu

    2002-01-01

    We develop a dynamic programming algorithm for haplotype block partitioning to minimize the number of representative single nucleotide polymorphisms (SNPs) required to account for most of the common haplotypes in each block. Any measure of haplotype quality can be used in the algorithm and of course the measure should depend on the specific application. The dynamic programming algorithm is applied to analyze the chromosome 21 haplotype data of Patil et al. [Patil, N., Berno, A. J., Hinds, D. A., Barrett, W. A., Doshi, J. M., Hacker, C. R., Kautzer, C. R., Lee, D. H., Marjoribanks, C., McDonough, D. P., et al. (2001) Science 294, 1719–1723], who searched for blocks of limited haplotype diversity. Using the same criteria as in Patil et al., we identify a total of 3,582 representative SNPs and 2,575 blocks that are 21.5% and 37.7% smaller, respectively, than those identified using a greedy algorithm of Patil et al. We also apply the dynamic programming algorithm to the same data set based on haplotype diversity. A total of 3,982 representative SNPs and 1,884 blocks are identified to account for 95% of the haplotype diversity in each block. PMID:12032283

  17. Human dopamine transporter gene: differential regulation of 18-kb haplotypes

    PubMed Central

    Zhao, Ying; Xiong, Nian; Liu, Yang; Zhou, Yanhong; Li, Nuomin; Qing, Hong; Lin, Zhicheng

    2013-01-01

    Aim Since previous functional studies of short haplotypes and polymorphic sites of SLC6A3 have shown variant-dependent and drug-sensitive promoter activity, this study aimed to understand whether a large SLC6A3 regulatory region, containing these small haplotypes and polymorphic sites, can display haplotype-dependent promoter activity in a drug-sensitive and pathway-related manner. Materials & methods By creating and using a single copy number luciferase-reporter vector, we examined regulation of two different SLC6A3 haplotypes (A and B) of the 5? 18-kb promoter and two known downstream regulatory variable number tandem repeats by 17 drugs in four different cellular models. Results The two regulatory haplotypes displayed up to 3.2-fold difference in promoter activity. The regulations were drug selective (37.5% of the drugs showed effects), and both haplotype and cell type dependent. Pathway analysis revealed at least 13 main signaling hubs targeting SLC6A3, including histone deacetylation, AKT, PKC and CK2 ?-chains. Conclusion SLC6A3 may be regulated via either its promoter or the variable number tandem repeats independently by specific signaling pathways and in a haplotype-dependent manner. Furthermore, we have developed the first pathway map for SLC6A3 regulation. These findings provide a framework for understanding complex and variant-dependent regulations of SLC6A3. PMID:24024899

  18. No effect of C-reactive protein (CRP) haplotypes on CRP levels and post-transplant morbidity and mortality in renal transplantation.

    PubMed

    Krüger, Bernd; Böger, Carsten A; Schröppel, Bernd; Farkas, Stefan; Schnitzbauer, Andreas A; Hoffmann, Ute; Obed, Aiman; Murphy, Barbara T; Banas, Bernhard; Krämer, Bernhard K

    2008-05-01

    Increased serum C-reactive protein (CRP) levels have been associated with all-cause and cardiovascular mortality after kidney transplantation. As genetic variations within the CRP gene determine CRP serum levels, we analyzed the association of both serum CRP levels, and post-transplant morbidity/mortality with CRP-genotypes/haplotypes. We determined CRP levels pretransplant, at 3 and 6 months post-transplant in 402 first kidney recipients, genotyped the three functionally distinct polymorphisms, and subsequently reconstructed the different haplotypes. Four different CRP-haplotypes were observed with a frequency >1%: CGC (33.3%), CGT (30.2%), CAT (29.7%) and GGT (6.8%). CRP levels pretransplantation or 3 and 6 months post-transplant were not different in patients with different CRP-haplotypes. Furthermore, no association of CRP-haplotypes/diplotypes was found with acute rejection, delayed graft function, all-cause mortality or cardiovascular events. In our renal transplant population, we found no association of CRP-haplotypes/diplotypes with either CRP levels or with post-transplant morbidity/mortality. In this inflammation-prone population, rather small genetically determined differences in serum CRP observed in normal populations presumably are overridden by background inflammation. Life long genetically determined increased serum CRP levels appear not to have an impact in our study, implying that CRP is more likely only a marker of current inflammation than a causative agent of cardiovascular morbidity and mortality. PMID:18266777

  19. GENOMIC TECHNOLOGIES FACILITY: Single SNP Genotyping USER/BILLING AGREEMENT

    E-print Network

    Wurtele, Eve Syrkin

    applicable. Invoices will be sent out on a monthly basis and will include charges as follows: Item Fee Single SNP genotyping / reaction (Reagents and labor are included) $0.29/data point Initial consultation $35 Name of User _____________________________________________________________________ Position

  20. Glucocorticoid receptor polymorphisms and haplotypes and their expression in health and disease.

    PubMed

    Koper, Jan W; van Rossum, Elisabeth F C; van den Akker, Erica L T

    2014-12-01

    Cortisol is involved in many physiological processes, including immunosuppressive and anti-inflammatory actions, and therefore cortisol and its synthetic analogs are widely used to treat a large number of diseases. In glucocorticoid treatment, a large variability of clinical responses is observed. This variability may, in part, be ascribed to genetic variation in the glucocorticoid receptor (GR) gene. In this review we present a catalogue of the various single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor gene and their consequences for human health and disease. Many different GR SNP association studies have been described. However, most studies come down to only a few SNPs reported with different annotations. In this review we clarified these different annotations to uniform names. Most associations between GR SNPs and phenotype have been found in body composition, metabolism, the cardiovascular system, the immune system and psychiatric illnesses. However, many associations have not been replicated (yet), and future replication studies and meta-analyses are needed. There is a substantial body of evidence for GR SNPs to have effects on clinical phenotype. However, as most SNP frequencies are low and their variation is within the range of the general population, the impact of a single SNP for health and disease in the general population is probably modest. However, in-depth studying of the molecular mechanisms of repeatedly observed clinical associations could lead to new possibilities for drug development. In particular the development of selective glucocorticoid receptor modulators holds promise. PMID:25150015

  1. 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

  2. A novel efficient dynamic programming algorithm for haplotype block partitioning.

    PubMed

    Zahiri, J; Mahdevar, G; Nowzari-Dalini, A; Ahrabian, H; Sadeghi, M

    2010-11-21

    In this paper, a new efficient algorithm is presented for haplotype block partitioning based on haplotype diversity. In this algorithm, finding the largest meaningful block that satisfies the diversity condition is the main goal as an optimization problem. The algorithm can be performed in polynomial time complexity with regard to the number of haplotypes and SNPs. We apply our algorithm on three biological data sets from chromosome 21 in three different population data sets from HapMap data bulk; the obtained results show the efficiency and better performance of our algorithm in comparison with three other well known methods. PMID:20728452

  3. The Perils of SNP Microarray Testing: Uncovering Unexpected Consanguinity

    PubMed Central

    Tarini, Beth A.; Konczal, Laura; Goldenberg, Aaron J.; Goldman, Edward B.; McCandless, Shawn E.

    2013-01-01

    Background While single nucleotide polymorphism (SNP) chromosomal microarrays identify areas of small genetic deletions/duplications, they can also reveal regions of homozygosity indicative of consanguinity. As more non-geneticists order SNP microarrays, they must prepare for the potential ethical, legal and social issues that result from revelation of unanticipated consanguinity. Patient An infant with multiple congenital anomalies underwent SNP microarray testing. Results The results of the SNP microarray revealed several large regions of homozygosity that indicated identity by descent most consistent with a second or third degree relative mating (e.g., uncle/ niece, half brother/sister, first cousins). Mother was not aware of the test's potential to reveal consanguinity. When informed of the test results, she reluctantly admitted to being raped by her half-brother around the time of conception. Conclusions During the pre-testing consent process, providers should inform parents that SNP microarray testing could reveal consanguinity. Providers must also understand the psychological implications, as well as the legal and moral obligations, that accompany SNP microarray results that indicate consanguinity. PMID:23827427

  4. Human Leukocyte Antigen Class II Haplotypes Affect Clinical Characteristics and Progression of Type 1 Autoimmune Hepatitis in Japan

    PubMed Central

    Umemura, Takeji; Katsuyama, Yoshihiko; Yoshizawa, Kaname; Kimura, Takefumi; Joshita, Satoru; Komatsu, Michiharu; Matsumoto, Akihiro; Tanaka, Eiji; Ota, Masao

    2014-01-01

    Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P?=?1.2×10?10; odds ratio [OR] ?=?3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P?=?0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P?=?0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P?=?0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P?=?0.00057; OR?=?0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P?=?0.017; OR?=?6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P?=?0.034; OR?=?4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH. PMID:24956105

  5. Detecting Signatures of Selection Through Haplotype Differentiation Among Hierarchically Structured Populations

    PubMed Central

    Fariello, María Inés; Boitard, Simon; Naya, Hugo; SanCristobal, Magali; Servin, Bertrand

    2013-01-01

    The detection of molecular signatures of selection is one of the major concerns of modern population genetics. A widely used strategy in this context is to compare samples from several populations and to look for genomic regions with outstanding genetic differentiation between these populations. Genetic differentiation is generally based on allele frequency differences between populations, which are measured by FST or related statistics. Here we introduce a new statistic, denoted hapFLK, which focuses instead on the differences of haplotype frequencies between populations. In contrast to most existing statistics, hapFLK accounts for the hierarchical structure of the sampled populations. Using computer simulations, we show that each of these two features—the use of haplotype information and of the hierarchical structure of populations—significantly improves the detection power of selected loci and that combining them in the hapFLK statistic provides even greater power. We also show that hapFLK is robust with respect to bottlenecks and migration and improves over existing approaches in many situations. Finally, we apply hapFLK to a set of six sheep breeds from Northern Europe and identify seven regions under selection, which include already reported regions but also several new ones. We propose a method to help identifying the population(s) under selection in a detected region, which reveals that in many of these regions selection most likely occurred in more than one population. Furthermore, several of the detected regions correspond to incomplete sweeps, where the favorable haplotype is only at intermediate frequency in the population(s) under selection. PMID:23307896

  6. Genomewide-Linkage and Haplotype-Association Studies Map Intracranial Aneurysm to Chromosome 7q11

    PubMed Central

    Onda, Hideaki; Kasuya, Hidetoshi; Yoneyama, Taku; Takakura, Kintomo; Hori, Tomokatsu; Takeda, Jun; Nakajima, Toshiaki; Inoue, Ituro

    2001-01-01

    Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage, a devastating condition with high morbidity and mortality. Angiographic and autopsy studies show that IA is a common disorder, with a prevalence of 3%–6%. Although IA has a substantial genetic component, little attention has been given to the genetic determinants. We report here a genomewide linkage study of IA in 104 Japanese affected sib pairs in which positive evidence of linkage on chromosomes 5q22-31 (maximum LOD score [MLS] 2.24), 7q11 (MLS 3.22), and 14q22 (MLS 2.31) were found. The best evidence of linkage is detected at D7S2472, in the vicinity of the elastin gene (ELN), a candidate gene for IA. Fourteen distinct single-nucleotide polymorphisms (SNPs) were identified in ELN, and no obvious allelic association between IA and each SNP was observed. The haplotype between the intron-20/intron-23 polymorphism of ELN is strongly associated with IA (P=3.81×10-6), and homozygous patients are at high risk (P=.002), with an odds ratio of 4.39. These findings suggest that a genetic locus for IA lies within or close to the ELN locus on chromosome 7. PMID:11536080

  7. X-chromosome as a marker for population history: linkage disequilibrium and haplotype study in Eurasian populations

    PubMed Central

    Laan, Maris; Wiebe, Victor; Khusnutdinova, Elza; Remm, Maido; Pääbo, Svante

    2005-01-01

    Linkage disequilibrium structure is still unpredictable because the interplay of regional recombination rate and demographic history is poorly understood. We have compared the distribution of LD across two genomic regions differing in crossing-over activity – Xq13 (0.166 cM/Mb) and Xp22 (1.3 cM/Mb) – in 15 Eurasian populations. Demographic events predicted to increase the LD level – genetic drift, bottleneck and admixture – had a very strong impact on extent and patterns of regional LD across Xq13 compared to Xp22. The haplotype distribution of the DXS1225-DXS8082 microsatellites from Xq13 exhibiting strong association in all populations was remarkably influenced by population history. European populations shared one common haplotype with a frequency of 25-40%. The Volga-Ural populations studied, living at the geographic borderline of Europe, showed elevated LD as well as harboring a significant fraction of haplotypes originating from East Asia, thus reflecting their past migrations and admixture. In the young Kuusamo isolate from Finland, a bottleneck has led to allelic associations between loci and shifted the haplotype distribution, but has much less affected single microsatellite allele frequencies compared to the main Finnish population. The data show that the footprint of a demographic event is longer preserved in haplotype distribution within a region of low crossing-over rate, than in the information content of a single marker, or between actively recombining markers. As the knowledge of LD patterns is often chosen to assist association mapping of common disease, our conclusions emphasise the importance of understanding the history, structure and variation of a study population. PMID:15657606

  8. Finding markers that make a difference: DNA pooling and SNP-arrays identify population informative markers for genetic stock identification.

    PubMed

    Ozerov, Mikhail; Vasemägi, Anti; Wennevik, Vidar; Diaz-Fernandez, Rogelio; Kent, Matthew; Gilbey, John; Prusov, Sergey; Niemelä, Eero; Vähä, Juha-Pekka

    2013-01-01

    Genetic stock identification (GSI) using molecular markers is an important tool for management of migratory species. Here, we tested a cost-effective alternative to individual genotyping, known as allelotyping, for identification of highly informative SNPs for accurate genetic stock identification. We estimated allele frequencies of 2880 SNPs from DNA pools of 23 Atlantic salmon populations using Illumina SNP-chip. We evaluated the performance of four common strategies (global F ST, pairwise F ST, Delta and outlier approach) for selection of the most informative set of SNPs and tested their effectiveness for GSI compared to random sets of SNP and microsatellite markers. For the majority of cases, SNPs selected using the outlier approach performed best followed by pairwise F ST and Delta methods. Overall, the selection procedure reduced the number of SNPs required for accurate GSI by up to 53% compared with randomly chosen SNPs. However, GSI accuracy was more affected by populations in the ascertainment group rather than the ranking method itself. We demonstrated for the first time the compatibility of different large-scale SNP datasets by compiling the largest population genetic dataset for Atlantic salmon to date. Finally, we showed an excellent performance of our top SNPs on an independent set of populations covering the main European distribution range of Atlantic salmon. Taken together, we demonstrate how combination of DNA pooling and SNP arrays can be applied for conservation and management of salmonids as well as other species. PMID:24358184

  9. Finding Markers That Make a Difference: DNA Pooling and SNP-Arrays Identify Population Informative Markers for Genetic Stock Identification

    PubMed Central

    Ozerov, Mikhail; Vasemägi, Anti; Wennevik, Vidar; Diaz-Fernandez, Rogelio; Kent, Matthew; Gilbey, John; Prusov, Sergey; Niemelä, Eero; Vähä, Juha-Pekka

    2013-01-01

    Genetic stock identification (GSI) using molecular markers is an important tool for management of migratory species. Here, we tested a cost-effective alternative to individual genotyping, known as allelotyping, for identification of highly informative SNPs for accurate genetic stock identification. We estimated allele frequencies of 2880 SNPs from DNA pools of 23 Atlantic salmon populations using Illumina SNP-chip. We evaluated the performance of four common strategies (global FST, pairwise FST, Delta and outlier approach) for selection of the most informative set of SNPs and tested their effectiveness for GSI compared to random sets of SNP and microsatellite markers. For the majority of cases, SNPs selected using the outlier approach performed best followed by pairwise FST and Delta methods. Overall, the selection procedure reduced the number of SNPs required for accurate GSI by up to 53% compared with randomly chosen SNPs. However, GSI accuracy was more affected by populations in the ascertainment group rather than the ranking method itself. We demonstrated for the first time the compatibility of different large-scale SNP datasets by compiling the largest population genetic dataset for Atlantic salmon to date. Finally, we showed an excellent performance of our top SNPs on an independent set of populations covering the main European distribution range of Atlantic salmon. Taken together, we demonstrate how combination of DNA pooling and SNP arrays can be applied for conservation and management of salmonids as well as other species. PMID:24358184

  10. Genetic Variants in Germline TP53 and MDM2 SNP309 Are Not Associated With Early Onset Colorectal Cancer

    PubMed Central

    KHAN, SAJID A.; IDREES, KAMRAN; FORSLUND, ANN; ZENG, ZHAOSHI; ROSENBERG, SHOSHANA; PINCAS, HANNA; BARANY, FRANCIS; OFFIT, KENNETH; LAQUAGLIA, MICHAEL P.; PATY, PHILIP B.

    2015-01-01

    Background and Objectives Colorectal cancer (CRC) arising in patients under age 30 is a rare disease, and few cases have been reported within Li-Fraumeni kindreds. To determine how often alterations in the p53 pathway genes contribute to disease susceptibility, we have evaluated patients with early onset CRC for the presence of germline variants in the p53 gene and MDM2 SNP309. Methods Thirty-five patients with CRC diagnosed before age 30 were included in this study-based on tissue availability. DNA samples from peripheral blood leukocytes were analyzed for constitutional mutations and polymorphisms in p53 as well as polymorphisms in MDM2 SNP309. Results No mutations were found in exons 4–10 of the p53 gene. The frequencies of polymorphisms in p53 and in MDM2 SNP309 did not differ from rates previously reported for normal control populations, and no polymorphism in either gene could be associated with early onset CRC. Conclusions Neither germline variants in p53 nor MDM2 SNP309 play an underlying role in the development of very early onset CRC. For the large majority of cases, the genetic basis of this disease remains unknown. PMID:18381604

  11. snp-search: simple processing, manipulation and searching of SNPs from high-throughput sequencing

    PubMed Central

    2013-01-01

    Background A typical bacterial pathogen genome mapping project can identify thousands of single nucleotide polymorphisms (SNP). Interpreting SNP data is complex and it is difficult to conceptualise the data contained within the large flat files that are the typical output from most SNP calling algorithms. One solution to this problem is to construct a database that can be queried using simple commands so that SNP interrogation and output is both easy and comprehensible. Results Here we present snp-search, a tool that manages SNP data and allows for manipulation and searching of SNP data. After creation of a SNP database from a VCF file, snp-search can be used to convert the selected SNP data into FASTA sequences, construct phylogenies, look for unique SNPs, and output contextual information about each SNP. The FASTA output from snp-search is particularly useful for the generation of robust phylogenetic trees that are based on SNP differences across the conserved positions in whole genomes. Queries can be designed to answer critical genomic questions such as the association of SNPs with particular phenotypes. Conclusions snp-search is a tool that manages SNP data and outputs useful information which can be used to test important biological hypotheses. PMID:24246037

  12. PCR/oligonucleotide probe typing of HLA class II alleles in a Filipino population reveals an unusual distribution of HLA haplotypes

    SciTech Connect

    Bugawan, T.L.; Chang, J.D.; Erlich, H.A. (Roche Molecular Systems, Alameda, CA (United States)); Klitz, W. (Univ. of California, Berkeley, CA (United States))

    1994-02-01

    The authors have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population by PCR amplification of the DRB1, DQB1, and DPB1 second-exon sequences from buccal swabs obtained from 124 family members and 53 unrelated individuals. The amplified DNA was typed by using nonradioactive sequence-specific oligonucleotide probes. Twenty-two different DRB1 alleles, including the novel Filipino *1105, and 46 different DRB1/DQB1 haplotypes, including the unusual DRB1*0405-DQB1*0503, were identified. An unusually high frequency (f = .383) of DPB1*0101, a rare allele in other Asian populations, was also observed. In addition, an unusual distribution of DRB1 alleles and haplotypes was seen in this population, with DR2 (f = .415) and DRB1*1502-DQB1*0502 (f = .233) present at high frequencies. This distribution of DRB1 alleles differs from the typical HLA population distribution, in which the allele frequencies are more evenly balanced. The distribution of HLA class II alleles and haplotypes in this Filipino population is different from that of other Asian and Pacific groups: of those populations studied to date, the Indonesian population is the most similar. DRB1*1502-DQB1*0502 was in strong linkage disequilibrium (D[prime] = .41) with DPB 1*0101 (f = .126, for the extended haplotype), which is consistent with selection for this DR, DQ, DP haplotype being responsible for the high frequency of these three class II alleles in this populations. 30 refs., 2 figs., 6 tabs.

  13. Prevalence of HLA-DQA1 alleles and haplotypes in blood donors resident in Wales.

    PubMed

    Lemin, A J; Darke, C

    2014-12-01

    Two hundred and fifty-four normal blood donors, from a largely UK European population, were sequence-based typed for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1 and HLA-DQB1. The fit to Hardy-Weinberg expectations was good for all loci (all P values >0.5). Fifteen DQA1 alleles were identified to the second field. DQA1 carriage, allele and DQA1-DQB1 and DRB1-DQA1-DQB1 haplotype frequencies, linkage disequilibria and related values are presented. PMID:25345618

  14. Detection of Chromosomal Structural Alterations in Single Cells by SNP Arrays: A Systematic Survey of Amplification Bias and Optimized Workflow

    Microsoft Academic Search

    Kazuya Iwamoto; Miki Bundo; Junko Ueda; Yoko Nakano; Wataru Ukai; Eri Hashimoto; Toshikazu Saito; Tadafumi Kato; Jean-Nicolas Volff

    2007-01-01

    BackgroundIn single-cell human genome analysis using whole-genome amplified product, a strong amplification bias involving allele dropout and preferential amplification hampers the quality of results. Using an oligonucleotide single nucleotide polymorphism (SNP) array, we systematically examined the nature of this amplification bias, including frequency, degree, and preference for genomic location, and we assessed the effects of this amplification bias on subsequent

  15. Characterization of Bison bison major histocompatibility complex class IIa haplotypes.

    PubMed

    Traul, Donald L; Bhushan, Bharat; Eldridge, Jennifer A; Crawford, Timothy B; Li, Hong; Davies, Christopher J

    2005-12-01

    American bison (Bison bison) and domestic cattle (Bos taurus and Bos indicus) evolved from a common ancestor 1-1.4 million years ago. Nevertheless, they show dramatic differences in their susceptibility to infectious diseases, including malignant catarrhal fever (MCF). Although bison are highly susceptible to ovine herpesvirus-2 (OvHV-2) associated MCF, about 20% of healthy domesticated and wild bison are positive for OvHV-2 antibody. We are interested in testing the hypothesis that, within the bison population, the polymorphism of major histocompatibility complex (MHC) class II genes influences resistance to MCF. However, since little was known about the MHC class II genes of bison, it was necessary to first characterize class II haplotypes present in Bi. bison (Bibi). Thus, the MHC class II haplotypes carried by 14 bison were characterized by the PCR-based cloning and sequencing of their DRB3, DQA, and DQB alleles. Twelve MHC class II haplotypes were identified in the 14 bison. These haplotypes comprised six previously reported and six new Bibi-DRB3 alleles, along with 11 Bibi-DQA and 10 Bibi-DQB alleles. For each bison class II allele, it was possible to identify closely related cattle sequences. The closest bison and bovine DQA, DQB, and DRB3 alleles, on average, differed by only 1.3, 3.5, and 5.8 amino acids, respectively. Furthermore, bison MHC haplotypes with both nonduplicated and duplicated DQ genes were identified; these haplotypes appear to have originated from the same ancestral haplotypes as orthologous cattle haplotypes. PMID:16331512

  16. Bayesian Haplotype Inference for Multiple Linked Single-Nucleotide Polymorphisms

    Microsoft Academic Search

    Tianhua Niu; Zhaohui S. Qin; Xiping Xu; Jun S. Liu

    2002-01-01

    Haplotypes have gained increasing attention in the mapping of complex-disease genes, because of the abundance of single-nucleotide polymorphisms (SNPs) and the limited power of conventional single-locus analyses. It has been shown that haplotype-inference methods such as Clark's algorithm, the expectation-maximization algorithm, and a coalescence-based iterative-sampling algorithm are fairly effective and economical alternatives to molecular-hap-lotyping methods. To contend with some weaknesses

  17. DNA variation at the rp49 gene region of Drosophila simulans: evolutionary inferences from an unusual haplotype structure.

    PubMed Central

    Rozas, J; Gullaud, M; Blandin, G; Aguadé, M

    2001-01-01

    An approximately 1.3-kb region including the rp49 gene plus its 5' and 3' flanking regions was sequenced in 24 lines of Drosophila simulans (10 from Spain and 14 from Mozambique). Fifty-four nucleotide and 8 length polymorphisms were detected. All nucleotide polymorphisms were silent: 52 in noncoding regions and 2 at synonymous sites in the coding region. Estimated silent nucleotide diversity was similar in both populations (pi = 0.016, for the total sample). Nucleotide variation revealed an unusual haplotype structure showing a subset of 11 sequences with a single polymorphism. This haplotype was present at intermediate frequencies in both the European and the African samples. The presence of such a major haplotype in a highly recombining region is incompatible with the neutral equilibrium model. This haplotype structure in both a derived and a putatively ancestral population can be most parsimoniously explained by positive selection. As the rate of recombination in the rp49 region is high, the target of selection should be close to or within the region studied. PMID:11454763

  18. Selection in the Making: A Worldwide Survey of Haplotypic Diversity Around a Causative Mutation in Porcine IGF2

    PubMed Central

    Ojeda, A.; Huang, L.-S.; Ren, J.; Angiolillo, A.; Cho, I.-C.; Soto, H.; Lemús-Flores, C.; Makuza, S. M.; Folch, J. M.; Pérez-Enciso, M.

    2008-01-01

    Domestic species allow us to study dramatic evolutionary changes at an accelerated rate due to the effectiveness of modern breeding techniques and the availability of breeds that have undergone distinct selection pressures. We present a worldwide survey of haplotype variability around a known causative mutation in porcine gene IGF2, which increases lean content. We genotyped 34 SNPs spanning 27 kb in 237 domestic pigs and 162 wild boars. Although the selective process had wiped out variability for at least 27 kb in the haplotypes carrying the mutation, there was no indication of an overall reduction in genetic variability of international vs. European local breeds; there was also no evidence of a reduction in variability caused by domestication. The haplotype structure and a plot of Tajima's D against the frequency of the causative mutation across breeds suggested a temporal pattern, where each breed corresponded to a different selective stage. This was observed comparing the haplotype neighbor-joining (NJ) trees of breeds that have undergone increasing selection pressures for leanness, e.g., European local breeds vs. Pietrain. These results anticipate that comparing current domestic breeds will decisively help to recover the genetic history of domestication and contemporary selective processes. PMID:18245828

  19. Impact of Repetitive Transcranial Magnetic Stimulation on Post-Stroke Dysmnesia and the Role of BDNF Val66Met SNP

    PubMed Central

    Lu, Haitao; Zhang, Tong; Wen, Mei; Sun, Li

    2015-01-01

    Background Little is known about the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on dysmnesia and the impact of brain nucleotide neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism (SNP). This study investigated the impact of low-frequency rTMS on post-stroke dysmnesia and the impact of BDNF Val66Met SNP. Material/Methods Forty patients with post-stroke dysmnesia were prospectively randomized into the rTMS and sham groups. BDNF Val66Met SNP was determined using restriction fragment length polymorphism. Montreal Cognitive Assessment (MoCA), Loewenstein Occupational Therapy of Cognitive Assessment (LOTCA), and Rivermead Behavior Memory Test (RBMT) scores, as well as plasma BDNF concentrations, were measured at baseline and at 3 days and 2 months post-treatment. Results MoCA, LOTCA, and RBMT scores were higher after rTMS. Three days after treatment, BDNF decreased in the rTMS group but it increased in the sham group (P<0.05). Two months after treatment, RMBT scores in the rTMS group were higher than in the sham group, but not MoCA and LOTCA scores. Conclusions Low-frequency rTMS may improve after-stoke memory through various pathways, which may involve polymorphisms and several neural genes, but not through an increase in BDNF levels. PMID:25770310

  20. Impact of Repetitive Transcranial Magnetic Stimulation on Post-Stroke Dysmnesia and the Role of BDNF Val66Met SNP.

    PubMed

    Lu, Haitao; Zhang, Tong; Wen, Mei; Sun, Li

    2015-01-01

    Background Little is known about the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on dysmnesia and the impact of brain nucleotide neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism (SNP). This study investigated the impact of low-frequency rTMS on post-stroke dysmnesia and the impact of BDNF Val66Met SNP. Material and Methods Forty patients with post-stroke dysmnesia were prospectively randomized into the rTMS and sham groups. BDNF Val66Met SNP was determined using restriction fragment length polymorphism. Montreal Cognitive Assessment (MoCA), Loewenstein Occupational Therapy of Cognitive Assessment (LOTCA), and Rivermead Behavior Memory Test (RBMT) scores, as well as plasma BDNF concentrations, were measured at baseline and at 3 days and 2 months post-treatment. Results MoCA, LOTCA, and RBMT scores were higher after rTMS. Three days after treatment, BDNF decreased in the rTMS group but it increased in the sham group (P<0.05). Two months after treatment, RMBT scores in the rTMS group were higher than in the sham group, but not MoCA and LOTCA scores. Conclusions Low-frequency rTMS may improve after-stoke memory through various pathways, which may involve polymorphisms and several neural genes, but not through an increase in BDNF levels. PMID:25770310

  1. Novel PKU mutation on haplotype 2 in French-Canadians.

    PubMed Central

    John, S W; Rozen, R; Laframboise, R; Laberge, C; Scriver, C R

    1989-01-01

    We analyzed DNA from nine French-Canadian probands from eastern Quebec province; all had hyperphenylalaninemia (phenylketonuria [PKU] or non-PKU forms) caused by mutations at the phenylalanine hydroxylase locus. Analysis of RFLP haplotypes and mutations revealed a novel mutation, an A-to-G transition (met----val) in codon 1 (the translation-initiation codon). It occurred on 5 of the 18 mutant chromosomes and was associated each time with haplotype 2. A proband homozygous for this mutation had the PKU phenotype. In other probands, the codon 1 mutation was inherited once with the splice junction mutation in exon 12 (on haplotype 3), conferring PKU, and was inherited twice with a mutation on haplotype 1, conferring PKU in one proband and non-PKU hyperphenylalaninemia in the other. The other five probands carried mutations, conferring PKU, on the following haplotype combinations: 1/3 (twice), 1/9, 3/4, and 1/1. The mutations on haplotypes 1, 4, and 9 are not yet characterized. This preliminary study reveals a novel PKU mutation and considerable genetic heterogeneity at the phenylalanine hydroxylase locus in French-Canadians. Images Figure 1 Figure 2 PMID:2574002

  2. Identification of SNP and SSR markers in eggplant using RAD tag sequencing

    PubMed Central

    2011-01-01

    Background The eggplant (Solanum melongena L.) genome is relatively unexplored, especially compared to those of the other major Solanaceae crops tomato and potato. In particular, no SNP markers are publicly available; on the other hand, over 1,000 SSR markers were developed and publicly available. We have combined the recently developed Restriction-site Associated DNA (RAD) approach with Illumina DNA sequencing for rapid and mass discovery of both SNP and SSR markers for eggplant. Results RAD tags were generated from the genomic DNA of a pair of eggplant mapping parents, and sequenced to produce ~17.5 Mb of sequences arrangeable into ~78,000 contigs. The resulting non-redundant genomic sequence dataset consisted of ~45,000 sequences, of which ~29% were putative coding sequences and ~70% were in common between the mapping parents. The shared sequences allowed the discovery of ~10,000 SNPs and nearly 1,000 indels, equivalent to a SNP frequency of 0.8 per Kb and an indel frequency of 0.07 per Kb. Over 2,000 of the SNPs are likely to be mappable via the Illumina GoldenGate assay. A subset of 384 SNPs was used to successfully fingerprint a panel of eggplant germplasm, producing a set of informative diversity data. The RAD sequences also included nearly 2,000 putative SSRs, and primer pairs were designed to amplify 1,155 loci. Conclusion The high throughput sequencing of the RAD tags allowed the discovery of a large number of DNA markers, which will prove useful for extending our current knowledge of the genome organization of eggplant, for assisting in marker-aided selection and for carrying out comparative genomic analyses within the Solanaceae family. PMID:21663628

  3. A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking

    PubMed Central

    Daniels, Rachel; Volkman, Sarah K; Milner, Danny A; Mahesh, Nira; Neafsey, Daniel E; Park, Daniel J; Rosen, David; Angelino, Elaine; Sabeti, Pardis C; Wirth, Dyann F; Wiegand, Roger C

    2008-01-01

    Background Single nucleotide polymorphism (SNP) genotyping provides the means to develop a practical, rapid, inexpensive assay that will uniquely identify any Plasmodium falciparum parasite using a small amount of DNA. Such an assay could be used to distinguish recrudescence from re-infection in drug trials, to monitor the frequency and distribution of specific parasites in a patient population undergoing drug treatment or vaccine challenge, or for tracking samples and determining purity of isolates in the laboratory during culture adaptation and sub-cloning, as well as routine passage. Methods A panel of twenty-four SNP markers has been identified that exhibit a high minor allele frequency (average MAF > 35%), for which robust TaqMan genotyping assays were constructed. All SNPs were identified through whole genome sequencing and MAF was estimated through Affymetrix array-based genotyping of a worldwide collection of parasites. These assays create a "molecular barcode" to uniquely identify a parasite genome. Results Using 24 such markers no two parasites known to be of independent origin have yet been found to have the same allele signature. The TaqMan genotyping assays can be performed on a variety of samples including cultured parasites, frozen whole blood, or whole blood spotted onto filter paper with a success rate > 99%. Less than 5 ng of parasite DNA is needed to complete a panel of 24 markers. The ability of this SNP panel to detect and identify parasites was compared to the standard molecular methods, MSP-1 and MSP-2 typing. Conclusion This work provides a facile field-deployable genotyping tool that can be used without special skills with standard lab equipment, and at reasonable cost that will unambiguously identify and track P. falciparum parasites both from patient samples and in the laboratory. PMID:18959790

  4. A SNP resource for Douglas-fir: de novo transcriptome assembly and SNP detection and validation

    PubMed Central

    2013-01-01

    Background Douglas-fir (Pseudotsuga menziesii), one of the most economically and ecologically important tree species in the world, also has one of the largest tree breeding programs. Although the coastal and interior varieties of Douglas-fir (vars. menziesii and glauca) are native to North America, the coastal variety is also widely planted for timber production in Europe, New Zealand, Australia, and Chile. Our main goal was to develop a SNP resource large enough to facilitate genomic selection in Douglas-fir breeding programs. To accomplish this, we developed a 454-based reference transcriptome for coastal Douglas-fir, annotated and evaluated the quality of the reference, identified putative SNPs, and then validated a sample of those SNPs using the Illumina Infinium genotyping platform. Results We assembled a reference transcriptome consisting of 25,002 isogroups (unique gene models) and 102,623 singletons from 2.76 million 454 and Sanger cDNA sequences from coastal Douglas-fir. We identified 278,979 unique SNPs by mapping the 454 and Sanger sequences to the reference, and by mapping four datasets of Illumina cDNA sequences from multiple seed sources, genotypes, and tissues. The Illumina datasets represented coastal Douglas-fir (64.00 and 13.41 million reads), interior Douglas-fir (80.45 million reads), and a Yakima population similar to interior Douglas-fir (8.99 million reads). We assayed 8067 SNPs on 260 trees using an Illumina Infinium SNP genotyping array. Of these SNPs, 5847 (72.5%) were called successfully and were polymorphic. Conclusions Based on our validation efficiency, our SNP database may contain as many as ~200,000 true SNPs, and as many as ~69,000 SNPs that could be genotyped at ~20,000 gene loci using an Infinium II array—more SNPs than are needed to use genomic selection in tree breeding programs. Ultimately, these genomic resources will enhance Douglas-fir breeding and allow us to better understand landscape-scale patterns of genetic variation and potential responses to climate change. PMID:23445355

  5. Linkage disequilibrium between S65C HFE mutation and HLA A29-B44 haplotype in Terceira Island, Azores.

    PubMed

    Couto, Ana Rita; Peixoto, Maria José; Garrett, Francisco; Laranjeira, Francisco; Cipriano, Tania; Armas, Jácome Bruges

    2003-06-01

    Our objective was to investigate the frequency of HFE gene mutations and to study linkage disequilibrium (LD) between HLA-Class I alleles and these mutations in the population of Terceira Island, Azores, Portugal. A total of 218 unrelated individuals were investigated. Three HFE mutations--C282Y, H63D, and S65C--were identified by restriction endonuclease digestion of polymerase chain reaction (PCR)-amplified genomic DNA. HLA-Class I alleles were typed by PCR-single-strand polymorphism. Gene frequencies and LD were estimated using Arlequin V 1.1. Six genotypes were found in the population: WT/WT (58.3%), H63D/WT (31.2%), H63D/H63D (2.3%), H63D/C282Y (0.9%), S65C/WT (4.1%), and C282Y/WT (3.2%). No cases of C282Y or S65C homozygosity were identified. HLA haplotype A3-B7 was in LD with C282Y; HLA alleles A29, B44, and HLA haplotype A29-B44 were in LD with S65C mutation. HFE gene frequencies in this population are similar to those in other European populations; HFE S65C mutation was found in LD with the alleles A29, B44, and with A29-B44 HLA haplotype. PMID:12770794

  6. Association of vascular endothelial growth factor - A gene polymorphisms and haplotypes with breast cancer metastases.

    PubMed

    Langsenlehner, Uwe; Hofmann, Günter; Renner, Wilfried; Gerger, Armin; Krenn-Pilko, Sabine; Thurner, Eva-Maria; Krippl, Peter; Langsenlehner, Tanja

    2015-03-01

    Abstract Background. Vascular endothelial growth factor (VEGF-A) is a key regulator of tumor-induced angiogenesis and essential for tumor growth and distant tumor spread. The aim of the present study was to evaluate the role of VEGF-A polymorphisms and haplotypes for metastatic progression in breast cancer patients. Material and methods. We performed a prospective study including 801 breast cancer patients. Occurrence of metastases was examined in regular follow-up investigations. Seven VEGF-A polymorphisms were selected and determined by 5'-nuclease assays (TaqMan). The selection of VEGF-A variants was based upon their location (promoter or UTR) as well as a minor allele frequency of at least 0.10. Haplotypes and linkage disequilibrium were determined using the Haploview program. Results. Within a median follow-up time of 84 months, 165 (21%) patients developed distant metastases. In univariate analysis, carriers of the CCCCC haplotype formed by five polymorphisms upstream the coding region were at decreased risk of distant metastases [hazard ratio (HR) = 0.743; 95% CI 0.579-0.953; p = 0.019]. Univariate analysis also revealed a decreased risk of distant metastases for postmenopausal patients carrying the -634G> C polymorphism (HR 0.704; 95% CI 0.514-0.965; p = 0.029) and the CCCCC haplotype (HR = 0.645; 95% CI 0.464-0.898; p = 0.009). After adjustment for other co-variates, the HR for distant metastases was 0.651 (95% CI 0.447-0.948) for postmenopausal carriers of the -634G> C polymorphism (p = 0.025; corrected p-value = 0.262), and 0.586 (95% CI 0.393-0.873) for postmenopausal patients with the CCCCC haplotype (p = 0.009, corrected p-value = 0.189). Conclusion. The results from univariate and multivariate analyses suggest an influence of VEGF-A gene variants on the development of distant metastases in breast cancer patients. However, none of the observed associations reached statistical significance after correction for the effects of multiple testing. Additional prospective and sufficiently powered studies are essential before firm conclusions about the role of VEGF-A gene variants for distant progression in breast cancer can be drawn. PMID:25152223

  7. Respiratory symptoms among infants at risk for asthma: association with surfactant protein A haplotypes

    PubMed Central

    Pettigrew, Melinda M; Gent, Janneane F; Zhu, Yong; Triche, Elizabeth W; Belanger, Kathleen D; Holford, Theodore R; Bracken, Michael B; Leaderer, Brian P

    2007-01-01

    Background We examined the association between single nucleotide polymorphisms (SNPs) in loci encoding surfactant protein A (SFTPA) and risk of wheeze and persistent cough during the first year of life among a cohort of infants at risk for developing asthma. Methods Between September 1996 and December 1998, mothers of newborn infants were invited to participate if they had an older child with clinician-diagnosed asthma. Each mother was given a standardized questionnaire within 4 months of her infant's birth. Infant respiratory symptoms were collected during quarterly telephone interviews at 6, 9 and 12 months of age. Due to the association of SFTPA polymorphisms and race/ethnicity, analyses were restricted to 221 white infants for whom whole blood and respiratory data were available. Ordered logistic regression models were used to examine the association between respiratory symptom frequency and SFTPA haplotypes. Results The 6A allele haplotype of SFTPA1, with an estimated frequency of 6% among our study infants, was associated with an increased risk of persistent cough (OR 3.69, 95% CI 1.71, 7.98) and wheeze (OR 4.72, 95% CI 2.20, 10.11). The 6A/1A haplotype of SFTPA, found among approximately 5% of the infants, was associated with an increased risk of persistent cough (OR 3.20, 95% CI 1.39, 7.36) and wheeze (OR 3.25, 95% CI 1.43, 7.37). Conclusion Polymorphisms within SFTPA loci may be associated with wheeze and persistent cough in white infants at risk for asthma. These associations require replication and exploration in other ethnic/racial groups. PMID:17407567

  8. SNP discovery and development of genetic markers for mapping innate immune response genes in common carp (Cyprinus carpio).

    PubMed

    Kongchum, Pawapol; Palti, Yniv; Hallerman, Eric M; Hulata, Gideon; David, Lior

    2010-08-01

    Single nucleotide polymorphisms (SNPs) in immune response genes have been reported as markers for susceptibility to infectious diseases in human and livestock. A disease caused by cyprinid herpesvirus 3 (CyHV-3) is highly contagious and virulent in common carp (Cyprinus carpio). With the aim to develop molecular tools for breeding CyHV-3-resistant carp, we have amplified and sequenced 11 candidate genes for viral disease resistance including TLR2, TLR3, TLR4ba, TLR7, TLR9, TLR21, TLR22, MyD88, TRAF6, type I IFN and IL-1beta. For each gene, we initially cloned and sequenced PCR amplicons from 8 to 12 fish (2-3 fish per strain) from the SNP discovery panel. We then identified and evaluated putative SNPs for their polymorphisms in the SNP discovery panel and validated their usefulness for linkage analysis in a full-sib family using the SNaPshot method. Our sequencing results and phylogenetic analyses suggested that TLR3, TLR7 and MyD88 genes are duplicated in the common carp genome. We, therefore, developed locus-specific PCR primers and SNP genotyping assays for the duplicated loci. A total of 48 SNP markers were developed from PCR fragments of the 13 loci (7 single-locus and 3 duplicated genes). Thirty-nine markers were polymorphic with estimated minor allele frequencies of more than 0.1. The utility of the SNP markers was evaluated in one full-sib family and revealed that 20 markers from 9 loci segregated in a disomic and Mendelian pattern and would be useful for linkage analysis. PMID:20420915

  9. DoGSD: the dog and wolf genome SNP database

    PubMed Central

    Bai, Bing; Zhao, Wen-Ming; Tang, Bi-Xia; Wang, Yan-Qing; Wang, Lu; Zhang, Zhang; Yang, He-Chuan; Liu, Yan-Hu; Zhu, Jun-Wei; Irwin, David M.; Wang, Guo-Dong; Zhang, Ya-Ping

    2015-01-01

    The rapid advancement of next-generation sequencing technology has generated a deluge of genomic data from domesticated dogs and their wild ancestor, grey wolves, which have simultaneously broadened our understanding of domestication and diseases that are shared by humans and dogs. To address the scarcity of single nucleotide polymorphism (SNP) data provided by authorized databases and to make SNP data more easily/friendly usable and available, we propose DoGSD (http://dogsd.big.ac.cn), the first canidae-specific database which focuses on whole genome SNP data from domesticated dogs and grey wolves. The DoGSD is a web-based, open-access resource comprising ?19 million high-quality whole-genome SNPs. In addition to the dbSNP data set (build 139), DoGSD incorporates a comprehensive collection of SNPs from two newly sequenced samples (1 wolf and 1 dog) and collected SNPs from three latest dog/wolf genetic studies (7 wolves and 68 dogs), which were taken together for analysis with the population genetic statistics, Fst. In addition, DoGSD integrates some closely related information including SNP annotation, summary lists of SNPs located in genes, synonymous and non-synonymous SNPs, sampling location and breed information. All these features make DoGSD a useful resource for in-depth analysis in dog-/wolf-related studies. PMID:25404132

  10. Substantial SNP-based heritability estimates for working memory performance.

    PubMed

    Vogler, C; Gschwind, L; Coynel, D; Freytag, V; Milnik, A; Egli, T; Heck, A; de Quervain, D J-F; Papassotiropoulos, A

    2014-01-01

    Working memory (WM) is an important endophenotype in neuropsychiatric research and its use in genetic association studies is thought to be a promising approach to increase our understanding of psychiatric disease. As for any genetically complex trait, demonstration of sufficient heritability within the specific study context is a prerequisite for conducting genetic studies of that trait. Recently developed methods allow estimating trait heritability using sets of common genetic markers from genome-wide association study (GWAS) data in samples of unrelated individuals. Here we present single-nucleotide polymorphism (SNP)-based heritability estimates (h(2)SNP) for a WM phenotype. A Caucasian sample comprising a total of N=2298 healthy and young individuals was subjected to an N-back WM task. We calculated the genetic relationship between all individuals on the basis of genome-wide SNP data and performed restricted maximum likelihood analyses for variance component estimation to derive the h(2)SNP estimates. Heritability estimates for three 2-back derived WM performance measures based on all autosomal chromosomes ranged between 31 and 41%, indicating a substantial SNP-based heritability for WM traits. These results indicate that common genetic factors account for a prominent part of the phenotypic variation in WM performance. Hence, the application of GWAS on WM phenotypes is a valid method to identify the molecular underpinnings of WM. PMID:25203169

  11. Substantial SNP-based heritability estimates for working memory performance

    PubMed Central

    Vogler, C; Gschwind, L; Coynel, D; Freytag, V; Milnik, A; Egli, T; Heck, A; de Quervain, D J-F; Papassotiropoulos, A

    2014-01-01

    Working memory (WM) is an important endophenotype in neuropsychiatric research and its use in genetic association studies is thought to be a promising approach to increase our understanding of psychiatric disease. As for any genetically complex trait, demonstration of sufficient heritability within the specific study context is a prerequisite for conducting genetic studies of that trait. Recently developed methods allow estimating trait heritability using sets of common genetic markers from genome-wide association study (GWAS) data in samples of unrelated individuals. Here we present single-nucleotide polymorphism (SNP)-based heritability estimates (h2SNP) for a WM phenotype. A Caucasian sample comprising a total of N=2298 healthy and young individuals was subjected to an N-back WM task. We calculated the genetic relationship between all individuals on the basis of genome-wide SNP data and performed restricted maximum likelihood analyses for variance component estimation to derive the h2SNP estimates. Heritability estimates for three 2-back derived WM performance measures based on all autosomal chromosomes ranged between 31 and 41%, indicating a substantial SNP-based heritability for WM traits. These results indicate that common genetic factors account for a prominent part of the phenotypic variation in WM performance. Hence, the application of GWAS on WM phenotypes is a valid method to identify the molecular underpinnings of WM. PMID:25203169

  12. Heterogeneous computing architecture for fast detection of SNP-SNP interactions

    PubMed Central

    2014-01-01

    Background The extent of data in a typical genome-wide association study (GWAS) poses considerable computational challenges to software tools for gene-gene interaction discovery. Exhaustive evaluation of all interactions among hundreds of thousands to millions of single nucleotide polymorphisms (SNPs) may require weeks or even months of computation. Massively parallel hardware within a modern Graphic Processing Unit (GPU) and Many Integrated Core (MIC) coprocessors can shorten the run time considerably. While the utility of GPU-based implementations in bioinformatics has been well studied, MIC architecture has been introduced only recently and may provide a number of comparative advantages that have yet to be explored and tested. Results We have developed a heterogeneous, GPU and Intel MIC-accelerated software module for SNP-SNP interaction discovery to replace the previously single-threaded computational core in the interactive web-based data exploration program SNPsyn. We report on differences between these two modern massively parallel architectures and their software environments. Their utility resulted in an order of magnitude shorter execution times when compared to the single-threaded CPU implementation. GPU implementation on a single Nvidia Tesla K20 runs twice as fast as that for the MIC architecture-based Xeon Phi P5110 coprocessor, but also requires considerably more programming effort. Conclusions General purpose GPUs are a mature platform with large amounts of computing power capable of tackling inherently parallel problems, but can prove demanding for the programmer. On the other hand the new MIC architecture, albeit lacking in performance reduces the programming effort and makes it up with a more general architecture suitable for a wider range of problems. PMID:24964802

  13. A fast and accurate algorithm for single individual haplotyping

    PubMed Central

    2012-01-01

    Background Due to the difficulty in separating two (paternal and maternal) copies of a chromosome, most published human genome sequences only provide genotype information, i.e., the mixed information of the underlying two haplotypes. However, phased haplotype information is needed to completely understand complex genetic polymorphisms and to increase the power of genome-wide association studies for complex diseases. With the rapid development of DNA sequencing technologies, reconstructing a pair of haplotypes from an individual's aligned DNA fragments by computer algorithms (i.e., Single Individual Haplotyping) has become a practical haplotyping approach. Results In the paper, we combine two measures "errors corrected" and "fragments cut" and propose a new optimization model, called Balanced Optimal Partition (BOP), for single individual haplotyping. The model generalizes two existing models, Minimum Error Correction (MEC) and Maximum Fragments Cut (MFC), and could be made either model by using some extreme parameter values. To solve the model, we design a heuristic dynamic programming algorithm H-BOP. By limiting the number of intermediate solutions at each iteration to an appropriately chosen small integer k, H-BOP is able to solve the model efficiently. Conclusions Extensive experimental results on simulated and real data show that when k = 8, H-BOP is generally faster and more accurate than a recent state-of-art algorithm ReFHap in haplotype reconstruction. The running time of H-BOP is linearly dependent on some of the key parameters controlling the input size and H-BOP scales well to large input data. The code of H-BOP is available to the public for free upon request to the corresponding author. PMID:23282221

  14. Whole-genome haplotyping by dilution, amplification, and sequencing.

    PubMed

    Kaper, Fiona; Swamy, Sajani; Klotzle, Brandy; Munchel, Sarah; Cottrell, Joseph; Bibikova, Marina; Chuang, Han-Yu; Kruglyak, Semyon; Ronaghi, Mostafa; Eberle, Michael A; Fan, Jian-Bing

    2013-04-01

    Standard whole-genome genotyping technologies are unable to determine haplotypes. Here we describe a method for rapid and cost-effective long-range haplotyping. Genomic DNA is diluted and distributed into multiple aliquots such that each aliquot receives a fraction of a haploid copy. The DNA template in each aliquot is amplified by multiple displacement amplification, converted into barcoded sequencing libraries using Nextera technology, and sequenced in multiplexed pools. To assess the performance of our method, we combined two male genomic DNA samples at equal ratios, resulting in a sample with diploid X chromosomes with known haplotypes. Pools of the multiplexed sequencing libraries were subjected to targeted pull-down of a 1-Mb contiguous region of the X-chromosome Duchenne muscular dystrophy gene. We were able to phase the Duchenne muscular dystrophy region into two contiguous haplotype blocks with a mean length of 494 kb. The haplotypes showed 99% agreement with the consensus base calls made by sequencing the individual DNAs. We subsequently used the strategy to haplotype two human genomes. Standard genomic sequencing to identify all heterozygous SNPs in the sample was combined with dilution-amplification-based sequencing data to resolve the phase of identified heterozygous SNPs. Using this procedure, we were able to phase >95% of the heterozygous SNPs from the diploid sequence data. The N50 for a Yoruba male DNA was 702 kb whereas the N50 for a European female DNA was 358 kb. Therefore, the strategy described here is suitable for haplotyping of a set of targeted regions as well as of the entire genome. PMID:23509297

  15. HLA-B51 and haplotypic diversity of B-Cw associations: implications for matching in unrelated hematopoietic stem cell transplantation.

    PubMed

    Bettens, F; Nicoloso de Faveri, G; Tiercy, J-M

    2009-04-01

    In unrelated hematopoietic stem cell transplantation (HSCT), human leukocyte antigen (HLA)-C locus incompatibilities occur frequently and are associated with increased risk of posttransplant complications. Because HLA-B51 is associated with a high rate of Cw disparities, we performed a comprehensive four-digit typing analysis of 140 ABCDRB1 B51 genotypes proven by pedigree analysis and 311 unrelated donors selected for 75 B51-positive patients. In addition, 145 A1/Ax-B8/B51-DR3/DRx donors were HLA typed at a high-resolution level and tested for three microsatellite (Msat) polymorphisms located in the HLA class I and III regions. Based on these data sets, 182 different ABCDR haplotypes with 14 different B-Cw associations were detected. Rates of Cw mismatches were shown to be highly correlated with the ABDRB1 haplotypes. We have computed 21 B51 haplotypes that disclose a high probability of HLA-C allele matching and 30 haplotypes with a low (<25%) probability. The HLA-C allele frequency profiles were quite different in these two groups, with a more heterogeneous distribution in the low matching probability group. HLA-Cw*1502 was inversely correlated with the likelihood to identify a Cw-mismatched donor: it was present in 61% of the high vs 18% of the low probability group (P < 0.0001). The analysis of three Msats in the class I and III regions showed a higher allelic diversity in B51-positive haplotypes compared with the conserved A1-B8-DR3 haplotype. HLA-B51 haplotypes therefore exhibit a high diversity at the level of B-Cw associations and of non-HLA polymorphisms in the class I and III regions. Such heterogeneity negatively impacts on overall matching in HSCT. PMID:19317740

  16. Haplotype analysis of HLA-A, -B antigens and -DRB1 alleles in south Indian HIV-1-infected patients with and without pulmonary tuberculosis.

    PubMed

    Raghavan, S; Selvaraj, P; Swaminathan, S; Alagarasu, K; Narendran, G; Narayanan, P R

    2009-06-01

    We have shown earlier the association of human leucocyte antigen (HLA)-A11 with resistance and HLA-B40 and -DR2 with susceptibility to HIV and HIV-TB. In the present study, we have attempted to find out the HLA-DR2 subtypes and the possible HLA-A/-B/-DRB1 haplotype combinations that are associated with susceptibility or resistance to HIV and HIV with pulmonary tuberculosis (HIV+PTB+). HLA-DR2 subtyping was carried out by polymerase chain reaction-based sequence-specific oligonucleotide probe method. Overrepresentation of HLA-DRB1*1501 in HIV-positive PTB-negative (HIV+PTB-) patients (P = 0.004, P(c) = 0.06) and -DRB1*1502 in HIV-positive PTB-positive (HIV+PTB+) patients (P = 0.019) was observed as compared to healthy controls. Haplotype analysis revealed an increased frequency of HLA-A2-DRB1*1501 haplotype in HIV+PTB- patients (P = 0.008) and HLA-A2-DRB1*1502 among HIV+PTB+ patients (P = 0.01) compared to healthy controls. The haplotypes B40-DRB1*1501 and B40-DRB1*04 were found to be moderately increased in HIV+PTB(-) and HIV+PTB+ patients (P < 0.05). The study suggests that HLA-A2-DRB1*1501 haplotype may be associated with HIV infection while HLA-A2-DRB1*1502 haplotype might be associated with susceptibility to PTB in HIV patients. Moreover, HLA-B40-DRB1*1501 and HLA-B40-DRB1*04 haplotypes may be associated with susceptibility to HIV infection and to PTB in HIV patients. PMID:19392836

  17. Mutation-haplotype analysis of steroid 21-hydroxylase (CYP21) deficiency in Finland. Implications for the population history of defective alleles.

    PubMed

    Levo, A; Partanen, J

    1997-04-01

    Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common inherited defect of adrenal steroid hormone biosynthesis. Unusually for genetic disorders, the majority of mutations causing CAH apparently result from recombinations between the CYP21 gene encoding the 21-hydroxylase enzyme and the closely linked, highly homologous pseudogene CYP21P. The CYP21 and CYP21P genes are located in the major histocompatibility complex class III region on chromosome 6p21.3. We analyzed the mutations and recombination breakpoints in the CYP21 gene and determined the associated haplotypes in 51 unrelated Finnish families with CAH. They represent no less than half of all CYP21 deficiency patients in Finland. The results indicate the existence of multiple founder mutation-haplotype combinations in the population of Finnish CAH patients. The three most common haplotypes constituted half of all affected chromosomes; only one-sixth of the haplotypes represented single cases. Each of the common haplotypes was shown consistently to carry a typical CYP21 mutation and only in some cases was additional variation observed. Surprisingly, comparisons with previous published data revealed that several of the frequent mutation-haplotype combinations in Finland are in fact also found in many other populations of patients of European origin, thus suggesting that these haplotypes are of ancient origin. This is in clear contrast to many reports, including the present one, where a high frequency of de novo mutations in the CYP21 gene has been reported. In addition, two unique sequence aberrations in CYP21 (W302X and R356Q), not known to exist in the CYP21P pseudogene, were detected. PMID:9099839

  18. Conditions for the validity of SNP-based heritability estimation

    PubMed Central

    2014-01-01

    The heritability of a trait (h2) is the proportion of its population variance caused by genetic differences, and estimates of this parameter are important for interpreting the results of genome-wide association studies (GWAS). In recent years, researchers have adopted a novel method for estimating a lower bound on heritability directly from GWAS data that uses realized genetic similarities between nominally unrelated individuals. The quantity estimated by this method is purported to be the contribution to heritability that could in principle be recovered from association studies employing the given panel of SNPs (hSNP2). Thus far, the validity of this approach has mostly been tested empirically. Here, we provide a mathematical explication and show that the method should remain a robust means of obtaining hSNP2 SNP under circumstances wider than those under which it has so far been derived. PMID:24744256

  19. A robust SNP barcode for typing Mycobacterium tuberculosis complex strains

    PubMed Central

    Coll, Francesc; McNerney, Ruth; Guerra-Assunçăo, José Afonso; Glynn, Judith R.; Perdigăo, Joăo; Viveiros, Miguel; Portugal, Isabel; Pain, Arnab; Martin, Nigel; Clark, Taane G.

    2014-01-01

    Strain-specific genomic diversity in the Mycobacterium tuberculosis complex (MTBC) is an important factor in pathogenesis that may affect virulence, transmissibility, host response and emergence of drug resistance. Several systems have been proposed to classify MTBC strains into distinct lineages and families. Here, we investigate single-nucleotide polymorphisms (SNPs) as robust (stable) markers of genetic variation for phylogenetic analysis. We identify ~92k SNP across a global collection of 1,601 genomes. The SNP-based phylogeny is consistent with the gold-standard regions of difference (RD) classification system. Of the ~7k strain-specific SNPs identified, 62 markers are proposed to discriminate known circulating strains. This SNP-based barcode is the first to cover all main lineages, and classifies a greater number of sublineages than current alternatives. It may be used to classify clinical isolates to evaluate tools to control the disease, including therapeutics and vaccines whose effectiveness may vary by strain type. PMID:25176035

  20. Fine definition of the pedigree haplotypes of closely related rice cultivars by means of genome-wide discovery of single-nucleotide polymorphisms

    PubMed Central

    2010-01-01

    Background To create useful gene combinations in crop breeding, it is necessary to clarify the dynamics of the genome composition created by breeding practices. A large quantity of single-nucleotide polymorphism (SNP) data is required to permit discrimination of chromosome segments among modern cultivars, which are genetically related. Here, we used a high-throughput sequencer to conduct whole-genome sequencing of an elite Japanese rice cultivar, Koshihikari, which is closely related to Nipponbare, whose genome sequencing has been completed. Then we designed a high-throughput typing array based on the SNP information by comparison of the two sequences. Finally, we applied this array to analyze historical representative rice cultivars to understand the dynamics of their genome composition. Results The total 5.89-Gb sequence for Koshihikari, equivalent to 15.7× the entire rice genome, was mapped using the Pseudomolecules 4.0 database for Nipponbare. The resultant Koshihikari genome sequence corresponded to 80.1% of the Nipponbare sequence and led to the identification of 67 051 SNPs. A high-throughput typing array consisting of 1917 SNP sites distributed throughout the genome was designed to genotype 151 representative Japanese cultivars that have been grown during the past 150 years. We could identify the ancestral origin of the pedigree haplotypes in 60.9% of the Koshihikari genome and 18 consensus haplotype blocks which are inherited from traditional landraces to current improved varieties. Moreover, it was predicted that modern breeding practices have generally decreased genetic diversity Conclusions Detection of genome-wide SNPs by both high-throughput sequencer and typing array made it possible to evaluate genomic composition of genetically related rice varieties. With the aid of their pedigree information, we clarified the dynamics of chromosome recombination during the historical rice breeding process. We also found several genomic regions decreasing genetic diversity which might be caused by a recent human selection in rice breeding. The definition of pedigree haplotypes by means of genome-wide SNPs will facilitate next-generation breeding of rice and other crops. PMID:20423466

  1. Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques.

    PubMed

    Kraft, Peter; Cox, David G; Paynter, Randi A; Hunter, David; De Vivo, Immaculata

    2005-04-01

    Population-based case-control studies measuring associations between haplotypes of single nucleotide polymorphisms (SNPs) are increasingly popular, in part because haplotypes of a few "tagging" SNPs may serve as surrogates for variation in relatively large sections of the genome. Due to current technological limitations, haplotypes in cases and controls must be inferred from unphased genotypic data. Using individual-specific inferred haplotypes as covariates in standard epidemiologic analyses (e.g., conditional logistic regression) is an attractive analysis strategy, as it allows adjustment for nongenetic covariates, provides omnibus and haplotype-specific tests of association, and can estimate haplotype and haplotype x environment interaction effects. In principle, some adjustment for the uncertainty in inferred haplotypes should be made. Via simulation, we compare the performance (bias and mean squared error of haplotype and haplotype x environment interaction effect estimates) of several analytic strategies using inferred haplotypes in the context of matched case-control data. These strategies include using only the most likely haplotype assignment, the expectation substitution approach described by Stram et al. ([2003b] Hum. Hered. 55:179-190) and others, and an improper version of multiple imputation. For relatively uncomplicated haplotype structures and moderate haplotype relative risks (haplotype and multiple imputation strategies showed noticeable bias towards the null; the expectation substitution strategy still performed well. When there was more uncertainty in the inferred haplotypes, the most likely and multiple imputation strategies showed even more bias towards the null, while the expectation substitution method had slightly smaller than nominal confidence intervals for larger relative risks (>/=5). An application to progesterone-receptor haplotypes and endometrial cancer further illustrates that the performance of all these methods depends on how well the observed haplotypes "tag" the unobserved causal variant. PMID:15637718

  2. Genetic variability and haplotype profile of MDR1 (ABCB1) in Roma and Hungarian population samples with a review of the literature.

    PubMed

    Sipeky, Csilla; Csongei, Veronika; Jaromi, Luca; Safrany, Eniko; Maasz, Anita; Takacs, Istvan; Beres, Judit; Fodor, Lajos; Szabo, Melinda; Melegh, Bela

    2011-01-01

    The genetic variability, haplotype profile and ethnic differences of MDR1 polymorphisms in healthy Roma and Hungarian populations were analyzed and the results were compared with those of other populations available from the literature. Healthy subjects (465 Roma and 503 Hungarian) were genotyped for C1236T, G2677T/A and C3435T variants of MDR1 by PCR-RFLP assay. Differences were found between the Roma and Hungarian populations in the frequencies of MDR1 1236 CC (20.7 vs. 33.2%) and TT genotypes (30.8 vs. 21.9%), in T allele frequency (0.551 vs. 0.443) (p < 0.002), and in 3435T allele frequency (0.482 vs. 0.527, p < 0.04). Furthermore, the frequency of CGC, CGT and CTT haplotypes was significantly higher in the Hungarian population than in Roma (41.4 vs. 35.3%, 9.04 vs. 6.02% and 2.88 vs. 1.08%, respectively; p < 0.009), whereas the frequency of TGC and TTC haplotypes was higher in the Roma population than in the Hungarian (7.31 vs. 1.68% and 6.67 vs. 2.08%, respectively; p < 0.001). The prevalence of MDR1 polymorphisms in the Hungarian population is similar to that of other European populations; however, some differences were observed in the haplotype structures. In contrast, the Roma population differs from Hungarians, from Caucasians and from populations from India in the incidence of MDR1 common variants and haplotypes. PMID:21178299

  3. 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. PMID:25703136

  4. 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.

  5. Analysis of MHC class I genes across horse MHC haplotypes

    PubMed Central

    Tallmadge, Rebecca L.; Campbell, Julie A.; Miller, Donald C.; Antczak, Douglas F.

    2010-01-01

    The genomic sequences of 15 horse Major Histocompatibility Complex (MHC) class I genes and a collection of MHC class I homozygous horses of five different haplotypes were used to investigate the genomic structure and polymorphism of the equine MHC. A combination of conserved and locus-specific primers was used to amplify horse MHC class I genes with classical and non-classical characteristics. Multiple clones from each haplotype identified three to five classical sequences per homozygous animal, and two to three non-classical sequences. Phylogenetic analysis was applied to these sequences and groups were identified which appear to be allelic series, but some sequences were left ungrouped. Sequences determined from MHC class I heterozygous horses and previously described MHC class I sequences were then added, representing a total of ten horse MHC haplotypes. These results were consistent with those obtained from the MHC homozygous horses alone, and 30 classical sequences were assigned to four previously confirmed loci and three new provisional loci. The non-classical genes had few alleles and the classical genes had higher levels of allelic polymorphism. Alleles for two classical loci with the expected pattern of polymorphism were found in the majority of haplotypes tested, but alleles at two other commonly detected loci had more variation outside of the hypervariable region than within. Our data indicate that the equine Major Histocompatibility Complex is characterized by variation in the complement of class I genes expressed in different haplotypes in addition to the expected allelic polymorphism within loci. PMID:20099063

  6. H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population.

    PubMed

    Almos, P Z; Horváth, S; Czibula, A; Raskó, I; Sipos, B; Bihari, P; Béres, J; Juhász, A; Janka, Z; Kálmán, J

    2008-11-01

    In this study, we examine the frequency of a 900 kb inversion at 17q21.3 in the Gypsy and Caucasian populations of Hungary, which may reflect the Asian origin of Gypsy populations. Of the two haplotypes (H1 and H2), H2 is thought to be exclusively of Caucasian origin, and its occurrence in other racial groups is likely to reflect admixture. In our sample, the H1 haplotype was significantly more frequent in the Gypsy population (89.8 vs 75.5%, P<0.001) and was in Hardy-Weinberg disequilibrium (P=0.017). The 17q21.3 region includes the gene of microtubule-associated protein tau, and this result might imply higher sensitivity to H1 haplotype-related multifactorial tauopathies among Gypsies. PMID:18648385

  7. SNP genotyping of animal and human derived isolates of Mycobacterium avium subsp. paratuberculosis.

    PubMed

    Wynne, James W; Beller, Christie; Boyd, Victoria; Francis, Barry; Gwo?d?, Jacek; Carajias, Marios; Heine, Hans G; Wagner, Josef; Kirkwood, Carl D; Michalski, Wojtek P

    2014-08-27

    Mycobacterium avium subsp. paratuberculosis (MAP) is the aetiological agent of Johne's disease (JD), a chronic granulomatous enteritis that affects ruminants worldwide. While the ability of MAP to cause disease in animals is clear, the role of this bacterium in human inflammatory bowel diseases remains unresolved. Previous whole genome sequencing of MAP isolates derived from human and three animal hosts showed that human isolates were genetically similar and showed a close phylogenetic relationship to one bovine isolate. In contrast, other animal derived isolates were more genetically diverse. The present study aimed to investigate the frequency of this human strain across 52 wild-type MAP isolates, collected predominantly from Australia. A Luminex based SNP genotyping approach was utilised to genotype SNPs that had previously been shown to be specific to the human, bovine or ovine isolate types. Fourteen SNPs were initially evaluated across a reference panel of isolates with known genotypes. A subset of seven SNPs was chosen for analysis within the wild-type collection. Of the seven SNPs, three were found to be unique to paediatric human isolates. No wild-type isolates contain these SNP alleles. Interestingly, and in contrast to the paediatric isolates, three additional adult human isolates (derived from adult Crohn's disease patients) also did not contain these SNP alleles. Furthermore we identified two SNPs, which demonstrate extensive polymorphism within the animal-derived MAP isolates. One of which appears unique to ovine and a single camel isolate. From this study we suggest the existence of genetic heterogeneity between human derived MAP isolates, some of which are highly similar to those derived from bovine hosts, but others of which are more divergent. PMID:24970365

  8. A custom correlation coefficient (CCC) approach for fast identification of multi-SNP association patterns in genome-wide SNPs data.

    PubMed

    Climer, Sharlee; Yang, Wei; de las Fuentes, Lisa; Dávila-Román, Victor G; Gu, C Charles

    2014-11-01

    Complex diseases are often associated with sets of multiple interacting genetic factors and possibly with unique sets of the genetic factors in different groups of individuals (genetic heterogeneity). We introduce a novel concept of custom correlation coefficient (CCC) between single nucleotide polymorphisms (SNPs) that address genetic heterogeneity by measuring subset correlations autonomously. It is used to develop a 3-step process to identify candidate multi-SNP patterns: (1) pairwise (SNP-SNP) correlations are computed using CCC; (2) clusters of so-correlated SNPs identified; and (3) frequencies of these clusters in disease cases and controls compared to identify disease-associated multi-SNP patterns. This method identified 42 candidate multi-SNP associations with hypertensive heart disease (HHD), among which one cluster of 22 SNPs (six genes) included 13 in SLC8A1 (aka NCX1, an essential component of cardiac excitation-contraction coupling) and another of 32 SNPs had 29 from a different segment of SLC8A1. While allele frequencies show little difference between cases and controls, the cluster of 22 associated alleles were found in 20% of controls but no cases and the other in 3% of controls but 20% of cases. These suggest that both protective and risk effects on HHD could be exerted by combinations of variants in different regions of SLC8A1, modified by variants from other genes. The results demonstrate that this new correlation metric identifies disease-associated multi-SNP patterns overlooked by commonly used correlation measures. Furthermore, computation time using CCC is a small fraction of that required by other methods, thereby enabling the analyses of large GWAS datasets. PMID:25168954

  9. 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. [Univ. of Ioannina (Greece)] [and others] [Univ. of Ioannina (Greece); and others

    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.

  10. Determination of beta-globin gene cluster haplotypes and prevalence of alpha-thalassemia in sickle cell anemia patients in Venezuela.

    PubMed

    Arends, A; Alvarez, M; Velázquez, D; Bravo, M; Salazar, R; Guevara, J M; Castillo, O

    2000-06-01

    Sickle cell anemia and alpha-thalassemia have a heterogeneous distribution in Venezuela with a high frequency in the coastal area (sea level) and few cases in the mountains. Most of our population is an ethnic admixture of Europeans (Spaniards colonists), Africans (slaves), and Amerindians. The purpose of our study was to determine the origin of the beta(s) globin haplotype, age and survival dependency, and the admixture among the different African groups in our population. The alpha(3.7) globin gene deletion status was also studied and found in a very high frequency. DNA from peripheral blood of 191 non-related patients (81 with HbS homozygous and 15 patients compound heterozygous for HbS, HbC, HbD with beta-thalassemia, and 95 with sickle cell trait) were studied. The beta(s) chromosome was linked 51% to the Benin Haplotype, 29.5% with the CAR, 12.5% to the Senegal, and 2.5% to the Cameroon. We did not find any significant difference between the haplotype distribution among adults and children and among sickle cell patients and traits. Only 8.6% of the patients have homozygosity for the Benin haplotype. These results show a very high frequency of admixture in our African origin population. PMID:10814985

  11. snpTree - a web-server to identify and construct SNP trees from whole genome sequence data

    PubMed Central

    2012-01-01

    Background The advances and decreasing economical cost of whole genome sequencing (WGS), will soon make this technology available for routine infectious disease epidemiology. In epidemiological studies, outbreak isolates have very little diversity and require extensive genomic analysis to differentiate and classify isolates. One of the successfully and broadly used methods is analysis of single nucletide polymorphisms (SNPs). Currently, there are different tools and methods to identify SNPs including various options and cut-off values. Furthermore, all current methods require bioinformatic skills. Thus, we lack a standard and simple automatic tool to determine SNPs and construct phylogenetic tree from WGS data. Results Here we introduce snpTree, a server for online-automatic SNPs analysis. This tool is composed of different SNPs analysis suites, perl and python scripts. snpTree can identify SNPs and construct phylogenetic trees from WGS as well as from assembled genomes or contigs. WGS data in fastq format are aligned to reference genomes by BWA while contigs in fasta format are processed by Nucmer. SNPs are concatenated based on position on reference genome and a tree is constructed from concatenated SNPs using FastTree and a perl script. The online server was implemented by HTML, Java and python script. The server was evaluated using four published bacterial WGS data sets (V. cholerae, S. aureus CC398, S. Typhimurium and M. tuberculosis). The evalution results for the first three cases was consistent and concordant for both raw reads and assembled genomes. In the latter case the original publication involved extensive filtering of SNPs, which could not be repeated using snpTree. Conclusions The snpTree server is an easy to use option for rapid standardised and automatic SNP analysis in epidemiological studies also for users with limited bioinformatic experience. The web server is freely accessible at http://www.cbs.dtu.dk/services/snpTree-1.0/. PMID:23281601

  12. Morbidity, beta S haplotype and alpha-globin gene patterns among sickle cell anemia patients in Kuwait.

    PubMed

    Adekile, A D; Haider, M Z

    1996-01-01

    Admission records of children with sickle cell anemia (SS), in the two main teaching hospitals in Kuwait, were reviewed for a 1-year period. The haplotypes of 92 beta s chromosomes (from 39 SS, 11 AS, 2 S beta-thalassemia [S beta-thal] and 1 SD individuals) were determined using an allele-specific oligonucleotide (ASO) hybridization technique, while the alpha-globin gene status of 27 SS and 33 AS individuals, i.e. 120 chromosomes, was determined with a combination of polymerase chain reaction and AS techniques. A vasooclusive crisis was the most common (60.0%) cause of hospitalization, followed by infections (20%). Hospital admissions were most common during the hottest month of the year (July). Few complications of the disease were seen among patients on follow-up; however, splenomegaly was present in 24.0%, hepatomegaly in 15.2%, gallstones in 15.2% and aseptic necrosis of the femoral head in 6.1%. Haplotype 31 (Saudi Arabia/India) is the most frequent in this community, being present in 80.4% of the chromosomes tested; Benin haplotype 19 was found in 12.0% and Bantu haplotype 20 in 6.5%. Hb F in the haplotype 31 homozygotes and heterozygotes ranged from 11.4 to 35.1% (mean 22.5 +/- 5.2%). The frequency of alpha-thal determinants in the study was 40.0%, the commonest being the -alpha 3.7-kb deletion (27.5%), the alpha 2 polyadenylation signal (AATAAA-> AATAAG) mutation (10.2%) and the IVS-I 5' end GAGGT-GAGG->GAGG pentanucleotide (5 nt) deletion (3.3%). SS patients with coexistent alpha-thal trait did not have severe recurrent infections and none had gallstones. The high frequencies of the Saudi Arabia/India beta s haplotype and alpha-thalassemia trait contribute to the mild nature of SS disease among Kuwaiti Arabs comparable to that in eastern Saudi Arabia. PMID:8876612

  13. The distribution of human leukocyte antigen-A, B, and -DRB1 alleles and haplotypes based on high-resolution genotyping of 167 families from Jiangsu Province, China

    Microsoft Academic Search

    Qin-Qin Pan; Su Fan; Xiao-Yan Wang; Meng Pan; Xing Zhao; Xiao-Yu Zhou; Cheng-Ya Wang; Jie Shen

    2011-01-01

    We investigated the human leukocyte antigen (HLA)-A, -B, and -DRB1 allele frequencies, the A–B–DRB1, A–B, B–DRB1, and A–DRB1 haplotype frequencies, and the characteristics of linkage disequilibrium between 2 loci in high resolution based on 167 unrelated families from Jiangsu Province, China. A total of 26 alleles at the A locus, 55 alleles at the B locus, and 34 alleles at

  14. Absence of photoperiod effects on mating and ovarian maturation by three haplotypes of potato psyllid, Bactericera cockerelli (Hemiptera: Triozidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We examined the effects of photoperiod on reproductive diapause of three haplotypes of potato psyllid, Bactericera cockerelli (Hemiptera: Triozidae), collected from three geographic locations: south Texas (Central haplotype), California (Western haplotype), and Washington State (Northwestern haploty...

  15. Chloroquine-Resistant Haplotype Plasmodium falciparum Parasites, Haiti

    PubMed Central

    Londono, Berlin L.; Eisele, Thomas P.; Keating, Joseph; Bennett, Adam; Chattopadhyay, Chandon; Heyliger, Gaetan; Mack, Brian; Rawson, Ian; Vely, Jean-Francois; Désinor, Olbeg

    2009-01-01

    Plasmodium falciparum parasites have been endemic to Haiti for >40 years without evidence of chloroquine (CQ) resistance. In 2006 and 2007, we obtained blood smears for rapid diagnostic tests (RDTs) and filter paper blots of blood from 821 persons by passive and active case detection. P. falciparum infections diagnosed for 79 persons by blood smear or RDT were confirmed by PCR for the small subunit rRNA gene of P. falciparum. Amplification of the P. falciparum CQ resistance transporter (pfcrt) gene yielded 10 samples with amplicons resistant to cleavage by ApoI. A total of 5 of 9 samples had threonine at position 76 of pfcrt, which is consistent with CQ resistance (haplotypes at positions 72–76 were CVIET [n = 4] and CVMNT [n = 1]); 4 had only the wild-type haplotype associated with CQ susceptibility (CVMNK). These results indicate that CQ-resistant haplotype P. falciparum malaria parasites are present in Haiti. PMID:19402959

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

    PubMed

    Wu, Jingli; Chen, Xixi; Li, Xianchen

    2014-01-01

    The minimum error correction model is an important combinatorial model for haplotyping a single individual. In this article, triploid individual haplotype reconstruction problem is studied by using the model. A genetic algorithm based method GTIHR is presented for reconstructing the triploid individual haplotype. A novel coding method and an effectual hill-climbing operator are introduced for the GTIHR algorithm. This relatively short chromosome code can lead to a smaller solution space, which plays a positive role in speeding up the convergence process. The hill-climbing operator ensures algorithm GTIHR converge at a good solution quickly, and prevents premature convergence simultaneously. The experimental results prove that algorithm GTIHR can be implemented efficiently, and can get higher reconstruction rate than previous algorithms. PMID:25227091

  17. The Usage of an SNP-SNP Relationship Matrix for Best Linear Unbiased Prediction (BLUP) Analysis Using a Community-Based Cohort Study

    PubMed Central

    Lee, Young-Sup; Kim, Hyeon-Jeong; Cho, Seoae

    2014-01-01

    Best linear unbiased prediction (BLUP) has been used to estimate the fixed effects and random effects of complex traits. Traditionally, genomic relationship matrix-based (GRM) and random marker-based BLUP analyses are prevalent to estimate the genetic values of complex traits. We used three methods: GRM-based prediction (G-BLUP), random marker-based prediction using an identity matrix (so-called single-nucleotide polymorphism [SNP]-BLUP), and SNP-SNP variance-covariance matrix (so-called SNP-GBLUP). We used 35,675 SNPs and R package "rrBLUP" for the BLUP analysis. The SNP-SNP relationship matrix was calculated using the GRM and Sherman-Morrison-Woodbury lemma. The SNP-GBLUP result was very similar to G-BLUP in the prediction of genetic values. However, there were many discrepancies between SNP-BLUP and the other two BLUPs. SNP-GBLUP has the merit to be able to predict genetic values through SNP effects. PMID:25705167

  18. Determination of ?S haplotypes in patients with sickle-cell anemia in the state of Rio Grande do Norte, Brazil

    PubMed Central

    Cabral, Cynthia Hatsue Kitayama; Serafim, Édvis Santos Soares; de Medeiros, Waleska Rayane Dantas Bezerra; de Medeiros Fernandes, Thales Allyrio Araújo; Kimura, Elza Miyuki; Costa, Fernando Ferreira; de Fátima Sonati, Maria; Rebecchi, Ivanise Marina Moretti; de Medeiros, Tereza Maria Dantas

    2011-01-01

    ?S haplotypes were studied in 47 non-related patients with sickle-cell anemia from the state of Rio Grande do Norte, Brazil. Molecular analysis was conducted by PCR/RFLP using restriction endonucleases XmnI, HindIII, HincII and HinfI to analyze six polymorphic sites from the beta cluster. Twenty-seven patients (57.5%) were identified with genotype CAR/CAR, 9 (19.1%) CAR/BEN, 6 (12.8%) CAR/CAM, 1 (2.1%) BEN/BEN, 2 (4.3%) CAR/Atp, 1 (2.1%) BEN/Atp and 1 (2.1%) with genotype Atp/Atp. The greater frequency of Cameroon haplotypes compared to other Brazilian states suggests the existence of a peculiarity of African origin in the state of Rio Grande do Norte. PMID:21931513

  19. Distribution of MICA alleles and haplotypes associated with HLA in the Korean population.

    PubMed

    Pyo, Chul-Woo; Hur, Seong-Suk; Kim, Yang-Kyum; Choi, Hee-Baeg; Kim, Tae-Yoon; Kim, Tai-Gyu

    2003-03-01

    The MICA (MHC class I chain-related gene A) is a polymorphic gene located 46 kb centromeric of the HLA-B gene, and is preferentially expressed in epithelial cells and intestinal mucosa. The MICA gene, similar to human leukocyte antigen (HLA) class I, displays a high degree of genetic polymorphism in exons 2, 3, 4, and 5, amounting to 54 alleles. In this study, we investigated the polymorphisms at exons coding for extracellular domains (exons 2, 3, and 4), and the GCT repeat polymorphism at the transmembrane (exon 5) of MICA in 199 unrelated healthy Koreans. Eight alleles were observed in the Korean population, with allele frequencies for MICA*010, MICA*00201, MICA*027, MICA*004, MICA*012, MICA*00801, MICA*00901, and MICA*00701 being 18.3%, 17.8%, 13.6%, 12.3%, 11.1%, 10.8%, 10.6%, and 3.3%, respectively. Strong linkage disequilibria were also observed between the MICA and HLA-B gene-MICA*00201-B58, MICA*004-B44, MICA*00701-B27, MICA*00801-B60, MICA*00901-B51, MICA*010-B62, MICA*012-B54, and MICA*027-B61. In the analysis of the haplotypes of HLA class I genes (HLA-A, B, and C) and the MICA, the most common haplotype was MICA*004-A33-B44-Cw*07, followed by MICA*00201-A2-B58-Cw*0302 and MICA*012-A2-B54-Cw*0102. The MICA null haplotype might be identified in the HLA-B48 homozygous individual. These results will provide an understanding of the role of MICA in transplantation, disease association, and population analyses in Koreans. PMID:12590984

  20. Haplotype analysis of ApoAI gene and sepsis-associated acute lung injury

    PubMed Central

    2014-01-01

    Background Apolipoprotein A1 (ApoA1) is the major apoprotein constituent of high density lipoprotein (HDL) which exerts innate protective effects in systemic inflammation. However, its role in the acute lung injury (ALI) has not been well studied. In the present study we investigated the association between polymorphisms of ApoA1 gene and ALI in a Chinese population. Methods Three polymorphisms of the ApoA1 gene (rs11216153, rs2070665, and rs632153) were genotyped by TaqMan method in 290 patients with sepsis-associated ALI, 285 patients sepsis alone and 330 age- and sex-matched healthy controls. Results We found rs11216153 polymorphism of ApoA1 was associated with ALI, the GG genotype and G allele was common in the ALI patients (76.9%, 88.1%, respectively) than both in the control subjects (55.8%, 75.8%, respectively) and in the sepsis alone patients (58.2%, 78.4%, respectively). Haplotype consisting of these three SNPs strengthened the association with ALI susceptibility. The frequency of haplotype GTG in the ALI samples was significantly higher than that in the healthy control group (OR?=?2.261, 95% CI: 1.735?~?2.946, P <0.001) and the sepsis alone group (OR?=?1.789, 95% CI: 1.373?~?2.331.P?haplotype TTG had a lower risk for ALI compared with healthy control group (OR?=?0.422, 95% CI: 0.310?~?0.574, P?

  1. Linkage Analysis with Dense SNP Maps in Isolated Populations

    Microsoft Academic Search

    Céline Bellenguez; Carole Ober; Catherine Bourgain

    2009-01-01

    Objective: SNP maps are becoming the gold standard for genetic markers, even for linkage analyses. However, because of the density of SNPs on most high throughput platforms, the resulting significant linkage disequilibrium (LD) can bias classical nonparametric multipoint linkage analyses. This problem may be even stronger in population isolates where LD can extend over larger distances and with a more

  2. A Database of Single Nucleotide Polymorphisms: dbSNP

    NSDL National Science Digital Library

    One key aspect of genetics research is associating variations in gene sequences with heritable phenotypes. To that end, the NCBI (National Center for Biotechnology Information) has released the database of human genetic variation (dbSNP), containing "both the experimental conditions used to find each mutation and each mutation's observed variation for populations and individuals."

  3. DISCOVERY AND MAPPING OF FUNCTIONALLY IMPORTANT SNP IN COW GENOME

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cow genome sequencing is underway at Baylor College of Medicine (BCM) sequencing center and will be completed in the next few months. A recent white paper indicated a goal to identify 100,000 SNP for use in identification and mapping of QTL regions. In September 2004, the preliminary assembly of Her...

  4. SNPs in forensic genetics: a review on SNP typing methodologies

    Microsoft Academic Search

    Beatriz Sobrino; María Brión; Angel Carracedo

    2005-01-01

    There is an increasing interest in single nucleotide polymorphism (SNP) typing in the forensic field, not only for the usefulness of SNPs for defining Y chromosome or mtDNA haplogroups or for analyzing the geographical origin of samples, but also for the potential applications of autosomal SNPs. The interest of forensic researchers in autosomal SNPs has been attracted due to the

  5. SEAN: SNP PREDICTION AND DISPLAY PROGRAM UTILIZING EST SEQUENCE CLUSTERS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    SEAN is an application that predicts SNPs using multiple sequence alignments produced from EST clusters. The algorithm uses rules of sequence identity and SNP abundance to determine the quality of the prediction. A Java viewer is provided to display the EST alignments and predicted SNPs....

  6. GENOMIC TECHNOLOGIES FACILITY: Single SNP Genotyping USER/BILLING AGREEMENT

    E-print Network

    Wurtele, Eve Syrkin

    applicable. Invoices will be sent out on a monthly basis and will include charges as follows: Item Fee Single SNP genotyping / reaction (Reagents and labor are included) $0.31/data point Initial consultation $37 indicate that I understand and agree to abide by the above billing procedures Name of User

  7. Analysis of genetic diversity using SNP markers in oat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A large-scale single nucleotide polymorphism (SNP) discovery was carried out in cultivated oat using Roche 454 sequencing methods. DNA sequences were generated from cDNAs originating from a panel of 20 diverse oat cultivars, and from Diversity Array Technology (DArT) genomic complexity reductions fr...

  8. SNP Discovery through Next-Generation Sequencing and Its Applications

    PubMed Central

    Kumar, Santosh; Banks, Travis W.; Cloutier, Sylvie

    2012-01-01

    The decreasing cost along with rapid progress in next-generation sequencing and related bioinformatics computing resources has facilitated large-scale discovery of SNPs in various model and nonmodel plant species. Large numbers and genome-wide availability of SNPs make them the marker of choice in partially or completely sequenced genomes. Although excellent reviews have been published on next-generation sequencing, its associated bioinformatics challenges, and the applications of SNPs in genetic studies, a comprehensive review connecting these three intertwined research areas is needed. This paper touches upon various aspects of SNP discovery, highlighting key points in availability and selection of appropriate sequencing platforms, bioinformatics pipelines, SNP filtering criteria, and applications of SNPs in genetic analyses. The use of next-generation sequencing methodologies in many non-model crops leading to discovery and implementation of SNPs in various genetic studies is discussed. Development and improvement of bioinformatics software that are open source and freely available have accelerated the SNP discovery while reducing the associated cost. Key considerations for SNP filtering and associated pipelines are discussed in specific topics. A list of commonly used software and their sources is compiled for easy access and reference. PMID:23227038

  9. Development of Single Nucleotide Polymorphism (SNP) Markers for Use in Commercial Maize (Zea Mays L.) Germplasm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The development of single nucleotide polymorphism (SNP) markers in maize offer the opportunity to utilize DNA markers in many new areas of population genetics, gene discovery, plant breeding, and germplasm identification. However, the steps from sequencing and SNP discovery to SNP marker design and ...

  10. High-throughput SNP genotyping for breeding applications in rice using the BeadXpress platform

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Multiplexed single nucleotide polymorphism (SNP) markers have the potential to increase the speed and cost-effectiveness of genotyping, provided that an optimal SNP density is used for each application. To test the efficiency of multiplexed SNP genotyping for diversity, mapping and breeding applicat...

  11. Measuring inbreeding and inbreeding depression on pig growth from pedigree or SNP-derived metrics.

    PubMed

    Silió, L; Rodríguez, M C; Fernández, A; Barragán, C; Benítez, R; Óvilo, C; Fernández, A I

    2013-10-01

    Multilocus homozygosity, measured as the proportion of the autosomal genome in homozygous genotypes or in runs of homozygosity, was compared with the respective pedigree inbreeding coefficients in 64 Iberian pigs genotyped using the Porcine SNP60 Beadchip. Pigs were sampled from a set of experimental animals with a large inbreeding variation born in a closed strain with a completely recorded multi-generation genealogy. Individual inbreeding coefficients calculated from pedigree were strongly correlated with the different SNP-derived metrics of homozygosity (r = 0.814-0.919). However, unequal correlations between molecular and pedigree inbreeding were observed at chromosomal level being mainly dependent on the number of SNPs and on the correlation between heterozygosities measured across different loci. A panel of 192 SNPs of intermediate frequencies was selected for genotyping 322 piglets to test inbreeding depression on postweaning growth performance (daily gain and weight at 90 days). The negative effects on these traits of homozygosities calculated from the genotypes of 168 quality-checked SNPs were similar to those of inbreeding coefficients. The results support that few hundreds of SNPs may be useful for measuring inbreeding and inbreeding depression, when the population structure or the mating system causes a large variance of inbreeding. PMID:24074172

  12. SNP discovery in complex allotetraploid genomes (Gossypium spp., Malvaceae) using genotyping by sequencing1

    PubMed Central

    Logan-Young, Carla Jo; Yu, John Z.; Verma, Surender K.; Percy, Richard G.; Pepper, Alan E.

    2015-01-01

    Premise of the study: Single-nucleotide polymorphism (SNP) marker discovery in plants with complex allotetraploid genomes is often confounded by the presence of homeologous loci (along with paralogous and orthologous loci). Here we present a strategy to filter for SNPs representing orthologous loci. Methods and Results: Using Illumina next-generation sequencing, 54 million reads were collected from restriction enzyme–digested DNA libraries of a diversity of Gossypium taxa. Loci with one to three SNPs were discovered using the Stacks software package, yielding 25,529 new cotton SNP combinations, including those that are polymorphic at both interspecific and intraspecific levels. Frequencies of predicted dual-homozygous (aa/bb) marker polymorphisms ranged from 6.7–11.6% of total shared fragments in intraspecific comparisons and from 15.0–16.4% in interspecific comparisons. Conclusions: This resource provides dual-homozygous (aa/bb) marker polymorphisms. Both in silico and experimental validation efforts demonstrated that these markers are enriched for single orthologous loci that are homozygous for alternative alleles.

  13. An HMM-based boundary-flexible model of human haplotype variation

    E-print Network

    Sheffi, Jonathan, 1981-

    2004-01-01

    The construction of a meaningful and detailed description of haplotype variation holds the promise for more powerful genetic association studies. The segmentation of the human genome into blocks of limited haplotype diversity ...

  14. Effect of 593C>T GPx1 SNP alone and in synergy with 47C>T SOD2 SNP on the outcome of critically ill patients.

    PubMed

    Majolo, Fernanda; Oliveira Paludo, Francis Jackson de; Ponzoni, Aline; Graebin, Pietra; Dias, Fernando Suparregui; Alho, Clarice Sampaio

    2015-02-01

    During critical illness and sepsis there is severe antioxidant depletion, and this scenario raises the critical ill patient's mortality risk. Glutathione peroxidase (GPx) is one of the first endogenous antioxidant defense enzymes, and it works cooperatively with superoxide dismutase (SOD) and catalase (CAT) to detoxify free radicals from the cellular environment. Genetic studies are important to understand the complexity of human oxidative stress and how the organism responds to an extreme situation such as critically care conditions. Previous studies with a GPx1 single nucleotide polymorphism (593C>T SNP; rs1050450; protein variant in GPx1: Pro198Leu) showed 593T carriers and 593TT homozygotes present higher risk to develop different diseases. We assessed the relationship of the genotype distribution of GPx1 SNP in critically ill patients with their conditions (organ dysfunction, sepsis, and septic shock) and their outcome. We monitored 626 critically ill patients daily from the ICU (intensive care unit) admission to their discharge from hospital, or death. Our study revealed a significant association between 593TT GPx1 genotype and mortality; the mortality rate was higher in homozygous 593TT GPx1 (N=94) when compared with the group of subjects with genotypes 593CT or 593CC GPx1 (N=532) (52% vs. 38%, P=0.009; OR=1.79; 95% CI=1.13-2.85). Evaluating the subgroup of 293 ICU patients with sepsis, a pooled analysis including two genetic variants GPx1 and SOD2 (47C>T SNP, rs4880; protein variant in MnSOD: Ala-9Val) showed a significant difference in relation to progression to septic shock. The frequency of septic shock among septic patients with 593T GPx1 and 47C SOD2 alleles (N=122) was higher when compared with septic patients carrying other settings of genotypes (N=174) (78% vs. 66%; P=0.028; OR=1.81; 95% CI=1.03-3.18). Accepting the previously reported functional effects of these two SNPs on GPx1 and SOD2 gene expressions and, consequently, on GPx1 and MnSOD enzyme activities, we believe our results may be considered as an important contribution for the understanding of oxidative imbalance during the critical ill. PMID:25497738

  15. High throughput SNP discovery and validation in the pig: towards the development of a high density swine SNP chip

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent developments in sequencing technology have allowed the generation of millions of short read sequences in a fast and inexpensive way. This enables the cost effective large scale identification of hundreds of thousands of SNPs needed for the development of high density SNP arrays. Currently, a ...

  16. Summarizing techniques that combine three non-parametric scores to detect disease-associated 2-way SNP-SNP interactions.

    PubMed

    Sengupta Chattopadhyay, Amrita; Hsiao, Ching-Lin; Chang, Chien Ching; Lian, Ie-Bin; Fann, Cathy S J

    2014-01-01

    Identifying susceptibility genes that influence complex diseases is extremely difficult because loci often influence the disease state through genetic interactions. Numerous approaches to detect disease-associated SNP-SNP interactions have been developed, but none consistently generates high-quality results under different disease scenarios. Using summarizing techniques to combine a number of existing methods may provide a solution to this problem. Here we used three popular non-parametric methods-Gini, absolute probability difference (APD), and entropy-to develop two novel summary scores, namely principle component score (PCS) and Z-sum score (ZSS), with which to predict disease-associated genetic interactions. We used a simulation study to compare performance of the non-parametric scores, the summary scores, the scaled-sum score (SSS; used in polymorphism interaction analysis (PIA)), and the multifactor dimensionality reduction (MDR). The non-parametric methods achieved high power, but no non-parametric method outperformed all others under a variety of epistatic scenarios. PCS and ZSS, however, outperformed MDR. PCS, ZSS and SSS displayed controlled type-I-errors (<0.05) compared to GS, APDS, ES (>0.05). A real data study using the genetic-analysis-workshop 16 (GAW 16) rheumatoid arthritis dataset identified a number of interesting SNP-SNP interactions. PMID:24076437

  17. Large-Scale SNP Discovery through RNA Sequencing and SNP Genotyping by Targeted Enrichment Sequencing in Cassava (Manihot esculenta Crantz)

    PubMed Central

    Pootakham, Wirulda; Shearman, Jeremy R.; Ruang-areerate, Panthita; Sonthirod, Chutima; Sangsrakru, Duangjai; Jomchai, Nukoon; Yoocha, Thippawan; Triwitayakorn, Kanokporn; Tragoonrung, Somvong; Tangphatsornruang, Sithichoke

    2014-01-01

    Cassava (Manihot esculenta Crantz) is one of the most important crop species being the main source of dietary energy in several countries. Marker-assisted selection has become an essential tool in plant breeding. Single nucleotide polymorphism (SNP) discovery via transcriptome sequencing is an attractive strategy for genome complexity reduction in organisms with large genomes. We sequenced the transcriptome of 16 cassava accessions using the Illumina HiSeq platform and identified 675,559 EST-derived SNP markers. A subset of those markers was subsequently genotyped by capture-based targeted enrichment sequencing in 100 F1 progeny segregating for starch viscosity phenotypes. A total of 2,110 non-redundant SNP markers were used to construct a genetic map. This map encompasses 1,785 cM and consists of 19 linkage groups. A major quantitative trait locus (QTL) controlling starch pasting properties was identified and shown to coincide with the QTL previously reported for this trait. With a high-density SNP-based linkage map presented here, we also uncovered a novel QTL associated with starch pasting time on LG 10. PMID:25551642

  18. Detecting recent positive selection in the human genome from haplotype structure

    Microsoft Academic Search

    Pardis C. Sabeti; David E. Reich; John M. Higgins; Haninah Z. P. Levine; Daniel J. Richter; Stephen F. Schaffner; Stacey B. Gabriel; Jill V. Platko; Nick J. Patterson; Gavin J. McDonald; Hans C. Ackerman; Sarah J. Campbell; David Altshuler; Richard Cooper; Dominic Kwiatkowski; Ryk Ward; Eric S. Lander

    2002-01-01

    The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the

  19. Computational Problems in Perfect Phylogeny Haplotyping: Xor-Genotypes and Tag SNPs

    E-print Network

    Shamir, Ron

    0 Computational Problems in Perfect Phylogeny Haplotyping: Xor-Genotypes and Tag SNPs Tamar Barzuza phylogeny model for haplotype evolution has been successfully applied to haplotype resolution from genotype in the design and analysis of genetic studies. We consider a novel type of data, xor-genotypes, which

  20. An approach to mapping haplotype-specific recombination sites in human MHC class III

    SciTech Connect

    Levo, A.; Westman, P.; Partanen, J. [Finnish Red Cross Blood Transfusion Service, Helsinki (Finland)

    1996-12-31

    Studies of the major histocompatibility complex (MHC) in mouse indicate that the recombination sites are not randomly distributed and their occurrence is haplotype-dependent. No data concerning haplotype-specific recombination sites in human are available due to the low number of informative families. To investigate haplotype-specific recombination sites in human MHC, we describe an approach based on identification of recombinant haplotypes derived from one conserved haplotype at the population level. The recombination sites were mapped by comparing polymorphic markers between the recombinant and assumed original haplotypes. We tested this approach on the extended haplotype HLA A3; B47; Bf{sup *}F; C4A{sup *}1; C4B{sup *}Q0; DR7, which is most suitable for this analysis. First, it carries a number of rare markers, and second, the haplotype, albeit rare in the general population, is frequent in patients with 21-hydroxylase (21OH) defect. We observed recombinants derived from this haplotype in patients with 21OH defect. All these haplotypes had the centromeric part (from Bf to DR) identical to the original haplotype, but they differed in HLA A and B. We therefore assumed that they underwent recombinations in the segment that separates the Bf and HLA B genes. Polymorphic markers indicated that all break points mapped to two segments near the TNF locus. This approach makes possible the mapping of preferential recombination sites in different haplotypes. 20 refs., 1 fig., 1 tab.

  1. The Architecture of Long-Range Haplotypes Shared within and across Populations

    PubMed Central

    Gusev, Alexander; Palamara, Pier Francesco; Aponte, Gregory; Zhuang, Zhong; Darvasi, Ariel; Gregersen, Peter; Pe'er, Itsik

    2012-01-01

    Homologous long segments along the genomes of close or remote relatives that are identical by descent (IBD) from a common ancestor provide clues for recent events in human genetics. We set out to extensively map such IBD segments in large cohorts and investigate their distribution within and across different populations. We report analysis of several data sets, demonstrating that IBD is more common than expected by naďve models of population genetics. We show that the frequency of IBD pairs is population dependent and can be used to cluster individuals into populations, detect a homogeneous subpopulation within a larger cohort, and infer bottleneck events in such a subpopulation. Specifically, we show that Ashkenazi Jewish individuals are all connected through transitive remote family ties evident by sharing of 50 cM IBD to a publicly available data set of less than 400 individuals. We further expose regions where long-range haplotypes are shared significantly more often than elsewhere in the genome, observed across multiple populations, and enriched for common long structural variation. These are inconsistent with recent relatedness and suggest ancient common ancestry, with limited recombination between haplotypes. PMID:21984068

  2. On Detecting Incomplete Soft or Hard Selective Sweeps Using Haplotype Structure

    PubMed Central

    Ferrer-Admetlla, Anna; Liang, Mason; Korneliussen, Thorfinn; Nielsen, Rasmus

    2014-01-01

    We present a new haplotype-based statistic (nSL) for detecting both soft and hard sweeps in population genomic data from a single population. We compare our new method with classic single-population haplotype and site frequency spectrum (SFS)-based methods and show that it is more robust, particularly to recombination rate variation. However, all statistics show some sensitivity to the assumptions of the demographic model. Additionally, we show that nSL has at least as much power as other methods under a number of different selection scenarios, most notably in the cases of sweeps from standing variation and incomplete sweeps. This conclusion holds up under a variety of demographic models. In many aspects, our new method is similar to the iHS statistic; however, it is generally more robust and does not require a genetic map. To illustrate the utility of our new method, we apply it to HapMap3 data and show that in the Yoruban population, there is strong evidence of selection on genes relating to lipid metabolism. This observation could be related to the known differences in cholesterol levels, and lipid metabolism more generally, between African Americans and other populations. We propose that the underlying causes for the selection on these genes are pleiotropic effects relating to blood parasites rather than their role in lipid metabolism. PMID:24554778

  3. Evaluation of Association Between HLA Class II DR4–DQ8 Haplotype and Type I Diabetes Mellitus in Children of East Azerbaijan State of Iran

    PubMed Central

    Sohrabi, Nasrin; Shekari Khaniani, Mahmoud; Mansoori Derakhshan, Sima

    2015-01-01

    Purpose: Association between HLA-DR4–DQ8 haplotype and type 1 Diabetes Mellitus (DM-1A) was investigated in children of East Azerbaijan state of Iran because such an association has not been previously studied in this population. Methods: HLA-typing was performed by polymerase chain reaction sequence-specific priming. For haplotype analysis, the logistic regression model was performed. Results: Of the three investigated alleles, the frequency of DRB1*0401 was significantly higher among patients compared with that in healthy subjects (76.74% vs. 23.26%). Conclusion: The findings of the current study are consistent with those of previous studies and show that DRB1*0401 is associated with DM-1A; the frequencies of the two other alleles were also higher among patients, although the differences were not statistically significant. Two haplotypes associated with these alleles were also surveyed, and DRB1*0401?-DQA1*0301?, and DRB1*0401?-DQA1*0301?-DQB1*0302? were the most frequent haplotypes among the patient group. PMID:25789232

  4. Prion gene haplotypes of U.S. cattle

    Microsoft Academic Search

    Michael L Clawson; Michael P Heaton; John W Keele; Timothy PL Smith; Gregory P Harhay; William W Laegreid

    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

  5. Haplotype Inference in Complex Pedigrees Bonnie Kirkpatrick1

    E-print Network

    Kirkpatrick, Bonnie

    -allelic with both of the al- leles appearing in at least 5% of the population. Current genotyping #12;technologies results due to confounding population structure effects. However, a major challenge for the applicability- lotypes from genotype data. Existing haplotype inference methods either do not efficiently scales

  6. Constrained Hidden Markov Models for Population-based Haplotyping

    E-print Network

    Mannila, Heikki

    (H | G). It is usually assumed that the sample G is in Hardy-Weinberg equi- librium, i.e., that P((h1 g between haplotypes and the available genotype data is defined by Hardy-Weinberg equi- librium. 3 (Hidden

  7. A Survey of Computational Methods for Determining Haplotypes

    Microsoft Academic Search

    Bjarni V. Halldórsson; Vineet Bafna; Nathan Edwards; Ross Lippert; Shibu Yooseph; Sorin Istrail

    2002-01-01

    It is widely anticipated that the study of variation in the human genome will provide a means of predicting risk of a variety of complex diseases. Single nucleotide polymorphisms (SNPs) are the most common form of genomic variation. Haplotypes have been suggested as one means for reducing the complexity of studying SNPs. In this paper we review some of the

  8. HUMAN GENOME VARIATION: HAPLOTYPES, LINKAGE DISEQUILIBRIUM, AND POPULATIONS

    E-print Network

    Kidd, Kenneth

    HUMAN GENOME VARIATION: HAPLOTYPES, LINKAGE DISEQUILIBRIUM, AND POPULATIONS FRANCISCO M. DE LA VEGA@appliedbiosystems.com KENNETH K. KIDD Department of Genetics, Yale University School of Medicine 333 Cedar Street, New Haven, CT_Kohane@Harvard.edu The working draft of a reference sequence of the human genome is nearing completion and is providing a basis

  9. Polymorphisms and haplotype structure of bovine PRND (doppel) and PRNT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE) is a fatal neurological disorder characterized by abnormal deposits of a protease-resistant isoform of the prion protein. In previous studies, we have characterized linkage disequilibrium (LD) and haplotype networks within the bovine prion gene (PRNP). Other ...

  10. Nomenclature of mitochondrial DNA haplotypes for Oncorhynchus mykiss

    USGS Publications Warehouse

    Graziano, S.L.; Brown, K.H.; Nielsen, J.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 presented as a resource for future investigations of this species. ?? Copyright by the American Fisheries Society 2005.

  11. 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 presented as a resource for future investigations of this species.

  12. Inferring Demographic History from a Spectrum of Shared Haplotype Lengths

    E-print Network

    Nielsen, Rasmus

    over a variety of ancient and recent time scales. Using the same technique, we analyze deeply sequenced hominids. In particular, we infer that recent African-European gene flow and ancient ghost admixture haplotype trees of mitochondria and the Y chromosome [1,2] changed our view of human origins by prompting

  13. Analysis of Haplotype Structure in the Bovine Major Histocompatibility Complex

    E-print Network

    Fritz, Krista L.

    2011-02-22

    genes were selected for use in this study. These markers revealed eleven recombination events, low levels of recombination in BoLA IIa-III-I, a sharp break in haplotype structure in the region centromeric to class IIa, prolonged linkage disequilibrium...

  14. Haplotypes of 'Candidatus Liberibacter solanacearum' suggest long-standing separation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Three haplotypes of the recently discovered bacterium species “Candidatus Liberibacter solanacearum” are described and related to geographic ranges. The first two are associated with Zebra Chip/Psyllid Yellows of potatoes and other solanaceous plants, vectored by the tomato/potato psyllid Bacterice...

  15. Lack of association between microRNA-137 SNP rs1625579 and schizophrenia in a replication study of Han Chinese.

    PubMed

    Yuan, Jianmin; Cheng, Zaohuo; Zhang, Fuquan; Zhou, Zhenhe; Yu, Shui; Jin, Chunhui

    2015-02-01

    Schizophrenia (SCZ) is a common, complex and severe psychiatric disorder associated with many different genetic and environmental risk factors. A recent genome-wide association study identified a single-nucleotide polymorphism (SNP, rs1625579) in microRNA-137 (miR-137) as a possible susceptibility locus for SCZ. Hoping to validate this finding, we conducted a case-control study of the Han Chinese population, with 506 SCZ cases and 522 healthy controls, using the Ligase detection reaction-polymerase chain reaction method to genotype the polymorphism rs1625579 in the miR-137 gene. However, we found no significant difference (P > 0.05) in either allele or genotype frequency in this SNP between patients and controls. In addition, a meta-analysis indicated that the 'T' allele of SNP rs1625579 was not associated with susceptibility to SCZ in Han Chinese populations (pooled OR 1.087, 95 % CI 0.847-1.396, P = 0.512). Thus, these results do not support the previous finding suggesting further replication studies using a large-scale association analysis that should be warranted in Han Chinese populations. PMID:25241074

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

    PubMed Central

    Lai, Te-Jen; Wu, Chia-Yen; Tsai, Hsu-Wen; Lin, Yi-Mei J; Sun, H Sunny

    2005-01-01

    Background Disturbances in serotonin neurotransmission are implicated in the etiology of many psychiatric disorders, including bipolar affective disorder (BPD). The tryptophan hydroxylase gene (TPH), which codes for the enzyme catalyzing the rate-limiting step in serotonin biosynthetic pathway, is one of the leading candidate genes for psychiatric and behavioral disorders. In a preliminary study, we found that TPH1 intron7 A218C polymorphism was associated with BPD. This study was designed to investigate sequence variants of the TPH1 gene in Taiwanese and to test whether the TPH1 gene is a susceptibility factor for the BPD. Methods Using a systematic approach, we have searched the exons and promoter region of the TPH1 gene for sequence variants in Taiwanese Han and have identified five variants, A-1067G, G-347T, T3804A, C27224T, and A27237G. These five variants plus another five taken from the literature and a public database were examined for an association in 108 BPD patients and 103 controls; no association was detected for any of the 10 variants. Results Haplotype constructions using these 10 SNPs showed that the 3 most common haplotypes in both patients and controls were identical. One of the fourth common haplotype in the patient group (i.e. GGGAGACCCA) was unique and showed a trend of significance with the disease (P = 0.028). However, the significance was abolished after Bonferroni correction thus suggesting the association is weak. In addition, three haplotype-tagged SNPs (htSNPs) were selected to represent all haplotypes with frequencies larger than 2% in the Taiwanese Han population. The defined TPH1 htSNPs significantly reduce the marker number for haplotype analysis thus provides useful information for future association studies in our population. Conclusion Results of this study did not support the role of TPH1 gene in BPD etiology. As the current studies found the TPH1 gene under investigation belongs to the peripheral serotonin system and may link to a cardiac dysfunction phenotype, a second TPH gene that functions predominantly in the brain (i.e., nTPH or TPH2) should be the target for the future association study. PMID:15799788

  17. 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

  18. SNP discovery and High Resolution Melting Analysis from massive transcriptome sequencing in the California red abalone Haliotis rufescens.

    PubMed

    Valenzuela-Muńoz, Valentina; Araya-Garay, José Miguel; Gallardo-Escárate, Cristian

    2013-06-01

    The California red abalone, Haliotis rufescens that belongs to the Haliotidae family, is the largest species of abalone in the world that has sustained the major fishery and aquaculture production in the USA and Mexico. This native mollusk has not been evaluated or assigned a conservation category even though in the last few decades it was heavily exploited until it disappeared in some areas along the California coast. In Chile, the red abalone was introduced in the 1970s from California wild abalone stocks for the purposes of aquaculture. Considering the number of years that the red abalone has been cultivated in Chile crucial genetic information is scarce and critical issues remain unresolved. This study reports and validates novel single nucleotide polymorphisms (SNP) markers for the red abalone H. rufescens using cDNA pyrosequencing. A total of 622 high quality SNPs were identified in 146 sequences with an estimated frequency of 1 SNP each 1000bp. Forty-five SNPs markers with functional information for gene ontology were selected. Of these, 8 were polymorphic among the individuals screened: Heat shock protein 70 (HSP70), vitellogenin (VTG), lysin, alginate lyase enzyme (AL), Glucose-regulated protein 94 (GRP94), fructose-bisphosphate aldolase (FBA), sulfatase 1A precursor (S1AP) and ornithine decarboxylase antizyme (ODC). Two additional sequences were also identified with polymorphisms but no similarities with known proteins were achieved. To validate the putative SNP markers, High Resolution Melting Analysis (HRMA) was conducted in a wild and hatchery-bred population. Additionally, SNP cross-amplifications were tested in two further native abalone species, Haliotis fulgens and Haliotis corrugata. This study provides novel candidate genes that could be used to evaluate loss of genetic diversity due to hatchery selection or inbreeding effects. PMID:23353006

  19. Development of high-density SNP genotyping arrays for white spruce (Picea glauca) and transferability to subtropical and nordic congeners.

    PubMed

    Pavy, Nathalie; Gagnon, France; Rigault, Philippe; Blais, Sylvie; Deschęnes, Astrid; Boyle, Brian; Pelgas, Betty; Deslauriers, Marie; Clément, Sébastien; Lavigne, Patricia; Lamothe, Manuel; Cooke, Janice E K; Jaramillo-Correa, Juan P; Beaulieu, Jean; Isabel, Nathalie; Mackay, John; Bousquet, Jean

    2013-03-01

    High-density SNP genotyping arrays can be designed for any species given sufficient sequence information of high quality. Two high-density SNP arrays relying on the Infinium iSelect technology (Illumina) were designed for use in the conifer white spruce (Picea glauca). One array contained 7338 segregating SNPs representative of 2814 genes of various molecular functional classes for main uses in genetic association and population genetics studies. The other one contained 9559 segregating SNPs representative of 9543 genes for main uses in population genetics, linkage mapping of the genome and genomic prediction. The SNPs assayed were discovered from various sources of gene resequencing data. SNPs predicted from high-quality sequences derived from genomic DNA reached a genotyping success rate of 64.7%. Nonsingleton in silico SNPs (i.e. a sequence polymorphism present in at least two reads) predicted from expressed sequenced tags obtained with the Roche 454 technology and Illumina GAII analyser resulted in a similar genotyping success rate of 71.6% when the deepest alignment was used and the most favourable SNP probe per gene was selected. A variable proportion of these SNPs was shared by other nordic and subtropical spruce species from North America and Europe. The number of shared SNPs was inversely proportional to phylogenetic divergence and standing genetic variation in the recipient species, but positively related to allele frequency in P. glauca natural populations. These validated SNP resources should open up new avenues for population genetics and comparative genetic mapping at a genomic scale in spruce species. PMID:23351128

  20. Global Phylogeny of Mycobacterium tuberculosis Based on Single Nucleotide Polymorphism (SNP) Analysis: Insights into Tuberculosis Evolution, Phylogenetic Accuracy of Other DNA Fingerprinting Systems, and Recommendations for a Minimal Standard SNP Set

    Microsoft Academic Search

    Ingrid Filliol; Alifiya S. Motiwala; Magali Cavatore; Weihong Qi; Manzour Hernando Hazbon; Miriam Bobadilla del Valle; Janet Fyfe; L. Garcia-Garcia; Nalin Rastogi; Christophe Sola; Thierry Zozio; M. I. Guerrero; C. I. Leon; J. Crabtree; S. Angiuoli; K. D. Eisenach; R. Durmaz; M. L. Joloba; A. Rendon; J. Sifuentes-Osornio; A. Ponce de Leon; M. D. Cave; R. Fleischmann; T. S. Whittam; D. Alland

    2006-01-01

    We analyzed a global collection of Mycobacterium tuberculosis strains using 212 single nucleotide polymorphism (SNP) markers. SNP nucleotide diversity was high (average across all SNPs, 0.19), and 96% of the SNP locus pairs were in complete linkage disequilibrium. Cluster analyses identified six deeply branching, phylogenetically distinct SNP cluster groups (SCGs) and five subgroups. The SCGs were strongly associated with the

  1. Ancestral Asian source(s) of new world Y-chromosome founder haplotypes.

    PubMed Central

    Karafet, T M; Zegura, S L; Posukh, O; Osipova, L; Bergen, A; Long, J; Goldman, D; Klitz, W; Harihara, S; de Knijff, P; Wiebe, V; Griffiths, R C; Templeton, A R; Hammer, M F

    1999-01-01

    Haplotypes constructed from Y-chromosome markers were used to trace the origins of Native Americans. Our sample consisted of 2,198 males from 60 global populations, including 19 Native American and 15 indigenous North Asian groups. A set of 12 biallelic polymorphisms gave rise to 14 unique Y-chromosome haplotypes that were unevenly distributed among the populations. Combining multiallelic variation at two Y-linked microsatellites (DYS19 and DXYS156Y) with the unique haplotypes results in a total of 95 combination haplotypes. Contra previous findings based on Y- chromosome data, our new results suggest the possibility of more than one Native American paternal founder haplotype. We postulate that, of the nine unique haplotypes found in Native Americans, haplotypes 1C and 1F are the best candidates for major New World founder haplotypes, whereas haplotypes 1B, 1I, and 1U may either be founder haplotypes and/or have arrived in the New World via recent admixture. Two of the other four haplotypes (YAP+ haplotypes 4 and 5) are probably present because of post-Columbian admixture, whereas haplotype 1G may have originated in the New World, and the Old World source of the final New World haplotype (1D) remains unresolved. The contrasting distribution patterns of the two major candidate founder haplotypes in Asia and the New World, as well as the results of a nested cladistic analysis, suggest the possibility of more than one paternal migration from the general region of Lake Baikal to the Americas. PMID:10053017

  2. Alternative Fitness Models with the Same Allele Frequency Dynamics

    PubMed Central

    Denniston, C.; Crow, J. F.

    1990-01-01

    For any set of one- or two-locus genotypic fitnesses there are alternative sets, usually frequency-dependent and often with quite different biological meanings, that give rise to the same equations for change of allele or haplotype frequencies. Therefore, it is not possible to distinguish among alternative fitness models from allele or haplotype frequency trajectories or equilibrium distributions. For a single locus and for two loci when linkage equilibrium can be assumed, a simple procedure generates some of the alternative fitness sets. PMID:2341032

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

    PubMed Central

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

    2010-01-01

    Background Previous studies indicate that the frequency distributions of HLA alleles and haplotypes vary from one ethnic group to another or between the members of the same ethnic group living in different geographic areas. It is necessary and meaningful to study the high-resolution allelic and haplotypic distributions of HLA loci in different groups. Methodology/Principal Findings High-resolution HLA typing for the Uyghur ethnic minority group using polymerase chain reaction-sequence-based-typing method was first reported. HLA-A, -B and -DRB1 allelic distributions were determined in 104 unrelated healthy Uyghur individuals and haplotypic frequencies and linkage disequilibrium parameters for HLA loci were estimated using the maximum-likelihood method. A total of 35 HLA-A, 51 HLA-B and 33 HLA-DRB1 alleles were identified at the four-digit level in the population. High frequency alleles were HLA-A*1101 (13.46%), A*0201 (12.50%), A*0301 (10.10%); HLA-B*5101(8.17%), B*3501(6.73%), B*5001 (6.25%); HLA-DRB1*0701 (16.35%), DRB1*1501 (8.65%) and DRB1*0301 (7.69%). The two-locus haplotypes at the highest frequency were HLA-A*3001-B*1302 (2.88%), A*2402-B*5101 (2.86%); HLA-B*5001-DRB1*0701 (4.14%) and B*0702-DRB1*1501 (3.37%). The three-locus haplotype at the highest frequency was HLA-A*3001-B*1302-DRB1*0701(2.40%). Significantly high linkage disequilibrium was observed in six two-locus haplotypes, with their corresponding relative linkage disequilibrium parameters equal to 1. Neighbor-joining phylogenetic tree between the Uyghur group and other previously reported populations was constructed on the basis of standard genetic distances among the populations calculated using the four-digit sequence-level allelic frequencies at HLA-A, HLA-B and HLA-DRB1 loci. The phylogenetic analyses reveal that the Uyghur group belongs to the northwestern Chinese populations and is most closely related to the Xibe group, and then to Kirgiz, Hui, Mongolian and Northern Han. Conclusions/Significance The present findings could be useful to elucidate the genetic background of the population and to provide valuable data for HLA matching in clinical bone marrow transplantation, HLA-linked disease-association studies, population genetics, human identification and paternity tests in forensic sciences. PMID:21079793

  4. Linkage disequilibrium and haplotype studies of chromosome 8p 11. 1-21. 1 markers and Werner syndrome

    SciTech Connect

    Yu, Chang-En; Schellenberg, G.D.; Oshima, Junko; Martin, G.M.; Goddard, K.A.B.; Wijsman, E.M. (Univ. of Washington, Seattle (United States)); Miki, Tetsuro; Nakura, Jun; Ogihara, Toshio (Osaka Univ. (Japan)); Poot, M.; Hoehn, H. (Univ. of Wurzburg (Germany)) (and others)

    1994-08-01

    Werner syndrome (WS) is an autosomal recessive disorder, characterized as a progeroid syndrome, previously mapped to the 8p 11.2-21.1 region. 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. Here the authors present the results of a search for a region that exhibits linkage disequilibrium with the disorder, under the assumption that identification of such a region may provide an alternative method of narrowing down the location of WRN, the gene responsible for WS. They present allele frequencies in Japanese and Caucasian cases and controls for D8S137, D8S131, D8S87, D8S278, D8S259, D8S283, fibroblast growth factor receptor 1, ankyrin 1, D8S339, and two polymorphisms in glutathione reductase (GSR), covering [approximately] 16.5 cM in total. They show that three of the markers examined - D8S339 and both polymorphisms in the GSR locus - show strong statistically significant evidence of disequilibrium with WRN in the Japanese population but not in the Caucasian population. In addition, they show that a limited number of haplotypes are associated with the disease in both populations and that these haplotypes define clusters of apparently related haplotypes that may identify as many as eight or nine independent WRN mutations in these two populations. 36 refs., 1 fig., 4 tabs.

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

    PubMed

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

    2014-08-01

    Skin color is one of the most visible and important phenotypes of modern humans. Melanocyte-stimulating hormone and its receptor played an important role in regulating skin color. In this article, we present evidence of Neanderthal introgression encompassing the melanocyte-stimulating hormone receptor gene MC1R. The haplotypes from Neanderthal introgression diverged with the Altai Neanderthal 103.3 ka, which postdates the anatomically modern human-Neanderthal divergence. We further discovered that all of the putative Neanderthal introgressive haplotypes carry the Val92Met variant, a loss-of-function variant in MC1R that is associated with multiple dermatological traits including skin color and photoaging. Frequency of this Neanderthal introgression is low in Europeans (?5%), moderate in continental East Asians (?30%), and high in Taiwanese aborigines (60-70%). As the putative Neanderthal introgressive haplotypes carry a loss-of-function variant that could alter the function of MC1R and is associated with multiple traits related to skin color, we speculate that the Neanderthal introgression may have played an important role in the local adaptation of Eurasians to sunlight intensity. PMID:24916031

  6. Development and Evaluation of SoySNP50K, a High-Density Genotyping Array for Soybean

    PubMed Central

    Song, Qijian; Hyten, David L.; Jia, Gaofeng; Quigley, Charles V.; Fickus, Edward W.; Nelson, Randall L.; Cregan, Perry B.

    2013-01-01

    The objective of this research was to identify single nucleotide polymorphisms (SNPs) and to develop an Illumina Infinium BeadChip that contained over 50,000 SNPs from soybean (Glycine max L. Merr.). A total of 498,921,777 reads 35–45bp in length were obtained from DNA sequence analysis of reduced representation libraries from several soybean accessions which included six cultivated and two wild soybean (G. soja Sieb. et Zucc.) genotypes. These reads were mapped to the soybean whole genome sequence and 209,903 SNPs were identified. After applying several filters, a total of 146,161 of the 209,903 SNPs were determined to be ideal candidates for Illumina Infinium II BeadChip design. To equalize the distance between selected SNPs, increase assay success rate, and minimize the number of SNPs with low minor allele frequency, an iteration algorithm based on a selection index was developed and used to select 60,800 SNPs for Infinium BeadChip design. Of the 60,800 SNPs, 50,701 were targeted to euchromatic regions and 10,000 to heterochromatic regions of the 20 soybean chromosomes. In addition, 99 SNPs were targeted to unanchored sequence scaffolds. Of the 60,800 SNPs, a total of 52,041 passed Illumina’s manufacturing phase to produce the SoySNP50K iSelect BeadChip. Validation of the SoySNP50K chip with 96 landrace genotypes, 96 elite cultivars and 96 wild soybean accessions showed that 47,337 SNPs were polymorphic and generated successful SNP allele calls. In addition, 40,841 of the 47,337 SNPs (86%) had minor allele frequencies ?10% among the landraces, elite cultivars and the wild soybean accessions. A total of 620 and 42 candidate regions which may be associated with domestication and recent selection were identified, respectively. The SoySNP50K iSelect SNP beadchip will be a powerful tool for characterizing soybean genetic diversity and linkage disequilibrium, and for constructing high resolution linkage maps to improve the soybean whole genome sequence assembly. PMID:23372807

  7. Association of ATP binding cassette transporter G8 rs4148217 SNP and serum lipid levels in Mulao and Han nationalities

    PubMed Central

    2012-01-01

    Background The association of ATP binding cassette transporter G8 gene (ABCG8) rs4148217 single nucleotide polymorphism (SNP) and serum lipid profiles is still controversial in diverse racial/ethnic groups. Mulao nationality is an isolated minority in China. The aim of this study was to evaluate the association of ABCG8 rs4148217 SNP and several environmental factors with serum lipid levels in the Guangxi Mulao and Han populations. Methods A total of 634 subjects of Mulao nationality and 717 participants of Han nationality were randomly selected from our previous samples. Genotyping of the ABCG8 rs4148217 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The genotypic and allelic frequencies of ABCG8 rs4148217 SNP were different between the two nationalities (P?frequency of A allele was higher in Mulao than in Han. The A allele carriers in Han had lower high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 levels than the A allele noncarriers (P?SNP is associated with serum TG, HDL-C and ApoA1 levels in our study populations, but this association is different between the Mulao and Han populations. There is a sex (female)-specific association in both ethnic groups. PMID:22548731

  8. Admixture patterns and genetic differentiation in negrito groups from West Malaysia estimated from genome-wide SNP data.

    PubMed

    Jinam, Timothy A; Phipps, Maude E; Saitou, Naruya

    2013-01-01

    Southeast Asia houses various culturally and linguistically diverse ethnic groups. In Malaysia, where the Malay, Chinese, and Indian ethnic groups form the majority, there exist minority groups such as the "negritos" who are believed to be descendants of the earliest settlers of Southeast Asia. Here we report patterns of genetic substructure and admixture in two Malaysian negrito populations (Jehai and Kensiu), using ~50,000 genome-wide single-nucleotide polymorphism (SNP) data. We found traces of recent admixture in both the negrito populations, particularly in the Jehai, with the Malay through principal component analysis and STRUCTURE analysis software, which suggested that the admixture was as recent as one generation ago. We also identified significantly differentiated nonsynonymous SNPs and haplotype blocks related to intracellular transport, metabolic processes, and detection of stimulus. These results highlight the different levels of admixture experienced by the two Malaysian negritos. Delineating admixture and differentiated genomic regions should be of importance in designing and interpretation of molecular anthropology and disease association studies. PMID:24297225

  9. Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649)

    PubMed Central

    Knappskog, Stian; Gansmo, Liv B.; Dibirova, Khadizha; Metspalu, Andres; Cybulski, Cezary; Peterlongo, Paolo; Aaltonen, Lauri; Vatten, Lars; Romundstad, Pĺl; Hveem, Kristian; Devilee, Peter; Evans, Gareth D.; Lin, Dongxin; Camp, Guy Van; Manolopoulos, Vangelis G.; Osorio, Ana; Milani, Lili; Ozcelik, Tayfun; Zalloua, Pierre; Mouzaya, Francis; Bliznetz, Elena; Balanovska, Elena; Pocheshkova, Elvira; Ku?inskas, Vaidutis; Atramentova, Lubov; Nymadawa, Pagbajabyn; Titov, Konstantin; Lavryashina, Maria; Yusupov, Yuldash; Bogdanova, Natalia; Koshel, Sergey; Zamora, Jorge; Wedge, David C.; Charlesworth, Deborah; Dörk, Thilo; Balanovsky, Oleg; Lřnning, Per E.

    2014-01-01

    The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 – 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk. PMID:25327560

  10. Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649).

    PubMed

    Knappskog, Stian; Gansmo, Liv B; Dibirova, Khadizha; Metspalu, Andres; Cybulski, Cezary; Peterlongo, Paolo; Aaltonen, Lauri; Vatten, Lars; Romundstad, Pĺl; Hveem, Kristian; Devilee, Peter; Evans, Gareth D; Lin, Dongxin; Van Camp, Guy; Manolopoulos, Vangelis G; Osorio, Ana; Milani, Lili; Ozcelik, Tayfun; Zalloua, Pierre; Mouzaya, Francis; Bliznetz, Elena; Balanovska, Elena; Pocheshkova, Elvira; Ku?inskas, Vaidutis; Atramentova, Lubov; Nymadawa, Pagbajabyn; Titov, Konstantin; Lavryashina, Maria; Yusupov, Yuldash; Bogdanova, Natalia; Koshel, Sergey; Zamora, Jorge; Wedge, David C; Charlesworth, Deborah; Dörk, Thilo; Balanovsky, Oleg; Lřnning, Per E

    2014-09-30

    The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 - 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk. PMID:25327560

  11. Identification of polymorphisms in bovine TLR2 and CARD15,associations between CARD15 polymorphisms and milk somatic cell score in Canadian Holsteins, and functional relevance of SNP c.3020A>T.

    PubMed

    Pant, S D; Schenkel, F S; Leyva-Baca, I; Sharma, B S; Karrow, N A

    2008-01-01

    Toll-like receptor-2 (TLR2) and caspase recruitmentdomain 15 (CARD15) are important pattern recognition receptors that play a role in the initiation of the inflammatory and subsequent immune response. They have been previously identified as susceptibility loci for inflammatory bowel diseases in humans and are, therefore, suitable candidate genes for inflammatory disease resistance in cattle. The objective of this study was to identify single nucleotide polymorphisms (SNPs) in the bovine TLR2 and CARD15 and evaluate the association of these SNPs with health and production traits in a population of Canadian Holstein bulls. A selective DNA pool was constructed based on the estimated breeding values (EBVs) for somatic cell score (SCS). Gene segments were amplified from this pool in PCR reactions and the amplicons sequenced to reveal polymorphisms. A total of four SNPs, including one in intron 10 (c.2886-14A>G) and three in exon 12 (c.3020A>T, c.4500A>C and c.4950C>T)were identified in CARD15; nonewere identified in TLR2. Canadian Holstein bulls (n=338) were genotyped and haplotypes were reconstructed. Two SNPs, c.3020A>T and c.4500A>C, were associated with EBVs for health and production traits. The SNP, c.3020A>T for example, was associated with SCS EBVs (p = 0.0097) with an allele substitution effect of 0.07 score. When compared to the most frequent haplotype Hap12(AC), Hap22(TC) was associated with increased milk (p < 0.0001) and protein (p = 0.0007) yield EBVs, and hap21(TA) was significantly associated with increased SCS EBV (p = 0.0120). All significant comparison-wise associations retained significance at 8% experimental-wise level by permutation test. The role of SNP c.3020A>T in MDP induced IL-1beta expression was investigated by real-time quantitative reverse transcription-PCR (real-time quantitative RT-PCR). The induction of IL-1beta by MDP was highly variable between individuals, and no association was observed between IL-1beta expression and SNP c.3020A>T genotypes. In summary, the association study indicates that SNP c.3020A>T might play a role in the host response against mastitis; however, it is not the sole determinant of MDP induced IL-1beta expression in blood leukocytes. Further detailed studies are needed to understand the functional implications of SNP c.3020A>T. PMID:18817309

  12. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations.

    PubMed

    Pillai, Nisha Esakimuthu; Okada, Yukinori; Saw, Woei-Yuh; Ong, Rick Twee-Hee; Wang, Xu; Tantoso, Erwin; Xu, Wenting; Peterson, Trevor A; Bielawny, Thomas; Ali, Mohammad; Tay, Koon-Yong; Poh, Wan-Ting; Tan, Linda Wei-Lin; Koo, Seok-Hwee; Lim, Wei-Yen; Soong, Richie; Wenk, Markus; Raychaudhuri, Soumya; Little, Peter; Plummer, Francis A; Lee, Edmund J D; Chia, Kee-Seng; Luo, Ma; De Bakker, Paul I W; Teo, Yik-Ying

    2014-08-15

    The major histocompatibility complex (MHC) containing the classical human leukocyte antigen (HLA) Class I and Class II genes is among the most polymorphic and diverse regions in the human genome. Despite the clinical importance of identifying the HLA types, very few databases jointly characterize densely genotyped single nucleotide polymorphisms (SNPs) and HLA alleles in the same samples. To date, the HapMap presents the only public resource that provides a SNP reference panel for predicting HLA alleles, constructed with four collections of individuals of north-western European, northern Han Chinese, cosmopolitan Japanese and Yoruba Nigerian ancestry. Owing to complex patterns of linkage disequilibrium in this region, it is unclear whether the HapMap reference panels can be appropriately utilized for other populations. Here, we describe a public resource for the Singapore Genome Variation Project with: (i) dense genotyping across ? 9000 SNPs in the MHC; (ii) four-digit HLA typing for eight Class I and Class II loci, in 96