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1

Minimum Conflict Individual Haplotyping from SNP Fragments and Related Genotype  

PubMed Central

The Minimum Error Correction (MEC) is an important model for haplotype reconstruction from SNP fragments. However, this model is effective only when the error rate of SNP fragments is low. In this paper, we propose a new computational model called Minimum Conflict Individual Haplotyping (MCIH) as an extension to MEC. In contrast to the conventional approaches, the new model employs SNP fragment information and also related genotype information, thereby a high accurate inference can be expected. We first prove the MCIH problem to be NP-hard. To evaluate the practicality of the new model we design an exact algorithm (a dynamic programming procedure) to implement MCIH on a special data structure. The numerical experience indicates that it is fairly effective to use MCIH at the cost of related genotype information, especially in the case of SNP fragments with a high error rate. Moreover, we present a feed-forward neural network algorithm to solve MCIH for general data structure and large size instances. Numerical results on real biological data and simulation data show that the algorithm works well and MCIH is a potential alternative in individual haplotyping. PMID:19455219

Zhang, Xiang-Sun; Wang, Rui-Sheng; Wu, Ling-Yun; Zhang, Wei

2007-01-01

2

Grouping preprocess for haplotype inference from SNP and CNV data  

NASA Astrophysics Data System (ADS)

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.

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

2009-12-01

3

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

Microsoft Academic Search

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

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

2008-01-01

4

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

PubMed

Genome-wide single nucleotide polymorphism (SNP) analysis is a promising tool to examine the genetic diversity of rice populations and genetic traits of scientific and economic importance. Next-generation sequencing technology has accelerated the re-sequencing of diverse rice varieties and the discovery of genome-wide SNPs. Notably, validation of these SNPs by a high-throughput genotyping system, such as an SNP array, could provide a manageable and highly accurate SNP set. To enhance the potential utility of genome-wide SNPs for geneticists and breeders, analysis tools need to be developed. Here, we constructed an SNP haplotype database, which allows visualization of the allele frequency of all SNPs in the genome browser. We calculated the allele frequencies of 3,334 SNPs in 76 accessions from the world rice collection and 3,252 SNPs in 177 Japanese rice accessions; all these SNPs have been validated in our previous studies. The SNP haplotypes were defined by the allele frequency in each cultivar group (aus, indica, tropical japonica and temperate japonica) for the world rice accessions, and in non-irrigated and three irrigated groups (three variety registration periods) for Japanese rice accessions. We also developed web tools for finding polymorphic SNPs between any two rice accessions and for the primer design to develop cleaved amplified polymorphic sequence markers at any SNP. The 'HapRice' database and the web tools can be accessed at http://qtaro.abr.affrc.go.jp/index.html. In addition, we established a core SNP set consisting of 768 SNPs uniformly distributed in the rice genome; this set is of a practically appropriate size for use in rice genetic analysis. PMID:24334415

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

2014-01-01

5

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

E-print Network

was a foundation for constructing a haplotype map of the human genome using common SNP markers. The HapMap data partition among populations from different regions (agreeing with previous studies including the HapMap of the International HapMap project.8,9 The effort to construct a haplotype map or maps of the human genome based

Kidd, Kenneth

6

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

PubMed Central

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

2014-01-01

7

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

E-print Network

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

Lacy, Bob

8

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

PubMed Central

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

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

2002-01-01

9

Haplotyping and estimation of haplotype frequencies for closely linked biallelic multilocus genetic phenotypes including nuclear family information  

Microsoft Academic Search

With the discovery of single nucleotide polymorphisms (SNP) along the genome, genotyping of large samples of biallelic multilocus genetic phenotypes for (fine) mapping of disease genes or for population studies has become standard practice. A genetic trait, however, is mainly caused by an underlying defective haplotype, and populations are best characterized by their haplotype frequen- cies. Therefore, it is essential

K. Rohde; R. Fuerst

2001-01-01

10

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

PubMed

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

Vattathil, Selina; Scheet, Paul

2013-01-01

11

A Novel Class of Simple PCR Markers with SNP-Level Sensitivity for Mapping and Haplotype Characterization in Solanum Species  

Microsoft Academic Search

The RB gene from wild potato Solanum bulbocastanum imparts broad-spectrum late blight resistance to cultivated potato. To explore marker associations and haplotype frequencies\\u000a near RB, we developed, optimized, validated, and employed a set of markers specific to the haplotype associated with the RB resistance allele. Our markers, developed using a mismatch amplification mutation assay (MAMA)-PCR approach, have single\\u000a nucleotide polymorphism-level

Ryan L. Syverson; James M. Bradeen

2011-01-01

12

High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy  

Microsoft Academic Search

Two extended haplotypes exist across the tau gene—H1 and H2—with H1 consistently associated with increased risk of progressive supranuclear palsy (PSP). Using 15 haplotype tagging SNPs (htSNPs), capturing >95% of MAPT haplotype diversity, we performed association analysis in a US sample of 274 predominantly pathologically confirmed PSP patients and 424 matched control individuals. We found that PSP risk is associated

Rosa Rademakers; Stacey Melquist; Marc Cruts; Jessie Theuns; Jurgen Del-Favero; Parvoneh Poorkaj; Matt Baker; Kristel Sleegers; Richard Crook; Tim De Pooter; Samira Bel Kacem; Jennifer Adamson; Dirk Van den Bossche; Marleen Van den Broeck; Jennifer Gass; Ellen Corsmit; Peter De Rijk; Natalie Thomas; Sebastiaan Engelborghs; Michael Heckman; Irene Litvan; Julia Crook; Peter P. De Deyn; Dennis Dickson; Gerard D. Schellenberg; Christine Van Broeckhoven; Michael L. Hutton

2005-01-01

13

Rapid gene-based SNP and haplotype marker development in non-model eukaryotes using 3'UTR sequencing  

PubMed Central

Background Sweet cherry (Prunus avium L.), a non-model crop with narrow genetic diversity, is an important member of sub-family Amygdoloideae within Rosaceae. Compared to other important members like peach and apple, sweet cherry lacks in genetic and genomic information, impeding understanding of important biological processes and development of efficient breeding approaches. Availability of single nucleotide polymorphism (SNP)-based molecular markers can greatly benefit breeding efforts in such non-model species. RNA-seq approaches employing second generation sequencing platforms offer a unique avenue to rapidly identify gene-based SNPs. Additionally, haplotype markers can be rapidly generated from transcript-based SNPs since they have been found to be extremely utile in identification of genetic variants related to health, disease and response to environment as highlighted by the human HapMap project. Results RNA-seq was performed on two sweet cherry cultivars, Bing and Rainier using a 3' untranslated region (UTR) sequencing method yielding 43,396 assembled contigs. In order to test our approach of rapid identification of SNPs without any reference genome information, over 25% (10,100) of the contigs were screened for the SNPs. A total of 207 contigs from this set were identified to contain high quality SNPs. A set of 223 primer pairs were designed to amplify SNP containing regions from these contigs and high resolution melting (HRM) analysis was performed with eight important parental sweet cherry cultivars. Six of the parent cultivars were distantly related to Bing and Rainier, the cultivars used for initial SNP discovery. Further, HRM analysis was also performed on 13 seedlings derived from a cross between two of the parents. Our analysis resulted in the identification of 84 (38.7%) primer sets that demonstrated variation among the tested germplasm. Reassembly of the raw 3'UTR sequences using upgraded transcriptome assembly software yielded 34,620 contigs containing 2243 putative SNPs in 887 contigs after stringent filtering. Contigs with multiple SNPs were visually parsed to identify 685 putative haplotypes at 335 loci in 301 contigs. Conclusions This approach, which leverages the advantages of RNA-seq approaches, enabled rapid generation of gene-linked SNP and haplotype markers. The general approach presented in this study can be easily applied to other non-model eukaryotes irrespective of the ploidy level to identify gene-linked polymorphisms that are expected to facilitate efficient Gene Assisted Breeding (GAB), genotyping and population genetics studies. The identified SNP haplotypes reveal some of the allelic differences in the two sweet cherry cultivars analyzed. The identification of these SNP and haplotype markers is expected to significantly improve the genomic resources for sweet cherry and facilitate efficient GAB in this non-model crop. PMID:22239826

2012-01-01

14

Comparative SNP and Haplotype Analysis Reveals a Higher Genetic Diversity and Rapider LD Decay in Tropical than Temperate Germplasm in Maize  

Microsoft Academic Search

Understanding of genetic diversity and linkage disequilibrium (LD) decay in diverse maize germplasm is fundamentally important for maize improvement. A total of 287 tropical and 160 temperate inbred lines were genotyped with 1943 single nucleotide polymorphism (SNP) markers of high quality and compared for genetic diversity and LD decay using the SNPs and their haplotypes developed from genic and intergenic

Yanli Lu; Trushar Shah; Zhuanfang Hao; Suketoshi Taba; Shihuang Zhang; Shibin Gao; Jian Liu; Moju Cao; Jing Wang; A. Bhanu Prakash; Tingzhao Rong; Yunbi Xu; Pär K. Ingvarsson

2011-01-01

15

SNP and haplotype analysis reveals new HFE variants associated with iron overload trait.  

PubMed

Hereditary hemochromatosis is a common-recessive-autosomal disease characterized by progressive iron overload, and its prevalence correlates with c.845G>A (p. C282Y) mutation of the HFE gene. Two other variants c.187C>G and c.193A>T are associated with a mild iron overload phenotype. The correlation studies have revealed incompletely penetrance of the HFE mutations, as well as the lack of mutation on some chromosomes from patients. We screened for SNPs before examining allele and haplotype association with elevated iron parameters. We confirmed that the c.845G>A mutation is in complete linkage disequilibrium with a unique haplotype, whereas two haplotypes proved to account for 79.8 and 20.2% of the c.187G chromosomes whose only difference was the g.4694C>G variation. A greater prevalence of the g.4694G allele among patients' chromosomes, compared to controls, was observed. In addition, among non-mutant chromosomes the analyses revealed a risk haplotype and a protective haplotype, and the g.4694G and the c.1007-47A alleles were associated with a higher risk of elevated iron parameters. We determined that the g.4694C allele was located within a putative hypoxia-response element, protein binding was evidenced and was reduced with the g.4694C>G change. In addition, IVS4 was not spliced as well in the c.1007-47A allele compared to the c.1007-47G allele. PMID:21412944

Yang, Yizhen; Férec, Claude; Mura, Catherine

2011-04-01

16

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

SciTech Connect

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.

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

17

The Structure of Haplotype Blocks in the Human Genome  

Microsoft Academic Search

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

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

18

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

PubMed

Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication. 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 data. 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

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

2010-04-01

19

Comparative SNP and Haplotype Analysis Reveals a Higher Genetic Diversity and Rapider LD Decay in Tropical than Temperate Germplasm in Maize  

PubMed Central

Understanding of genetic diversity and linkage disequilibrium (LD) decay in diverse maize germplasm is fundamentally important for maize improvement. A total of 287 tropical and 160 temperate inbred lines were genotyped with 1943 single nucleotide polymorphism (SNP) markers of high quality and compared for genetic diversity and LD decay using the SNPs and their haplotypes developed from genic and intergenic regions. Intronic SNPs revealed a substantial higher variation than exonic SNPs. The big window size haplotypes (3-SNP slide-window covering 2160 kb on average) revealed much higher genetic diversity than the 10 kb-window and gene-window haplotypes. The polymorphic information content values revealed by the haplotypes (0.436–0.566) were generally much higher than individual SNPs (0.247–0.259). Cluster analysis classified the 447 maize lines into two major groups, corresponding to temperate and tropical types. The level of genetic diversity and subpopulation structure were associated with the germplasm origin and post-domestication selection. Compared to temperate lines, the tropical lines had a much higher level of genetic diversity with no significant subpopulation structure identified. Significant variation in LD decay distance (2–100 kb) was found across the genome, chromosomal regions and germplasm groups. The average of LD decay distance (10–100 kb) in the temperate germplasm was two to ten times larger than that in the tropical germplasm (5–10 kb). In conclusion, tropical maize not only host high genetic diversity that can be exploited for future plant breeding, but also show rapid LD decay that provides more opportunity for selection. PMID:21949770

Lu, Yanli; Shah, Trushar; Hao, Zhuanfang; Taba, Suketoshi; Zhang, Shihuang; Gao, Shibin; Liu, Jian; Cao, Moju; Wang, Jing; Prakash, A. Bhanu; Rong, Tingzhao; Xu, Yunbi

2011-01-01

20

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

PubMed

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

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

2015-03-01

21

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

PubMed Central

Background: HLA allele identification is used in bone marrow transplant programs as HLA compatibility between the donor and recipient may prevent graft rejection. Objective: This study aimed to estimate the frequency of alleles and haplotypes of the HLA system in the region of Bauru and compare these with the frequencies found in other regions of the country. Methods: HLA-A*, HLA-B*, and HLA-DRB1* allele frequencies and haplotypes were analyzed in a sample of 3542 volunteer donors at the National Registry of Voluntary Bone Marrow Donors (REDOME) in Bauru. HLA low resolution typing was performed using reverse line blot with the Dynal Reli(tm) SSO-HLA Typing Kit and automated Dynal AutoReli(tm)48 device (Invitrogen, USA). Results: Twenty, 36, and 13 HLA-A*, HLA-B*, and HLA-DRB1* allele groups, respectively, were identified. The most common alleles for each locus were HLA-A*02, HLA-B*35, and HLA-DRB1*07. The most frequent haplotype was A*01-B*08-DRB1*03. Allele and haplotype frequencies were compared to other regions in Brazil and the similarities and differences among populations are shown. Conclusion: The knowledge of the immunogenic profile of a population contributes to the comprehension of the historical and anthropological aspects of different regions. Moreover, this helps to find suitable donors quickly, thereby shortening waiting lists for transplants and thus increasing survival rates among recipients. PMID:24790535

Salvadori, Luana de Cassia; Santana, Fabiana Covolo de Souza; Marcos, Elaine Valim Camarinha

2014-01-01

22

Transcriptional Defect of an Inherited NKX2-5 Haplotype Comprising a SNP, a Nonsynonymous and a Synonymous Mutation, Associated with Human Congenital Heart Disease  

PubMed Central

Germline mutations in cardiac-specific transcription factor genes have been associated with congenital heart disease (CHD) and the homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. In pursuit of understanding causes of CHD, we analyzed n?=?49 cardiac biopsies from 28 patients and identified by direct sequencing two nonsynonymous NKX2-5 alterations affecting alanine 119, namely c.356C>A (p.A119E) and c.355G>T, (p.A119S), in patients with AVSD and HLHS, respectively. In functional assays, a significant reduction in transcriptional activities could be determined for the NKX2-5 variants. Importantly, in one family the mother, besides p.A119E, carried a synonymous mutant allele in the homeodomain (c.543G>A, p.Q181), and a synonymous dbSNP (c.63A>G, p.E21) in the transactivation domain of the protein, that were transmitted to the CHD daughter. The presence of these variants in-cis with the p.A119E mutation led to a further reduction in transcriptional activities. Such difference in activity may be in part related to reduced protein expression for the double variant c.356C>A and c.543G>A. We propose changes in mRNA stability and folding, due to a silent mutation and a dbSNP in the NKX2-5 coding region to contribute to the functional defect. Although the clinical significance of the NKX2-5 haplotype identified in the CHD patients remains to be ascertained, we provide evidence of an interaction of a dbSNP, with synonymous and nonsynonymous mutations to negatively impact NKX2-5 transcriptional activity. PMID:24376681

Reamon-Buettner, Stella Marie; Sattlegger, Evelyn; Ciribilli, Yari; Inga, Alberto; Wessel, Armin; Borlak, Jürgen

2013-01-01

23

HLA-A, -B, -DR haplotype frequencies from DNA typing data of 26,266 Chinese bone marrow donors.  

PubMed

HLA phenotypes of 26,266 Chinese individuals who were recruited as potential hematopoietic stem cell donors by the Shanghai Red Cross Marrow Donor Registry, part of the China Marrow Donor Program, were determined for HLA-A, -B, and -DRB1 alleles at low to intermediate resolution using DNA-based typing methods. The large sample size of the study allowed accurate calculation of the Chinese HLA haplotype frequencies. The observed alleles correspond to 19 HLA-A, 44 -B, and 13 -DR split antigens. The serologic equivalents of HLA-A36, -A80, -B78, and -DR18 alleles were not observed. A total of 2,241 distinct HLA-A, -B, -DRB1 haplotypes were identified. Three-locus haplotype frequency was estimated using the maximum likelihood method. The lowest haplotype frequency that can be reliably estimated at a 95% confidence level was 0.000057. Using this cutoff value, 1,220 haplotypes (54%) were statistically reliable and their cumulative haplotype frequency was 0.9730. The cumulative haplotype frequency of the remaining 1,021 haplotypes (46%) was 0.0270. A regression equation of p = 0.192 log N - 0.576 was derived to estimate the probability (p) of finding an HLA-A, -B, -DR split antigens-matched donor in a pool of N Chinese donors. PMID:17961775

Du, Ke-Ming; Ji, Yun; Xie, Jun-Hua; Fu, Min; Sun, Ying; Jin, Ye; Sun, Ji-Li; Yang, Jian-Hao; Zhang, Zheng; Mao, Zhen; Liu, Da-Zhuang; Qian, Kai-Cheng; Zhao, Tong-Mao

2007-10-01

24

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

PubMed Central

Background It was demonstrated previously that the three-locus RFLP haplotype, TaqI B-TaqI D-TaqI A (B-D-A), at the DRD2 locus constitutes a powerful genetic marker and probably reflects the most ancient dispersal of anatomically modern humans. Results We investigated TaqI B, BclI, MboI, TaqI D, and TaqI A RFLPs in 17 contemporary populations of the East European Plain and Siberia. Most of these populations belong to the Indo-European or Uralic language families. We identified three common haplotypes, which occurred in more than 90% of chromosomes investigated. The frequencies of the haplotypes differed according to linguistic and geographical affiliation. Conclusion Populations in the northwestern (Byelorussians from Mjadel'), northern (Russians from Mezen' and Oshevensk), and eastern (Russians from Puchezh) parts of the East European Plain had relatively high frequencies of haplotype B2-D2-A2, which may reflect admixture with Uralic-speaking populations that inhabited all of these regions in the Early Middle Ages. PMID:19793394

Flegontova, Olga V; Khrunin, Andrey V; Lylova, Olga I; Tarskaia, Larisa A; Spitsyn, Victor A; Mikulich, Alexey I; Limborska, Svetlana A

2009-01-01

25

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.  

PubMed

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes. PMID:16998491

de Bakker, Paul I W; McVean, Gil; Sabeti, Pardis C; Miretti, Marcos M; Green, Todd; Marchini, Jonathan; Ke, Xiayi; Monsuur, Alienke J; Whittaker, Pamela; Delgado, Marcos; Morrison, Jonathan; Richardson, Angela; Walsh, Emily C; Gao, Xiaojiang; Galver, Luana; Hart, John; Hafler, David A; Pericak-Vance, Margaret; Todd, John A; Daly, Mark J; Trowsdale, John; Wijmenga, Cisca; Vyse, Tim J; Beck, Stephan; Murray, Sarah Shaw; Carrington, Mary; Gregory, Simon; Deloukas, Panos; Rioux, John D

2006-10-01

26

The new Y Chromosome Haplotype Reference Database.  

PubMed

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

Willuweit, Sascha; Roewer, Lutz

2015-03-01

27

SNP frequency, haplotype structure and linkage disequilibrium in elite maize inbred lines  

Microsoft Academic Search

BACKGROUND: Recent studies of ancestral maize populations indicate that linkage disequilibrium tends to dissipate rapidly, sometimes within 100 bp. We set out to examine the linkage disequilibrium and diversity in maize elite inbred lines, which have been subject to population bottlenecks and intense selection by breeders. Such population events are expected to increase the amount of linkage disequilibrium, but reduce

Ada Ching; Katherine S Caldwell; Mark Jung; Maurine Dolan; Scott Tingey; Michele Morgante; Antoni J Rafalski

2002-01-01

28

Single nucleotide polymorphism (SNP) allele frequency estimation in DNA pools using Pyrosequencing.  

PubMed

Identifying the genetic variation underlying complex disease requires analysis of many single nucleotide polymorphisms (SNPs) in a large number of samples. Several high-throughput SNP genotyping techniques are available; however, their cost promotes the use of association screening with pooled DNA. This protocol describes the estimation of SNP allele frequencies in pools of DNA using the quantitative sequencing method Pyrosequencing (PSQ). PSQ is a relatively recently described high-throughput method for genotyping, allele frequency estimation and DNA methylation analysis based on the detection of real-time pyrophosphate release during synthesis of the complementary strand to a PCR product. The protocol involves the following steps: (i) quantity and quality assessment of individual DNA samples; (ii) DNA pooling, which may be undertaken at the pre- or post-PCR stage; (iii) PCR amplification of PSQ template containing the variable sequence region of interest; and (iv) PSQ to determine the frequency of alleles at a particular SNP site. Once the quantity and quality of individual DNA samples has been assessed, the protocol usually requires a few days for setting up pre-PCR pools, depending on sample number. After PCR amplification, preparation and analysis of PCR amplicon by PSQ takes 1 h per plate. PMID:17406511

Lavebratt, Catharina; Sengul, Selim

2006-01-01

29

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

PubMed Central

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

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

30

HLA class II allele and haplotype frequencies in Ethiopian Amhara and Oromo populations.  

PubMed

HLA class II alleles were identified in 181 healthy unrelated Ethiopian children of both sexes and in 350 European controls from the South of France. The Ethiopian individuals belonged to the two major ethnic groups of the country: Oromo (N=83) and Amhara (N=98). In both panels, genetic polymorphism of HLA class II alleles was analysed for the first time by molecular typing of DRB1, DQA1 and DQB1 loci. Allelic and phenotypic frequencies were compared with those of European controls and other African populations. Construction of HLA class II three-locus haplotypes was also performed. The study revealed some differences between the two groups. Characteristic features of Central and North African populations appeared on the Ethiopian HLA genotypes. Surprisingly, DRB1*11 presented one of the lowest gene frequencies in both Ethiopian ethnic groups in contrast to Europeans and West Africans. Furthermore, this decrease was more marked than those observed using serological techniques in other geographically close East African countries. Oromo and Amhara only showed minor differences in spite of their different origins and histories. One significant difference consisted of a lower DRB1*01 gene frequency in Oromo as reported in most West African people. Some new or rare haplotypes were also observed in the Oromo group. Our results underline the distinctive features of the Ethiopian populations among the few HLA genotyping data available for East African groups and emphasise the major interest of such investigations in this region of Africa. PMID:9583804

Fort, M; de Stefano, G F; Cambon-Thomsen, A; Giraldo-Alvarez, P; Dugoujon, J M; Ohayon, E; Scano, G; Abbal, M

1998-04-01

31

Molecular analysis of human leukocyte antigen class I and class II allele frequencies and haplotype distribution in Pakistani population  

PubMed Central

AIM: Distribution of HLA class I and II alleles and haplotype was studied in Pakistani population and compared with the data reported for Caucasoid, Africans, Orientals and Arab populations. MATERIALS AND METHODS: HLA class I and II polymorphisms in 1000 unrelated Pakistani individuals was studied using sequence-specific primers and polymerase chain reaction and assay. RESULTS: The most frequent class I alleles observed were A*02, B*35 and CW*07, with frequencies of 19.2, 13.7 and 20%, respectively. Fifteen distinct HLA-DRB1 alleles and eight HLA-DQB1 alleles were recognized. The most frequently observed DRB1 alleles which represented more than 60% of the subjects were DRB1 *03, *07, *11 and *15. The rare DRB1 alleles detected in this study were HLADRB1 *08 and *09, having frequencies of 0.9 and 1.7%, respectively. In addition, at DRB1-DQB1 loci there were 179 different haplotypes and 285 unique genotypes and the most common haplotype was DRB1*15-DQB1*06 which represented 17% of the total DRB1-DQB1 haplotypes. In our population, haplotype A*33-B*58-Cw*03 comprised 2.8% of the total class I haplotypes observed. This haplotype was seen only in the oriental populations and has not been reported in the African or European Caucasoid. CONCLUSION: Our study showed a close similarity of HLA class I and II alleles with that of European Caucasoid and Orientals. In Pakistani population, two rare loci and three haplotypes were identified, whereas haplotypes characteristic of Caucasians, Africans and Orientals were also found, suggesting an admixture of different races due to migration to and from this region. PMID:21206703

Moatter, T.; Aban, M.; Tabassum, S.; Shaikh, U.; Pervez, S.

2010-01-01

32

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

33

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

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

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

2014-01-01

34

Detecting local haplotype sharing and haplotype association.  

PubMed

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

Xu, Hanli; Guan, Yongtao

2014-07-01

35

Detecting Local Haplotype Sharing and Haplotype Association  

PubMed Central

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

Xu, Hanli; Guan, Yongtao

2014-01-01

36

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...

37

Using Case-parent Triads to Estimate Relative Risks Associated with a Candidate Haplotype  

PubMed Central

SUMMARY Estimating haplotype relative risks in a family-based study is complicated by phase ambiguity and the many parameters needed to quantify relative risks for all possible diplotypes. This problem becomes manageable if a particular haplotype has been implicated previously as relevant to risk. We fit log-linear models to estimate the risks associated with a candidate haplotype relative to the aggregate of other haplotypes. Our approach uses existing haplotype-reconstruction algorithms but requires assumptions about the distribution of haplotypes among triads in the source population. We consider three levels of stringency for those assumptions: Hardy-Weinberg Equilibrium (HWE), random mating, and no assumptions at all. We assessed our method’s performance through simulations encompassing a range of risk haplotype frequencies, missing data patterns, and relative risks for either offspring or maternal genetic effects. The unconstrained model provides robustness to bias from population structure but requires excessively large sample sizes unless there are few haplotypes. Assuming HWE accommodates many more haplotypes but sacrifices robustness. The model assuming random mating is intermediate, both in the number of haplotypes it can handle and in robustness. To illustrate, we reanalyze data from a study of orofacial clefts to investigate a 9-SNP candidate haplotype of the IRF6 gene. PMID:19344450

SHI, M; UMBACH, D M; WEINBERG, C R

2009-01-01

38

Reducing Bias of Allele Frequency Estimates by Modeling SNP Genotype Data with Informative Missingness  

PubMed Central

The presence of missing single-nucleotide polymorphism (SNP) genotypes is common in genetic studies. For studies with low-density SNPs, the most commonly used approach to dealing with genotype missingness is to simply remove the observations with missing genotypes from the analyses. This naïve method is straightforward but is valid only when the missingness is random. However, a given assay often has a different capability in genotyping heterozygotes and homozygotes, causing the phenomenon of “differential dropout” in the sense that the missing rates of heterozygotes and homozygotes are different. In practice, differential dropout among genotypes exists in even carefully designed studies, such as the data from the HapMap project and the Wellcome Trust Case Control Consortium. Under the assumption of Hardy–Weinberg equilibrium and no genotyping error, we here propose a statistical method to model the differential dropout among different genotypes. Compared with the naïve method, our method provides more accurate allele frequency estimates when the differential dropout is present. To demonstrate its practical use, we further apply our method to the HapMap data and a scleroderma data set. PMID:22719749

Lin, Wan-Yu; Liu, Nianjun

2012-01-01

39

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.  

PubMed Central

In order to deduce the predominant haplotypes in Japanese narcoleptics, we have studied a total of 111 Japanese patients with narcolepsy and six multiple-case families for HLA class I and class II antigens, and for class III HLA-linked complement markers. In Japanese narcoleptics, the most frequent haplotypes were B35-DR2, B15-DR2, and B51-DR2. These haplotypes were rare in normal Japanese population. In contrast, the most frequent haplotype of HLA-DR2 in normal Japanese, A24-C blank-Bw52-C4A*2 B*Q0-BF *S-C2*C-DR2-DQw1, had a decreased frequency to one-third of the normal controls. Haplotypes B35-DR2, B15-DR2, and B51-DR2, which were more frequent among Japanese narcoleptics, were different from the haplotype found more frequently among Caucasoid narcoleptics, A3-Cw7-B7-DR2-DQw1. Haplotype analysis on six families showed that B35-DR2 and other rare haplotypes in normal Japanese were associated with narcolepsy. There were four cases without any signs of narcolepsy among 19 subjects with the disease susceptibility haplotypes. This finding suggests an incomplete penetrance of hypersomnia. Haplotype analysis of family members was also useful for the early detection of the high risk children to narcolepsy. PMID:3865934

Matsuki, K; Juji, T; Tokunaga, K; Naohara, T; Satake, M; Honda, Y

1985-01-01

40

HLA allele and haplotype frequencies in the Albanian population and their relationship with the other European populations.  

PubMed

Human leucocyte antigen (HLA) alleles are very interesting markers in identifying population relationships. Moreover, their frequency distribution data are important in the implementation of donor-recipient registry programs for transplantation purposes and also in determining the genetic predisposition for many diseases. For these reasons, we studied the HLA class I and II allele and haplotype frequencies in 160 healthy, unrelated Albanian individuals originating from all regions of the country. The HLA genotyping was performed through a 2-digit resolution SSOP method. The data were analysed with Arlequin and Phylip programs. No deviation was found from the Hardy-Weinberg equilibrium. A total of 17 A*, 30 B*, 12 Cw*, 13 DRB1* and 5 DQB1* alleles were identified. The six most frequent HLA-A-B-DRB1 haplotypes were A*02-B*18-DRB1*11 (5.60%), A*02-B*51-DRB1*16 (4.74%), A*01-B*08-DRB1*03 (3.48%), A*24-B*35-DRB1*11 (2.77%), A*02-B*51-DRB1*13 (2.21%), A*24-B*35-DRB1*14 (1.89%). Interestingly, 12 HLA-A-B-Cw-DRB1-DQB1 haplotypes occurred at a frequency >1%. When compared with the other populations, a close relationship was found with North Greek, Bulgarian, Macedonian, Romanian, Turkish, Cretan, Serbian, Croatian and Italian populations. A higher differentiation in allele frequency level was found with Western Europe populations. These data are the first report of HLA allele and haplotype distribution in an Albanian population inside this country. When compared with other populations, their distribution frequencies show close similarities with neighbouring populations of the entire Balkan area. PMID:19703234

Sulcebe, G; Sanchez-Mazas, A; Tiercy, J-M; Shyti, E; Mone, I; Ylli, Z; Kardhashi, V

2009-12-01

41

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

PubMed Central

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

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

42

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

PubMed Central

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

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

43

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

PubMed

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

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

44

Haplotyping Problem, A Clustering Approach  

SciTech Connect

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.

Eslahchi, Changiz [Faculty of Mathematics, Shahid-Beheshti University, Tehran (Iran, Islamic Republic of); Bioinformatics Group, School of Computer Science, Institute for Studies in Theoretical Physics and Mathematics (IPM), Tehran (Iran, Islamic Republic of); Sadeghi, Mehdi [National Institute for Genetic Engineering and Biotechnology, Tehran-Karaj Highway, Tehran (Iran, Islamic Republic of); Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Pezeshk, Hamid [Center of Excellence in Biomathematics, School of Mathematics, Statistics and Computer Science, University College of Science, University of Tehran, Tehran (Iran, Islamic Republic of); Kargar, Mehdi [Department of Computer Engineering, Sharif University of Technology, Tehran (Iran, Islamic Republic of); Poormohammadi, Hadi [Faculty of Mathematics, Shahid-Beheshti University, Tehran (Iran, Islamic Republic of)

2007-09-06

45

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

SciTech Connect

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

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

2005-05-15

46

Frequency of the delta F508 mutation and flanking marker haplotypes at the CF locus from 167 Czech families.  

PubMed

This study analyses distribution patterns of the delta F508 mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene and the cystic fibrosis (CF)-linked marker loci MET, D7S23, D7S399, and D7S8 in a sample of 167 (116 complete) CF families from Bohemia and Moravia (Czechoslovakia). DNA typing was performed by polymerase chain reaction amplification, restriction analysis, and agarose or polyacrylamide gel electrophoresis. The frequency of the delta F508 mutation in this sample is 67% and the frequency of the B haplotype is 77.6% on CF chromosomes. Linkage disequilibrium was found between delta F508 and all markers tested. PMID:2210755

Macek, M; Vavrová, V; Böhm, I; Stuhrmann, M; Reis, A; Duspivová, R; Macek, M; Sperling, K; Krawczak, M; Schmidtke, J

1990-09-01

47

Asian population frequencies and haplotype distribution of killer cell immunoglobulin-like receptor (KIR) genes among Chinese, Malay, and Indian in Singapore.  

PubMed

Killer cell immunoglobulin-like receptors (KIR) gene frequencies have been shown to be distinctly different between populations and contribute to functional variation in the immune response. We have investigated KIR gene frequencies in 370 individuals representing three Asian populations in Singapore and report here the distribution of 14 KIR genes (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) with two pseudogenes (2DP1, 3DP1) among Singapore Chinese (n = 210); Singapore Malay (n = 80), and Singapore Indian (n = 80). Four framework genes (KIR3DL3, 3DP1, 2DL4, 3DL2) and a nonframework pseudogene 2DP1 were detected in all samples while KIR2DS2, 2DL2, 2DL5, and 2DS5 had the greatest significant variation across the three populations. Fifteen significant linkage patterns, consistent with associations between genes of A and B haplotypes, were observed. Eighty-four distinct KIR profiles were determined in our populations, 38 of which had not been described in other populations. KIR haplotype studies were performed using nine Singapore Chinese families comprising 34 individuals. All genotypes could be resolved into corresponding pairs of existing haplotypes with eight distinct KIR genotypes and eight different haplotypes. The haplotype A2 with frequency of 63.9% was dominant in Singapore Chinese, comparable to that reported in Korean and Chinese Han. The A haplotypes predominate in Singapore Chinese, with ratio of A to B haplotypes of approximately 3:1. Comparison with KIR frequencies in other populations showed that Singapore Chinese shared similar distributions with Chinese Han, Japanese, and Korean; Singapore Indian was found to be comparable with North Indian Hindus while Singapore Malay resembled the Thai. PMID:18668235

Lee, Yi Chuan; Chan, Soh Ha; Ren, Ee Chee

2008-11-01

48

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

PubMed

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

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

2007-04-01

49

Determination of detection and quantification limits for SNP allele frequency estimation in DNA pools using real time PCR  

PubMed Central

The quantification of single nucleotide polymorphism (SNP) allele frequencies in pooled DNA samples using real time PCR is a promising approach for large-scale diagnostics and genotyping. The limits of detection (LOD) and limits of quantification (LOQ) for mutant SNP alleles are of particular importance for determination of the working range, which, in the case of allele-specific real time PCR, can be limited by the variance of calibration data from serially diluted mutant allele samples as well as by the variance of the 100% wild-type allele samples (blank values). In this study, 3? and 10? criteria were applied for the calculation of LOD and LOQ values. Alternatively, LOQ was derived from a 20% threshold for the relative standard deviation (%RSD) of measurements by fitting a curve for the relationship between %RSD and copy numbers of the mutant alleles. We found that detection and quantification of mutant alleles were exclusively limited by the variance of calibration data since the estimated LODcalibration (696 in 30?000?000 copies, 0.0023%), LOQ20%RSD (1470, 0.0049%) and LOQcalibration (2319, 0.0077) values were significantly higher than the LODblank (130, 0.0004%) and LOQblank (265, 0.0009%) values derived from measurements of wild-type allele samples. No significant matrix effects of the genomic background DNA on the estimation of LOD and LOQ were found. Furthermore, the impact of large genome sizes and the general application of the procedure for the estimation of LOD and LOQ in quantitative real time PCR diagnostics are discussed. PMID:14960708

Schwarz, Gerhard; Bäumler, Stefan; Block, Annette; Felsenstein, Friedrich G.; Wenzel, Gerhard

2004-01-01

50

The human leukocyte antigen class III haplotype approach: new insight in Alzheimer's disease inflammation hypothesis.  

PubMed

The Alzheimer's disease "inflammation hypothesis" has emerged only recently, suggesting the risk of developing AD might be influenced by variants of genes encoding for inflammatory mediators. In order to investigate in this direction, genomic DNA from 194 Italian AD cases and 454 healthy controls matched by gender and ethnicity was analyzed for the Receptor for Advanced Glycation End products (RAGE, HLA class III-centromere portion) -374 and - 429 SNPs and for the Tumor Necrosis Factor-alpha (TNF-?, HLA class III-telomere portion) -857, -308 and -238 SNPs by RFLP and Real Time PCR. Our data show statistically significant deviations between AD patients and healthy controls concerning RAGE -374 SNP genotype (TT: p=0.0084) and allele (T, A: p=0.0081) frequencies; TNF-? -308 SNP AA genotype (p=0.0433) and TNF-? -238 SNP genotype (GG: p=0.0138) and allele (G, A: p=0.0151) frequencies. Furthermore, significant differences between the study groups and regarding RAGE TC (p=0.05) and AC (p=0.009) haplotypes are present, while TNF-? haplotype reconstruction point out a statistically significant difference between patients and controls regarding AGG haplotype (p=0.002). Finally, from the combination of the individually significant SNPs of the two genes (RAGE -374, TNF-? -238 and -308) we performed an HLA class III haplotype reconstruction finding significant differences between AD subjects and controls regarding the TAG (p=0.019) and TGA (p=0.008) haplotypes. The implication of these haplotypes with the disease points to a possible involvement of entire HLA class III region in AD susceptibility. PMID:24156267

Maggioli, Elisa; Boiocchi, Chiara; Zorzetto, Michele; Sinforiani, Elena; Cereda, Cristina; Ricevuti, Giovanni; Cuccia, Mariaclara

2013-12-01

51

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

PubMed

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

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

2013-10-01

52

Genotype, allele and haplotype frequencies of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in the South Indian descent  

PubMed Central

Introduction: Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1A gene polymorphisms in Indians. Methods: In this pilot study, we used TaqMan fluorescent probes to assess the genotypes of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in 247 healthy homogenous South Indian subjects on real time thermocycler. Haplotype estimation and pairwise linkage disequilibrium (LD) analysis were executed by Haploview. Results: The incidence of polymorphic variant allele (G) frequencies of rs7158782, rs7159713, rs2369049 and rs11849538 were 22.1%, 23.5%, 18.2% and 22.9% in the study population, respectively. The polymorphisms were found to be in complete LD with each other. Four different haplotypes, each of which having a frequency of above 1% were inferred in South Indians using an expectation-maximization algorithm. Notably, three haplotypes were found to be population specific viz H4 A-A-A-G (1.2%) for South India, H5 G-G-A-C (1.3%) for JPT and H6 G-G-G-C (40.4%) for YRI. Further, H3 G-G-A-G (2.3-16.3%) haplotype occurs primarily in Asians and is virtually absent in Africans. Overall, the genetic variability and haplotype profile of South Indian population revealed significant inter-racial variability compared with HapMap data. Conclusion: This documentation contributes for further investigations on the pharmacogenetics of AIs in South Indians. PMID:25035853

Umamaheswaran, Gurusamy; Dkhar, Steven Aibor; Kumar, Annan Sudarsan Arun; Srinivasa, Rao Katiboina; Kadambari, Dharanipragada; Adithan, Chandrasekaran

2014-01-01

53

Combining haplotypers  

E-print Network

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

Kääriäinen, Matti; Lappalainen, Sampsa; Mielikäinen, Taneli

2007-01-01

54

SNP genotyping by heteroduplex analysis.  

PubMed

Heteroduplex-based genotyping methods have proven to be technologically effective and economically efficient for low- to medium-range throughput single-nucleotide polymorphism (SNP) determination. In this chapter we describe two protocols that were successfully applied for SNP detection and haplotype analysis of candidate genes in association studies. The protocols involve (1) enzymatic mismatch cleavage with endonuclease CEL1 from celery, associated with fragment separation using capillary electrophoresis (CEL1 cleavage), and (2) differential retention of the homo/heteroduplex DNA molecules under partial denaturing conditions on ion pair reversed-phase liquid chromatography (dHPLC). Both methods are complementary since dHPLC is more versatile than CEL1 cleavage for identifying multiple SNP per target region, and the latter is easily optimized for sequences with fewer SNPs or small insertion/deletion polymorphisms. Besides, CEL1 cleavage is a powerful method to localize the position of the mutation when fragment resolution is done using capillary electrophoresis. PMID:25373754

Paniego, Norma; Fusari, Corina; Lia, Verónica; Puebla, Andrea

2015-01-01

55

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

PubMed Central

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

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

56

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

PubMed Central

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

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

57

Haplotype analysis of sucrose synthase gene family in three Saccharum species  

PubMed Central

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

2013-01-01

58

Association of MDR1 Gene SNPs and Haplotypes with the Tacrolimus Dose Requirements in Han Chinese Liver Transplant Recipients  

PubMed Central

Background This work seeks to evaluate the association between the C/D ratios (plasma concentration of tacrolimus divided by daily dose of tacrolimus per body weight) of tacrolimus and the haplotypes of MDR1 gene combined by C1236T (rs1128503), G2677A/T (rs2032582) and C3435T (rs1045642), and to further determine the functional significance of haplotypes in the clinical pharmacokinetics of oral tacrolimus in Han Chinese liver transplant recipients. Methodology/Principal Findings The tacrolimus blood concentrations were continuously recorded for one month after initial administration, and the peripheral blood DNA from a total of 62 liver transplant recipients was extracted. Genotyping of C1236T, G2677A/T and C3435T was performed, and SNP frequency, Hardy-Weinberg equilibrium, linkage disequilibrium, haplotypes analysis and multiple testing were achieved by software PLINK. C/D ratios of different SNP groups or haplotype groups were compared, with a p value<0.05 considered statistically significant. Linkage studies revealed that C1236T, G2677A/T and C3435T are genetically associated with each other. Patients carrying T-T haplotype combined by C1236T and G2677A/T, and an additional T/T homozygote at either position would require higher dose of tacrolimus. Tacrolimus C/D ratios of liver transplant recipients varied significantly among different haplotype groups of MDR1 gene. Conclusions Our studies suggest that the genetic polymorphism could be used as a valuable molecular marker for the prediction of tacrolimus C/D ratios of liver transplant recipients. PMID:22110582

Yu, Xiaobo; Xie, Haiyang; Wei, Bajin; Zhang, Min; Wang, Weilin; Wu, Jian; Yan, Sheng; Zheng, Shusen; Zhou, Lin

2011-01-01

59

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

PubMed Central

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

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

60

Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence.  

PubMed

We examined 13 single nucleotide polymorphisms (SNPs) spanning the coding region of the mu-opioid receptor gene (OPRM1), among 382 European Americans (EAs) affected with substance dependence [alcohol dependence (AD) and/or drug dependence (DD)] and 338 EA healthy controls. These SNPs delineated two haplotype blocks. Genotype distributions for all SNPs were in Hardy-Weinberg equilibrium (HWE) in controls, but in cases, four SNPs in Block I and three SNPs in Block II showed deviation from HWE. Significant differences were found between cases and controls in allele and/or genotype frequencies for six SNPs in Block I and two SNPs in Block II. Association of SNP4 in Block I with DD (allele: P=0.004), SNP5 in Block I with AD and DD (allele: P< or =0.005 for both) and two SNPs in Block II with AD (SNP11 genotype: P=0.002; SNP12 genotype: P=0.001) were significant after correction for multiple testing. Frequency distributions of haplotypes (constructed by five tag SNPs) differed significantly for cases and controls (P<0.001 for both AD and DD). Logistic regression analyses confirmed the association between OPRM1 variants and substance dependence, when sex and age of subjects and alleles, genotypes, haplotypes or diplotypes of five tag SNPs were considered. Population structure analyses excluded population stratification artifact. Additional supporting evidence for association between OPRM1 and AD was obtained in a smaller Russian sample (247 cases and 100 controls). These findings suggest that OPRM1 intronic variants play a role in susceptibility to AD and DD in populations of European ancestry. PMID:16476706

Zhang, Huiping; Luo, Xingguang; Kranzler, Henry R; Lappalainen, Jaakko; Yang, Bao-Zhu; Krupitsky, Evgeny; Zvartau, Edwin; Gelernter, Joel

2006-03-15

61

Haplotype inference constrained by plausible haplotype data.  

PubMed

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

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

2011-01-01

62

Copyright 2002 by the Genetics Society of America The Evolution of Isochores: Evidence From SNP Frequency Distributions  

E-print Network

Frequency Distributions Martin J. Lercher,*,1 Nick G. C. Smith, Adam Eyre-Walker and Laurence D. Hurst compositional variation is due to lutionary time (Lobry 1997; Powell and Moriyama mutation bias variation alone

Eyre-Walker, Adam

63

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

PubMed Central

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

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

64

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

PubMed Central

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

Knappskog, Stian; Lønning, Per E.

2011-01-01

65

A hidden Markov model for haplotype inference for present-absent data of clustered genes using identified haplotypes and haplotype patterns  

PubMed Central

The majority of killer cell immunoglobin-like receptor (KIR) genes are detected as either present or absent using locus-specific genotyping technology. Ambiguity arises from the presence of a specific KIR gene since the exact copy number (one or two) of that gene is unknown. Therefore, haplotype inference for these genes is becoming more challenging due to such large portion of missing information. Meantime, many haplotypes and partial haplotype patterns have been previously identified due to tight linkage disequilibrium (LD) among these clustered genes thus can be incorporated to facilitate haplotype inference. In this paper, we developed a hidden Markov model (HMM) based method that can incorporate identified haplotypes or partial haplotype patterns for haplotype inference from present-absent data of clustered genes (e.g., KIR genes). We compared its performance with an expectation maximization (EM) based method previously developed in terms of haplotype assignments and haplotype frequency estimation through extensive simulations for KIR genes. The simulation results showed that the new HMM based method outperformed the previous method when some incorrect haplotypes were included as identified haplotypes and/or the standard deviation of haplotype frequencies were small. We also compared the performance of our method with two methods that do not use previously identified haplotypes and haplotype patterns, including an EM based method, HPALORE, and a HMM based method, MaCH. Our simulation results showed that the incorporation of identified haplotypes and partial haplotype patterns can improve accuracy for haplotype inference. The new software package HaploHMM is available and can be downloaded at http://www.soph.uab.edu/ssg/files/People/KZhang/HaploHMM/haplohmm-index.html. PMID:25161663

Wu, Jihua; Chen, Guo-Bo; Zhi, Degui; Liu, Nianjun; Zhang, Kui

2014-01-01

66

Methods of tagSNP selection and other variables affecting imputation accuracy in swine  

PubMed Central

Background Genotype imputation is a cost efficient alternative to use of high density genotypes for implementing genomic selection. The objective of this study was to investigate variables affecting imputation accuracy from low density tagSNP (average distance between tagSNP from 100kb to 1Mb) sets in swine, selected using LD information, physical location, or accuracy for genotype imputation. We compared results of imputation accuracy based on several sets of low density tagSNP of varying densities and selected using three different methods. In addition, we assessed the effect of varying size and composition of the reference panel of haplotypes used for imputation. Results TagSNP density of at least 1 tagSNP per 340kb (?7000 tagSNP) selected using pairwise LD information was necessary to achieve average imputation accuracy higher than 0.95. A commercial low density (9K) tagSNP set for swine was developed concurrent to this study and an average accuracy of imputation of 0.951 based on these tagSNP was estimated. Construction of a haplotype reference panel was most efficient when these haplotypes were obtained from randomly sampled individuals. Increasing the size of the original reference haplotype panel (128 haplotypes sampled from 32 sire/dam/offspring trios phased in a previous study) led to an overall increase in imputation accuracy (IA?=?0.97 with 512 haplotypes), but was especially useful in increasing imputation accuracy of SNP with MAF below 0.1 and for SNP located in the chromosomal extremes (within 5% of chromosome end). Conclusion The new commercially available 9K tagSNP set can be used to obtain imputed genotypes with high accuracy, even when imputation is based on a comparably small panel of reference haplotypes (128 haplotypes). Average imputation accuracy can be further increased by adding haplotypes to the reference panel. In addition, our results show that randomly sampling individuals to genotype for the construction of a reference haplotype panel is more cost efficient than specifically sampling older animals or trios with no observed loss in imputation accuracy. We expect that the use of imputed genotypes in swine breeding will yield highly accurate predictions of GEBV, based on the observed accuracy and reported results in dairy cattle, where genomic evaluation of some individuals is based on genotypes imputed with the same accuracy as our Yorkshire population. PMID:23433396

2013-01-01

67

No association between polymorphisms/haplotypes of the vascular endothelial growth factor gene and preeclampsia  

PubMed Central

Background Preeclampsia (PE) is the first worldwide cause of death in pregnant women, intra-uterine growth retardation, and fetal prematurity. Some vascular endothelial grown factor gene (VEGF) polymorphisms have been associated to PE and other pregnancy disturbances. We evaluated the associations between VEGF genotypes/haplotypes and PE in Mexican women. Methods 164 pregnant women were enrolled in a case-control study (78 cases and 86 normotensive pregnant controls). The rs699947 (-2578C/A), rs1570360 (-1154G/A), rs2010963 (+405G/C), and rs25648 (-7C/T), VEGF variants were discriminated using Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) methods or Taqman single nucleotide polymorphism (SNP) assays. Results The proportions of the minor allele for rs699947, rs1570360, rs2010963, and rs25648 VEGF SNPs were 0.33, 0.2, 0.39, and 0.17 in controls, and 0.39, 0.23, 0.41, and 0.15 in cases, respectively (P values > 0.05). The most frequent haplotypes of rs699947, rs1570360, rs2010963, and rs25648 VEGF SNPs, were C-G-C-C and C-G-G-C with frequencies of 0.39, 0.21 in cases and 0.37, 0.25 in controls, respectively (P values > 0.05) Conclusion There was no evidence of an association between VEGF alleles, genotypes, or haplotypes frequencies and PE in our study. PMID:21575227

2011-01-01

68

SNP and mutation analysis.  

PubMed

Genetic variation and SNP analysis starts with generation of sequence-specific signal, followed by the collection of that signal. The final step is extensive data analysis, which starts with conversion of quantifiable raw data and ends up with identified SNPs, frequencies, and sometimes tissue-specific expression patterns (levels). In this chapter we describe and compare the mechanisms of signal generation of several representative SNP analysis platforms. DNA microarray no doubt has its advantage in applications involving the classification and identification of tumor classes, gene discovery, drug dependent transcription mechanisms, as well as prediction of drug response. PCR, xMAP, invader assay, mass spectrometry, and pyrosequencing, on the other hand, are alternative methods of genotyping employed following the large scale screening and discovery of genetic variations. In addition, they offer higher specificity and sensitivity in analysis of both genomic DNA, as well as RNA. By exploiting these technologies, correlative study of the effects of putative genetic variations on cells, tissue-specific and developmentally specific expression is possible. Of extreme value are the many forms of Mass Spectrometry in the areas of sensitive, early cancer diagnosis. Finally, microarray and xMAP are suitable for protein analysis. While protein array offers higher throughput, xMAP is more amendable to the native 3D structure of protein molecules. PMID:17265721

Wang, Lu; Luhm, Robert; Lei, Ming

2007-01-01

69

Whole-genome molecular haplotyping of single cells  

Microsoft Academic Search

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

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

2010-01-01

70

Genotype Error Detection using Hidden Markov Models of Haplotype Diversity  

E-print Network

levels remain present in SNP genotype data due to factors ranging from human error and sample quality markers, where error rates as low as 0.1% may invalidate some statistical tests for disease associationGenotype Error Detection using Hidden Markov Models of Haplotype Diversity Justin Kennedy Ion

Mandoiu, Ion

71

Subtyping of phosphoglucomutase locus 1 (PGM1) polymorphism in some populations of Rwanda: description of variant phenotypes, "haplotype" frequencies, and linkage disequilibrium data.  

PubMed Central

Some populations of Rwanda (South Twa Pygmies, Hutu, and Tutsi) have been analyzed by acid starch gel electrophoresis for the subtyping of PGM1 polymorphism. The new polymorphic third PGM11 allele, the PGM1(1Twa), which we recently detected in Twa Pygmies from North Rwanda, has not been found in this survey, whereas the rare PGM1(6) allele attains subpolymorphic frequencies in all groups. Comparison between the various populations of Rwanda shows that they differ significantly from each other with the exception of South Twa Pygmies and Tutsi. A relatively low frequency (9.6%) of the PGM1(2S) allele appears to be typical of North Twa Pygmies; a low frequency of PGM1(2F) (1.2%-3.6%) has been found in all these groups but not in the Hutu (6.4%); and a particularly high incidence of the PGM1(1F) allele (the highest so far reported) has been observed in the South Twa Pygmies (20%) and in the Tutsi (18%). The PGM1(1Twa) and PGM1(6) enzymes, which in acid starch gel are not distinguishable, can be clearly differentiated by isoelectric focusing. In addition, the same technique has shown that the rare PGM1(7) allele observed in one Hutu is different from that found at polymorphic frequency in the Japanese and from a rare PGM1(7) allele found in Germany. On the very likely hypothesis that the PGM1(1S), PGM1(1F), PGM1(2S), and PGM1(2F) result from variations at two different polymorphic sites, 1/2 and F/S, within the PGM1 structural gene, all the available population data have been analyzed to investigate whether preferential combinations (haplotypes) were identifiable. Whereas Caucasians show a prevalence of 2F and 1S combination with an 8.02% mean value of linkage disequilibrium expressed as % Dmax, from the very few and scattered African data, it is impossible to draw any inference at present. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:6462057

Santachiara-Benerecetti, A S; Ranzani, G N; Antonini, G; Beretta, M

1982-01-01

72

Imputation of microsatellite alleles from dense SNP genotypes for parentage verification across multiple Bos taurus and Bos indicus breeds  

PubMed Central

To assist cattle producers transition from microsatellite (MS) to single nucleotide polymorphism (SNP) genotyping for parental verification we previously devised an effective and inexpensive method to impute MS alleles from SNP haplotypes. While the reported method was verified with only a limited data set (N = 479) from Brown Swiss, Guernsey, Holstein, and Jersey cattle, some of the MS-SNP haplotype associations were concordant across these phylogenetically diverse breeds. This implied that some haplotypes predate modern breed formation and remain in strong linkage disequilibrium. To expand the utility of MS allele imputation across breeds, MS and SNP data from more than 8000 animals representing 39 breeds (Bos taurus and B. indicus) were used to predict 9410 SNP haplotypes, incorporating an average of 73 SNPs per haplotype, for which alleles from 12 MS markers could be accurately be imputed. Approximately 25% of the MS-SNP haplotypes were present in multiple breeds (N = 2 to 36 breeds). These shared haplotypes allowed for MS imputation in breeds that were not represented in the reference population with only a small increase in Mendelian inheritance inconsistancies. Our reported reference haplotypes can be used for any cattle breed and the reported methods can be applied to any species to aid the transition from MS to SNP genetic markers. While ~91% of the animals with imputed alleles for 12 MS markers had ?1 Mendelian inheritance conflicts with their parents' reported MS genotypes, this figure was 96% for our reference animals, indicating potential errors in the reported MS genotypes. The workflow we suggest autocorrects for genotyping errors and rare haplotypes, by MS genotyping animals whose imputed MS alleles fail parentage verification, and then incorporating those animals into the reference dataset. PMID:24065982

McClure, Matthew C.; Sonstegard, Tad S.; Wiggans, George R.; Van Eenennaam, Alison L.; Weber, Kristina L.; Penedo, Cecilia T.; Berry, Donagh P.; Flynn, John; Garcia, Jose F.; Carmo, Adriana S.; Regitano, Luciana C. A.; Albuquerque, Milla; Silva, Marcos V. G. B.; Machado, Marco A.; Coffey, Mike; Moore, Kirsty; Boscher, Marie-Yvonne; Genestout, Lucie; Mazza, Raffaele; Taylor, Jeremy F.; Schnabel, Robert D.; Simpson, Barry; Marques, Elisa; McEwan, John C.; Cromie, Andrew; Coutinho, Luiz L.; Kuehn, Larry A.; Keele, John W.; Piper, Emily K.; Cook, Jim; Williams, Robert; Van Tassell, Curtis P.

2013-01-01

73

[Identification of a novel Y-SNP in the USP9Y gene and its impact on genotyping alleles of the M46 locus].  

PubMed

Y-chromosomal SNP markers are becoming increasingly more popular among forensic geneticists, but since they constitute variants specific to the ethnic origin, detailed population studies are required. Research into frequency of haplogroup N-M46 in the Belarusian population detected a mutated allele in 22 males, including one with a very distinct Y-STR haplotype. Sequencing of the M46 locus of this individual revealed the presence of a novel Y-SNP nearby the M46 locus, which was responsible for the erroneous assignment of the Y chromosome to the haplogroup N-M46. An impact of the identified polymorphism on discrimination of alleles of the M46 locus with various techniques was discussed, and solutions ensuring correctness of the genotyping results were proposed. PMID:23650841

Reba?a, Krzysztof; Tsybovsky, Iosif S; Mikulich, Alexei I; Szczerkowska, Zofia

2012-01-01

74

Evidence for Association between the Brain-Derived Neurotrophic Factor Gene and Panic Disorder: A Novel Haplotype Analysis  

PubMed Central

Objective Panic disorder (PD) is a common psychiatric disorder with a complex etiology, and several studies have suggested that it has a genetic component. Brain-derived neurotrophic factor (BDNF) is the most abundant of the neurotrophins in the brain and is recognized for its important role in the survival, differentiation and growth of neurons. Several lines of research have suggested possible associations between the BDNF gene and PD. In this study, we investigated the BDNF 196G/A (rs6265), 11757G/C (rs16917204), and 270C/T (rs56164415) single nucleotide polymorphisms (SNPs) in order to determine an association with PD. We also identified the genetic sequence associations with PD via haplotype analysis. Methods Participants in this study included 136 PD patients and 263 healthy controls. Male and female subjects were analyzed separately. The genotype and allele frequencies of the PD patients and controls were analyzed using ?2 statistics. Frequencies and haplotype reconstructions were calculated using the SNP analyzer 2.0. Results We found no significant statistical differences in the genotype distributions or allele frequencies of the three tested polymorphisms between the PD and control groups. In addition, no differences were found between PD patients and the controls in either male or female subgroups. However, we found that, the frequency of the G-C haplotype for 196G/A and 11757G/C was significantly higher in PD patients than in the controls. Conclusion Our result suggest that patients with the G-C haplotype for 196G/A and 11757G/C may be more susceptible to the development of PD. Further studies are needed to replicate the associations that we observed.

Han, Eun-Jin; Hwang, Jung-A; Kim, Seung-Hyun; Lee, Heon-Jeong; Yoon, Ho-Kyoung; Na, Kyeong-Sae

2015-01-01

75

Variantes del ADNmt en isleños 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

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

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

2004-01-01

76

Analysis of DNA polymorphisms in sugar beet (Beta vulgaris L.) and development of an SNP-based map of expressed genes.  

PubMed

A panel of 13 sugar beet lines and one genotype each of the Beta vulgaris cultivars red beet and Swiss chard, and B. vulgaris ssp. maritima were used to identify polymorphisms in alignments of genomic DNA sequences derived from 315 EST- and 43 non-coding RFLP-derived loci. In sugar beet lines, loci of expressed genes showed an average SNP frequency of 1/72 bp, 1 in 58 bp in non-coding sequences, increasing to 1/47 bp upon the addition of the remaining genotypes. Within analysed DNA fragments, alleles at different SNP positions displayed linkage disequilibrium indicative of haplotype structures. On average 2.7 haplotypes were found in sugar beet lines, and haplotype conservation in expressed genes appeared to exceed 500 bp in length. Seven different genotyping techniques including SNP detection by MALDI-TOF mass spectrometry, pyrosequencing and fluorescence scanning of labelled nucleotides were employed to perform 712 segregation analyses for 538 markers in three F(2) populations. Functions were predicted for 492 mapped sequences. Genetic maps comprised 305 loci covering 599.8 cM in population K1, 241 loci distributed over 636.6 cM in population D2, and 166 loci over 507.1 cM in population K2, respectively. Based on 156 markers common to more than one population an integrated map was constructed with 524 loci covering 664.3 cM. For 377 loci the genome positions of the most similar sequences from A. thaliana were identified, but little evidence for previously presented ancestral genome structures was found. PMID:17622508

Schneider, Katharina; Kulosa, Dagmar; Soerensen, Thomas Rosleff; Möhring, Silke; Heine, Martin; Durstewitz, Gregor; Polley, Andreas; Weber, Eberhard; Jamsari; Lein, Jens; Hohmann, Uwe; Tahiro, Emma; Weisshaar, Bernd; Schulz, Britta; Koch, Georg; Jung, Christian; Ganal, Martin

2007-09-01

77

A Practical Exact Algorithm for the Individual Haplotyping Problem MEC\\/GI  

Microsoft Academic Search

Given the genotype and the aligned single nucleotide polymorphism (SNP) fragments of an individual, Minimum Error Correction with Genotype Information (MEC\\/GI) is an important computational model to infer a pair of haplotypes compatible with the genotype by correcting minimum\\u000a number of SNPs in the given SNP fragments. For the problem, there has been no practical exact algorithm. In DNA sequencing

Minzhu Xie; Jianxin Wang; Jianer Chen

2008-01-01

78

Haplotype reconstruction using perfect phylogeny and sequence data  

PubMed Central

Haplotype phasing is a well studied problem in the context of genotype data. With the recent developments in high-throughput sequencing, new algorithms are needed for haplotype phasing, when the number of samples sequenced is low and when the sequencing coverage is blow. High-throughput sequencing technologies enables new possibilities for the inference of haplotypes. Since each read is originated from a single chromosome, all the variant sites it covers must derive from the same haplotype. Moreover, the sequencing process yields much higher SNP density than previous methods, resulting in a higher correlation between neighboring SNPs. We offer a new approach for haplotype phasing, which leverages on these two properties. Our suggested algorithm, called Perfect Phlogeny Haplotypes from Sequencing (PPHS) uses a perfect phylogeny model and it models the sequencing errors explicitly. We evaluated our method on real and simulated data, and we demonstrate that the algorithm outperforms previous methods when the sequencing error rate is high or when coverage is low. PMID:22537042

2012-01-01

79

FSHR single nucleotide polymorphism frequencies in proven fathers and infertile men in Southeast Turkey.  

PubMed

The influence of FSH receptor (FSHR) variants on male infertility is not completely understood. The present investigation is the first screening study for SNP at nucleotide position -29 in the core promoter region and codon 680 in exon 10 of the FSHR and the effect of the serum levels of FSH on male infertility in Southeast Turkey. The SNPs in codon 680 and at position -29 of the FSHR gene were analyzed by PCR-RFLP technique in 240 men with proven fathers, and 270 infertile men (150 nonobstructive azoospermic and 120 severe oligozoospermic). The separate analysis for SNP at nucleotide position -29 did not show any difference in genotypic frequencies and serum FSH levels. The genotype distribution of SNP at position 680 was different but does not influence serum FSH levels. Together the two SNPs form four discrete haplotypes (A-Thr-Asn, G-Thr-Asn, A-Ala-Ser, and G-Ala-Ser) occurring in 10 combinations. A statistically significant difference in the allelic distribution of G-Asn/G-Ser and G-Ser/G-Ser genotype between proven fathers and infertile men but there were not any statistically significant difference in the overall frequency of the four FSHR haplotypes. We conclude that the FSHR haplotype does not associate with different serum FSH levels but it is differently distributed in proven fathers and infertile men. PMID:20454649

Balkan, Mahmut; Gedik, Abdullah; Akkoc, Hasan; Izci Ay, Ozlem; Erdal, M Emin; Isi, Hilmi; Budak, Turgay

2010-01-01

80

FSHR Single Nucleotide Polymorphism Frequencies in Proven Fathers and Infertile Men in Southeast Turkey  

PubMed Central

The influence of FSH receptor (FSHR) variants on male infertility is not completely understood. The present investigation is the first screening study for SNP at nucleotide position ?29 in the core promoter region and codon 680 in exon 10 of the FSHR and the effect of the serum levels of FSH on male infertility in Southeast Turkey. The SNPs in codon 680 and at position ?29 of the FSHR gene were analyzed by PCR-RFLP technique in 240 men with proven fathers, and 270 infertile men (150 nonobstructive azoospermic and 120 severe oligozoospermic). The separate analysis for SNP at nucleotide position ?29 did not show any difference in genotypic frequencies and serum FSH levels. The genotype distribution of SNP at position 680 was different but does not influence serum FSH levels. Together the two SNPs form four discrete haplotypes (A-Thr-Asn, G-Thr-Asn, A-Ala-Ser, and G-Ala-Ser) occurring in 10 combinations. A statistically significant difference in the allelic distribution of G-Asn/G-Ser and G-Ser/G-Ser genotype between proven fathers and infertile men but there were not any statistically significant difference in the overall frequency of the four FSHR haplotypes. We conclude that the FSHR haplotype does not associate with different serum FSH levels but it is differently distributed in proven fathers and infertile men. PMID:20454649

Balkan, Mahmut; Gedik, Abdullah; Akkoc, Hasan; Izci Ay, Ozlem; Erdal, M. Emin; Isi, Hilmi; Budak, Turgay

2010-01-01

81

RET Variants and Haplotype Analysis in a Cohort of Czech Patients with Hirschsprung Disease  

PubMed Central

Hirschsprung disease (HSCR) is a congenital aganglionosis of myenteric and submucosal plexuses in variable length of the intestine. This study investigated the influence and a possible modifying function of RET proto-oncogene's single nucleotide polymorphisms (SNPs) and haplotypes in the development and phenotype of the disease in Czech patients. Genotyping of 14 SNPs was performed using TaqMan Genotyping Assays and direct sequencing. The frequencies of SNPs and generated haplotypes were statistically evaluated using chi-square test and the association with the risk of HSCR was estimated by odds ratio. SNP analysis revealed significant differences in frequencies of 11 polymorphic RET variants between 162 HSCR patients and 205 unaffected controls. Particularly variant alleles of rs1864410, rs2435357, rs2506004 (intron 1), rs1800858 (exon 2), rs1800861 (exon 13), and rs2565200 (intron 19) were strongly associated with increased risk of HSCR (p<0.00000) and were over-represented in males vs. females. Conversely, variant alleles of rs1800860, rs1799939 and rs1800863 (exons 7, 11, 15) had a protective role. The haploblock comprising variants in intron 1 and exon 2 was constructed. It represented a high risk of HSCR, however, the influence of other variants was also found after pruning from effect of this haploblock. Clustering patients according to genotype status in haploblock revealed a strong co-segregation with several SNPs and pointed out the differences between long and short form of HSCR. This study involved a large number of SNPs along the entire RET proto-oncogene with demonstration of their risk/protective role also in haplotype and diplotype analysis in the Czech population. The influence of some variant alleles on the aggressiveness of the disease and their role in gender manifestation differences was found. These data contribute to worldwide knowledge of the genetics of HSCR. PMID:24897126

Vaclavikova, Eliska; Dvorakova, Sarka; Skaba, Richard; Pos, Lucie; Sykorova, Vlasta; Halkova, Tereza; Vcelak, Josef; Bendlova, Bela

2014-01-01

82

A whole genome SNP genotyping by DNA microarray and candidate gene association study for kidney stone disease  

PubMed Central

Background Kidney stone disease (KSD) is a complex disorder with unknown etiology in majority of the patients. Genetic and environmental factors may cause the disease. In the present study, we used DNA microarray to genotype single nucleotide polymorphisms (SNP) and performed candidate gene association analysis to determine genetic variations associated with the disease. Methods A whole genome SNP genotyping by DNA microarray was initially conducted in 101 patients and 105 control subjects. A set of 104 candidate genes reported to be involved in KSD, gathered from public databases and candidate gene association study databases, were evaluated for their variations associated with KSD. Results Altogether 82 SNPs distributed within 22 candidate gene regions showed significant differences in SNP allele frequencies between the patient and control groups (P?frequencies between the patient and control groups within the gene. The total of 26 SNPs showed significant differences of allele frequencies between the patient and control groups and haplotypes associated with disease risk were identified. The SNP rs759330 located 144 bp downstream of BGLAP where it is a predicted microRNA binding site at 3?UTR of PAQR6 – a gene encoding progestin and adipoQ receptor family member VI, was genotyped in 216 patients and 216 control subjects and found to have significant differences in its genotype and allele frequencies (P?=?0.0007, OR 2.02 and P?=?0.0001, OR 2.02, respectively). Conclusions Our results suggest that these candidate genes are associated with KSD and PAQR6 comes into our view as the most potent candidate since associated SNP rs759330 is located in the miRNA binding site and may affect mRNA expression level. PMID:24886237

2014-01-01

83

Estimation of haplotypes Cavan Reilly  

E-print Network

vs. Bayesian statistics Estimating haplotypes with the EM algorithm Individual level haplotypes't be determined directly from the genotypic data in humans. Thus we need methods for estimating haplotypes measurements of the same quantity but that quantity is subject to measurement error. #12;Frequentist vs

Reilly, Cavan

84

Pyrosequencing for SNP genotyping.  

PubMed

Pyrosequencing is a real-time DNA sequencing method. It is based on the transformation of pyrophosphates, released during DNA elongation by DNA polymerase, into measurable light. During DNA elongation, a single pyrophosphate molecule is released following incorporation of a single nucleotide. In the pyrosequencing reaction, released pyrophosphates are then rapidly converted by sulfurylase to adenosine triphosphate, which in turn is utilized by luciferase to produce light. Within standardized conditions, this reaction is accomplished in a few milliseconds and the light produced can be registered with a CCD camera. Therefore, it becomes possible to quantitatively measure the nucleotides incorporated. This approach has been automated in different platforms and can be used for a wide variety of applications, such as single-nucleotide polymorphism (SNP) genotyping, DNA sequencing, loss of heterozygosity analysis, and CpG methylation studies. Here we describe the entire process, focusing our attention on SNP genotyping, and giving examples of some other applications. PMID:19768590

Royo, Jose Luis; Galán, Jose Jorge

2009-01-01

85

Comparative analysis of haplotype association mapping algorithms  

PubMed Central

Background Finding the genetic causes of quantitative traits is a complex and difficult task. Classical methods for mapping quantitative trail loci (QTL) in miceuse an F2 cross between two strains with substantially different phenotype and an interval mapping method to compute confidence intervals at each position in the genome. This process requires significant resources for breeding and genotyping, and the data generated are usually only applicable to one phenotype of interest. Recently, we reported the application of a haplotype association mapping method which utilizes dense genotyping data across a diverse panel of inbred mouse strains and a marker association algorithm that is independent of any specific phenotype. As the availability of genotyping data grows in size and density, analysis of these haplotype association mapping methods should be of increasing value to the statistical genetics community. Results We describe a detailed comparative analysis of variations on our marker association method. In particular, we describe the use of inferred haplotypes from adjacent SNPs, parametric and nonparametric statistics, and control of multiple testing error. These results show that nonparametric methods are slightly better in the test cases we study, although the choice of test statistic may often be dependent on the specific phenotype and haplotype structure being studied. The use of multi-SNP windows to infer local haplotype structure is critical to the use of a diverse panel of inbred strains for QTL mapping. Finally, because the marginal effect of any single gene in a complex disease is often relatively small, these methods require the use of sensitive methods for controlling family-wise error. We also report our initial application of this method to phenotypes cataloged in the Mouse Phenome Database. Conclusion The use of inbred strains of mice for QTL mapping has many advantages over traditional methods. However, there are also limitations in comparison to the traditional linkage analysis from F2 and RI lines. Application of these methods requires careful consideration of algorithmic choices based on both theoretical and practical factors. Our findings suggest general guidelines, though a complete evaluation of these methods can only be performed as more genetic data in complex diseases becomes available. PMID:16466585

McClurg, Phillip; Pletcher, Mathew T; Wiltshire, Tim; Su, Andrew I

2006-01-01

86

HLA Type Inference via Haplotypes Identical by Descent  

NASA Astrophysics Data System (ADS)

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.

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

87

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

PubMed

Sickle cell disease is an inherited autosomal recessive disorder of the beta-globin chain. In Palestine it is accompanied by a low level of Hb F (mean 5.14%) and a severe clinical presentation. In this study, 59 Palestinian patients, homozygotes for Hb S were studied for their haplotype background. Eight polymorphic sites in the beta-globin gene cluster were examined. The Benin haplotype was predominant with a frequency of 88.1%, followed by a frequency of 5.1% for the Bantu haplotype. One chromosome was found to carry the Cameroon haplotype (0.85%). Three atypical haplotypes were also found (5.95%). Heterogeneity was observed in Hb F production, ranging between 1.5 and 17.0%, whereas the (G)gamma ratio was homogeneous among all haplotypes with a normal amount of about 41%. Our results are in agreement with previous reports of the Benin haplotype origin in the Mediterranean. PMID:19373591

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

2009-01-01

88

Recent radiation within Y-chromosomal haplogroup R-M269 resulted in high Y-STR haplotype resemblance.  

PubMed

Y-chromosomal short tandem repeats (Y-STRs) are often used in addition to Y-chromosomal single-nucleotide polymorphisms (Y-SNP) to detect subtle patterns in a population genetic structure. There are, however, indications for Y-STR haplotype resemblance across different subhaplogroups within haplogroup R1b1b2 (R-M269) which may lead to erosion in the observation of the population genetic pattern. Hence the question arises whether Y-STR haplotypes are still informative beyond high-resolution Y-SNP genotyping for population genetic studies. To address this question, we genotyped the Y chromosomes of more than 1000 males originating from the West-European regions of Flanders (Belgium), North-Brabant and Limburg (the Netherlands) at the highest resolution of the current Y-SNP tree together with 38 commonly used Y-STRs. We observed high resemblance of Y-STR haplotypes between males belonging to different subhaplogroups of haplogroup R-M269. Several subhaplogroups within R-M269 could not be distinguished from each other based on differences in Y-STR haplotype variation. The most likely hypothesis to explain this similarity of Y-STR haplotypes within the population of R-M269 members is a recent radiation where various subhaplogroups originated within a relatively short time period. We conclude that high-resolution Y-SNP typing rather than Y-STR typing might be more useful to study population genetic patterns in (Western) Europe. PMID:24571229

Larmuseau, Maarten H D; Vanderheyden, Nancy; Van Geystelen, Anneleen; van Oven, Mannis; de Knijff, Peter; Decorte, Ronny

2014-03-01

89

Validation of SNP Allele Frequencies Determined by Pooled Next-Generation Sequencing in Natural Populations of a Non-Model Plant Species  

PubMed Central

Sequencing of pooled samples (Pool-Seq) using next-generation sequencing technologies has become increasingly popular, because it represents a rapid and cost-effective method to determine allele frequencies for single nucleotide polymorphisms (SNPs) in population pools. Validation of allele frequencies determined by Pool-Seq has been attempted using an individual genotyping approach, but these studies tend to use samples from existing model organism databases or DNA stores, and do not validate a realistic setup for sampling natural populations. Here we used pyrosequencing to validate allele frequencies determined by Pool-Seq in three natural populations of Arabidopsis halleri (Brassicaceae). The allele frequency estimates of the pooled population samples (consisting of 20 individual plant DNA samples) were determined after mapping Illumina reads to (i) the publicly available, high-quality reference genome of a closely related species (Arabidopsis thaliana) and (ii) our own de novo draft genome assembly of A. halleri. We then pyrosequenced nine selected SNPs using the same individuals from each population, resulting in a total of 540 samples. Our results show a highly significant and accurate relationship between pooled and individually determined allele frequencies, irrespective of the reference genome used. Allele frequencies differed on average by less than 4%. There was no tendency that either the Pool-Seq or the individual-based approach resulted in higher or lower estimates of allele frequencies. Moreover, the rather high coverage in the mapping to the two reference genomes, ranging from 55 to 284x, had no significant effect on the accuracy of the Pool-Seq. A resampling analysis showed that only very low coverage values (below 10-20x) would substantially reduce the precision of the method. We therefore conclude that a pooled re-sequencing approach is well suited for analyses of genetic variation in natural populations. PMID:24244686

Rellstab, Christian; Zoller, Stefan; Tedder, Andrew; Gugerli, Felix; Fischer, Martin C.

2013-01-01

90

Genome diversity and gene haplotypes in the grapevine ( Vitis vinifera L.), as revealed by single nucleotide polymorphisms  

Microsoft Academic Search

EST (expressed sequence tags) sequencing, SNP (single nucleotide polymorphisms) development and haplotype assessment are powerful tools for the support of marker-assisted selection. The grapevine genome is currently being scavenged in our laboratory using an EST-SNP approach. Nine parental genotypes, used to create five inter- or intra-specific hybrids, have been tested to evaluate the degree of polymorphism between Vitis vinifera, Vitis

Marzia Salmaso; Giorgia Faes; Cinzia Segala; Marco Stefanini; Ilkhom Salakhutdinov; Eva Zyprian; Reinhard Toepfer; M. Stella Grando; Riccardo Velasco

2005-01-01

91

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

PubMed

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

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

2015-03-10

92

Are Molecular Haplotypes Worth the Time and Expense? A Cost-Effective Method for Applying Molecular Haplotypes  

PubMed Central

Because current molecular haplotyping methods are expensive and not amenable to automation, many researchers rely on statistical methods to infer haplotype pairs from multilocus genotypes, and subsequently treat these inferred haplotype pairs as observations. These procedures are prone to haplotype misclassification. We examine the effect of these misclassification errors on the false-positive rate and power for two association tests. These tests include the standard likelihood ratio test (LRTstd) and a likelihood ratio test that employs a double-sampling approach to allow for the misclassification inherent in the haplotype inference procedure (LRTae). We aim to determine the cost–benefit relationship of increasing the proportion of individuals with molecular haplotype measurements in addition to genotypes to raise the power gain of the LRTae over the LRTstd. This analysis should provide a guideline for determining the minimum number of molecular haplotypes required for desired power. Our simulations under the null hypothesis of equal haplotype frequencies in cases and controls indicate that (1) for each statistic, permutation methods maintain the correct type I error; (2) specific multilocus genotypes that are misclassified as the incorrect haplotype pair are consistently misclassified throughout each entire dataset; and (3) our simulations under the alternative hypothesis showed a significant power gain for the LRTae over the LRTstd for a subset of the parameter settings. Permutation methods should be used exclusively to determine significance for each statistic. For fixed cost, the power gain of the LRTae over the LRTstd varied depending on the relative costs of genotyping, molecular haplotyping, and phenotyping. The LRTae showed the greatest benefit over the LRTstd when the cost of phenotyping was very high relative to the cost of genotyping. This situation is likely to occur in a replication study as opposed to a whole-genome association study. PMID:16933998

Levenstien, Mark A; Ott, Jürg; Gordon, Derek

2006-01-01

93

MHC Class II haplotypes of Colombian Amerindian tribes  

PubMed Central

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

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

2013-01-01

94

SNP deserts of Asian cultivated rice: genomic regions under domestication.  

PubMed

When performing a genome-wide comparison between indica (93-11) and japonica (Nipponbare), we find 8% of the genome, which have an extremely low SNP rate (< 1 SNP/kb). Inside these 'SNP deserts', experimentally confirmed genes show increased K(a)/K(s) that indicate adaptive selection. To further elucidate this connection, we survey the level and pattern of genetic variation in both cultivated and wild rice groups, using 155 noncoding regions located within SNP deserts. The results suggest that cultivated rice has greatly reduced genetic variation within SNP deserts as compared to either the nondesert or corresponding genomic regions in wild rice. Consistent with this reduction in genetic variation, we find a biased distribution of derived allele frequency in the cultivated group, indicative of positive selection. Furthermore, over half of the confirmed, domestication-related genes are found within SNP deserts, also suggesting that SNP deserts are strongly related to domestication, and might be the key sites in the process of domestication. PMID:19243488

Wang, L; Hao, L; Li, X; Hu, S; Ge, S; Yu, J

2009-04-01

95

TGFBR1 haplotypes and risk of non-small cell lung cancer  

PubMed Central

Transforming growth factor beta (TGF-?) receptors are centrally involved in TGF-?-mediated cell growth and differentiation and are frequently inactivated in non-small cell lung cancer (NSCLC). Constitutively decreased type I TGF-? receptor (TGFBR1) expression is emerging as a novel tumor-predisposing phenotype. The association of TGFBR1 haplotypes with risk for NSCLC has not yet been studied. We tested the hypothesis that single nucleotide polymorphisms (SNPs) and/or TGFBR1 haplotypes are associated with risk of NSCLC. We genotyped six TGFBR1 haplotype tagging SNPs (htSNPs) by PCR-restriction fragment length polymorphism (PCR-RFLP) assays and one htSNP by PCR-single strand conformation polymorphism (PCR-SSCP) assay in two case-control studies. Case-control study 1 included 102 NSCLC patients and 104 healthy controls from Suzhou. Case-control study 2 included 131 patients with NSCLC and 133 healthy controls from Wuxi. Individuals included in both case-control studies were Han Chinese. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium (LD) status of these seven htSNPs. None of the htSNP was associated with NSCLC risk in either study. However, a four-marker haplotype CTGC was significantly more common among controls than among cases in both studies (P=0.014 and P=0.010, respectively) indicating that this haplotype is associated with decreased NSCLC risk (adjusted OR, 0.09; 95% CI, 0.01-0.61 and adjusted OR, 0.11; 95% CI, 0.02-0.59, respectively). Combined analysis of both studies shows a strong association of this four-marker haplotype with decreased NSCLC risk (adjusted OR, 0.11; 95% CI, 0.03-0.39). This is the first evidence of an association between a TGFBR1 haplotype and risk for NSCLC. PMID:19690145

Lei, Zhe; Liu, Reng Yun; Zhao, Jun; Liu, Zeyi; Jiang, Xiefang; You, Weiming; Chen, Xiao Feng; Liu, Xia; Zhang, Kui; Pasche, Boris; Zhang, Hong Tao

2009-01-01

96

High-Throughput SNP Genotyping  

Microsoft Academic Search

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.

Suzanne Jenkins; Neil Gibson

2002-01-01

97

SNP genotyping using KASPar assays.  

PubMed

In a separate chapter we describe a simple method for single nucleotide polymorphism (SNP) discovery using genomic reduction. Here we describe a scalable and cost-effective SNP genotyping method based on KBioscience's competitive allele-specific PCR amplification of target sequences and endpoint fluorescence genotyping (KASPar™) using a FRET capable plate reader or Fluidigm's dynamic array high-throughput platform. PMID:25373762

Smith, Scott M; Maughan, Peter J

2015-01-01

98

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

PubMed Central

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

Barendse, William

2011-01-01

99

Accelerating Haplotype-Based Genome-Wide Association Study Using Perfect Phylogeny and Phase-Known Reference Data  

PubMed Central

The genome-wide association study (GWAS) has become a routine approach for mapping disease risk loci with the advent of large-scale genotyping technologies. Multi-allelic haplotype markers can provide superior power compared with single-SNP markers in mapping disease loci. However, the application of haplotype-based analysis to GWAS is usually bottlenecked by prohibitive time cost for haplotype inference, also known as phasing. In this study, we developed an efficient approach to haplotype-based analysis in GWAS. By using a reference panel, our method accelerated the phasing process and reduced the potential bias generated by unrealistic assumptions in phasing process. The haplotype-based approach delivers great power and no type I error inflation for association studies. With only a medium-size reference panel, phasing error in our method is comparable to the genotyping error afforded by commercial genotyping solutions. PMID:21789217

Amos, Christopher I.; Xiong, Momiao; Ling, Hua; Jin, Li

2011-01-01

100

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

PubMed Central

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

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

2015-01-01

101

Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer  

Microsoft Academic Search

PURPOSE: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine. EXPERIMENTAL DESIGN: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab +\\/- cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases

M. J. Deenen; J. Tol; A. M. Burylo; V. D. Doodeman; A. de Boer; A. Vincent; H. J. Guchelaar; P. H. Smits; J. H. Beijnen; C. J. A. Punt; J. H. Schellens; A. Cats

2011-01-01

102

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

PubMed Central

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

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.; Røed, Knut H.; Ryder, Oliver A.; Swinburne, June E.; Tozaki, Teruaki; Valberg, Stephanie J.; Vaudin, Mark; Lindblad-Toh, Kerstin

2012-01-01

103

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

PubMed Central

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

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

2012-01-01

104

Beta-globin gene cluster haplotypes in Afro-Uruguayans from two geographical regions (South and North).  

PubMed

The beta-globin gene cluster haplotypes were identified in 52 and 40 chromosomes from two Afro-Uruguayan populations located in the South and North of the country, respectively. In both regions, the 5' haplotype 2 (+ - - - -), characteristic of non-African populations, was the most frequent, reflecting a strong process of admixture in Afro-Uruguayans (0.355 and 0.262, respectively). The haplotypes 3 (- - - - +) and 4 (- + - - +), characteristics of African sub-Saharan populations, present inverse frequencies in North and South: whereas in the South haplotype 3 is the second most frequent (0.232), and haplotype 4 presents a low frequency (0.019), in the North haplotype 4 is the third most frequent (0.140), and haplotype 3 only reaches an intermediate frequency (0.088). The pairwise F(ST) and the exact test of differentiation show genetic heterogeneity between both regions. Nei's genetic distance show that South and North present affinities with Bantu groups, although the North present the smallest genetic distance with the Mandenka, a Senegalese population. With respect to 3' haplotypes, haplotype I was the most frequent in both populations, followed by haplotype II, characteristic of sub-Saharan Africans. The high frequencies of haplotype III-Asian could indicate admixture with Native American populations. The differences observed between both Uruguayan regions could be explained by microevolutionary events as genetic drift, founder effects, differential admixture, and/or distinct origin of the African slaves introduced in those regions. PMID:19533614

Da Luz, Julio; Kimura, Elza Miyuki; Costa, Fernando Ferreira; Sonati, Maria de Fatima; Sans, Mónica

2010-01-01

105

Genome-Wide Haplotype Changes Produced by Artificial Selection during Modern Rice Breeding in Japan  

PubMed Central

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

Yamamoto, Eiji; Nagasaki, Hideki; Shibaya, Taeko; Yano, Masahiro

2012-01-01

106

[Analysis of mitochondrial DNA haplotypes in yakut population].  

PubMed

To study the mitochondrial gene pool structure in Yakuts, polymorphism of mtDNA hypervariable segment I (16,024-16,390) was analyzed in 191 people sampled from the indigenous population of the Sakha Republic. In total, 67 haplotypes of 14 haplogroups were detected. Most (91.6%) haplotypes belonged to haplogroups A, B, C, D, F, G, M*, and Y, which are specific for East Eurasian ethnic groups; 8.4% haplotypes represented Caucasian haplogroups H, HV1, J, T, U, and W. A high frequency of mtDNA types belonging to Asian supercluster M was peculiar for Yakuts: mtDNA types belonging to haplogroup C, D, or G and undifferentiated mtDNA types of haplogroup M (M*) accounted for 81% of all haplotypes. The highest diversity was observed for haplogroups C and D, which comprised respectively 22 (44%) and 18 (30%) haplotypes. Yakuts showed the lowest genetic diversity (H = 0.964) among all Turkic ethnic groups. Phylogenetic analysis testified to a common genetic substrate of Yakuts, Mongols, and Central Asian (Kazakh, Kyrgyz, Uigur) populations. Yakuts proved to share 21 (55.5%) mtDNA haplogroups with the Central Asian ethnic groups and Mongols. Comparisons with modern paleo-Asian populations (Chukcha, Itelmen, Koryaks) revealed three (8.9%) haplotypes common for Yakuts and Koryaks. The results of mtDNA analysis disagree with the hypothesis of an appreciable paleo-Asian contribution to the modern Yakut gene pool. PMID:12942638

Fedorova, S A; Bermisheva, M A; Villems, R; Maksimova, N R; Khusnutdinova, E K

2003-01-01

107

PanSNPdb: The Pan-Asian SNP Genotyping Database  

PubMed Central

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

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

2011-01-01

108

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

PubMed Central

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

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

2011-01-01

109

SNP calling by sequencing pooled samples  

PubMed Central

Background Performing high throughput sequencing on samples pooled from different individuals is a strategy to characterize genetic variability at a small fraction of the cost required for individual sequencing. In certain circumstances some variability estimators have even lower variance than those obtained with individual sequencing. SNP calling and estimating the frequency of the minor allele from pooled samples, though, is a subtle exercise for at least three reasons. First, sequencing errors may have a much larger relevance than in individual SNP calling: while their impact in individual sequencing can be reduced by setting a restriction on a minimum number of reads per allele, this would have a strong and undesired effect in pools because it is unlikely that alleles at low frequency in the pool will be read many times. Second, the prior allele frequency for heterozygous sites in individuals is usually 0.5 (assuming one is not analyzing sequences coming from, e.g. cancer tissues), but this is not true in pools: in fact, under the standard neutral model, singletons (i.e. alleles of minimum frequency) are the most common class of variants because P(f) ? 1/f and they occur more often as the sample size increases. Third, an allele appearing only once in the reads from a pool does not necessarily correspond to a singleton in the set of individuals making up the pool, and vice versa, there can be more than one read – or, more likely, none – from a true singleton. Results To improve upon existing theory and software packages, we have developed a Bayesian approach for minor allele frequency (MAF) computation and SNP calling in pools (and implemented it in a program called snape): the approach takes into account sequencing errors and allows users to choose different priors. We also set up a pipeline which can simulate the coalescence process giving rise to the SNPs, the pooling procedure and the sequencing. We used it to compare the performance of snape to that of other packages. Conclusions We present a software which helps in calling SNPs in pooled samples: it has good power while retaining a low false discovery rate (FDR). The method also provides the posterior probability that a SNP is segregating and the full posterior distribution of f for every SNP. In order to test the behaviour of our software, we generated (through simulated coalescence) artificial genomes and computed the effect of a pooled sequencing protocol, followed by SNP calling. In this setting, snape has better power and False Discovery Rate (FDR) than the comparable packages samtools, PoPoolation, Varscan : for N = 50 chromosomes, snape has power ? 35%and FDR ? 2.5%. snape is available at http://code.google.com/p/snape-pooled/ (source code and precompiled binaries). PMID:22992255

2012-01-01

110

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

Microsoft Academic Search

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

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

111

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

PubMed Central

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

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

1989-01-01

112

[The origin of Yakuts: analysis of Y-chromosome haplotypes].  

PubMed

Gene pool structure of Sakha Republic (Yakutia) native population has been studied: we defined composition and frequencies of Y-chromosome haplogroups for Yakuts. Six haplogroups: C3 x M77, C3c, N*, N2, N3a and R1a1 have been revealed in Yakut gene pool. A greater part of Y-chromosome in Yakut population belongs to N3a haplogroup (89%). All investigated Yakut population samples have low values of gene diversity, calculated based on haplogroup frequencies. Gene differentiation of the investigated samples estimated using the analysis of molecular variance (AMOVA) by two marker systems (haplogroup frequencies and microsatellite haplotypes of Y-chromosome) revealed a portion of interpopulation differences amounting to 0.24 and 2.85%, respectively. Frequencies and molecular phylogeny of YSTR-haplotypes were revealed for N3a haplogroup of Y-chromosome. Altogether forty haplotypes were found in Yakuts. Evenks and Yakuts are characterized by overlapping and very specific spectrum of N3a haplotypes, which is not typical for other Siberian ethnic groups. Cluster analysis of populations by N3a YSTR-haplotypes shows Yakut isolation from Turkic-speaking populations in the South Siberia. Genetic diversity generation time for a specific spectrum of Yakut haplotypes was estimated as 4.45 +/- 1.96 thousand years. As opposed to the data on mtDNA, the obtained results give an evidence for significant contribution of a local palaeolithic component into Y-chromosomal Yakut gene pool. Ethnogenetic reconstruction of the present picture of genetic diversity in N3a haplogroup in the territory of Siberia is under consideration. PMID:18610830

Khar'kov, V N; Stepanov, V A; Medvedev, O F; Spiridonova, M G; Maksimova, N R; Nogovitsyna, A N; Puzyrev, V P

2008-01-01

113

A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites  

PubMed Central

Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ?1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22?Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10?Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ?1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity. PMID:21610747

Chong, Jessica X; Oktay, A Af?in; Dai, Zunyan; Swoboda, Kathryn J; Prior, Thomas W; Ober, Carole

2011-01-01

114

Haplotype phasing after joint estimation of recombination and linkage disequilibrium in breeding populations.  

PubMed

A novel method for haplotype phasing in families after joint estimation of recombination fraction and linkage disequilibrium is developed. Results from Monte Carlo computer simulations show that the newly developed E.M. algorithm is accurate if true recombination fraction is 0 even for single families of relatively small sizes. Estimates of recombination fraction and linkage disequilibrium were 0.00 (SD 0.00) and 0.19 (SD 0.03) for simulated recombination fraction and linkage disequilibrium of 0.00 and 0.20, respectively. A genome fragmentation phasing strategy was developed and used for phasing haplotypes in a sire and 36 progeny using the 50 k Illumina BeadChip by: a) estimation of the recombination fraction and LD in consecutive SNPs using family information, b) linkage analyses between fragments, c) phasing of haplotypes in parents and progeny and in following generations. Homozygous SNPs in progeny allowed determination of paternal fragment inheritance, and deduction of SNP sequence information of haplotypes from dams. The strategy also allowed detection of genotyping errors. A total of 613 recombination events were detected after linkage analysis was carried out between fragments. Hot and cold spots were identified at the individual (sire level). SNPs for which the sire and calf were heterozygotes became informative (over 90%) after the phasing of haplotypes. Average of regions of identity between half-sibs when comparing its maternal inherited haplotypes (with at least 20 SNP) in common was 0.11 with a maximum of 0.29 and a minimum of 0.05. A Monte-Carlo simulation of BTA1 with the same linkage disequilibrium structure and genetic linkage as the cattle family yielded a 99.98 and 99.94% of correct phases for informative SNPs in sire and calves, respectively. PMID:23916349

Gomez-Raya, Luis; Hulse, Amanda M; Thain, David; Rauw, Wendy M

2013-01-01

115

High-resolution haplotype structure in the human genome  

Microsoft Academic Search

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

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

2001-01-01

116

Effects on Production Traits of Haplotypes Among Casein Genes in Norwegian Goats and Evidence for a Site of Preferential Recombination  

PubMed Central

In goat milk the most abundant proteins are the casein genes, CSN1S1, CSN2, CSN1S2, and CSN3. Mutations have been identified within these genes affecting the level of gene expression, and effects on milk production traits have been reported. The aim of this study was to detect polymorphisms (SNPs) in the casein genes of Norwegian goats, resolve haplotype structures within the loci, and assess the effect of these haplotypes on milk production traits. Four hundred thirty-six Norwegian bucks were genotyped for 39 polymorphic sites across the four loci. The numbers of unique haplotypes present in each locus were 10, 6, 4, and 8 for CSN1S1, CSN2, CSN1S2, and CSN3, respectively. The effects of the CSN1S1 haplotypes on protein percentage and fat kilograms were significant, as were the effects of CSN3 haplotypes on fat percentage and protein percentage. A deletion in exon 12 of CSN1S1, unique to the Norwegian goat population, explained the effects of CSN1S1 haplotypes on fat kilograms, but not protein percentage. Investigation of linkage disequilibrium between all possible pairs of SNPs revealed higher levels of linkage disequilbrium for SNP pairs within casein loci than for SNP pairs between casein loci, likely reflecting low levels of intragenic recombination. Further, there was evidence for a site of preferential recombination between CSN2 and CSN1S2. The value of the haplotypes for haplotype-assisted selection (HAS) is discussed. PMID:16849606

Hayes, Ben; Hagesæther, Nina; Ådnøy, Tormod; Pellerud, Grunde; Berg, Paul R.; Lien, Sigbjørn

2006-01-01

117

Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies.  

PubMed

Single nucleotide polymorphism arrays (SNP-As) have emerged as an important tool in the identification of chromosomal defects undetected by metaphase cytogenetics (MC) in hematologic cancers, offering superior resolution of unbalanced chromosomal defects and acquired copy-neutral loss of heterozygosity. Myelodysplastic syndromes (MDSs) and related cancers share recurrent chromosomal defects and molecular lesions that predict outcomes. We hypothesized that combining SNP-A and MC could improve diagnosis/prognosis and further the molecular characterization of myeloid malignancies. We analyzed MC/SNP-A results from 430 patients (MDS = 250, MDS/myeloproliferative overlap neoplasm = 95, acute myeloid leukemia from MDS = 85). The frequency and clinical significance of genomic aberrations was compared between MC and MC plus SNP-A. Combined MC/SNP-A karyotyping lead to higher diagnostic yield of chromosomal defects (74% vs 44%, P < .0001), compared with MC alone, often through detection of novel lesions in patients with normal/noninformative (54%) and abnormal (62%) MC results. Newly detected SNP-A defects contributed to poorer prognosis for patients stratified by current morphologic and clinical risk schemes. The presence and number of new SNP-A detected lesions are independent predictors of overall and event-free survival. The significant diagnostic and prognostic contributions of SNP-A-detected defects in MDS and related diseases underscore the utility of SNP-A when combined with MC in hematologic malignancies. PMID:21285439

Tiu, Ramon V; Gondek, Lukasz P; O'Keefe, Christine L; Elson, Paul; Huh, Jungwon; Mohamedali, Azim; Kulasekararaj, Austin; Advani, Anjali S; Paquette, Ronald; List, Alan F; Sekeres, Mikkael A; McDevitt, Michael A; Mufti, Ghulam J; Maciejewski, Jaroslaw P

2011-04-28

118

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

PubMed

Prenatal diagnosis of congenital adrenal hyperplasia (CAH) is of clinical significance because in utero treatment is available to prevent virilization of an affected female fetus. However, traditional prenatal diagnosis of CAH relies on genetic testing of fetal genomic DNA obtained using amniocentesis or chorionic villus sampling, which is associated with an increased risk of miscarriage. The aim of this study was to demonstrate the feasibility of a new haplotype-based approach for the noninvasive prenatal testing of CAH due to 21-hydroxylase deficiency. Parental haplotypes were constructed using target-region sequencing data of the parents and the proband. With the assistance of the parental haplotypes, we recovered fetal haplotypes using a hidden Markov model (HMM) through maternal plasma DNA sequencing. In the genomic region around the CYP21A2 gene, the fetus inherited the paternal haplotype '0' alleles linked to the mutant CYP21A2 gene, but the maternal haplotype '1' alleles linked to the wild-type gene. The fetus was predicted to be an unaffected carrier of CAH, which was confirmed by genetic analysis of fetal genomic DNA from amniotic fluid cells. This method was further validated by comparing the inferred SNP genotypes with the direct sequencing data of fetal genomic DNA. The result showed an accuracy of 96.41% for the inferred maternal alleles and an accuracy of 97.81% for the inferred paternal alleles. The haplotype-based approach is feasible for noninvasive prenatal testing of CAH. PMID:24768736

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

2014-07-10

119

Gene Polymorphisms of Novel Immunotolerant Molecule BTLA: Distribution of Alleles, Genotypes and Haplotypes in Polish Caucasian Population.  

PubMed

B and T lymphocyte attenuator (BTLA) is one of the members of immunoglobulin superfamily which, like CTLA-4 and PD-1, is involved in down regulation of immune response. Despite the important role of BTLA in maintaining immune homeostasis, relatively little studies were devoted to the relationship of polymorphisms in the gene encoding BTLA with susceptibility to autoimmune disease and cancer. Moreover, all published works were done in Asian populations. BTLA gene is located on chromosome 3 in q13.2 and consists of five exons. The aim of this study was to investigate the alleles, genotypes and haplotypes frequency of selected BTLA gene polymorphisms in Caucasian population originating from Poland. For this study, the single-nucleotide polymorphisms (SNPs) were chosen on the basis of literature data. Additionally, the tag dSNP under linkage equilibrium r (2) > 0.8 and available at the National Center for Biotechnology Information (NCBI) for Caucasian population of rare alleles at a frequency greater than 5 % have been chosen using the NCBI database. The ten BTLA SNPs investigated were: rs1844089, rs2705535, rs9288952, rs9288953, rs1982809, rs2633580, rs2705511, rs2705565, rs76844316, rs16859633. For all SNPs selected on the basis of literature data the significantly different distributions of genotypes between Asian and Caucasian populations were observed. PMID:25182981

Partyka, Anna; Woszczyk, Dariusz; Strza?a, Tomasz; Szczepa?ska, Anna; Tomkiewicz, Anna; Frydecka, Irena; Karabon, Lidia

2015-02-01

120

Estimation of haplotypes Cavan Reilly  

E-print Network

quantity but that quantity is subject to measurement error. #12;Frequentist vs. Bayesian statistics Most. Bayesian statistics #12;Overview If there is substantial LD over a region containing a disease mutation directly from the genotypic data in humans. Thus we need methods for estimating haplotypes and testing

Reilly, Cavan

121

Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction.  

PubMed

The kappa opioid receptor (KOR) plays a role in stress responsivity, opiate withdrawal and responses to cocaine. KOR activation by its endogenous ligand dynorphin A(1-17) decreases basal and drug-induced striatal levels of dopamine. The complete structure of the human KOR gene (hOPRK1) has not been previously determined. This study: (i) characterized the genomic structure of the hOPRK1 gene; (ii) identified single nucleotide polymorphisms (SNPs) in the hOPRK1 gene; and (iii) investigated possible associations of these variants with vulnerability to develop heroin addiction. Analysis of 5'-RACE cDNA clones revealed the presence of a novel exon 1 ranging in length from 167 to 251 nucleotides in the 5' 5'-untranslated region of the hOPRK1 mRNA. We found that the hOPRK1 gene has four major exons and three introns, similar to rodent OPRK1 genes. Direct sequencing of amplified DNA containing all four exons and intron 1 of the hOPRK1 gene were evaluated for polymorphisms in 291 subjects (145 former heroin addicts and 146 controls). Twelve SNPs were identified, nine novel variants and three previously reported SNPs. Using logistic regression with opioid dependence as the dependent variable, the 36G>T SNP exhibited a point-wise significant association (P = 0.016) with disease status. The number of haplotypes seen in the three ethnic groups were nine, six and five for African-Americans, Caucasians, and Hispanics, respectively, with corresponding significance levels for differences in haplotype frequencies between cases and controls of P = 0.0742, 0.1015 and 0.0041. Combining ethnicities by Fisher's method yields an empirical significance level of P = 0.0020. PMID:15608558

Yuferov, Vadim; Fussell, David; LaForge, K Steven; Nielsen, David A; Gordon, Derek; Ho, Ann; Leal, Suzanne M; Ott, Jurg; Kreek, Mary Jeanne

2004-12-01

122

A common TPH2 haplotype regulates the neural processing of a cognitive control demand.  

PubMed

The monoamine neurotransmitter, serotonin, critically regulates the function of the cerebral cortex and is involved in psychiatric disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin with the neuron-specific TPH2 isoform present exclusively in the brain and encoded by the TPH2 gene on chromosome 12q21. The haplotype structure of TPH2 was defined for 16 single-nucleotide polymorphisms (SNPs) in a healthy subject population and a haplotype block analysis confirmed the presence of a six SNP haplotype in a yin configuration that has previously been associated with risk for suicidality, depression, and anxiety disorders. Functional magnetic resonance imaging (fMRI) was used to assess the influence of TPH2 variation on brain function related to cognitive control using the Multi-Source Interference Task (MSIT). The MSIT-related blood oxygen level-dependent (BOLD) response was increased with increasing copies of the TPH2 yin haplotype for the dorsal anterior cingulate cortex (dACC), right inferior frontal cortex (IFC), and anterior striatum. A functional connectivity analysis further revealed that increasing numbers of the TPH2 yin haplotype was associated with diminished functional coupling between the dACC and the right IFC, precentral gyrus, parietal cortex and dlPFC. A moderation analysis indicated that the relationship between neural processing networks and cognitive control was significantly modulated by allelic variation for the TPH2 yin haplotype. These findings suggest that the association of risk for psychiatric disorders with a common TPH2 yin haplotype is related to the inefficient functional engagement of cortical areas involved in cognitive control and alterations in the mode of functional connectivity of dACC pathways. PMID:22915309

Kennedy, Ashley P; Binder, Elisabeth B; Bowman, Dubois; Harenski, Keith; Ely, Timothy; Cisler, Josh M; Tripathi, Shanti P; VanNess, Sidney; Kilts, Clinton D

2012-10-01

123

UASIS: Universal Automatic SNP Identification System  

PubMed Central

Background SNP (Single Nucleotide Polymorphism), the most common genetic variations between human beings, is believed to be a promising way towards personalized medicine. As more and more research on SNPs are being conducted, non-standard nomenclatures may generate potential problems. The most serious issue is that researchers cannot perform cross referencing among different SNP databases. This will result in more resources and time required to track SNPs. It could be detrimental to the entire academic community. Results UASIS (Universal Automated SNP Identification System) is a web-based server for SNP nomenclature standardization and translation at DNA level. Three utilities are available. They are UASIS Aligner, Universal SNP Name Generator and SNP Name Mapper. UASIS maps SNPs from different databases, including dbSNP, GWAS, HapMap and JSNP etc., into an uniform view efficiently using a proposed universal nomenclature and state-of-art alignment algorithms. UASIS is freely available at http://www.uasis.tk with no requirement of log-in. Conclusions UASIS is a helpful platform for SNP cross referencing and tracking. By providing an informative, unique and unambiguous nomenclature, which utilizes unique position of a SNP, we aim to resolve the ambiguity of SNP nomenclatures currently practised. Our universal nomenclature is a good complement to mainstream SNP notations such as rs# and HGVS guidelines. UASIS acts as a bridge to connect heterogeneous representations of SNPs. PMID:22369494

2011-01-01

124

A 48 SNP set for grapevine cultivar identification  

PubMed Central

Background Rapid and consistent genotyping is an important requirement for cultivar identification in many crop species. Among them grapevine cultivars have been the subject of multiple studies given the large number of synonyms and homonyms generated during many centuries of vegetative multiplication and exchange. Simple sequence repeat (SSR) markers have been preferred until now because of their high level of polymorphism, their codominant nature and their high profile repeatability. However, the rapid application of partial or complete genome sequencing approaches is identifying thousands of single nucleotide polymorphisms (SNP) that can be very useful for such purposes. Although SNP markers are bi-allelic, and therefore not as polymorphic as microsatellites, the high number of loci that can be multiplexed and the possibilities of automation as well as their highly repeatable results under any analytical procedure make them the future markers of choice for any type of genetic identification. Results We analyzed over 300 SNP in the genome of grapevine using a re-sequencing strategy in a selection of 11 genotypes. Among the identified polymorphisms, we selected 48 SNP spread across all grapevine chromosomes with allele frequencies balanced enough as to provide sufficient information content for genetic identification in grapevine allowing for good genotyping success rate. Marker stability was tested in repeated analyses of a selected group of cultivars obtained worldwide to demonstrate their usefulness in genetic identification. Conclusions We have selected a set of 48 stable SNP markers with a high discrimination power and a uniform genome distribution (2-3 markers/chromosome), which is proposed as a standard set for grapevine (Vitis vinifera L.) genotyping. Any previous problems derived from microsatellite allele confusion between labs or the need to run reference cultivars to identify allele sizes disappear using this type of marker. Furthermore, because SNP markers are bi-allelic, allele identification and genotype naming are extremely simple and genotypes obtained with different equipments and by different laboratories are always fully comparable. PMID:22060012

2011-01-01

125

Mining of haplotype-based expressed sequence tag single nucleotide polymorphisms in citrus  

PubMed Central

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

2013-01-01

126

Contrasting signals of positive selection in genes involved in human skin-color variation from tests based on SNP scans and resequencing  

PubMed Central

Background Numerous genome-wide scans conducted by genotyping previously ascertained single-nucleotide polymorphisms (SNPs) have provided candidate signatures for positive selection in various regions of the human genome, including in genes involved in pigmentation traits. However, it is unclear how well the signatures discovered by such haplotype-based test statistics can be reproduced in tests based on full resequencing data. Four genes (oculocutaneous albinism II (OCA2), tyrosinase-related protein 1 (TYRP1), dopachrome tautomerase (DCT), and KIT ligand (KITLG)) implicated in human skin-color variation, have shown evidence for positive selection in Europeans and East Asians in previous SNP-scan data. In the current study, we resequenced 4.7 to 6.7 kb of DNA from each of these genes in Africans, Europeans, East Asians, and South Asians. Results Applying all commonly used neutrality-test statistics for allele frequency distribution to the newly generated sequence data provided conflicting results regarding evidence for positive selection. Previous haplotype-based findings could not be clearly confirmed. Although some tests were marginally significant for some populations and genes, none of them were significant after multiple-testing correction. Combined P values for each gene-population pair did not improve these results. Application of Approximate Bayesian Computation Markov chain Monte Carlo based to these sequence data using a simple forward simulator revealed broad posterior distributions of the selective parameters for all four genes, providing no support for positive selection. However, when we applied this approach to published sequence data on SLC45A2, another human pigmentation candidate gene, we could readily confirm evidence for positive selection, as previously detected with sequence-based and some haplotype-based tests. Conclusions Overall, our data indicate that even genes that are strong biological candidates for positive selection and show reproducible signatures of positive selection in SNP scans do not always show the same replicability of selection signals in other tests, which should be considered in future studies on detecting positive selection in genetic data. PMID:22133426

2011-01-01

127

Detecting disease-predisposing variants: The haplotype method  

SciTech Connect

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.

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

1997-03-01

128

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

PubMed Central

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

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

2014-01-01

129

The Neutrino and the SNP  

NSDL National Science Digital Library

This site from the Sudbury Neutrino Observatory provides an explanation of neutrinos and of the former discrepancy between theoretical models and solar neutrino data known as the Solar Neutrino Problem (SNP). The site contains a brief history of the study of neutrinos, a graph of the solar neutrinos spectrum, and a discussion of their flux. The role of the Sudbury Neutrino Observatory in collecting neutrinos data is also presented.

2006-12-03

130

Association of prolactin haplotypes with reproductive traits in Tsaiya ducks.  

PubMed

A previous cDNA microarray study showed that the prolactin (PRL) gene may be involved in the duck ovarian follicle development and egg formation process. The purpose of this study was to investigate the relationship between PRL genotypes of single nucleotide polymorphism (SNP) and reproductive traits of Tsaiya ducks. Primer pairs for the coding regions in the PRL were designed based on the duck genomic sequence database. Polymorphisms were detected by polymerase chain reaction (PCR)-single strand polymorphism (SSCP) and were verified by DNA sequencing. Six novel SNPs (T233C, T295C, G309T, C381A, G3941T and A3975C) were identified in the 1972 bp region of duck PRL gene, and all of them were located in non-coding regions. Single SNP-trait association analysis showed that each SNP was associated with at least one duck reproductive trait (P<0.05). Haplotype combinations constructed on these SNPs were associated with egg weight at 40 weeks of age (EW40), fertility rate (FR) and maximum duration of fertility (MDF) (P<0.0001). In particular, diplotype H1H2 had positive effect on EW40, whereas it had negative effect on FR and MDF (P<0.05). Positive effects of the diplotype H1H5 were observed for FR and MDF, but a negative effect was observed for EW40 (P<0.05). This suggested that the PRL gene plays an important role in the regulation of egg weight and fertility-related traits and could be a potential marker in a marker assisted selection program during duck balancing selection. Further investigations on more duck populations with large sample sizes are needed to confirm this finding. PMID:22959514

Chang, Mu-Tzu; Cheng, Yu-Shin; Huang, Mu-Chiou

2012-11-01

131

RESEARCH ARTICLE Open Access The IGF1 small dog haplotype is derived from Middle Eastern grey wolves  

E-print Network

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

Melissa M Gray; Nathan B Sutter; Elaine A Ostr; Robert K Wayne

132

Haplotype analysis of two X-chromosome STR clusters in the Pakistani population.  

PubMed

Haplotype analysis of closely associated markers has proven to be a powerful tool in kinship analysis especially when X-chromosome short tandem repeats fail to resolve uncertainty in relationship analysis. Microsatellites located on the X chromosome show stronger linkage disequilibrium compared with autosomal microsatellites; hence, it is necessary to estimate the haplotype frequencies directly from population studies as linkage disequilibrium is population-specific. Here, we describe five markers residing in two clusters; cluster I harboring three STR markers DXS6801-DXS6809-DXS6789 and cluster II harboring two STR markers DXS7424-DXS101. A total of 302 male DNA samples of Pakistani descent were analyzed. Theoretically, 847 and 160 different combinations of haplotypes are possible in clusters I and II, but genotyping identified only 129 and 75 haplotypes, respectively. No evidence of linkage disequilibrium was detected, except for the pair (DXS6801-DXS6789), consistent with results obtained with the cluster I in a German population. Our results demonstrate that 83% haplotypes of cluster I and 65% haplotypes of cluster II show <1% frequency in the Pakistani population. This strongly suggests that haplotypes of these two clusters provide a powerful tool for kinship testing and relationship investigations. PMID:19011887

Tariq, Muhammad Akram; Sabir, Muhammad Farooq; Riazuddin, S Amer; Riazuddin, Sheikh

2009-01-01

133

Population dynamics of the 2 major mitochondrial DNA haplotypes in experimental populations of Drosophila subobscura.  

PubMed

The evolution of Drosophila subobscura mitochondrial DNA has been studied in experimental populations, founded with flies from a natural population from Calvià (Majorca, Balearic Islands, Spain). This population, like others founded in Europe, is characterized by the presence of 2 very common (>95%) mitochondrial haplotypes (named I and II) and rare and endemic haplotypes that appear at very low frequencies. Four experimental populations were established with flies having a heterogeneous nuclear genetic background, which was representative of the composition of the natural population. The populations were started with haplotypes I and II at an initial frequency of 50% each. After 33 generations, the 2 haplotypes coexisted. Random drift could be rejected as the only force responsible for the observed changes in haplotype frequencies. A slight but significant linear trend favouring a mtDNA (haploid) fitness effect has been detected, with a nonlinear deviation that could be due to a nuclear component. An analysis of chromosomal arrangements was made before the foundations of the cages and at generation 23. Our results indicated that the hypothesis that the maintenance of the frequencies of haplotypes I and II in natural populations could be due to their association with chromosomal arrangements remains controversial. PMID:16391670

Oliver, Pedro; Balanyà, Joan; Ramon, Maria Misericòrdia; Picornell, Antònia; Serra, Lluis; Moya, Andrés; Castro, José A

2005-12-01

134

Design and Characterization of a 52K SNP Chip for Goats  

PubMed Central

The success of Genome Wide Association Studies in the discovery of sequence variation linked to complex traits in humans has increased interest in high throughput SNP genotyping assays in livestock species. Primary goals are QTL detection and genomic selection. The purpose here was design of a 50–60,000 SNP chip for goats. The success of a moderate density SNP assay depends on reliable bioinformatic SNP detection procedures, the technological success rate of the SNP design, even spacing of SNPs on the genome and selection of Minor Allele Frequencies (MAF) suitable to use in diverse breeds. Through the federation of three SNP discovery projects consolidated as the International Goat Genome Consortium, we have identified approximately twelve million high quality SNP variants in the goat genome stored in a database together with their biological and technical characteristics. These SNPs were identified within and between six breeds (meat, milk and mixed): Alpine, Boer, Creole, Katjang, Saanen and Savanna, comprising a total of 97 animals. Whole genome and Reduced Representation Library sequences were aligned on >10 kb scaffolds of the de novo goat genome assembly. The 60,000 selected SNPs, evenly spaced on the goat genome, were submitted for oligo manufacturing (Illumina, Inc) and published in dbSNP along with flanking sequences and map position on goat assemblies (i.e. scaffolds and pseudo-chromosomes), sheep genome V2 and cattle UMD3.1 assembly. Ten breeds were then used to validate the SNP content and 52,295 loci could be successfully genotyped and used to generate a final cluster file. The combined strategy of using mainly whole genome Next Generation Sequencing and mapping on a contig genome assembly, complemented with Illumina design tools proved to be efficient in producing this GoatSNP50 chip. Advances in use of molecular markers are expected to accelerate goat genomic studies in coming years. PMID:24465974

Tosser-Klopp, Gwenola; Bardou, Philippe; Bouchez, Olivier; Cabau, Cédric; Crooijmans, Richard; Dong, Yang; Donnadieu-Tonon, Cécile; Eggen, André; Heuven, Henri C. M.; Jamli, Saadiah; Jiken, Abdullah Johari; Klopp, Christophe; Lawley, Cynthia T.; McEwan, John; Martin, Patrice; Moreno, Carole R.; Mulsant, Philippe; Nabihoudine, Ibouniyamine; Pailhoux, Eric; Palhière, Isabelle; Rupp, Rachel; Sarry, Julien; Sayre, Brian L.; Tircazes, Aurélie; Jun Wang; Wang, Wen; Zhang, Wenguang

2014-01-01

135

Design and characterization of a 52K SNP chip for goats.  

PubMed

The success of Genome Wide Association Studies in the discovery of sequence variation linked to complex traits in humans has increased interest in high throughput SNP genotyping assays in livestock species. Primary goals are QTL detection and genomic selection. The purpose here was design of a 50-60,000 SNP chip for goats. The success of a moderate density SNP assay depends on reliable bioinformatic SNP detection procedures, the technological success rate of the SNP design, even spacing of SNPs on the genome and selection of Minor Allele Frequencies (MAF) suitable to use in diverse breeds. Through the federation of three SNP discovery projects consolidated as the International Goat Genome Consortium, we have identified approximately twelve million high quality SNP variants in the goat genome stored in a database together with their biological and technical characteristics. These SNPs were identified within and between six breeds (meat, milk and mixed): Alpine, Boer, Creole, Katjang, Saanen and Savanna, comprising a total of 97 animals. Whole genome and Reduced Representation Library sequences were aligned on >10 kb scaffolds of the de novo goat genome assembly. The 60,000 selected SNPs, evenly spaced on the goat genome, were submitted for oligo manufacturing (Illumina, Inc) and published in dbSNP along with flanking sequences and map position on goat assemblies (i.e. scaffolds and pseudo-chromosomes), sheep genome V2 and cattle UMD3.1 assembly. Ten breeds were then used to validate the SNP content and 52,295 loci could be successfully genotyped and used to generate a final cluster file. The combined strategy of using mainly whole genome Next Generation Sequencing and mapping on a contig genome assembly, complemented with Illumina design tools proved to be efficient in producing this GoatSNP50 chip. Advances in use of molecular markers are expected to accelerate goat genomic studies in coming years. PMID:24465974

Tosser-Klopp, Gwenola; Bardou, Philippe; Bouchez, Olivier; Cabau, Cédric; Crooijmans, Richard; Dong, Yang; Donnadieu-Tonon, Cécile; Eggen, André; Heuven, Henri C M; Jamli, Saadiah; Jiken, Abdullah Johari; Klopp, Christophe; Lawley, Cynthia T; McEwan, John; Martin, Patrice; Moreno, Carole R; Mulsant, Philippe; Nabihoudine, Ibouniyamine; Pailhoux, Eric; Palhière, Isabelle; Rupp, Rachel; Sarry, Julien; Sayre, Brian L; Tircazes, Aurélie; Jun Wang; Wang, Wen; Zhang, Wenguang

2014-01-01

136

RESEARCH ARTICLE Open Access A genome-wide search for common SNP x SNP  

E-print Network

RESEARCH ARTICLE Open Access A genome-wide search for common SNP x SNP interactions on the risk-associated genes known before the GWAS era, ABO, F2, F5 and FGG [5]. As for most multifactorial diseases, risk

Paris-Sud XI, Université de

137

Development of the catfish 250K SNP array for genome-wide association studies  

PubMed Central

Background Quantitative traits, such as disease resistance, are most often controlled by a set of genes involving a complex array of regulation. The dissection of genetic basis of quantitative traits requires large numbers of genetic markers with good genome coverage. The application of next-generation sequencing technologies has allowed discovery of over eight million SNPs in catfish, but the challenge remains as to how to efficiently and economically use such SNP resources for genetic analysis. Results In this work, we developed a catfish 250K SNP array using Affymetrix Axiom genotyping technology. The SNPs were obtained from multiple sources including gene-associated SNPs, anonymous genomic SNPs, and inter-specific SNPs. A set of 640K high-quality SNPs obtained following specific requirements of array design were submitted. A panel of 250,113 SNPs was finalized for inclusion on the array. The performance evaluated by genotyping individuals from wild populations and backcross families suggested the good utility of the catfish 250K SNP array. Conclusions This is the first high-density SNP array for catfish. The array should be a valuable resource for genome-wide association studies (GWAS), fine QTL mapping, high-density linkage map construction, haplotype analysis, and whole genome-based selection. PMID:24618043

2014-01-01

138

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

Microsoft Academic Search

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

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

2010-01-01

139

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

Microsoft Academic Search

Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication. 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

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

2010-01-01

140

High-Throughput SNP Genotyping  

PubMed Central

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

Gibson, Neil

2002-01-01

141

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

PubMed Central

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

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

2014-01-01

142

SNPsyn: detection and exploration of SNP–SNP interactions  

PubMed Central

SNPsyn (http://snpsyn.biolab.si) is an interactive software tool for the discovery of synergistic pairs of single nucleotide polymorphisms (SNPs) from large genome-wide case-control association studies (GWAS) data on complex diseases. Synergy among SNPs is estimated using an information-theoretic approach called interaction analysis. SNPsyn is both a stand-alone C++/Flash application and a web server. The computationally intensive part is implemented in C++ and can run in parallel on a dedicated cluster or grid. The graphical user interface is written in Adobe Flash Builder 4 and can run in most web browsers or as a stand-alone application. The SNPsyn web server hosts the Flash application, receives GWAS data submissions, invokes the interaction analysis and serves result files. The user can explore details on identified synergistic pairs of SNPs, perform gene set enrichment analysis and interact with the constructed SNP synergy network. PMID:21576219

Curk, Tomaz; Rot, Gregor; Zupan, Blaz

2011-01-01

143

variantGPS: SNP500Cancer  

Cancer.gov

The goal of the SNP500Cancer project is to resequence 102 reference samples to find known or newly discovered single nucleotide polymorphisms (SNPs) which are of immediate importance to molecular epidemiology studies in cancer. SNP500Cancer provides a central resource for sequence verification of SNPs.

144

Conserved KIR Allele-Level Haplotypes Are Altered by Microvariation in Individuals with European Ancestry  

PubMed Central

Natural killer cell immunoglobulin-like receptor (KIR) haplotype-specific DNA fragments were sequenced to identify centromeric and telomeric allele level haplotype structures and their frequencies from 76 unrelated individuals with European ancestry. Analysis was simplified by redefining the 5’ boundary of the centromeric KIR gene cluster to include only exons 7-9 of KIR3DL3. Three consensus allele level haplotypes were identified for a centromeric gene presence/absence structure designated as Cen-A1. KIR3DL3*00201 (ex 7-9)—KIR2DL3*001—KIR2DL1*00302 was the most frequent (37.5%) centromeric structure. Single consensus haplotypes were observed for haplotype structures Cen-B1 and Cen-B2. Six Tel-A1 and two Tel-B1 consensus haplotypes were observed; the most prevalent (23.0%) was KIR2DL4*00102—KIR3DL1*002—KIR2DS4*00101—KIR3DL2*002. A small number of nucleotide substitutions (?3) in the coding regions of the functional KIR genes created microvariants of the consensus haplotypes. Eight less common haplotype structures were also detected. Four carried hybrid genes formed during gene deletion events, two carried an insertion with a 2DL5/3DP1 fusion gene, and two included a very large insertion. These data show that the KIR gene complex is composed of a limited number of conserved allele level centromeric and telomeric haplotypes that have diversified by mutation, recombination within a locus, and unequal crossing over. PMID:21796155

Hou, Lihua; Chen, Minghua; Ng, Jennifer; Hurley, Carolyn Katovich

2012-01-01

145

Most parsimonious haplotype allele sharing determination  

PubMed Central

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

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

2009-01-01

146

Islands of Tractability for Parsimony Haplotyping  

E-print Network

of possible haplotypes, due to population bottleneck effects and genetic drift. For example, Patil et al Terms--Biology and genetics, graph algorithms, analysis of algorithms and problem complexity. Ã? 1 a minimum set of haplotypes that explains them (a formal definition of PH is deferred to Section 2

Shamir, Ron

147

Casein haplotype variability in Apulian goat breeds  

Microsoft Academic Search

Due to the tight linkage among the casein genes, th e study of the haplotype variability is a necessary approach in order to identify important effects whi ch could be exploited for the genetic improvement o f goat species, showing considerable casein genetic variat ion. The aim of this paper was to analyse the casei n haplotype distribution, with particular

Chessa Stefania; Chiatti Francesca; Rignanese Daniel; Bolla Patrizia; Caroli Anna

148

Filling in missing genotypes using haplotypes  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

149

Network analysis of human Y microsatellite haplotypes  

Microsoft Academic Search

To investigate the utility of Y chromosome micro- satellites for studying human male-lineage evolution, we typed samples from three populations for five tetranucleotide repeats and an Alu insertion poly- morphism. We found very high levels of haplotype diversity and evidence that most mutations involve the gain or loss of only one repeat unit, implying that any given microsatellite haplotype may

Gillian Cooper; William Amos; Dorota Hoffman; David C. Rubinsztein

1996-01-01

150

Mutation screening and haplotype analysis of the rhodopsin gene locus in Japanese patients with retinitis pigmentosa  

PubMed Central

Purpose To identify nucleotide sequence variations in the rhodopsin (RHO) gene of Japanese patients with retinitis pigmentosa (RP) in order to search for mutations or haplotypes responsible for RP. Methods The entire region of RHO locus including a promoter region and introns was sequenced using blood-derived genomic DNA samples donated by 68 patients with RP and 68 control subjects. Results We found 39 single nucleotide substitutions including 17 rare substitutions of less than 1% in frequency, one insertion/deletion polymorphism, and one CA-repeat polymorphism in a 7.8 kbp region spanning the promoter, five exons, and four introns of the RHO gene locus. There were no affected subjects with amino acid substitutions in RHO, and there was 1 control subject with a novel substitution (Ala42Thr) who had no symptoms of RP. Fine analysis of single nucleotide polymorphism (SNPs) revealed eight haplotype structures of the Japanese RHO locus. There was no significant difference between RP patients and controls in terms of haplotype frequency. Conclusions No mutation causing an amino acid substitution of RHO was observed in 68 Japanese patients with RP, but 1 control subject did have a novel amino acid substitution. The Japanese RHO locus is comprised of eight major haplotypes. The RP-associated haplotype was not identified. The haplotype-tagging SNPs identified in this study will be useful as markers for the linkage-based screening of RP patients. PMID:17653048

Ando, Yuichiro; Ohmori, Masayuki; Ohtake, Hideki; Ohtoko, Kuniyo; Toyama, Shigeru; Usami, Ron; O’hira, Aya; Hata, Hiromi; Yanashima, Kenji

2007-01-01

151

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

PubMed Central

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

Griger, Zoltán; Dankó, Katalin

2015-01-01

152

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

PubMed Central

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

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

153

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

PubMed Central

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

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

2014-01-01

154

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

PubMed Central

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

2014-01-01

155

Development of a forensic identity SNP panel for Indonesia.  

PubMed

Genetic markers included in forensic identity panels must exhibit Hardy-Weinberg and linkage equilibrium (HWE and LE). "Universal" panels designed for global use can fail these tests in regional jurisdictions exhibiting high levels of genetic differentiation such as the Indonesian archipelago. This is especially the case where a single DNA database is required for allele frequency estimates to calculate random match probabilities (RMPs) and associated likelihood ratios (LRs). A panel of 65 single nucleotide polymorphisms (SNPs) and a reduced set of 52 SNPs have been selected from 15 Indonesian subpopulations in the HUGO Pan Asian SNP database using a SNP selection strategy that could be applied to any panel of forensic identity markers. The strategy consists of four screening steps: (1) application of a G test for HWE; (2) ranking for high heterozygosity; (3) selection for LE; and (4) selection for low inbreeding depression. SNPs in our Indonesian panel perform well in comparison to some other universal SNP and short tandem repeat (STR) panels as measured by Fisher's exact test for HWE and LE and Wright's F statistics. PMID:25104323

Augustinus, Daniel; Gahan, Michelle E; McNevin, Dennis

2014-08-01

156

Haplotype-Based Study of the Association of Alcohol Metabolizing Genes with Alcohol Dependence in Four Independent Populations  

PubMed Central

Background Ethanol is metabolized by two rate limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde, subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non-East Asian populations by performing systematic haplotype association analyses in order to maximize the chances of capturing functional variation. Methods Haplotype-tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case, control sample sizes were: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; Southwestern American (SW) Indians: 317, 72. Results In all four populations, as well as HapMap populations, five haplotype blocks were identified across the ADH gene cluster: (1) ADH5-ADH4; (2) ADH6-ADH1A-ADH1B; (3) ADH1C; (4) intergenic; (5) ADH7. The ALDH1A1 gene was defined by four blocks and ALDH2 by one block. No haplotype or SNP association results were significant after correction for multiple comparisons; however several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3? UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317 respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians. Conclusions The systematic evaluation of alcohol metabolizing genes in four non-East Asian populations has shown only modest associations with AD, largely for ALDH1A1 and ADH4. A concentration of signals for AD with ALDH1A1 yin yang haplotypes in several populations warrants further study. PMID:21083667

Liu, Jixia; Zhou, Zhifeng; Hodgkinson, Colin A.; Yuan, Qiaoping; Shen, Pei-Hong; Mulligan, Connie J.; Wang, Alex; Gray, Rebecca R.; Roy, Alec; Virkkunen, Matti; Goldman, David; Enoch, Mary-Anne

2010-01-01

157

Bayesian haplotype inference via the Dirichlet process.  

PubMed

The problem of inferring haplotypes from genotypes of single nucleotide polymorphisms (SNPs) is essential for the understanding of genetic variation within and among populations, with important applications to the genetic analysis of disease propensities and other complex traits. The problem can be formulated as a mixture model, where the mixture components correspond to the pool of haplotypes in the population. The size of this pool is unknown; indeed, knowing the size of the pool would correspond to knowing something significant about the genome and its history. Thus methods for fitting the genotype mixture must crucially address the problem of estimating a mixture with an unknown number of mixture components. In this paper we present a Bayesian approach to this problem based on a nonparametric prior known as the Dirichlet process. The model also incorporates a likelihood that captures statistical errors in the haplotype/genotype relationship trading off these errors against the size of the pool of haplotypes. We describe an algorithm based on Markov chain Monte Carlo for posterior inference in our model. The overall result is a flexible Bayesian method, referred to as DP-Haplotyper, that is reminiscent of parsimony methods in its preference for small haplotype pools. We further generalize the model to treat pedigree relationships (e.g., trios) between the population's genotypes. We apply DP-Haplotyper to the analysis of both simulated and real genotype data, and compare to extant methods. PMID:17563311

Xing, Eric P; Jordan, Michael I; Sharan, Roded

2007-04-01

158

Haplotype analysis for CF-linked DNA polymorphisms in Switzerland.  

PubMed

A total of 295 patients, parents and unaffected sibs from 106 CF-families in central and northeastern Switzerland were investigated with probes 7C22(D7S16), metH, metD, pKM19, pXV-2c and pJ3.11(D7S8) for eight DNA polymorphisms (RFLP's). Linkage disequilibrium to the CF locus and haplotype frequencies were compared to those in other populations. They are comparable to other Caucasian populations and, for pKM 19 and pXV-2c, very close to the findings in Italy. The prevalence of certain haplotypes among the CF and the normal allele-bearing chromosomes indicate that the majority of the CF cases are probably the result of one ancient mutation in a common ancestor, but that there may be allelic heterogeneity accounting for an important proportion of patients, that may differ between countries or regions. Informative family constellations for the different polymorphisms in Switzerland and strategies for carrier detection and prenatal diagnosis are discussed. Haplotype analyses for each country and its ethnic subgroups are recommended. PMID:1974485

Liechti-Gallati, S; Niederer, B U; Schneider, V; Mächler, M; Alkan, M; Malik, N; Braga, S; Moser, H

1990-06-01

159

Haplotype of smoothelin gene associated with essential hypertension.  

PubMed

Smoothelin is a specific cytoskeletal protein that is associated with smooth muscle cells. The human SMTN gene encodes smoothelin-A and smoothelin-B, and studies using SMTN gene knockout mice have demonstrated that these animals develop hypertension. The aim of the present study was to investigate the association between the human SMTN gene and essential hypertension (EH) using a haplotype-based case-control study. This is the first study to assess the association between essential hypertension and this gene. A total of 255 EH patients and 225 controls were genotyped for the five single-nucleotide polymorphisms (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304) used as genetic markers for the human SMTN gene. Data were analyzed for three separate groups: total subjects, men and women. Although there were no differences for genotype distributions, or the dominant and recessive model distributions noted for total subjects, men and women for all of the SNPs selected for the present study, for the total subjects group, the frequency of the G-C-A-C haplotype constructed with rs2074738-rs5997872-rs56095120-rs9621187 was significantly lower in the essential hypertension patients than in the controls (P = 0.002). The G-C-A-C haplotype appears to be a useful protective marker of essential hypertension in Japanese, and the SMTN gene might also be a genetic marker for essential hypertension. PMID:23121329

Jiang, Jie; Nakayama, Tomohiro; Shimodaira, Masanori; Sato, Naoyuki; Aoi, Noriko; Sato, Mikano; Izumi, Yoichi; Kasamaki, Yuji; Ohta, Masakatsu; Soma, Masayoshi; Matsumoto, Koichi; Kawamura, Hiroshi; Ozawa, Yukio; Ma, Yitong

2012-10-01

160

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

PubMed Central

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

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

2011-01-01

161

Online reference database of European Y-chromosomal short tandem repeat (STR) haplotypes.  

PubMed

The reference database of highly informative Y-chromosomal short tandem repeat (STR) haplotypes (YHRD), available online at http://ystr.charite.de, represents the largest collection of male-specific genetic profiles currently available for European populations. By September 2000, YHRD contained 4688 9-locus (so-called "minimal") haplotypes, 40% of which have been extended further to include two additional loci. Establishment of YHRD has been facilitated by the joint efforts of 31 forensic and anthropological institutions. All contributing laboratories have agreed to standardize their Y-STR haplotyping protocols and to participate in a quality assurance exercise prior to the inclusion of any data. In view of its collaborative character, and in order to put YHRD to its intended use, viz. the support of forensic caseworkers in their routine decision-making process, the database has been made publicly available via the Internet in February 2000. Online searches for complete or partial Y-STR haplotypes from evidentiary or non-probative material can be performed on a non-commercial basis, and yield observed haplotype counts as well as extrapolated population frequency estimates. In addition, the YHRD website provides information about the quality control test, genotyping protocols, haplotype formats and informativity, population genetic analysis, literature references, and a list of contact addresses of the contributing laboratories. PMID:11311820

Roewer, L; Krawczak, M; Willuweit, S; Nagy, M; Alves, C; Amorim, A; Anslinger, K; Augustin, C; Betz, A; Bosch, E; Cagliá, A; Carracedo, A; Corach, D; Dekairelle, A F; Dobosz, T; Dupuy, B M; Füredi, S; Gehrig, C; Gusmaõ, L; Henke, J; Henke, L; Hidding, M; Hohoff, C; Hoste, B; Jobling, M A; Kärgel, H J; de Knijff, P; Lessig, R; Liebeherr, E; Lorente, M; Martínez-Jarreta, B; Nievas, P; Nowak, M; Parson, W; Pascali, V L; Penacino, G; Ploski, R; Rolf, B; Sala, A; Schmidt, U; Schmitt, C; Schneider, P M; Szibor, R; Teifel-Greding, J; Kayser, M

2001-05-15

162

The TNP1 haplotype - GCG is associated with azoospermia.  

PubMed

Transition nuclear proteins (TNP1 and TNP2) are the major nuclear proteins that replace somatic histones during spermatogenesis. TNPs are required for the maintenance of normal spermatogenesis. Moreover, spermatogenesis was found to be compromised in both Tnp1 and Tnp2 null mice. As no study is available on the role of these genes in Indian infertile men, we have sequenced the entire TNP1 and TNP2 genes in 320 infertile men and 280 control fertile men drawn from two states in India. We identified 18 variants, including 8 previously known and 10 novel. Of the 10 novel variants, 3 were found only in azoospermic men, of which 2 (g.-688A>T in TNP1 and g.1030G>A in TNP2) were predicted to affect the transcription factor binding sites and therefore can cause deregulation of gene expression. Haplotype association analysis showed a significant omnibus association (omnibus ?(2) = 7.87, p = 0.0195) for the single nucleotide polymorphisms (SNPs) in the TNP1 gene with azoospermia. The frequency of the haplotype GCG (H3) was increased in azoospermic men (53.1%) compared with fertile men (43%; ?(2) = 7.964, p = 0.005). However, similar analysis of the TNP2 gene did not show any association with infertility. Furthermore, expression analysis of the TNP1 gene in obstructive azoospermic men showed that haplotypes of the TNP1 gene do not affect its expression level. Our results suggest that the individual SNPs of the TNP1 and TNP2 genes are not associated with infertility; however, the haplotype GCG of the TNP1 gene is a risk factor for azoospermia. PMID:20522125

Khattri, A; Bhushan, S S; Sireesha, V; Gupta, N J; Chakravarty, B N; Deendayal, M; Prasad, S; Singh, L; Thangaraj, K

2011-04-01

163

Haplotype of gene Nedd4 binding protein 2 associated with sporadic nasopharyngeal carcinoma in the Southern Chinese population  

PubMed Central

Background Bcl-3 as an oncoprotein is overexpressed in nasopharyngeal carcinoma (NPC). Nedd4 binding protein 2 (N4BP2), which is located in the NPC susceptibility locus, is a Bcl-3 binding protein. This study is aimed to explore the association between N4BP2 genetic polymorphism and the risk of NPC. Methods We performed a hospital-based case-control study, including 531 sporadic NPC and 480 cancer-free control subjects from southern China. PCR-sequencing was carried out on Exons, promoter region and nearby introns of the N4BP2 gene. The expression pattern of N4BP2 and Bcl-3 was also analyzed. Results We observed a statistically significant difference in haplotype blocks ATTA and GTTG between cases and controls. In addition, three novel SNPs were identified, two of which were in exons (loc123-e3l-snp2, position 39868005, A/G, Met171Val; RS17511668-SNP2, position 39926432, G/A, Glu118Lys), and one was in the intron6 (RS794001-SNP1, position 39944127, T/G). Moreover, N4BP2 was at higher levels in a majority of tumor tissues examined, relative to paired normal tissues. Conclusion These data suggest that haplotype blocks ATTA and GTTG of N4BP2 is correlation with the risk of sporadic nasopharyngeal carcinoma in the Southern Chinese population and N4BP2 has a potential role in the development of NPC. PMID:17626640

Zheng, Mei-Zhen; Qin, Hai-De; Yu, Xing-Juan; Zhang, Ru-Hua; Chen, Li-Zhen; Feng, Qi-Sheng; Zeng, Yi-Xin

2007-01-01

164

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

PubMed Central

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

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

1991-01-01

165

The Longest Haplotype Reconstruction Problem Revisited  

NASA Astrophysics Data System (ADS)

The Longest Haplotype Reconstruction (LHR) problem has been introduced in Computational Biology for the reconstruction of the haplotypes of an individual, starting from a matrix of incomplete haplotype fragments. In this paper, we reconsider the LHR problem, proving that it is NP-hard even in the restricted case when the input matrix is error-free. Then, we investigate the approximation complexity of the problem, showing that it cannot be approximated within factor 2^{log^{?}nm } for any constant ?< 1, unless NP ? DTIME[2 polylognm ]. Finally, we give a fixed-parameter algorithm, where the parameter is the size of the reconstructed haplotypes.

Dondi, Riccardo

166

Rapid haplotype inference for nuclear families  

E-print Network

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 ...

Williams, Amy L.

167

Fibroblast Growth Factor 20 Polymorphisms and Haplotypes Strongly Influence Risk of Parkinson Disease  

PubMed Central

The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3? regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD. PMID:15122513

van der Walt, Joelle M.; Noureddine, Maher A.; Kittappa, Raja; Hauser, Michael A.; Scott, William K.; McKay, Ron; Zhang, Fengyu; Stajich, Jeffrey M.; Fujiwara, Kenichiro; Scott, Burton L.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Martin, Eden R.

2004-01-01

168

A DRD2 and ANKK1 haplotype is associated with nicotine dependence.  

PubMed

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

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

169

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

PubMed Central

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

2014-01-01

170

Genetic stock structure of walleye pollock (Theragra chalcogramma) inferred by PCR-RFLP analysis of the mitochondrial DNA and SNP analysis of nuclear DNA.  

PubMed

Walleye pollock, Theragra chalocogramma, is one of the most important species in the North Pacific and Bering Sea ecosystems. However genetic population structuring of walleye pollock is uncertain. In the present study, genetic variation of walleye pollock collected in several spawning areas ranging from the Japan Sea to the Gulf of Alaska was investigated by DNA analysis. Three regions of the spacer control region, the ND5 and ND6 region (ND complex), and the ND1 and 16S rRNA region (rDNA complex) were amplified using the polymerase chain reaction (PCR). Restriction fragment length polymorphism (RFLP) was conducted on these PCR products and composite haplotypes were calculated. Furthermore, several nuclear DNA regions (actin, Calmodulin, S7 ribosomal protein, creatin kinase, and SypI gene) were investigated to study the stock structure of walleye pollock. It was considered that Calmodulin gene was one of good genetic marker, therefore we conducted SNP analysis for Calmodulin gene by SnaPshot kits. In RFLP analyses, there were no area-specific fragment patterns in the three regions, control region, ND complex and rDNA complex of mtDNA. However compositions of the fragment patterns for the three digested sets, control region/HinfI, rDNA complex/MspI and ND complex/MspI indicated that there are significant differences between around the Japan (Sado-Funka Bay-Wakkanai-Rausu) and the Bering Sea (Western Bering Sea-Nabarin-Atka I.-Bogoslof I). Furthermore, in the case of haplotype frequency, composition showed also significant genetic difference between two areas. Moreover, in Calmodulin analyses, haplotype compositions were changing from western area to eastern area gradually and the results of AMOVA analysis showed that there are interesting differences between western Pacific, western Bering Sea, and eastern Bering Sea. Judging from these results, it was considered that there are three populations of walleye pollock in the Northern Ocean. However, area-specific pattern was not found in some populations in the Northern Ocean. Therefore, we suggested that these populations were related by weak gene flow, and the walleye pollock was formed with meta-population around the Japan and the Bering Sea. PMID:22897958

Yanagimoto, Takashi; Kitamura, Toru; Kobayashi, Takanori

2012-09-01

171

Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa.  

PubMed

NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 × 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 × 10(-3), OR = 1.41 [95% CI 1.10-1.81], respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 × 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 × 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2-3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa. PMID:21514341

Arai, Takashi; Kakuta, Yoichi; Kinouchi, Yoshitaka; Kimura, Tomoya; Negoro, Kenichi; Aihara, Hiroyuki; Endo, Katsuya; Shiga, Hisashi; Kanazawa, Yoshitake; Kuroha, Masatake; Moroi, Rintaro; Nagasawa, Hitoshi; Shimodaira, Yosuke; Takahashi, Seiichi; Shimosegawa, Tooru

2011-07-01

172

Characterization of the Streptomyces sp. Strain C5 snp Locus and Development of snp-Derived Expression Vectors  

PubMed Central

The Streptomyces sp. strain C5 snp locus is comprised of two divergently oriented genes: snpA, a metalloproteinase gene, and snpR, which encodes a LysR-like activator of snpA transcription. The transcriptional start point of snpR is immediately downstream of a strong T-N11-A inverted repeat motif likely to be the SnpR binding site, while the snpA transcriptional start site overlaps the ATG start codon, generating a leaderless snpA transcript. By using the aphII reporter gene of pIJ486 as a reporter, the plasmid-borne snpR-activated snpA promoter was ca. 60-fold more active than either the nonactivated snpA promoter or the melC1 promoter of pIJ702. The snpR-activated snpA promoter produced reporter protein levels comparable to those of the up-mutated ermE? promoter. The SnpR-activated snpA promoter was built into a set of transcriptional and translational fusion expression vectors which have been used for the intracellular expression of numerous daunomycin biosynthesis pathway genes from Streptomyces sp. strain C5 as well as the expression and secretion of soluble recombinant human endostatin. PMID:12620855

DeSanti, Charles L.; Strohl, William R.

2003-01-01

173

Genotype imputation accuracy in a F2 pig population using high density and low density SNP panels  

PubMed Central

Background F2 resource populations have been used extensively to map QTL segregating between pig breeds. A limitation associated with the use of these resource populations for fine mapping of QTL is the reduced number of founding individuals and recombinations of founding haplotypes occurring in the population. These limitations, however, become advantageous when attempting to impute unobserved genotypes using within family segregation information. A trade-off would be to re-type F2 populations using high density SNP panels for founding individuals and low density panels (tagSNP) in F2 individuals followed by imputation. Subsequently a combined meta-analysis of several populations would provide adequate power and resolution for QTL mapping, and could be achieved at relatively low cost. Such a strategy allows the wealth of phenotypic information that has previously been obtained on experimental resource populations to be further mined for QTL identification. In this study we used experimental and simulated high density genotypes (HD-60K) from an F2 cross to estimate imputation accuracy under several genotyping scenarios. Results Selection of tagSNP using physical distance or linkage disequilibrium information produced similar imputation accuracies. In particular, tagSNP sets averaging 1 SNP every 2.1 Mb (1,200 SNP genome-wide) yielded imputation accuracies (IA) close to 0.97. If instead of using custom panels, the commercially available 9K chip is used in the F2, IA reaches 0.99. In order to attain such high imputation accuracy the F0 and F1 generations should be genotyped at high density. Alternatively, when only the F0 is genotyped at HD, while F1 and F2 are genotyped with a 9K panel, IA drops to 0.90. Conclusions Combining 60K and 9K panels with imputation in F2 populations is an appealing strategy to re-genotype existing populations at a fraction of the cost. PMID:23651538

2013-01-01

174

Phospholipase C epsilon 1 (PLCE1) Haplotypes are Associated with Increased Risk of Gastric Cancer in Kashmir Valley  

PubMed Central

Background/Aim: Phospholipase C epsilon 1 (PLCE1) plays a crucial role in carcinogenesis and progression of several types of cancers. A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus. The aim of the present study was to investigate the role of three potentially functional SNPs (rs2274223A > G, rs3765524C > T, and rs7922612C > T) of PLCE1 in gastric cancer patients from Kashmir Valley. Patients and Methods: The study was conducted in 108 GC cases and 195 healthy controls from Kashmir Valley. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism method. Data were statistically analyzed using ?2 test and logistic regression models. A P value of less than 0.05 was regarded as statistically significant. Results: The frequency of PLCE1 A2274223C3765524T7922612, G2274223C3765524T7922612, and G2274223T3765524C7922612 haplotypes were higher in patients compared with controls, conferred high risk for GC [odds ratio (OR) =6.29; P = 0.001; Pcorr = 0.003], (OR = 3.23; P = 0.011; Pcorr = 0.033), and (OR = 5.14; P = 0.011; Pcorr = 0.033), respectively. Smoking and salted tea are independent risk factors for GC, but we did not find any significant modulation of cancer risk by PLCE1 variants with smoking or excessive consumption of salted tea. Conclusion: These results suggest that variation in PLCE1 may be associated with GC risk in Kashmir Valley. PMID:25434319

Malik, Manzoor A.; Srivastava, Priya; Zargar, Showkat A.; Mittal, Balraj

2014-01-01

175

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

E-print Network

was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed Departments of 1 Genetics, 2 Epidemiology and Public Health, and 3 Psychology and Child Study Center, Yale that haplotype-frequency variation exists between some regions of the world. In European populations, linkage

Kidd, Kenneth

176

Efficient haplotype block recognition of very long and dense genetic sequences  

PubMed Central

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

2014-01-01

177

Founder mitochondrial haplotypes in Amerindian populations.  

PubMed Central

It had been proposed that the colonization of the New World took place by three successive migrations from northeastern Asia. The first one gave rise to Amerindians (Paleo-Indians), the second and third ones to Nadene and Aleut-Eskimo, respectively. Variation in mtDNA has been used to infer the demographic structure of the Amerindian ancestors. The study of RFLP all along the mtDNA and the analysis of nucleotide substitutions in the D-loop region of the mitochondrial genome apparently indicate that most or all full-blooded Amerindians cluster in one of four different mitochondrial haplotypes that are considered to represent the founder maternal lineages of Paleo-Indians. We have studied the mtDNA diversity in 109 Amerindians belonging to 3 different tribes, and we have reanalyzed the published data on 482 individuals from 18 other tribes. Our study confirms the existence of four major Amerindian haplotypes. However, we also found evidence supporting the existence of several other potential founder haplotypes or haplotype subsets in addition to the four ancestral lineages reported. Confirmation of a relatively high number of founder haplotypes would indicate that early migration into America was not accompanied by a severe genetic bottleneck. PMID:7517626

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

1994-01-01

178

Retrospective analysis of haplotype-based case–control studies under a flexible model for gene–environment association  

PubMed Central

Summary Genetic epidemiologic studies often involve investigation of the association of a disease with a genomic region in terms of the underlying haplotypes, that is the combination of alleles at multiple loci along homologous chromosomes. In this article, we consider the problem of estimating haplotype–environment interactions from case–control studies when some of the environmental exposures themselves may be influenced by genetic susceptibility. We specify the distribution of the diplotypes (haplotype pair) given environmental exposures for the underlying population based on a novel semiparametric model that allows haplotypes to be potentially related with environmental exposures, while allowing the marginal distribution of the diplotypes to maintain certain population genetics constraints such as Hardy–Weinberg equilibrium. The marginal distribution of the environmental exposures is allowed to remain completely nonparametric. We develop a semiparametric estimating equation methodology and related asymptotic theory for estimation of the disease odds ratios associated with the haplotypes, environmental exposures, and their interactions, parameters that characterize haplotype–environment associations and the marginal haplotype frequencies. The problem of phase ambiguity of genotype data is handled using a suitable expectation–maximization algorithm. We study the finite-sample performance of the proposed methodology using simulated data. An application of the methodology is illustrated using a case–control study of colorectal adenoma, designed to investigate how the smoking-related risk of colorectal adenoma can be modified by “NAT2,” a smoking-metabolism gene that may potentially influence susceptibility to smoking itself. PMID:17490987

CHEN, YI-HAU; CHATTERJEE, NILANJAN; CARROLL, RAYMOND J.

2009-01-01

179

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

PubMed

The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models the probability distribution of the Y-STR haplotypes. Creating a consistent statistical model of the haplotypes enables us to perform a wide range of analyses. Previously, haplotype frequency estimation using the discrete Laplace method has been validated. In this paper we investigate how the discrete Laplace method can be used for cluster analysis to further validate the discrete Laplace method. A very important practical fact is that the calculations can be performed on a normal computer. We identified two sub-clusters of the Eastern and Western European Y-STR haplotypes similar to results of previous studies. We also compared pairwise distances (between geographically separated samples) with those obtained using the AMOVA method and found good agreement. Further analyses that are impossible with AMOVA were made using the discrete Laplace method: analysis of the homogeneity in two different ways and calculating marginal STR distributions. We found that the Y-STR haplotypes from e.g. Finland were relatively homogeneous as opposed to the relatively heterogeneous Y-STR haplotypes from e.g. Lublin, Eastern Poland and Berlin, Germany. We demonstrated that the observed distributions of alleles at each locus were similar to the expected ones. We also compared pairwise distances between geographically separated samples from Africa with those obtained using the AMOVA method and found good agreement. PMID:24793845

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

2014-07-01

180

Powerful Haplotype-Based Hardy-Weinberg Equilibrium Tests for Tightly Linked Loci  

PubMed Central

Recently, there have been many case-control studies proposed to test for association between haplotypes and disease, which require the Hardy-Weinberg equilibrium (HWE) assumption of haplotype frequencies. As such, haplotype inference of unphased genotypes and development of haplotype-based HWE tests are crucial prior to fine mapping. The goodness-of-fit test is a frequently-used method to test for HWE for multiple tightly-linked loci. However, its degrees of freedom dramatically increase with the increase of the number of loci, which may lack the test power. Therefore, in this paper, to improve the test power for haplotype-based HWE, we first write out two likelihood functions of the observed data based on the Niu's model (NM) and inbreeding model (IM), respectively, which can cause the departure from HWE. Then, we use two expectation-maximization algorithms and one expectation-conditional-maximization algorithm to estimate the model parameters under the HWE, IM and NM models, respectively. Finally, we propose the likelihood ratio tests LRT and LRT for haplotype-based HWE under the NM and IM models, respectively. We simulate the HWE, Niu's, inbreeding and population stratification models to assess the validity and compare the performance of these two LRT tests. The simulation results show that both of the tests control the type I error rates well in testing for haplotype-based HWE. If the NM model is true, then LRT is more powerful. While, if the true model is the IM model, then LRT has better performance in power. Under the population stratification model, LRT is still more powerful. To this end, LRT is generally recommended. Application of the proposed methods to a rheumatoid arthritis data set further illustrates their utility for real data analysis. PMID:24167573

Mao, Wei-Gao; He, Hai-Qiang; Xu, Yan; Chen, Ping-Yan; Zhou, Ji-Yuan

2013-01-01

181

SNP-SNP Interaction Network in Angiogenesis Genes Associated with Prostate Cancer Aggressiveness  

PubMed Central

Angiogenesis has been shown to be associated with prostate cancer development. The majority of prostate cancer studies focused on individual single nucleotide polymorphisms (SNPs) while SNP-SNP interactions are suggested having a great impact on unveiling the underlying mechanism of complex disease. Using 1,151 prostate cancer patients in the Cancer Genetic Markers of Susceptibility (CGEMS) dataset, 2,651 SNPs in the angiogenesis genes associated with prostate cancer aggressiveness were evaluated. SNP-SNP interactions were primarily assessed using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach in the CGEMS group, and were then re-evaluated in the Moffitt group with 1,040 patients. For the identified gene pairs, cross-evaluation was applied to evaluate SNP interactions in both study groups. Five SNP-SNP interactions in three gene pairs (MMP16+ ROBO1, MMP16+ CSF1, and MMP16+ EGFR) were identified to be associated with aggressive prostate cancer in both groups. Three pairs of SNPs (rs1477908+ rs1387665, rs1467251+ rs7625555, and rs1824717+ rs7625555) were in MMP16 and ROBO1, one pair (rs2176771+ rs333970) in MMP16 and CSF1, and one pair (rs1401862+ rs6964705) in MMP16 and EGFR. The results suggest that MMP16 may play an important role in prostate cancer aggressiveness. By integrating our novel findings and available biomedical literature, a hypothetical gene interaction network was proposed. This network demonstrates that our identified SNP-SNP interactions are biologically relevant and shows that EGFR may be the hub for the interactions. The findings provide valuable information to identify genotype combinations at risk of developing aggressive prostate cancer and improve understanding on the genetic etiology of angiogenesis associated with prostate cancer aggressiveness. PMID:23593148

Lin, Hui-Yi; Amankwah, Ernest K.; Tseng, Tung-Sung; Qu, Xiaotao; Chen, Dung-Tsa; Park, Jong Y.

2013-01-01

182

Identification of genome-wide SNP-SNP and SNP-clinical Boolean interactions in age-related macular degeneration.  

PubMed

We propose here a methodology to uncover modularities in the network of SNP-SNP interactions most associated with disease. We start by computing all possible Boolean binary SNP interactions across the whole genome. By constructing a weighted graph of the most relevant interactions and via a combinatorial optimization approach, we find the most highly interconnected SNPs. We show that the method can be easily extended to find SNP/environment interactions. Using a modestly sized GWAS dataset of age-related macular degeneration (AMD), we identify a group of only 19 SNPs, which include those in previously reported regions associated to AMD. We also uncover a larger set of loci pointing to a matrix of key processes and functions that are affected. The proposed integrative methodology extends and overlaps traditional statistical analysis in a natural way. Combinatorial optimization techniques allow us to find the kernel of the most central interactions, complementing current methods of GWAS analysis and also enhancing the search for gene-environment interaction. PMID:25403535

Riveros, Carlos; Vimieiro, Renato; Holliday, Elizabeth G; Oldmeadow, Christopher; Wang, Jie Jin; Mitchell, Paul; Attia, John; Scott, Rodney J; Moscato, Pablo A

2015-01-01

183

[Microsatellite haplotypes of the Y-chromosome demonstrate the absence of subdivisions and presence of several components in the Tuvinian male gene pool].  

PubMed

The haplotype analysis of seven Y-chromosome microsatellites in three regional populations of Tuvinians revealed high intrapopulation variation in the male gene pool of the modern population of the Tuva Republic. In total, 49 haplotypes were found in 111 individuals; only four haplotypes occurred at a frequency higher than 5%. High genetic diversity (H = 0.935) suggested a high power of discrimination for the Y-chromosome haplotypes. The analysis of molecular variance (AMOVA) and other data did not reveal subdivision of the Tuvinian population with respect to Y-chromosome haplotypes. Most haplotypes found in Tuvinians formed two lines. Line A included approximately 64% of the haplotypes found, line B, approximately 24%. A putative ancestral haplotype of line B was similar to a haplotype most common in modern Caucasoids (Md = 3), whereas a putative ancestral haplotype of line A proved to be distant from the ancestral haplotype of line A and haplotypes common for Caucasoids and Mongoloids. Estimates of the age of the Y-chromosome lines showed that the male gene pool of modern Tuvinians originated in the late Paleolithic or Neolithic period. With two methods, the age of line A was estimated at 3500 or 18,000 years and the age of line B was approximately at 5500 or 15,000 years. Considering the less conservative estimates to be more reliable, line B was assumed to originate from the ancient Caucasoid population of the Tuva region. The more widespread and evolutionarily younger line A was associated with the peopling region by ancient Mongoloid tribes of the Turkic language group in the Hun-Sarmatian period. PMID:10779914

Stepanov, V A; Puzyrev, V P

2000-03-01

184

A novel method for identifying SNP disease association based on maximal information coefficient.  

PubMed

To improve single-nucleotide polymorphism (SNP) association studies, we developed a method referred to as maximal information coefficient (MIC)-based SNP searching (MICSNPs) by employing a novel statistical approach known as the MIC to identify SNP disease associations. MIC values varied with minor allele frequencies of SNPs and the odds ratios for disease. We used a Monte Carlo-based permutation test to eliminate the effects of fluctuating MIC values and included a sliding-window-based binary search whose time-cost was 0.58% that of a sequential search to save time. The experiments examining both simulation and actual data demonstrated that our method is computationally and statistically feasible after reducing the resampling count to 4 times the number of markers and applying a sliding-window-based binary search to the method. We found that our method outperforms existing approaches. PMID:25526206

Liu, H M; Rao, N; Yang, D; Yang, L; Li, Y; Ou, F

2014-01-01

185

Identification of multiple diagnostic SNP loci for differentiation of three salmonid species using SNP-arrays.  

PubMed

This paper reports the use of SNP-array technology in a cross-species study for non-ambiguous species identifications. Based on an existing SNP-array for Atlantic salmon (cross)hybridisations with samples of salmon, brown trout and rainbow trout were analyzed to identify species-specific diagnostic markers. In total 566 SNP loci were identified to be highly polymorphic across the three salmonid species providing the molecular basement for various monitoring applications in aquaculture and food industries. PMID:24703883

Drywa, Agata; Po?wierz-Kotus, Anita; Dobosz, Stefan; Kent, Matthew P; Lien, Sigbjørn; Wenne, Roman

2014-06-01

186

Forensic application of SNP-based resequencing array for individual identification.  

PubMed

In forensic field investigations using single nucleotide polymorphism (SNP) have been performed for various purposes. Based on the characteristics of SNP, it is essential to have a multi-amplification technology and a platform to analyze the amplified SNP markers accurately. Here, we have developed a platform based on the resequencing array of Affymetrix analyzing 169 SNP markers amplified via multiplex PCR and verified its forensic application. From the 1000 genomes database, the SNP markers were selected under the condition of less than 0.04 fixation index (Fst) and 0.3 linkage disequilibrium (LD) R(2) value, and 0.4-0.5 minor allele frequency (MAF). It was identified that more than 120 out of 169 SNPs were able to be typed with approximately 10pg of DNA and artificially degraded samples in various tests. The DNA extracted from bones also showed a similar rate of success. The results indicated that our platform has a potential role to assist the current short tandem repeat (STR) method in analyzing harsh samples, such as bone or degraded DNA. With a possibility to expand the platform, it was expected to apply to various uses in different areas in the future. PMID:25082136

Cho, Sohee; Yu, Hyung Jin; Han, Jisung; Kim, Yoonsoo; Lee, Jihyun; Lee, Soong Deok

2014-11-01

187

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

PubMed Central

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

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

188

RAD tag sequencing as a source of SNP markers in Cynara cardunculus L  

PubMed Central

Background The globe artichoke (Cynara cardunculus L. var. scolymus) genome is relatively poorly explored, especially compared to those of the other major Asteraceae crops sunflower and lettuce. No SNP markers are in the public domain. We have combined the recently developed restriction-site associated DNA (RAD) approach with the Illumina DNA sequencing platform to effect the rapid and mass discovery of SNP markers for C. cardunculus. Results RAD tags were sequenced from the genomic DNA of three C. cardunculus mapping population parents, generating 9.7 million reads, corresponding to ~1 Gbp of sequence. An assembly based on paired ends produced ~6.0 Mbp of genomic sequence, separated into ~19,000 contigs (mean length 312 bp), of which ~21% were fragments of putative coding sequence. The shared sequences allowed for the discovery of ~34,000 SNPs and nearly 800 indels, equivalent to a SNP frequency of 5.6 per 1,000 nt, and an indel frequency of 0.2 per 1,000 nt. A sample of heterozygous SNP loci was mapped by CAPS assays and this exercise provided validation of our mining criteria. The repetitive fraction of the genome had a high representation of retrotransposon sequence, followed by simple repeats, AT-low complexity regions and mobile DNA elements. The genomic k-mers distribution and CpG rate of C. cardunculus, compared with data derived from three whole genome-sequenced dicots species, provided a further evidence of the random representation of the C. cardunculus genome generated by RAD sampling. Conclusion The RAD tag sequencing approach is a cost-effective and rapid method to develop SNP markers in a highly heterozygous species. Our approach permitted to generate a large and robust SNP datasets by the adoption of optimized filtering criteria. PMID:22214349

2012-01-01

189

Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations.  

PubMed

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region. PMID:12964809

Adjalla, Charles E; Amouzou, Emile K; Sanni, Ambaliou; Abdelmouttaleb, Idrissia; Chabi, Nicodème W; Namour, Fares; Soussou, Batoma; Guéant, Jean-Louis

2003-08-01

190

A Haplotype of the GOSR2 Gene Is Associated with Myocardial Infarction in Japanese Men  

PubMed Central

Aims: The Golgi SNAP Receptor Complex Member 2 (GOSR2) gene is a Golgi-associated soluble factor attachment receptor (SNARE) protein. Some single-nucleotide polymorphisms (SNPs) in the GOSR2 gene have been found to be associated with myocardial infarction (MI). The aim of the present study was to assess the association between the human GOSR2 gene and MI using a haplotype-based case–control study. Methods: A total of 238 MI patients and 284 controls were genotyped for the five SNPs used as genetic markers for the human GOSR2 gene (rs197932, rs3785889, rs197922, rs17608766, and rs16941382). Data were analyzed for three separate groups: the total subjects, men, and women. Results: The overall distribution of the haplotypes in the total subjects and the men was significantly different between the MI patients and the control subjects (p=0.001, p=0.005, respectively). Additionally, the frequency of the T-G-G haplotype (rs197932-rs3785889-rs197922) for men was significantly lower in the MI patients than in the control subjects (p=0.040). Multiple logistic regression analysis also revealed that the frequency of the subjects with the T-G-G haplotype (homozygous and heterozygous diplotypes) was significantly lower compared with subjects without this haplotype in men after adjustment for the major confounding factors (odds ratio=0.455, p=0.041). Conclusions: The results of this study indicate that the T-G-G haplotype may be a protective genetic marker for MI in Japanese men. PMID:23675987

Pan, Shuo; Sato, Naoyuki; Izumi, Yoichi; Soma, Masayoshi; Aoi, Noriko; Ma, Yitong; Hinohara, Shigeaki; Doba, Nobutaka

2013-01-01

191

variantGPS: SNP500Cancer Project  

Cancer.gov

The SNP500Cancer is part of the Cancer Genome Anatomy Project and is specifically designed to generate resources for the identification and characterization of genetic variation in genes important in cancer. CGAP is dedicated to the development of technology, including both assays and utilization of technical platforms.

192

An EM algorithm and testing strategy for multiple-locus haplotypes  

Microsoft Academic Search

This paper gives an expectation maximization (EM) algorithm to obtain allele frequencies, haplotype frequencies, and gametic disequilibrium coefficients for multiple-locus systems. It permits high polymorphism and null alleles at all loci. This approach effectively deals with the primary estimation problems associated with such systems; that is, there is not a one-to-one correspondence between phenotypic and genotypic categories, and sample sizes

J. C. Long; R. C. Williams; M. Urbanek

1995-01-01

193

On the relationship between an Asian haplotype on chromosome 6 that reduces androstenone levels in boars and the differential expression of SULT2A1 in the testis  

PubMed Central

Background Androstenone is one of the major compounds responsible for boar taint, a pronounced urine-like odor produced when cooking boar meat. Several studies have identified quantitative trait loci (QTL) for androstenone level on Sus scrofa chromosome (SSC) 6. For one of the candidate genes in the region SULT2A1, a difference in expression levels in the testis has been shown at the protein and RNA level. Results Haplotypes were predicted for the QTL region and their effects were estimated showing that haplotype 1 was consistently related with a lower level, and haplotype 2 with a higher level of androstenone. A recombinant haplotype allowed us to narrow down the QTL region from 3.75 Mbp to 1.94 Mbp. An RNA-seq analysis of the liver and testis revealed six genes that were differentially expressed between homozygotes of haplotypes 1 and 2. Genomic sequences of these differentially expressed genes were checked for variations within potential regulatory regions. We identified one variant located within a CpG island that could affect expression of SULT2A1 gene. An allele-specific expression analysis in the testis did not show differential expression between the alleles of SULT2A1 located on the different haplotypes in heterozygous animals. However a synonymous mutation C166T (SSC6: 49,117,861 bp in Sscrofa 10.2; C/T) was identified within the exon 2 of SULT2A1 for which the haplotype 2 only had the C allele which was higher expressed than the T allele, indicating haplotype-independent allelic-imbalanced expression between the two alleles. A phylogenetic analysis for the 1.94 Mbp region revealed that haplotype 1, associated with low androstenone level, originated from Asia. Conclusions Differential expression could be observed for six genes by RNA-seq analysis. No difference in the ratio of C:T expression of SULT2A1 for the haplotypes was found by the allele-specific expression analysis, however, a difference in expression between the C over T allele was found for a variation within SULT2A1, showing that the difference in androstenone levels between the haplotypes is not caused by the SNP in exon 2. PMID:24405739

2014-01-01

194

Correcting Coalescent Analyses for Panel-Based SNP Ascertainment  

PubMed Central

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

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

2013-01-01

195

ASSOCIATION BETWEEN GAB2 HAPLOTYPE AND HIGHER GLUCOSE METABOLISM IN ALZHEIMER'S DISEASE-AFFECTED BRAIN REGIONS IN COGNITIVELY NORMAL APOE?4 CARRIERS  

PubMed Central

In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ?4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative presymptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOE?4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOE?4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOE?4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk. PMID:20888920

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

2010-01-01

196

Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect.  

PubMed

Due to patterns of migration, selection, and population expansion, founder effects are common among humans. In Southern Brazil, a recurrent TP53 mutation, p.R337H, is detected in families with cancer predisposition. We have used whole locus resequencing and high-density single nucleotide polymorphism (SNP) genotyping to refine TP53 locus haplotype definitions. Haplotyping of 12 unrelated p.R337H carriers using a set of 29 tag SNPs, revealed that all subjects carried the same haplotype, and presence of the mutation on this haplotype was confirmed by allele-specific PCR. The probability that this haplotype occurs independently in all index cases was of 3.1x10(-9), demonstrating a founder effect. Analysis of the patterns of 103 tumors diagnosed in 12 families showed that the presence of p.R337H is associated with multiple cancers of the Li-Fraumeni Syndrome (LFS) spectrum, with relatively low penetrance before the age of 30 but a lifetime risk comparable to classical LFS. The p.R337H families are mostly distributed along a road axis historically known as the main route used by merchants of Portuguese origin in the XVIII and XIX century. This historical circumstance and the relatively low penetrance before the age of 30 may have contributed to the maintenance of this pathogenic mutation in a large, open population. PMID:19877175

Garritano, Sonia; Gemignani, Federica; Palmero, Edenir Inez; Olivier, Magali; Martel-Planche, Ghyslaine; Le Calvez-Kelm, Florence; Brugiéres, Laurence; Vargas, Fernando Regla; Brentani, Ricardo Renzo; Ashton-Prolla, Patricia; Landi, Stefano; Tavtigian, Sean V; Hainaut, Pierre; Achatz, Maria Isabel W

2010-02-01

197

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...

198

Islands of Tractability for Parsimony Haplotyping  

E-print Network

haplotypes, due to population bottleneck effects and genetic drift. For example, Patil et al. report-3-640-5391, fax: +972-3-640-9357. B.V. Halld´orsson is with deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland Biology and Genetics, G.2.2.a Graph Algorithms, F.2.0 Analysis of algorithms and Problem Complexity I

Halldórsson, Bjarni V.

199

Original article Prion gene (PRNP) haplotype variation  

E-print Network

Original article Prion gene (PRNP) haplotype variation in United States goat breeds (Open Access not examined before at PRNP. scrapie / goat / polymorphism / resistance / prion 1. INTRODUCTION Scrapie that encodes prion protein have been associated with differential resistance and susceptibility to scrapie

Boyer, Edmond

200

Association of a Bovine Prion Gene Haplotype with Atypical BSE  

Microsoft Academic Search

Background: Atypical bovine spongiform encephalopathies (BSEs) are recently recognized prion diseases of cattle. Atypical BSEs are rare; approximately 30 cases have been identified worldwide. We tested prion gene (PRNP) haplotypes for an association with atypical BSE. Methodology\\/Principle Findings: Haplotype tagging polymorphisms that characterize PRNP haplotypes from the promoter region through the three prime untranslated region of exon 3 (25.2 kb)

Michael L. Clawson; Juergen A. Richt; Thierry Baron; Anne-Gaëlle Biacabe; Stefanie Czub; Michael P. Heaton; Timothy P. L. Smith; William W. Laegreid

2008-01-01

201

METHOD Open Access Rapid haplotype inference for nuclear families  

E-print Network

METHOD Open Access Rapid haplotype inference for nuclear families Amy L Williams1* , David E-recombinant and maximum likelihood haplotypes. When applied to a dataset con- taining 103 families, Hapi performs 3 family relationships [18-26]. These algorithms infer haplotypes using the laws of Mendelian inheritance

Gifford, David K.

202

A New Statistical Method for Haplotype Reconstruction from Population Data  

Microsoft Academic Search

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

Matthew Stephens; Nicholas J. Smith; Peter Donnelly

2001-01-01

203

A Haplotype-Based Haplotype Relative Risk’ Approach to Detecting Allelic Associations  

Microsoft Academic Search

A novel variation of the Haplotype Relative Risk (HRR) of Rubinstein et al. [Hum Immunol 1981;3:384] is proposed, in order to glean increased information about linkage disequilibrium or allelic associations by analyzing haplotype-based data rather than genotypic data. It is shown that statistical tests based on our design give much higher power than those based on the original HRR approach.

Joseph D. Terwilliger; Jurg Ott

1992-01-01

204

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

PubMed Central

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10?10). We finally searched for association between SNPs within the FRMD4A locus and A? plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma A?42/A?40 ratio (best signal, P=5.4 × 10?7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD. PMID:22430674

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

2013-01-01

205

Software for optimization of SNP and PCR-RFLP genotyping to discriminate many genomes with the fewest assays  

PubMed Central

Background Microbial forensics is important in tracking the source of a pathogen, whether the disease is a naturally occurring outbreak or part of a criminal investigation. Results A method and SPR Opt (SNP and PCR-RFLP Optimization) software to perform a comprehensive, whole-genome analysis to forensically discriminate multiple sequences is presented. Tools for the optimization of forensic typing using Single Nucleotide Polymorphism (SNP) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) analyses across multiple isolate sequences of a species are described. The PCR-RFLP analysis includes prediction and selection of optimal primers and restriction enzymes to enable maximum isolate discrimination based on sequence information. SPR Opt calculates all SNP or PCR-RFLP variations present in the sequences, groups them into haplotypes according to their co-segregation across those sequences, and performs combinatoric analyses to determine which sets of haplotypes provide maximal discrimination among all the input sequences. Those set combinations requiring that membership in the fewest haplotypes be queried (i.e. the fewest assays be performed) are found. These analyses highlight variable regions based on existing sequence data. These markers may be heterogeneous among unsequenced isolates as well, and thus may be useful for characterizing the relationships among unsequenced as well as sequenced isolates. The predictions are multi-locus. Analyses of mumps and SARS viruses are summarized. Phylogenetic trees created based on SNPs, PCR-RFLPs, and full genomes are compared for SARS virus, illustrating that purported phylogenies based only on SNP or PCR-RFLP variations do not match those based on multiple sequence alignment of the full genomes. Conclusion This is the first software to optimize the selection of forensic markers to maximize information gained from the fewest assays, accepting whole or partial genome sequence data as input. As more sequence data becomes available for multiple strains and isolates of a species, automated, computational approaches such as those described here will be essential to make sense of large amounts of information, and to guide and optimize efforts in the laboratory. The software and source code for SPR Opt is publicly available and free for non-profit use at . PMID:15904493

Gardner, Shea N; Wagner, Mark C

2005-01-01

206

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

PubMed

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

Chen, Hua; Hey, Jody; Slatkin, Montgomery

2015-02-01

207

Association of Variable Number of Tandem Repeats in the Coding Region of the FAM46A Gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP with Susceptibility to Tuberculosis  

PubMed Central

We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, Pcorr.<0.029, Odds ratio?=?2.42, 95% Confidence Interval?=?1.34–4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, pcorr.<0.024, Odds ratio 3.45, 95% Confidence Interval?=?1.26–9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease. PMID:24625963

Etokebe, Godfrey Essien; Bulat-Kardum, Ljiljana; Munthe, Ludvig Andre; Balen, Sanja; Dembic, Zlatko

2014-01-01

208

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.  

PubMed

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 disequilibrium (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

Im, Kate M; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M; Fredericksen, Zachary; Shane Pankratz, V; 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

2011-11-01

209

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers  

PubMed Central

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

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

210

Worldwide Distribution of the MYH9 Kidney Disease Susceptibility Alleles and Haplotypes: Evidence of Historical Selection in Africa  

PubMed Central

MYH9 was recently identified as renal susceptibility gene (OR 3–8, p<10?8) for major forms of kidney disease disproportionately affecting individuals of African descent. The risk haplotype (E-1) occurs at much higher frequencies in African Americans (?60%) than in European Americans (<4%), revealing a genetic basis for a major health disparity. The population distributions of MYH9 risk alleles and the E-1 risk haplotype and the demographic and selective forces acting on the MYH9 region are not well explored. We reconstructed MYH9 haplotypes from 4 tagging single nucleotide polymorphisms (SNPs) spanning introns 12–23 using available data from HapMap Phase II, and by genotyping 938 DNAs from the Human Genome Diversity Panel (HGDP). The E-1 risk haplotype followed a cline, being most frequent within sub-Saharan African populations (range 50–80%), less frequent in populations from the Middle East (9–27%) and Europe (0–9%), and rare or absent in Asia, the Americas, and Oceania. The fixation indexes (FST) for pairwise comparisons between the risk haplotypes for continental populations were calculated for MYH9 haplotypes; FST ranged from 0.27–0.40 for Africa compared to other continental populations, possibly due to selection. Uniquely in Africa, the Yoruba population showed high frequency extended haplotype length around the core risk allele (C) compared to the alternative allele (T) at the same locus (rs4821481, iHs?=?2.67), as well as high population differentiation (FST(CEU vs. YRI)?=?0.51) in HapMap Phase II data, also observable only in the Yoruba population from HGDP (FST?=?0.49), pointing to an instance of recent selection in the genomic region. The population-specific divergence in MYH9 risk allele frequencies among the world's populations may prove important in risk assessment and public health policies to mitigate the burden of kidney disease in vulnerable populations. PMID:20634883

Oleksyk, Taras K.; Nelson, George W.; An, Ping; Kopp, Jeffrey B.; Winkler, Cheryl A.

2010-01-01

211

Allele-Specific Amplification in Cancer Revealed by SNP Array Analysis  

PubMed Central

Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ. PMID:16322765

2005-01-01

212

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

PubMed Central

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

2014-01-01

213

An association and haplotype analysis of porcine maternal infanticide: a model for human puerperal psychosis?  

PubMed

An association analysis using the Illumina porcine SNP60 beadchip was performed to identify SNPs significantly associated with porcine maternal infanticide. We previously hypothesised that this was a good animal model for human puerperal psychosis, an extreme form of postnatal mood disorder. Animals were selected from carefully phenotyped unrelated infanticide and control groups (representing extremes of the phenotypic spectrum), from four different lines. Permutation and sliding window analyses and an analysis to see which haplotypes were in linkage disequilibrium (LD) were compared to identify concordant regions. Across all analyses, intervals on SSCs 1, 3, 4, 10, and 13 were constant, contained genes associated with psychiatric or neurological disorders and were significant in multiple lines. The strongest (near GWS) consistent candidate region across all analyses and all breeds was the one located on SSC3 with one peak at 23.4?Mb, syntenic to a candidate region for bipolar disorder and another at 31.9?Mb, syntenic to a candidate region for human puerperal psychosis (16p13). From the haplotype/LD analysis, two regions reached genome wide significance (GWS): the first on SSC4 (KHDRBS3 to FAM135B), which was significant (-logP 5.57) in one Duroc based breed and is syntenic to a region in humans associated with cognition and neurotism; the second on SSC15, which was significant (-log10P 5.68) in two breeds and contained PAX3, which is expressed in the brain. PMID:22976950

Quilter, C R; Sargent, C A; Bauer, J; Bagga, M R; Reiter, C P; Hutchinson, E L; Southwood, O I; Evans, G; Mileham, A; Griffin, D K; Affara, N A

2012-12-01

214

A Common Haplotype within the PON1 Promoter Region is Associated with Sporadic ALS  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder of upper and lower motor neurons. Genetic variants in the paraoxonase gene cluster have been associated with susceptibility to sporadic ALS. Because these studies have yielded conflicting results, we have further investigated this association in a larger data set. Twenty SNPs spanning the paraoxonase gene cluster were genotyped on a panel of 835 case and 924 control samples and tested for association with risk of sporadic ALS and with ALS sub-phenotypes. Our study revealed 2 SNPs, rs2074351 and rs705382, within the paraoxonase gene cluster that are associated with susceptibility to sporadic ALS (uncorrected p=0.0016 and 0.0022, respectfully). None of the 20 SNPs displayed significant associations with age of onset, site of onset or disease survival. Using a sliding window approach, we have also identified a 5-SNP haplotype that is significantly associated with risk of sporadic ALS (p=2.42E-04). We conclude that a common haplotype within the PON1 promoter region is associated with susceptibility to sporadic ALS. PMID:18618303

Landers, John E.; Shi, Lijia; Cho, Ting-Jan; Glass, Jonathan D.; Shaw, Christopher E.; Leigh, P. Nigel; Diekstra, Frank; Polak, Meraida; Rodriguez-Leyza, Ildefonso; Niemann, Stephan; Traynor, Bryan J.; McKenna-Yasek, Diane; Sapp, Peter C.; Al-Chalabi, Ammar; Wills, Anne-Marie A.; Brown, Robert H.

2009-01-01

215

The Evolution of Isochores: Evidence From SNP Frequency Distributions  

Microsoft Academic Search

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,

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

2002-01-01

216

SNP alleles in human disease and evolution  

Microsoft Academic Search

.   In two randomly selected human genomes, 99.9% of the DNA sequence is identical. The remaining 0.1% of DNA contains sequence\\u000a variations. The most common type of such variation is called a single-nucleotide polymorphism, or SNP. SNPs are highly abundant,\\u000a stable, and distributed throughout the genome. These variations are associated with diversity in the population, individuality,\\u000a susceptibility to diseases, and

Barkur S Shastry

2002-01-01

217

Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene  

SciTech Connect

Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been identified. The aim of this study was to look for clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metabolism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two copies, one copy, and no copies of the ancestral haplotype). We also examined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. These analyses indicate that (i) HC patients with two copies of the ancestral haplotype show significantly more severe expression of the disorder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the presence of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency. 18 refs., 3 tabs.

Crawford, D.H.G.; Powell, L.W.; Leggett, B.A. [Univ. of Queensland (Australia)] [and others

1995-08-01

218

Effective algorithms for tag SNP selection.  

PubMed

Single nucleotide polymorphisms (SNPs), due to their abundance and low mutation rate, are very useful genetic markers for genetic association studies. However, the current genotyping technology cannot afford to genotype all common SNPs in all the genes. By making use of linkage disequilibrium, we can reduce the experiment cost by genotyping a subset of SNPs, called Tag SNPs, which have a strong association with the ungenotyped SNPs, while are as independent from each other as possible. The problem of selecting Tag SNPs is NP-complete; when there are large number of SNPs, in order to avoid extremely long computational time, most of the existing Tag SNP selection methods first partition the SNPs into blocks based on certain block definitions, then Tag SNPs are selected in each block by brute-force search. The size of the Tag SNP set obtained in this way may usually be reduced further due to the inter-dependency among blocks. This paper proposes two algorithms, TSSA and TSSD, to tackle the block-independent Tag SNP selection problem. TSSA is based on A* search algorithm, and TSSD is a heuristic algorithm. Experiments show that TSSA can find the optimal solutions for medium-sized problems in reasonable time, while TSSD can handle very large problems and report approximate solutions very close to the optimal ones. PMID:16278949

Liu, Tie-Fei; Sung, Wing-Kin; Li, Yi; Liu, Jian-Jun; Mittal, Ankush; Mao, Pei-Lin

2005-10-01

219

Casein SNP in Norwegian goats: additive and dominance effects on milk composition and quality  

PubMed Central

Background The four casein proteins in goat milk are encoded by four closely linked casein loci (CSN1S1, CSN2, CSN1S2 and CSN3) within 250 kb on caprine chromosome 6. A deletion in exon 12 of CSN1S1, so far reported only in Norwegian goats, has been found at high frequency (0.73). Such a high frequency is difficult to explain because the national breeding goal selects against the variant's effect. Methods In this study, 575 goats were genotyped for 38 Single Nucleotide Polymorphisms (SNP) located within the four casein genes. Milk production records of these goats were obtained from the Norwegian Dairy Goat Control. Test-day mixed models with additive and dominance fixed effects of single SNP were fitted in a model including polygenic effects. Results Significant additive effects of single SNP within CSN1S1 and CSN3 were found for fat % and protein %, milk yield and milk taste. The allele with the deletion showed additive and dominance effects on protein % and fat %, and overdominance effects on milk quantity (kg) and lactose %. At its current frequency, the observed dominance (overdominance) effects of the deletion allele reduced its substitution effect (and additive genetic variance available for selection) in the population substantially. Conclusions The selection pressure of conventional breeding on the allele with the deletion is limited due to the observed dominance (overdominance) effects. Inclusion of molecular information in the national breeding scheme will reduce the frequency of this deletion in the population. PMID:21864407

2011-01-01

220

Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic.  

PubMed

The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362:A(1)>A(2), rs1042522:G>C, rs12947788:C>T, and rs17884306:G>A), CDKN1A (rs1801270:C>A and rs1059234:C>T), and CDKN2A (rs3731249:G>A, rs11515:C>G, and rs3088440:C>T) genes in 614 hospital-based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P<0.0001). The two most common haplotypes, A(1)GCG and A(2)CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A(1)GCG), the haplotype A(2)CCG was associated with an increased risk (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.07-1.82), while the four other haplotypes A(1)CCG (OR, 0.60; 95% CI, 0.45-0.79), A(2)GCG (OR, 0.53; 95% CI, 0.35-0.81), A(1)GTG (OR, 0.31; 95% CI, 0.15-0.64), and A(1)GCA (OR, 0.19; 95% CI, 0.07-0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P<0.0001) and rectal cancers (P=0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population. PMID:19224585

Polakova, V; Pardini, B; Naccarati, A; Landi, S; Slyskova, J; Novotny, J; Vodickova, L; Bermejo, J L; Hanova, M; Smerhovsky, Z; Tulupova, E; Kumar, R; Hemminki, K; Vodicka, P

2009-04-01

221

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

PubMed Central

Background The increasingly narrow genetic background characteristic of modern crop germplasm presents a challenge for the breeding of cultivars that require adaptation to the anticipated change in climate. Thus, high priority research aims at the identification of relevant allelic variation present both in the crop itself as well as in its progenitors. This study is based on the characterization of genetic variation in barley, with a view to enhancing its response to terminal drought stress. Results The expression patterns of drought regulated genes were monitored during plant ontogeny, mapped and the location of these genes was incorporated into a comprehensive barley SNP linkage map. Haplotypes within a set of 17 starch biosynthesis/degradation genes were defined, and a particularly high level of haplotype variation was uncovered in the genes encoding sucrose synthase (types I and II) and starch synthase. The ability of a panel of 50 barley accessions to maintain grain starch content under terminal drought conditions was explored. Conclusion The linkage/expression map is an informative resource in the context of characterizing the response of barley to drought stress. The high level of haplotype variation among starch biosynthesis/degradation genes in the progenitors of cultivated barley shows that domestication and breeding have greatly eroded their allelic diversity in current elite cultivars. Prospective association analysis based on core drought-regulated genes may simplify the process of identifying favourable alleles, and help to understand the genetic basis of the response to terminal drought. PMID:21205309

2011-01-01

222

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

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.

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

223

Haplotypes at the OPRM1 locus are associated with susceptibility to substance dependence in European-Americans.  

PubMed

Our objective was to investigate the relationship between the gene encoding the mu-opioid receptor (OPRM1) and susceptibility to substance dependence in European-American (EA) and African-American (AA) subjects. Eight single nucleotide polymorphisms (SNPs) at the OPRM1 locus, i.e., -2044C/A, -1793T/A, -1699insT, -1469T/C, -1320A/G, -111C/T, +17C/T (Ala6Val), and +118A/G (Asn40Asp) were genotyped in 676 subjects: 318 EA subjects and 124 AA subjects with substance dependence, and 179 EA normal controls, and 55 AA normal controls. Affection status was defined by each unique combination of alcohol, cocaine, and opioid dependence and analysis of association examined in relation to the possible combinations. We used a newly implemented permutation method to evaluate statistical significance. In EAs, a significant difference in haplotype frequency distributions was found between controls and "alcohol + opioid" dependent patients (P = 0.0036). This finding is also supported by logistic regression analysis and a simulation method. The frequencies of allele -2044A and haplotypes including -2044A are higher in these patients than in controls. In AAs, no allele, haplotype, or genotype frequencies were significantly different between cases and controls. There were highly significant differences in the allele, haplotype, and genotype frequencies between EA and AA controls. Four of the variants [-1793T/A, -1699insT, -1320A/G, and -111C/T] are in virtually complete linkage disequilibrium (LD) to compose a sequence pattern, which does not associate with any of the seven categories of substance dependence. In EAs, allele -2044A and haplotypes that include -2044A are the susceptibility allele and haplotypes for substance dependence. These findings suggest that OPRM1 may play a role in the pathophysiology of substance dependence and this role is population- and diagnosis-specific. PMID:12815747

Luo, Xingguang; Kranzler, Henry R; Zhao, Hongyu; Gelernter, Joel

2003-07-01

224

Haplotype analysis of the polymorphic 17 YSTR markers in Kerala nontribal populations.  

PubMed

The origin of the Kerala non tribal population has been a matter of contention for centuries. While some claim that Negritos were the first inhabitants, some historians suggest a Dravidian origin for all Keralites. The aim of our study has been to provide sufficient scientific evidence based on Y chromosome short tandem repeat (Y STR) analysis for tracing the paternal lineage and also to create a database of the Y STR haplotype of the male population for future forensic analysis. Whole blood samples (n = 168) were collected from unrelated healthy men of the Kerala non-tribal population over a period of 2 years from October 2009. Genomic DNA was extracted by salting out method. All samples were genotyped for the 17 Y STR loci by the AmpFLSTR Y-filer PCR Amplification Kit. The haplotype and allele frequencies were determined by direct counting and analyzed using Arlequin 3.1 software, and molecular variance was calculated with the Y chromosome haplotype reference database online analysis tool, www.yhrd.org . Haplotype diversity was calculated using HaPYDive ( http://portugene.com/hapydive.html ). The majority of haplotypes were unique (149/168). The variant allele 17.1 was observed in DYS 385 loci in three samples. Fifteen samples (8.93%) showed the presence of alleles that are not within the established marker range denoted as outside marker range (OMR). The allele frequency of Kerala non tribal population ranged from 0.00003 to 0.5809. The most polymorphic single locus marker was DYS 458. The haplotype diversity value for Kerala non tribal population was 0.9978. The pairwise difference value ranged from 0.0531 to 0.0854 on comparison of the haplotypes of the Kerala non tribals with other Indian populations. The multi dimensional scaling plot depicted the proximity of Kerala non tribal population with Vasterbotten population (Swedish) and Paiwan, Patyal population of Taiwan, Thailand, and Zhuang population of China. The results of the study indicate towards a European paternal lineage in the non tribal Kerala population. PMID:22311032

Parvathy, Seema Nair; Geetha, Aswathy; Jagannath, Chippy

2012-06-01

225

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

SciTech Connect

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.

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

1994-09-01

226

Allelic mRNA expression imbalance in C-type lectins reveals a frequent regulatory SNP in the human surfactant protein A (SP-A) gene.  

PubMed

Genetic variation in C-type lectins influences infectious disease susceptibility but remains poorly understood. We used allelic mRNA expression imbalance (AEI) technology for surfactant protein (SP)-A1, SP-A2, SP-D, dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), macrophage mannose receptor (MRC1) and Dectin-1, expressed in human macrophages and/or lung tissues. Frequent AEI, an indicator of regulatory polymorphisms, was observed in SP-A2, SP-D and DC-SIGN. AEI was measured for SP-A2 in 38 lung tissues using four marker single-nucleotide polymorphisms (SNPs) and was confirmed by next-generation sequencing of one lung RNA sample. Genomic DNA at the SP-A2 DNA locus was sequenced by Ion Torrent technology in 16 samples. Correlation analysis of genotypes with AEI identified a haplotype block, and, specifically, the intronic SNP rs1650232 (30% minor allele frequency); the only variant consistently associated with an approximately twofold change in mRNA allelic expression. Previously shown to alter a NAGNAG splice acceptor site with likely effects on SP-A2 expression, rs1650232 generates an alternative splice variant with three additional bases at the start of exon 3. Validated as a regulatory variant, rs1650232 is in partial linkage disequilibrium with known SP-A2 marker SNPs previously associated with risk for respiratory diseases including tuberculosis. Applying functional DNA variants in clinical association studies, rather than marker SNPs, will advance our understanding of genetic susceptibility to infectious diseases. PMID:23328842

Azad, A K; Curtis, A; Papp, A; Webb, A; Knoell, D; Sadee, W; Schlesinger, L S

2013-03-01

227

Molecular cloning and SNP association analysis of chicken PMCH gene.  

PubMed

The pre-melanin-concentrating hormone (PMCH) gene is an important gene functionally concerning the regulations of body fat content, feeding behavior and energy balance. In this study, the full-length cDNA of chicken PMCH gene was amplified by SMART RACE method. The single nucleotide polymorphisms (SNPs) in the PMCH gene were screened by comparative sequence analysis. The obtained non-synonymous coding SNPs (ncSNPs) were designed for genotyping firstly. Its effects on growth, carcass characteristics and meat quality traits were investigated employing the F2 resource population of Gushi chicken crossed with Anak broiler by AluI CRS-PCR-RFLP. Our results indicated that the cDNA of chicken PMCH shared 67.25 and 66.47% homology with that of human and bovine PMCH, respectively. The deduced amino acid sequence of chicken PMCH (163 amino acids) were 52.07 and 50.89% identical to those of human and bovine PMCH, respectively. The PMCH protein sequence is predicted to have several functional domains, including pro-MCH, CSP, IL7, XPGI and some low complexity sequence. It has 8 phosphorylation sites and no signal peptide sequence. gga-miR-18a, gga-miR-18b, gga-miR-499 microRNA targeting site was predicted in the 3' untranslated region of chicken PMCH mRNA. In addition, a total of seven SNPs including an ncSNP and a synonymous coding SNP, were identified in the PMCH gene. The ncSNP c.81 A>T was found to be in moderate polymorphic state (polymorphic index=0.365), and the frequencies for genotype AA, AB and BB were 0.3648, 0.4682 and 0.1670, respectively. Significant associations between the locus and shear force of breast and leg were observed. This polymorphic site may serve as a useful target for the marker assisted selection of the growth and meat quality traits in chicken. PMID:23670042

Sun, Guirong; Li, Ming; Li, Hong; Tian, Yadong; Chen, Qixin; Bai, Yichun; Kang, Xiangtao

2013-08-01

228

Single-nucleotide polymorphisms in genes relating to homocysteine metabolism: how applicable are public SNP databases to a typical European population?  

Microsoft Academic Search

To facilitate the association studies in complex diseases characterized by hyperhomocysteinemia, we collected structural and frequency data on single-nucleotide polymorphism (SNPs) in 24 genes relating to homocysteine metabolism. Firstly, we scanned ?1.2 Mbp of sequence in the NCBI SNP database (dbSNP) build 110 and we detected 1353 putative SNPs with an average in silico genic density of 1:683. Out of

Bohumila Janošíková; Petra Zavadáková; Viktor Kožich

2005-01-01

229

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

Microsoft Academic Search

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

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

230

Association of a Bovine Prion Gene Haplotype with Atypical BSE  

Microsoft Academic Search

BackgroundAtypical bovine spongiform encephalopathies (BSEs) are recently recognized prion diseases of cattle. Atypical BSEs are rare; approximately 30 cases have been identified worldwide. We tested prion gene (PRNP) haplotypes for an association with atypical BSE.Methodology\\/Principle FindingsHaplotype tagging polymorphisms that characterize PRNP haplotypes from the promoter region through the three prime untranslated region of exon 3 (25.2 kb) were used to

Michael L. Clawson; Juergen A. Richt; Thierry Baron; Anne-Gaëlle Biacabe; Stefanie Czub; Michael P. Heaton; Timothy P. L. Smith; William W. Laegreid; Matthew Baylis

2008-01-01

231

SNP haplotypes of the BADH1 gene and their association with aroma in rice ( Oryza sativa L.)  

Microsoft Academic Search

Betaine aldehyde dehydrogenase (BADH) is a key enzyme involved in the synthesis of glycinebetaine—a powerful osmoprotectant\\u000a against salt and drought stress in a large number of species. Rice is not known to accumulate glycinebetaine but it has two\\u000a functional genes coding for the BADH enzyme. A non-functional allele of the BADH2 gene located on chromosome 8 is a major factor

Anuradha Singh; Pradeep K. Singh; Rakesh Singh; Awadhesh Pandit; Ajay K. Mahato; Deepak K. Gupta; Kuldeep Tyagi; Ashok K. Singh; Nagendra K. Singh; Tilak R. Sharma

2010-01-01

232

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...

233

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

PubMed Central

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10?4, permutation p?=?1.0×10?3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10?7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

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

2010-01-01

234

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

PubMed

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10(-4), permutation p?=?1.0×10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

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

2010-01-01

235

Bayesian modeling of haplotype effects in multiparent populations.  

PubMed

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

Zhang, Zhaojun; Wang, Wei; Valdar, William

2014-09-01

236

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

PubMed Central

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

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

2014-01-01

237

Development of an Italian RM Y-STR haplotype database: Results of the 2013 GEFI collaborative exercise.  

PubMed

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

Robino, C; Ralf, A; Pasino, S; De Marchi, M R; Ballantyne, K N; Barbaro, A; Bini, C; Carnevali, E; Casarino, L; Di Gaetano, C; Fabbri, M; Ferri, G; Giardina, E; Gonzalez, A; Matullo, G; Nutini, A L; Onofri, V; Piccinini, A; Piglionica, M; Ponzano, E; Previderè, C; Resta, N; Scarnicci, F; Seidita, G; Sorçaburu-Cigliero, S; Turrina, S; Verzeletti, A; Kayser, M

2015-03-01

238

SNP marker detection and genotyping in tilapia.  

PubMed

We have generated a unique resource consisting of nearly 175 000 short contig sequences and 3569 SNP markers from the widely cultured GIFT (Genetically Improved Farmed Tilapia) strain of Nile tilapia (Oreochromis niloticus). In total, 384 SNPs were selected to monitor the wider applicability of the SNPs by genotyping tilapia individuals from different strains and different geographical locations. In all strains and species tested (O. niloticus, O. aureus and O. mossambicus), the genotyping assay was working for a similar number of SNPs (288-305 SNPs). The actual number of polymorphic SNPs was, as expected, highest for individuals from the GIFT population (255 SNPs). In the individuals from an Egyptian strain and in individuals caught in the wild in the basin of the river Volta, 197 and 163 SNPs were polymorphic, respectively. A pairwise calculation of Nei's genetic distance allowed the discrimination of the individual strains and species based on the genotypes determined with the SNP set. We expect that this set will be widely applicable for use in tilapia aquaculture, e.g. for pedigree reconstruction. In addition, this set is currently used for assaying the genetic diversity of native Nile tilapia in areas where tilapia is, or will be, introduced in aquaculture projects. This allows the tracing of escapees from aquaculture and the monitoring of effects of introgression and hybridization. PMID:22524158

Van Bers, N E M; Crooijmans, R P M A; Groenen, M A M; Dibbits, B W; Komen, J

2012-09-01

239

Multiplexing schemes for generic SNP genotyping assays.  

PubMed

Association studies in populations relate genomic variation among individuals with medical condition. Key to these studies is the development of efficient and affordable genotyping techniques. Generic genotyping assays are independent of the target SNPs and offer great flexibility in the genotyping process. Efficient use of such assays calls for identifying sets of SNPs that can be interrogated in parallel under constraints imposed by the genotyping technology. In this paper, we study problems arising in the design of genotyping experiments using generic assays. Our problem formulation deals with two main factors that affect the genotyping cost: the number of assays used and the number of PCR reactions required for sample preparation. We prove that the resulting computational problems are hard, but provide approximate and heuristic solutions to these problems. Our algorithmic approach is based on recasting the multiplexing problems as partitioning and packing problems on a bipartite graph. We tested our algorithmic approaches on an extensive collection of synthetic data and on data that was simulated using real SNP sequences. Our results show that the algorithms achieve near-optimal designs in many cases and demonstrate the applicability of generic assays to SNP genotyping. PMID:15952875

Sharan, Roded; Gramm, Jens; Yakhini, Zohar; Ben-Dor, Amir

2005-06-01

240

The non-inherited maternal HLA haplotype affects the risk for type 1 diabetes.  

PubMed

The aim was to test the hypothesis that the human leucocyte antigen (HLA) haplotype that is not inherited from the mother, that is, the non-inherited maternal antigen (NIMA) affects the risk for type 1 diabetes (T1D). A total of 563 children with T1D and 286 non-diabetic control children from Sweden were genotyped for DRB1, DQA1 and DQB1 alleles. The frequency of positively (DR4-DQA1*0301-B1*0302 and DR3-DQA1*0501-B1*0201), negatively (DR15-DQ A1*0102-B1*0602) or neutrally (all other) T1D associated HLA haplotypes were compared between NIMA and non-inherited paternal antigen (NIPA). All comparisons were carried out between HLA-matched patients and controls. The frequency of positively associated NIMA was higher among both DR4/X-positive healthy individuals compared wit DR4/X-positive patients (P < 0.00003) and DR3/X-positive healthy individuals compared with DR3/X-positive patients (P < 0.009). No such difference was observed for NIPA. High-risk NIMA was increased compared to NIPA among healthy DR3/X- and DR4/X-positive children (P < 0.05). There was no difference in frequency of positively associated haplotypes between patient NIMA and NIPA. The NIMA but not the NIPA affects the risk for T1D, suggesting that not only the inherited but also non-inherited maternal HLA haplotypes, perhaps through microchimerism or other mechanisms, may influence the risk for the disease. PMID:19055605

Akesson, K; Carlsson, A; Ivarsson, S-A; Johansson, C; Weidby, B-M; Ludvigsson, J; Gustavsson, B; Lernmark, A; Kockum, I

2009-02-01

241

Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR.  

PubMed

Psoriasis is a complex inflammatory disease of the skin affecting 1-2% of the Caucasian population. Associations with alleles from the HLA class I region (now known as PSORS1), particularly HLA-Cw*0602, were described over 20 years ago. However, extensive linkage disequilibrium (LD) within this region has made it difficult to identify the true susceptibility allele from this region. A variety of genes and regions from a 238-kb interval extending from HLA-B to corneodesmosin (CDSN) have been proposed to harbor PSORS1. In order to identify the minimum block of LD in the MHC class I region associated with psoriasis we performed a comprehensive case/control and family-based association study on 242 Northern European psoriasis families and two separate European control populations. High resolution HLA typing of HLA-A, -B and -C alleles was performed, in addition to the genotyping of 18 polymorphic microsatellites and 36 SNPs from a 772-kb segment of the HLA class I region harboring the previously described interval. This corresponded on average to one SNP every 7 kb in the candidate 238 kb region. With all tests, the association was the strongest with single markers and haplotypes from a block of LD harboring HLA-C and SNP n.9. Logistic regression analyses indicated that association seen with candidate genes from the interval such as CDSN and HCR was entirely dependent on association with HLA-Cw*0602 and SNP n.9-G alleles. The previously reported association with CDSN and HCR was observed to be due to the existence of the associated alleles lying on the most commonly over-transmitted haplotype. Rare over-transmitted haplotypes also harbored HLA-Cw*12 alleles. HLA-Cw*12 family members are closely related to HLA Cw*0602, sharing identical sequences in their alpha-2 domains, peptide-binding pockets A, D and E and all 3' introns. The introduction of a potential binding site for the RUNX/AML family of transcription factors in intron 7, is also specific to these HLA-C alleles. These variants need to be investigated further for their role as PSORS1. PMID:16235096

Helms, Cynthia; Saccone, Nancy L; Cao, Li; Daw, Jil A Wright; Cao, Kai; Hsu, Tony M; Taillon-Miller, Patricia; Duan, Shenghui; Gordon, Derek; Pierce, Brandon; Ott, Jurg; Rice, John; Fernandez-Vina, Marcelo A; Kwok, Pui-Yan; Menter, Alan; Bowcock, Anne M

2005-12-01

242

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

PubMed

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

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

2006-01-01

243

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

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

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

2010-02-01

244

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

PubMed Central

Background Pain is often a dominant clinical feature of chronic pancreatitis but the frequency and severity is highly variable between subjects. We hypothesized that genetic polymorphisms contribute to variations in clinical pain patterns. Since genetic variations in the GTP cyclohydrolase (GCH1) gene have been reported to protect some patients from pain, we investigated the effect of the "pain protective haplotype" in well characterized patients with chronic pancreatitis (CP) or recurrent acute pancreatitis (RAP) from the North American Pancreatitis Study 2 (NAPS2). Results Subjects in the NAPS2 study were asked to rank their pain in one of 5 categories reflecting different levels of pain frequency and severity. All subjects were genotyped at rs8007267 and rs3783641 to determine the frequency of the GCH1 pain-protective haplotype. In Caucasian subjects the frequency of the pain-protective GCH1 haplotype was no different in the control group (n = 236), CP patients (n = 265), RAP patients (N = 131), or in CP patients subclassified by pain category compared to previously reported haplotype frequencies in the general Caucasian population. Conclusion The GCH1 pain-protective haplotype does not have a significant effect on pain patterns or severity in RAP or CP. These results are important for helping to define the regulators of visceral pain, and to distinguish different mechanisms of pain. PMID:19014702

Lazarev, Mark; Lamb, Janette; Barmada, M Michael; Dai, Feng; Anderson, Michelle A; Max, Mitchell B; Whitcomb, David C

2008-01-01

245

Identification of RNA editing sites in the SNP database  

PubMed Central

The relationship between human inherited genomic variations and phenotypic differences has been the focus of much research effort in recent years. These studies benefit from millions of single-nucleotide polymorphism (SNP) records available in public databases, such as dbSNP. The importance of identifying false dbSNP records increases with the growing role played by SNPs in linkage analysis for disease traits. In particular, the emerging understanding of the abundance of DNA and RNA editing calls for a careful distinction between inherited SNPs and somatic DNA and RNA modifications. In order to demonstrate that some of the SNP database records are actually somatic modification, we focus on one type of these modifications, namely A-to-I RNA editing, and present evidence for hundreds of dbSNP records that are actually editing sites. We provide a list of 102 RNA editing sites previously annotated in dbSNP database as SNPs, and experimentally validate seven of these. Interestingly, we show how dbSNP can serve as a starting point to look for new editing sites. Our results, for this particular type of RNA editing, demonstrate the need for a careful analysis of SNP databases in light of the increasing recognition of the significance of somatic sequence modifications. PMID:16100382

Eisenberg, Eli; Adamsky, Konstantin; Cohen, Lital; Amariglio, Ninette; Hirshberg, Abraham; Rechavi, Gideon; Levanon, Erez Y.

2005-01-01

246

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...

247

Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults  

PubMed Central

Background: Several studies have shown linkage of chromosome 12q 13–24 with atopy related phenotypes. Among candidate genes in this region is STAT6 (signal transducer and activator of transcription), which is essential for Th2 cell differentiation, recruitment, and effector function. Methods: We evaluated six polymorphisms of STAT6 for evidence of associations with serum IgE levels and atopic diseases in a population based cross sectional cohort of 1407 German adults. Genotyping was performed using the matrix assisted laser desorption ionisation–time of flight mass spectrometry method. Haplotypes were estimated using the SAS/Genetics module, and population-derived IgE percentiles (50% IgE>53 kU/l, 66% IgE>99 kU/l and 90% IgE>307 kU/l) were modelled as outcome variables in haplotype trend regression analysis. Results: All polymorphisms were genotyped successfully. Haplotype reconstruction revealed 8/64 possible haplotypes, reaching estimated frequencies of 1% or more. One polymorphism in intron 2 (rs324011) showed a significant association with total serum IgE (p = 0.015). A STAT6 risk haplotype for elevated IgE showing odds ratios of 1.7 (p = 0.015) for IgE cut-off 100 kU/l, and 1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE percentiles 50%, 66%, and 90%, respectively was detected. The increased risk of this haplotype was confirmed by linear haplotype trend regression on log transformed IgE values (p = 0.007). Analysis further revealed a risk haplotype for specific sensitisation and a risk haplotype for asthma. Conclusion: The data indicate that genetic variants within STAT6 contribute significantly to IgE regulation and manifestation of atopic diseases. PMID:15342695

Weidinger, S; Klopp, N; Wagenpfeil, S; Rummler, L; Schedel, M; Kabesch, M; Schafer, T; Darsow, U; Jakob, T; Behrendt, H; Wichmann, H; Ring, J; Illig, T

2004-01-01

248

Islands of Tractability for Parsimony Haplotyping Roded Sharan  

E-print Network

haplotypes, due to population bottleneck effects and genetic drift. For ex- ample, Patil et al. report-Aviv University Tel-Aviv 69978, Israel roded@tau.ac.il Bjarni V. Halld´orsson deCode Genetics Sturlugata 8, 101 of haplotypes that explains them (a for- mal definition of PH is deferred to Section 2). Parsimony is a natural

Shamir, Ron

249

Haploview: analysis and visualization of LD and haplotype maps  

Microsoft Academic Search

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

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

2005-01-01

250

Haplotype Information and Linkage Disequilibrium Mapping for Single Nucleotide Polymorphisms  

Microsoft Academic Search

Single nucleotide polymorphisms in the human genome have become an increasingly popular topic in that their analyses promise to be a key step toward personalized medicine. We investigate two related questions, how much the haplotype information contributes to linkage disequilibrium (LD) mapping and whether an in silico haplotype construction preceding the LD analysis can help. For disease gene mapping, using

Xin Lu; Tianhua Niu; Jun S. Liu; E. R. Martin

2003-01-01

251

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...

252

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 ...

253

A Practical Exact Algorithm for the Individual Haplotyping Problem MEC  

Microsoft Academic Search

The individual haplotyping problem MEC is a computational problem that, given a set of DNA sequence fragment data of an individual, induces the corresponding haplotypes by changing the smallest number of SNPs. MEC problem is NP-hard and there has been no practical exact algorithm to solve the problem. In DNA sequencing experiments, due to technical limits, the maximum length of

Minzhu Xie; Jianxin Wang; Jianer Chen

2008-01-01

254

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

PubMed

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

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

2015-01-01

255

How Genome-Wide SNP-SNP Interactions Relate to Nasopharyngeal Carcinoma Susceptibility  

PubMed Central

This study is the first to use genome-wide association study (GWAS) data to evaluate the multidimensional genetic architecture underlying nasopharyngeal cancer. Since analysis of data from GWAS confirms a close and consistent association between elevated risk for nasopharyngeal carcinoma (NPC) and major histocompatibility complex class 1 genes, our goal here was to explore lesser effects of gene-gene interactions. We conducted an exhaustive genome-wide analysis of GWAS data of NPC, revealing two-locus interactions occurring between single nucleotide polymorphisms (SNPs), and identified a number of suggestive interaction loci which were missed by traditional GWAS analyses. Although none of the interaction pairs we identified passed the genome-wide Bonferroni-adjusted threshold for significance, using independent GWAS data from the same population (Stage 2), we selected 66 SNP pairs in 39 clusters with P<0.01. We identified that in several chromosome regions, multiple suggestive interactions group to form a block-like signal, effectively reducing the rate of false discovery. The strongest cluster of interactions involved the CREB5 gene and a SNP rs1607979 on chromosome 17q22 (P?=?9.86×10?11) which also show trans-expression quantitative loci (eQTL) association in Chinese population. We then detected a complicated cis-interaction pattern around the NPC-associated HLA-B locus, which is immediately adjacent to copy-number variations implicated in male susceptibility for NPC. While it remains to be seen exactly how and to what degree SNP-SNP interactions such as these affect susceptibility for nasopharyngeal cancer, future research on these questions holds great promise for increasing our understanding of this disease’s genetic etiology, and possibly also that of other gene-related cancers. PMID:24376627

Su, Wen-Hui; Yao Shugart, Yin; Chang, Kai-Ping; Tsang, Ngan-Ming; Tse, Ka-Po; Chang, Yu-Sun

2013-01-01

256

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

PubMed

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

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

257

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

PubMed

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

May, Kimberley Jane; Ristaino, Jean Beagle

2004-05-01

258

A haplotype map of the human genome  

PubMed Central

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

2007-01-01

259

Associations between Single Nucleotide Polymorphisms and Haplotypes in Cytokine and Cytokine Receptor Genes and Immunity to Measles Vaccination  

PubMed Central

Identification of host genetic determinants of measles vaccine-induced immunity can be used to design better vaccines and ultimately predict immune responses to vaccination. We performed a comprehensive candidate gene association study across 801 genetic markers in 56 cytokine/cytokine receptor genes, in a racially diverse cohort of 745 schoolchildren after two doses of MMR vaccine. Using linear regression methodologies we examined associations between SNPs/haplotypes and measles virus-specific immunity. Forty-eight significant SNP associations with variations in neutralizing antibodies and measles-specific IFN? Elispot responses were identified (p<0.05). Our study replicated an important previously found association of a functional IL12B genetic variant rs3212227 with variations in measles-specific humoral immunity (p=0.037). Similarly, two previously reported promoter IL10 and IL2 polymorphisms (rs1800890 and rs2069762) demonstrated associations with measles-specific cellular immunity in Caucasians (p?0.034). Multiple IL7R polymorphisms, including a non-synonymous functional SNP (rs6897932/Thr244Ile), were associated with humoral (p?0.024) and/or cellular (IFN? Elispot, p?0.023) measles-specific immune responses in Caucasians, but not African-Americans. Haplotype level analysis confirmed the association of IL7R genetic variants with measles vaccine-induced immunity in the Caucasian group (global p-value=0.003). Our results validate previous findings and identify new plausible genetic determinants, including IL7R polymorphisms, regulating measles vaccine-induced immunity in a race-specific manner. PMID:21875636

Haralambieva, Iana H.; Ovsyannikova, Inna G.; Kennedy, Richard B.; Vierkant, Robert A.; Pankratz, V. Shane; Jacobson, Robert M.; Poland, Gregory A.

2011-01-01

260

A novel A/G SNP in the -615th position of the dopamine D4 receptor promoter region as a source of misgenotyping of the -616 C/G SNP.  

PubMed

The polymorphic 5' upstream region of the dopamine D4 receptor (DRD4) gene containing several single nucleotide polymorphisms (SNPs) has recently become a focus of association studies in psychiatric genetics. Most SNP genotyping methods are based on the two-step procedure of restriction fragment length polymorphism (RFLP). An alternative technique is a single-step method of allele-specific amplification (ASA), previously introduced for genotyping the -521 C/T SNP of the DRD4 promoter region and applied here for the -616 C/G SNP. Parallel genotyping of individuals with the novel ASA method and the conventionally used Ava II RFLP showed a potential underestimation of the -616 GG genotype frequency by the conventional method. Sequencing the dubious samples clearly demonstrated a novel A/G SNP at the -615th position influencing the Ava II digestion and thus resulting in misgenotyping. To avoid this problem, we introduced the Sau96 I RFLP for the -616 C/G genotyping as this restriction enzyme is not sensitive for the -615 A/G sequence variation. Allele (-616 G = 0.48; -616 C = 0.52) and genotype (-616 GG = 0.25; -616 GC = 0.46; -616 CC = 0.29) frequencies were determined by both the novel ASA and the Sau96 I methods. The obtained genotype frequencies corresponded to the Hardy-Weinberg equilibrium in our healthy Caucasian sample (N = 534, P = 0.168). Using these methods, no association was found between the -616 C/G SNP and personality factors of Cloninger's temperament and character inventory (N = 153) in our population. PMID:15048652

Ronai, Z; Szantai, E; Szmola, R; Nemoda, Z; Szekely, A; Gervai, J; Guttman, A; Sasvari-Szekely, M

2004-04-01

261

Influence of HLA Class I Haplotypes on HIV-1 Seroconversion and Disease Progression in Pumwani Sex Worker Cohort  

PubMed Central

We examined the effect of HLA class I haplotypes on HIV-1 seroconversion and disease progression in the Pumwani sex worker cohort. This study included 595 HIV-1 positive patients and 176 HIV negative individuals. HLA-A, -B, and -C were typed to 4-digit resolution using sequence-based typing method. HLA class I haplotype frequencies were estimated using PyPop 32-0.6.0. The influence of haplotypes on time to seroconversion and CD4+ T cell decline to <200 cells/mm3 were analyzed by Kaplan-Meier analysis using SPSS 13.0. Before corrections for multiple comparisons, three 2-loci haplotypes were significantly associated with faster seroconversion, including A*23?01-C*02?02 (p?=?0.014, log rank(LR)?=?6.06, false-discovery rate (FDR)?=?0.056), B*42?01-C*17?01 (p?=?0.01, LR?=?6.60, FDR?=?0.08) and B*07?02-C*07?02 (p?=?0.013, LR?=?6.14, FDR?=?0.069). Two A*74?01 containing haplotypes, A*74?01-B*15?03 (p?=?0.047, LR?=?3.942, FDR?=?0.068) and A*74?01-B*15?03-C*02?02 (p?=?0.045, LR?=?4.01, FDR?=?0.072) and B*14?02-C*08?02 (p?=?0.021, LR?=?5.36, FDR?=?0.056) were associated with slower disease progression. Five haplotypes, including A*30?02-B*45?01 (p?=?0.0008, LR?=?11.183, FDR?=?0.013), A*30?02-C*16?01 (p?=?0.015, LR?=?5.97, FDR?=?0.048), B*53?01-C*04?01 (p?=?0.010, LR?=?6.61, FDR?=?0.08), B*15?10-C*03?04 (p?=?0.031, LR?=?4.65, FDR?=?0.062), and B*58?01-C*03?02 (p?=?0.037, LR?=?4.35, FDR?=?0.066) were associated with faster progression to AIDS. After FDR corrections, only the associations of A*30?02-B*45?01 and A*30?02-C*16?01 with faster disease progression remained significant. Cox regression and deconstructed Kaplan-Meier survival analysis showed that the associations of haplotypes of A*23?01-C*02?02, B*07?02-C*07?02, A*74?01-B*15?03, A*74?01-B*15?03-C*02?02, B*14?02-C*08?02 and B*58?01-C*03?02 with differential seroconversion or disease progression are due to the dominant effect of a single allele within the haplotypes. The true haplotype effect was observed with A*30?02-B*45?01, A*30?02-C*16?02, B*53?01-C*04?01 B*15?10-C*03?04, and B*42?01-C*17?01. In these cases, the presence of both alleles accelerated the disease progression or seroconversion than any of the single allele within the haplotypes. Our study showed that the true effects of HLA class I haplotypes on HIV seroconversion and disease progression exist and the associations of HLA class I haplotype can also be due to the dominant effect of a single allele within the haplotype. PMID:24992306

Sampathkumar, Raghavan; Peters, Harold O.; Mendoza, Lillian; Bielawny, Thomas; Ngugi, Elizabeth; Kimani, Joshua; Wachihi, Charles; Plummer, Francis A.; Luo, Ma

2014-01-01

262

HLA-G UTR Haplotype Conservation in the Malian Population: Association with Soluble HLA-G  

PubMed Central

The HLA-G molecule plays an important role in immunomodulation. In a previous study carried out on a southern French population our team showed that HLA-G haplotypes, defined by SNPs in the coding region and specific SNPs located in 5?URR and 3?UTR regulatory regions, are associated with differential soluble HLA-G expression (sHLA-G). Furthermore, the structure of these HLA-G haplotypes appears to be conserved in geographically distant populations. The aim of our study is to confirm these expectations in a sub-Saharan African population and to explore additional factors, such as HLA-A alleles, that might influence sHLA-G expression. DNA and plasma samples were collected from 229 Malians; HLA-G and HLA-A genotyping were respectively performed by the Snap Shot® method and by Luminex™ technology. sHLA-G dosage was performed using an ELISA kit. HLA-G and HLA-A allelic and haplotypic frequencies were estimated using an EM algorithm from the Gene[Rate] program. Associations between genetic and non genetic parameters with sHLA-G were performed using a non-parametric test with GRAPH PAD Prism 5. Our results reveal a good conservation of the HLA-G UTR haplotype structure in populations with different origins and demographic histories. These UTR haplotypes appear to be involved in different sHLA-G expression patterns. Specifically, the UTR-2 haplotype was associated with low sHLA-G levels, displaying a dominant negative effect. Furthermore, an allelic effect of both HLA-G and HLA-A, as well as non genetic parameters, such as age and gender possibly linked to osteogenesis and sexual hormones, also seem to be involved in the modulation of sHLA-G. These data suggest that further investigation in larger cohorts and in populations from various ethnical backgrounds is necessary not only to detect new functional polymorphism in HLA-G regulatory regions, but also to reveal the extent of biological phenomena that influence sHLA-G secretion and this might therefore have an impact on transplantation practice. PMID:24376542

Carlini, Federico; Traore, Karim; Cherouat, Nissem; Roubertoux, Pierre; Buhler, Stéphane; Cortey, Martì; Simon, Sophie; Doumbo, Ogobara; Chiaroni, Jacques; Picard, Christophe; Di Cristofaro, Julie

2013-01-01

263

HLA haplotype and supertype associations with cellular immune responses and cytokine production in healthy children after rubella vaccine  

PubMed Central

Secreted rubella virus-specific cytokines reflect the immunologic mechanisms underlying adoptive immune responses and are significant markers of immunity to rubella. We studied the association between measures of cellular (cytokine and frequency of cytokine-secreted cells) immune responses and HLA haplotypes (with frequencies of ?1%) and supertypes among 738 healthy children following two doses of rubella vaccine. Haplotype effects were estimated while accounting for linkage phase ambiguity via an expectation maximization algorithm. Importantly, the majority of HLA class I and class II haplotype associations with different cytokines were consistent between Th1, Th2 and/or innate/proinflammatory cytokine groups. We found few class I supertypes (A1, A2, A3, and B7) with potential associations with IL-10 ELISPOT counts and rubella-specific IL-2, IL-10, TNF-?, and IL-6 cytokine secretion levels. Our data indicate that the presence or absence of certain HLA haplotypes and/or supertypes may influence the cytokine immune response to rubella vaccine, and represents a more advanced analysis compared to individual candidate gene association studies. PMID:19200828

Ovsyannikova, Inna G.; Vierkant, Robert A.; Pankratz, V. Shane; O’Byrne, Megan M.; Jacobson, Robert M.; Poland, Gregory A.

2009-01-01

264

Association of the smoothelin (SMTN) gene with cerebral infarction in men: a haplotype-based case-control study.  

PubMed

Smoothelin is a specific type of cytoskeletal protein found in smooth muscle cells (SMCs). Several previous research studies have examined the relationship between smoothelin and atherosclerotic plaque. The aim of the present study was to further assess the association between the human SMTN gene and cerebral infarction (CI) using a haplotype-based case-control study. A total of 168 CI patients and 259 supercontrols were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human SMTN gene (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304). Data were analyzed for three separate groups that included total subjects, men and women. The genotypic distribution of rs10304 for men showed a significant difference between the control and CI groups. In addition, the frequency of the C-T-T-A haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) was significantly higher in the CI versus the control group (p = 0.013), while the frequency of the C-A-T-G haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) in the CI group was significantly lower than that seen in the controls (p = 0.021). In conclusion, we confirmed that the haplotype constructed using rs5997872, rs56095120, rs9621187 and rs10304 was a useful genetic marker of CI in Japanese men. PMID:23033319

Jiang, Jie; Nakayama, Tomohiro; Shimodaira, Masanori; Sato, Naoyuki; Aoi, Noriko; Sato, Mikano; Izumi, Yoichi; Kasamaki, Yuji; Ohta, Masakatsu; Soma, Masayoshi; Matsumoto, Koichi; Kawamura, Hiroshi; Ozawa, Yukio; Hinohara, Shigeaki; Doba, Nobutaka; Ma, Yitong

2012-10-01

265

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

PubMed

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

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

266

Extended HLA-DQw2 haplotypes: molecular analysis.  

PubMed

The HLA-DQw2 specificity, homogeneous in serology, is strongly associated to two HLA-DR specificities: DR3 and DR7. These alleles are found mainly on DQw2 bearing extended haplotypes with strong linkage disequilibrium. We describe, with BamHI, HindIII and RsaI, two restriction fragments length polymorphisms (RFLP) for the A gene of DQw2. These two subtypes correlated with the DR3 and DR7 specificities. Interestingly, by non-equilibrium pH gradient electrophoresis (NEPHGE), two DQ alpha chains were also found, respectively correlated with the same DR specificities. In addition, HincII polymorphism allowed us to distinguish several patterns of B genes for (DR7) DQw2 haplotypes but without any detectable association with another HLA marker. However, only one DQ beta chain was found by NEPHGE in the (DR7) DQw2 haplotype. Furthermore, HincII discriminated the B genes of the two extended haplotypes: (B8, DR3) DQw2 and (B18, DR3) DQw2. The same result was found by NEPHGE: two DQ beta chains were described, corresponding to the same extended haplotypes. The use of exon-specific DQB probes showed that the genomic polymorphism in DQw2 haplotypes is located, at least, at the 3' end of the gene. These data add new characteristics to the different DQw2 extended haplotypes. PMID:1684911

Avoustin, P A; Tkaczuk, J; Coppin, H L; Cambon-Thomsen, A; de Préval, C

1991-08-01

267

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

PubMed Central

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

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

2013-01-01

268

Japanese Alzheimer's Disease and Other Complex Disorders Diagnosis Based on Mitochondrial SNP Haplogroups  

PubMed Central

This paper first explains how the relations between Japanese Alzheimer's disease (AD) patients and their mitochondrial SNP frequencies at individual mtDNA positions examined using the radial basis function (RBF) network and a method based on RBF network predictions and that Japanese AD patients are associated with the haplogroups G2a and N9b1. It then describes a method for the initial diagnosis of Alzheimer's disease that is based on the mtSNP haplogroups of the AD patients. The method examines the relations between someone's mtDNA mutations and the mtSNPs of AD patients. As the mtSNP haplogroups thus obtained indicate which nucleotides of mtDNA loci are changed in the Alzheimer's patients, a person's probability of becoming an AD patient can be predicted by comparing those mtDNA mutations with that person's mtDNA mutations. The proposed method can also be used to diagnose diseases such as Parkinson's disease and type 2 diabetes and to identify people likely to become centenarians. PMID:22848858

Takasaki, Shigeru

2012-01-01

269

Japanese Alzheimer's disease and other complex disorders diagnosis based on mitochondrial SNP haplogroups.  

PubMed

This paper first explains how the relations between Japanese Alzheimer's disease (AD) patients and their mitochondrial SNP frequencies at individual mtDNA positions examined using the radial basis function (RBF) network and a method based on RBF network predictions and that Japanese AD patients are associated with the haplogroups G2a and N9b1. It then describes a method for the initial diagnosis of Alzheimer's disease that is based on the mtSNP haplogroups of the AD patients. The method examines the relations between someone's mtDNA mutations and the mtSNPs of AD patients. As the mtSNP haplogroups thus obtained indicate which nucleotides of mtDNA loci are changed in the Alzheimer's patients, a person's probability of becoming an AD patient can be predicted by comparing those mtDNA mutations with that person's mtDNA mutations. The proposed method can also be used to diagnose diseases such as Parkinson's disease and type 2 diabetes and to identify people likely to become centenarians. PMID:22848858

Takasaki, Shigeru

2012-01-01

270

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

PubMed

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

Sironi, Manuela; Biasin, Mara; Cagliani, Rachele; Gnudi, Federica; Saulle, Irma; Ibba, Salomè; 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

271

Pronounced intraspecific haplotype divergence at the RPP5 complex disease resistance locus of Arabidopsis.  

PubMed Central

In Arabidopsis ecotype Landsberg erecta (Ler), RPP5 confers resistance to the pathogen Peronospora parasitica. RPP5 is part of a clustered multigene family encoding nucleotide binding-leucine-rich repeat (LRR) proteins. We compared 95 kb of DNA sequence carrying the Ler RPP5 haplotype with the corresponding 90 kb of Arabidopsis ecotype Columbia (Col-0). Relative to the remainder of the genome, the Ler and Col-0 RPP5 haplotypes exhibit remarkable intraspecific polymorphism. The RPP5 gene family probably evolved by extensive recombination between LRRs from an RPP5-like progenitor that carried only eight LRRs. Most members have variable LRR configurations and encode different numbers of LRRs. Although many members carry retroelement insertions or frameshift mutations, codon usage analysis suggests that regions of the genes have been subject to purifying or diversifying selection, indicating that these genes were, or are, functional. The RPP5 haplotypes thus carry dynamic gene clusters with the potential to adapt rapidly to novel pathogen variants by gene duplication and modification of recognition capacity. We propose that the extremely high level of polymorphism at this complex resistance locus is maintained by frequency-dependent selection. PMID:10559437

Noël, L; Moores, T L; van Der Biezen, E A; Parniske, M; Daniels, M J; Parker, J E; Jones, J D

1999-01-01

272

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

PubMed Central

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

Fung, King Leung; Gottesman, Michael M.

2009-01-01

273

Re-sequencing regions of the ovine Y chromosome in domestic and wild sheep reveals novel paternal haplotypes.  

PubMed

The male-specific region of the ovine Y chromosome (MSY) remains poorly characterized, yet sequence variants from this region have the potential to reveal the wild progenitor of domestic sheep or examples of domestic and wild paternal introgression. The 5' promoter region of the sex-determining gene SRY was re-sequenced using a subset of wild sheep including bighorn (Ovis canadensis), thinhorn (Ovis dalli spp.), urial (Ovis vignei), argali (Ovis ammon), mouflon (Ovis musimon) and domestic sheep (Ovis aries). Seven novel SNPs (oY2-oY8) were revealed; these were polymorphic between but not within species. Re-sequencing and fragment analysis was applied to the MSY microsatellite SRYM18. It contains a complex compound repeat structure and sequencing of three novel size fragments revealed that a pentanucleotide element remained fixed, whilst a dinucleotide element displayed variability within species. Comparison of the sequence between species revealed that urial and argali sheep grouped more closely to the mouflon and domestic breeds than the pachyceriforms (bighorn and thinhorn). SNP and microsatellite data were combined to define six previously undetected haplotypes. Analysis revealed the mouflon as the only species to share a haplotype with domestic sheep, consistent with its status as a feral domesticate that has undergone male-mediated exchange with domestic animals. A comparison of the remaining wild species and domestic sheep revealed that O. aries is free from signatures of wild sheep introgression. PMID:19016675

Meadows, J R S; Kijas, J W

2009-02-01

274

The SNP genotypes of growth hormone gene associated with reproductive traits in Tsaiya ducks.  

PubMed

Our previous cDNA microarray study showed that the growth hormone (GH) gene may involve in the duck egg formation process. The purpose of this study was to investigate the relationship between GH genotypes of single nucleotide polymorphisms (SNPs) and reproductive traits of Tsaiya ducks. Primer pairs for the coding region in the GH were designed based on the duck genomic sequence. Polymorphisms were detected by polymerase chain reaction (PCR)-single strand polymorphism (SSCP) and were verified by DNA sequencing. Nineteen SNPs were identified in the duck GH gene, of which three coding SNPs (C3169T, C3700T and C5058G) were genotyped to investigate the associations with reproductive traits. The results showed that each SNP was associated with at least one duck fertility-related trait (p < 0.05). Haplotypes constructed on these three SNPs were associated with fertility rate (FR) and maximum duration of fertility (MDF) (p < 0.05). In particular, diplotype H1H1 was dominant for FR and MDF. This suggested that GH gene polymorphisms are associated with duck fertility-related traits. The SNPs in this gene may be used as potential markers for marker-assisted selection. PMID:22023026

Chang, Mu-Tzu; Cheng, Yu-Shin; Huang, Mu-Chiou

2012-08-01

275

Insights into HLA-G Genetics Provided by Worldwide Haplotype Diversity  

PubMed Central

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

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

276

IL23R Haplotypes Provide A Large Population Attributable Risk for Crohn’s Disease  

PubMed Central

The IL-23 pathway plays a pivotal role in the development of chronic mucosal inflammation seen in the inflammatory bowel diseases. Multiple studies have now established the contribution of the interleukin 23 receptor gene (IL23R) to Crohn’s Disease (CD) risk in general and of the IL23R R381Q variant in particular. The aim of this work was to estimate the total contribution of this gene to CD risk test using a haplotype approach. Methods 763 CD subjects and 254 controls were genotyped for single nucleotide polymorphisms in the IL23R gene using Illumina and ABI methods. Haplotypes were assigned using PHASEv2 and tested for association with CD by chi-square and permutation. Results Haplotypes with both increased and decreased risk for CD were observed in 2 of the 4 observed blocks (Block 2 H1: 55.4% control, 64% CD, p=0.019; H2: 64.5% control, 54.4% CD, p=0.006; Block 3 H1: 55.8% control, 64.4% CD, p=0.013; H2: 47.0% control, 36.6% CD, p=0.001). The population attributable risk for these haplotypes was substantially larger than that estimated for the IL23R R381Q variant (Block 2 H1 and block 3 H1 ~20%, compared with ~4% for Block 3 H6, containing the variant). Discussion These observations suggest that IL23R makes a substantial contribution to Crohn’s disease susceptibility, larger than that estimated from the population frequency of the R381Q variant. These observations also support the expectation that finding “hits” from genome wide association studies will be but an important chapter in the story of unraveling the genetic contribution to Crohn’s disease, rather than the final chapter that brings clarity to all the plot twists of a complicated story. PMID:18470928

Taylor, Kent D.; Targan, Stephan R.; Mei, Ling; Ippoliti, Andrew F.; McGovern, Dermot; Mengesha, Emebet; King, Lily; Rotter, Jerome I.

2008-01-01

277

Major copy proportion analysis of tumor samples using SNP arrays  

E-print Network

Background: Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the human genome and are useful as genomic markers. Oligonucleotide SNP microarrays have been developed for high-throughput ...

Li, Cheng

278

SAMPLING PROPERTIES OF ESTIMATORS OF NUCLEOTIDE DIVERSITY AT DISCOVERED SNP SITES  

Microsoft Academic Search

SNP sites are generally discovered by sequencing regions of the human genome in a limited number of individuals. This may leave SNP sites present in the region, but containing rare mutant nucleotides, undetected. Consequently, estimates of nucleotide diversity obtained from assays of detected SNP sites are biased. In this research we present a statistical model of the SNP discovery process,

ALEXANDER RENWICK; PENELOPE E. BONNEN; DIMITRA TRIKKA; DAVID L. NELSON; RANAJIT CHAKRABORTY; MAREK KIMMEL

2003-01-01

279

Nitrogen-metabolism related genes in barley - haplotype diversity, linkage mapping and associations with malting and kernel quality parameters  

PubMed Central

Background Several studies report about intra-specific trait variation of nitrogen-metabolism related traits, such as N(itrogen)-use efficiency, protein content, N-storage and remobilization in barley and related grass species. The goal of this study was to assess the intra-specific genetic diversity present in primary N-metabolism genes of barley and to investigate the associations of the detected haplotype diversity with malting and kernel quality related traits. Results Partial sequences of five genes related to N-metabolism in barley (Hordeum vulgare L.) were obtained, i.e. nitrate reductase 1, glutamine synthetase 2, ferredoxin-dependent glutamate synthase, aspartate aminotransferase and asparaginase. Two to five haplotypes in each gene were discovered in a set of 190 various varieties. The development of 33 SNP markers allowed the genotyping of all these barley varieties consisting of spring and winter types. Furthermore, these markers could be mapped in several doubled haploid populations. Cluster analysis based on haplotypes revealed a more uniform pattern of the spring barleys as compared to the winter barleys. Based on linear model approaches associations to several malting and kernel quality traits including soluble N and protein were identified. Conclusions A study was conducted to investigate the presence of sequence variation of several genes related to the primary N-metabolism in barley. The detected diversity could be related to particular phenotypic traits. Specific differences between spring and winter barleys most likely reflect different breeding aims. The developed markers can be used as tool for further genetic studies and marker-assisted selection during breeding of barley. PMID:24007272

2013-01-01

280

Heme Oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome  

PubMed Central

Objective Heme oxygenase-1 (HO-1) acts in cytoprotection against acute lung injury. The polymorphic (GT)n repeat in the HO-1 gene (HMOX1) promoter regulates HMOX1 expression. We investigated the associations of HMOX1 polymorphisms with ARDS risk and plasma HO-1 levels. Design Unmatched, nested case-control study. Setting Academic medical center. Patients Consecutive patients with ARDS risk factors upon ICU admission were prospectively enrolled. Cases were 437 Caucasians who developed ARDS and controls were 1014 Caucasians who did not. Measurements and results We genotyped the (GT)n polymorphism and three tagging single nucleotide polymorphisms (tSNPs) in 1451 patients, and measured the plasma HO-1 levels in 106 ARDS patients. We clustered the (GT)n repeats into: S-allele (< 24 repeats), M-allele (24–30 repeats) and L-allele (? 31 repeats). We found that longer (GT)n repeats were associated with reduced ARDS risk (Ptrend = 0.004 for both alleles and genotypes), but no individual tSNP was associated with ARDS risk. HMOX1 haplotypes were significantly associated with ARDS risk (global test, P = 0.016), and the haplotype S-TAG was associated with increased ARDS risk (OR, 1.75; 95% CI, 1.15–2.68; P = 0.010). Intermediate-phenotype analysis showed longer (GT)n repeats were associated with higher plasma HO-1 levels (Ptrend = 0.019 for alleles and 0.027 for genotypes). Conclusions Longer (GT)n repeats in the HMOX1 promoter are associated with higher plasma HO-1 levels and reduced ARDS risk. The common haplotype S-TAG is associated with increased ARDS risk. Our results suggest that HMOX1 variation may modulate ARDS risk through the promoter microsatellite polymorphism. PMID:19526221

Sheu, Chau-Chyun; Zhai, Rihong; Wang, Zhaoxi; Gong, Michelle N.; Tejera, Paula; Chen, Feng; Su, Li; Thompson, B. Taylor; Christiani, David C.

2009-01-01

281

Analysis of Haplotype Structure in the Bovine Major Histocompatibility Complex  

E-print Network

The goal of this project was to identify and characterize polymorphic markers spanning regions of the bovine major histocompatibility complex (BoLA) to analyze patterns of genetic variation and haplotype structure across diverse cattle breeds...

Fritz, Krista L.

2011-02-22

282

Association of a bovine prion gene haplotype with atypical BSE  

Technology Transfer Automated Retrieval System (TEKTRAN)

Background: Atypical bovine spongiform encephalopathies (BSEs) are recently recognized prion diseases of cattle. Atypical BSEs are rare; approximately 30 cases have been identified worldwide. We tested prion gene (PRNP) haplotypes for an association with atypical BSE. Methodology/Principal Findin...

283

Human Leukocyte Antigen Class II Haplotypes Affect Clinical Characteristics and Progression of Type 1 Autoimmune Hepatitis in Japan  

PubMed Central

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

Umemura, Takeji; Katsuyama, Yoshihiko; Yoshizawa, Kaname; Kimura, Takefumi; Joshita, Satoru; Komatsu, Michiharu; Matsumoto, Akihiro; Tanaka, Eiji; Ota, Masao

2014-01-01

284

Detecting Signatures of Selection Through Haplotype Differentiation Among Hierarchically Structured Populations  

PubMed Central

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

Fariello, María Inés; Boitard, Simon; Naya, Hugo; SanCristobal, Magali; Servin, Bertrand

2013-01-01

285

X-chromosome as a marker for population history: linkage disequilibrium and haplotype study in Eurasian populations  

PubMed Central

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

Laan, Maris; Wiebe, Victor; Khusnutdinova, Elza; Remm, Maido; Pääbo, Svante

2005-01-01

286

Association of a Bovine Prion Gene Haplotype with Atypical BSE  

PubMed Central

Background Atypical bovine spongiform encephalopathies (BSEs) are recently recognized prion diseases of cattle. Atypical BSEs are rare; approximately 30 cases have been identified worldwide. We tested prion gene (PRNP) haplotypes for an association with atypical BSE. Methodology/Principle Findings Haplotype tagging polymorphisms that characterize PRNP haplotypes from the promoter region through the three prime untranslated region of exon 3 (25.2 kb) were used to determine PRNP haplotypes of six available atypical BSE cases from Canada, France and the United States. One or two copies of a distinct PRNP haplotype were identified in five of the six cases (p?=?1.3×10?4, two-tailed Fisher's exact test; CI95% 0.263–0.901, difference between proportions). The haplotype spans a portion of PRNP that includes part of intron 2, the entire coding region of exon 3 and part of the three prime untranslated region of exon 3 (13 kb). Conclusions/Significance This result suggests that a genetic determinant in or near PRNP may influence susceptibility of cattle to atypical BSE. PMID:18350166

Clawson, Michael L.; Richt, Juergen A.; Baron, Thierry; Biacabe, Anne-Gaëlle; Czub, Stefanie; Heaton, Michael P.; Smith, Timothy P. L.; Laegreid, William W.

2008-01-01

287

Variable responses of formyl peptide receptor haplotypes toward bacterial peptides  

PubMed Central

The chemoattractant neutrophil formyl peptide receptor (FPR) binds bacterial and mitochondrial N-formylated peptides, which allows the neutrophils to find the bacterial source and/or site of tissue damage. Certain inflammatory disorders may be due in part to an impaired innate immune system that does not respond to acute bacterial damage in a timely fashion. Since the human FPR is encoded by a large number of different haplotypes arising from ten single nucleotide polymorphisms, we examined the possibility that some of these haplotypes are functionally distinct. We analyzed the response of three common FPR haplotypes to peptides from Escherichia coli, Mycobacterium avium ssp. paratuberculosis and human mitochondria. All three haplotypes responded similarly to the E. coli and mitochondrial peptides, whereas one required a higher concentration of the M. avium peptide fMFEDAVAWF for receptor downregulation, receptor signaling and chemotaxis. This raises the possibility of additional bacterial species differences in functional responses among FPR variants, and establishes a precedent with potentially important implications for our innate immune response against bacterial infections. We also investigated whether certain FPR haplotypes are associated with rheumatoid arthritis (RA) by sequencing FPR1 from 148 Caucasian individuals. The results suggested that FPR haplotypes do not significantly contribute toward RA. PMID:18253729

Gripentrog, Jeannie M.; Mills, John S.; Saari, George J.; Miettinen, Heini M.

2008-01-01

288

Assessment of two flexible and compatible SNP genotyping platforms: TaqMan SNP Genotyping Assays and the SNPlex Genotyping System.  

PubMed

In this review we describe the principles, protocols, and applications of two commercially available SNP genotyping platforms, the TaqMan SNP Genotyping Assays and the SNPlex Genotyping System. Combined, these two technologies meet the requirements of multiple SNP applications in genetics research and pharmacogenetics. We also describe a set of SNP selection tools and validated assay resources which we developed to accelerate the cycle of experimentation on these platforms. Criteria for selecting the more appropriate of these two genotyping technologies are presented: the genetic architecture of the trait of interest, the throughput required, and the number of SNPs and samples needed for a successful study. Overall, the TaqMan assay format is suitable for low- to mid-throughput applications in which a high assay conversion rate, simple assay workflow, and low cost of automation are desirable. The SNPlex Genotyping System, on the other hand, is well suited for SNP applications in which throughput and cost-efficiency are essential, e.g., applications requiring either the testing of large numbers of SNPs and samples, or the flexibility to select various SNP subsets. PMID:15829242

De la Vega, Francisco M; Lazaruk, Katherine D; Rhodes, Michael D; Wenz, Michael H

2005-06-01

289

Finding Markers That Make a Difference: DNA Pooling and SNP-Arrays Identify Population Informative Markers for Genetic Stock Identification  

PubMed Central

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

Ozerov, Mikhail; Vasemägi, Anti; Wennevik, Vidar; Diaz-Fernandez, Rogelio; Kent, Matthew; Gilbey, John; Prusov, Sergey; Niemelä, Eero; Vähä, Juha-Pekka

2013-01-01

290

High-resolution Y chromosome haplotypes of Israeli and Palestinian Arabs reveal geographic substructure and substantial overlap with haplotypes of Jews  

Microsoft Academic Search

High-resolution Y chromosome haplotype analysis was performed in 143 paternally unrelated Israeli and Palestinian Moslem Arabs\\u000a (I&P Arabs) by screening for 11 binary polymorphisms and six microsatellite loci. Two frequent haplotypes were found among\\u000a the 83 detected: the modal haplotype of the I&P Arabs (?14%) was spread throughout the region, while its one-step microsatellite\\u000a neighbor, the modal haplotype of the

Almut Nebel; Dvora Filon; Deborah A. Weiss; Michael Weale; Marina Faerman; Ariella Oppenheim; Mark G. Thomas

2000-01-01

291

Detection of Chromosomal Structural Alterations in Single Cells by SNP Arrays: A Systematic Survey of Amplification Bias and Optimized Workflow  

Microsoft Academic Search

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

Kazuya Iwamoto; Miki Bundo; Junko Ueda; Yoko Nakano; Wataru Ukai; Eri Hashimoto; Toshikazu Saito; Tadafumi Kato; Jean-Nicolas Volff

2007-01-01

292

16th IHIW: Global analysis of registry HLA haplotypes from 20 Million individuals: Report from the IHIW Registry Diversity Group  

PubMed Central

This project has the goal to validate bioinformatics methods and tools for HLA haplotype frequency analysis specifically addressing unique issues of haematopoietic stem cell registry data sets. In addition to generating new methods and tools for the analysis of registry data sets, the intent is to produce a comprehensive analysis of HLA data from 20 million donors from the Bone Marrow Donors Worldwide (BMDW) database. This report summarizes the activity on this project as of the 16IHIW meeting in Liverpool. PMID:23280139

Maiers, M; Gragert, L; Madbouly, A; Steiner, D; Marsh, S G E; Gourraud, P-A; Oudshoorn, M; Zanden, H; Schmidt, A H; Pingel, J; Hofmann, J; Müller, C; Eberhard, H-P

2013-01-01

293

HLA in Jaidukama: an Amerindian secluded Colombian population with new haplotypes and Asian and Pacific-shared alleles  

Microsoft Academic Search

America first inhabitants and peopling are still debated. In order to increase knowledge about these questions, we have aimed\\u000a to detect HLA genes of an Amerindian secluded community: Jaidukama, who lives in North Colombia Equatorial forest. HLA genotyping\\u000a and extended haplotype calculations were carried out in 39 healthy individuals belonging to 13 families. HLA frequencies were\\u000a compared to other Amerindians

J. Martinez-Laso; F. Montoya; C. Areces; J. Moscoso; C. Silvera; D. Rey; C. Parga-Lozano; P. Gomez-Prieto; M. Enriquez de Salamanca; A. Arnaiz-Villena

2011-01-01

294

A SNP resource for Douglas-fir: de novo transcriptome assembly and SNP detection and validation  

PubMed Central

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

2013-01-01

295

Identification of SNP and SSR markers in eggplant using RAD tag sequencing  

PubMed Central

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

2011-01-01

296

Effects of PON Polymorphisms and Haplotypes on Molecular Phenotype in Mexican-American Mothers and Children  

PubMed Central

Paraoxonase 1 (PON1) prevents oxidation of low density lipoproteins and inactivates toxic oxon derivatives of organophosphate pesticides (OPs). Over 250 SNPs have been previously identified in the PON1 gene, yet studies of PON1 genetic variation focus primarily on a few promoter SNPs (-108,-162) and coding SNPs (192, 55). We sequenced the PON1 gene in 30 subjects from a Mexican-American birth cohort and identified 94 polymorphisms with minor allele frequencies > 5%, including several novel variants (6 SNPs, 1 insertion, 2 deletions). Variants of the PON1 gene and 3 SNPs from PON2 and PON3 were genotyped in 700 children and mothers from the same cohort. PON1 phenotype was established using two substrate-specific assays: arylesterase (AREase) and paraoxonase (POase). Twelve PON1 and two PON2 polymorphisms were significantly associated with AREase activity, and 37 polymorphisms with POase activity, however only nine were not in strong linkage disequilibrium (LD) with either PON1-108 or PON1192 (r2>0.20), SNPs with known effects on PON1 quantity and substrate-specific activity. Single tagSNPs PON155 and PON1192 accounted for similar ranges of AREase variation compared to haplotypes comprised of multiple SNPs within their haplotype blocks. However, PON155 explained 11-16% of POase activity, while six SNPs in the same haplotype block explained 3-fold more variance (36-56%). Although LD structure in the PON cluster seems similar between Mexicans and Caucasians, allele frequencies for many polymorphisms differed strikingly. Functional effects of PON genetic variation related to susceptibility to OPs and oxidative stress also differed by age, and should be considered in protecting vulnerable subpopulations. PMID:20839225

Huen, Karen; Barcellos, Lisa; Beckman, Kenneth; Rose, Sherri; Eskenazi, Brenda; Holland, Nina

2010-01-01

297

Association of an MHC Class II Haplotype with Increased Risk of Polymyositis in Hungarian Vizsla Dogs  

PubMed Central

A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 “graded” controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR?=?1.92, p?=?0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR?=?4.08, p?=?0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis. PMID:23457575

Massey, Jonathan; Rothwell, Simon; Rusbridge, Clare; Tauro, Anna; Addicott, Diane; Chinoy, Hector; Cooper, Robert G.; Ollier, William E. R.; Kennedy, Lorna J.

2013-01-01

298

Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.  

PubMed Central

The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations. PMID:9585595

Stephens, J C; Reich, D E; Goldstein, D B; Shin, H D; Smith, M W; Carrington, M; Winkler, C; Huttley, G A; Allikmets, R; Schriml, L; Gerrard, B; Malasky, M; Ramos, M D; Morlot, S; Tzetis, M; Oddoux, C; di Giovine, F S; Nasioulas, G; Chandler, D; Aseev, M; Hanson, M; Kalaydjieva, L; Glavac, D; Gasparini, P; Kanavakis, E; Claustres, M; Kambouris, M; Ostrer, H; Duff, G; Baranov, V; Sibul, H; Metspalu, A; Goldman, D; Martin, N; Duffy, D; Schmidtke, J; Estivill, X; O'Brien, S J; Dean, M

1998-01-01

299

DoGSD: the dog and wolf genome SNP database.  

PubMed

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

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

2014-11-17

300

Heterogeneous computing architecture for fast detection of SNP-SNP interactions  

PubMed Central

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

2014-01-01

301

Prediction of cis-QTLs in a pair of inbred mouse strains with the use of expression and haplotype data from public databases.  

PubMed

Cis-QTLs are important candidates for any other trait that maps to the same locus. In this article we have used publicly available databases and a small microarray data set to "map" cis-QTLs in the ILS and ISS inbred mouse strains without the need to generate microarray data from an ILSXISS segregating population. Expression data were obtained from brains of C57BL/6, DBA/2, ILS, and ISS. Cis-QTLs were mapped for the 760 transcripts found to be differentially expressed between the C57BL/6 and DBA/2 using expression data previously obtained from the BXD RIs. The 469 detected cis-QTLs were then examined for SNP haplotypes and expression patterns that could relate the ILS and ISS to the C57BL/6 and DBA/2. Of the 338 cis-QTL transcripts that had informative haplotypes, 189 were significantly different between the ILS and ISS with 184 showing segregation of haplotype with expression. These were considered to be probable cis-QTLs in the ILS and ISS. There were almost certainly additional ILS/ISS cis-QTLs among the other transcripts with informative haplotypes, but in the absence of an ILS/ISS expression difference, the level of confidence was reduced. Several of the putative ILS/ISS cis-QTLs are considered important candidate genes because they are linked to ILS/ISS behavioral QTLs. A potential ascertainment bias related to strain-dependent target sequences was observed suggesting that as much as 35% of the cis-QTLs were hybridization artifacts. Nonetheless, the results suggest that this approach is an economical and widely applicable method for mapping cis-QTLs in a strain pair of interest. PMID:16783643

Radcliffe, Richard A; Lee, Michael J; Williams, Robert W

2006-06-01

302

Maternity validation using sire-only BovineSNP50 BeadChip data.  

PubMed

Based on pairwise identity-by-state (IBS) distances and whole-genome SNP data, kinship was investigated in the Israeli Holstein population. A total of 789 bulls, including most of the artificial insemination sires in service since 1987, were genotyped by the BovineSNP50 BeadChip. This sample included up to five generations. For each bull-by-bull combination, three states are possible for each marker: no match, a single match and both alleles match. Summing over all markers, the 932 598 IBS scores (three match frequencies*310 866 bull-by-bull combinations) were visualized using three-dimensional coordinates that corresponded to the frequencies of the three possible states. Results were reduced to two dimensions using the transformations x' = 0.7071(1 + freq1-freq2) and y' = 1.2247freq0. Bull-by-bull pairs were grouped according to their level of kinship, and canonical scores were calculated using discriminant analysis and the x' and y' features. Of the 474 pairs of recorded maternal grandsire-grandson with both individuals genotyped, the probability for 28 pairs to belong to this level of kinship was low (P < 0.05), suggesting an error rate of around 3% per generation in pedigree determination. PMID:23721510

Seroussi, E; Glick, G; Shirak, A; Ezra, E; Zeron, Y; Ron, M; Weller, J I

2013-12-01

303

Sex-specific association of ACAT-1 rs1044925 SNP and serum lipid levels in the hypercholesterolemic subjects  

PubMed Central

Background Acyl-CoA:cholesterol acyltransferase (ACAT) is a key enzyme in cellular cholesterol homeostasis and in atherosclerosis. The cellular cholesterol efflux correlated with serum high-density lipoprotein cholesterol (HDL-C) concentrations has shown to be impaired in hyperlipidemic mice. The present study was carried out to clarify the association of ACAT-1 rs1044925 single nucleotide polymorphism (SNP) and serum lipid levels in the hyperlipidemic subjects. Methods A total of 821 unrelated subjects (hyperlipidemia, 476; normolipidemia, 345) aged 15-80 were included in the study. Genotyping of the ACAT-1 rs1044925 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results There was no significant difference in the genotypic and allelic frequencies of ACAT-1 rs1044925 SNP between the normolipidemic and hyperlipidemic subjects. The levels of total cholesterol (TC), HDL-C and apolipoprotein (Apo) AI in hyperlipidemic subjects were different between the AA and AC/CC genotypes in male but not in female (P < 0.05-0.01), the C allele carriers had higher serum TC, HDL-C and ApoAI levels than the C allele noncarriers. The association of genotypes and serum HDL-C and ApoAI levels in hyperlipidemia was found mainly in the male subjects with hypercholesterolemia but not in those with hypertriglyceridemia. There were no significant differences in serum lipid levels between the AA and AC/CC genotypes in the normolipidemic subjects. Conclusions The present study shows that the C allele carriers of ACAT-1 rs1044925 SNP in male hyperlipidemic subjects had higher serum TC, HDL-C and ApoAI levels than the C allele noncarriers. There is a sex (male)-specific association of ACAT-1 rs1044925 SNP and serum HDL-C and ApoAI levels in the hypercholesterolemic subjects. PMID:22243772

2012-01-01

304

Varisnp, A Benchmark Database For Variations from dbSNP.  

PubMed

For development and evaluation of methods for predicting the effects of variations, benchmark datasets are needed. Some previously developed datasets are available for this purpose, but newer and larger benchmark sets for benign variants have largely been missing. VariSNP datasets are selected from dbSNP. These subsets were filtered against disease-related variants in the ClinVar, UniProtKB/Swiss-Prot and PhenCode databases, to identify neutral or non-pathogenic cases. All variant descriptions include mapping to reference sequences on chromosomal, genomic, coding DNA and protein levels. The datasets will be updated with automated scripts on a regular basis and are freely available at https://structure.bmc.lu.se/VariSNP. This article is protected by copyright. All rights reserved. PMID:25385275

Schaafsma, Gerard C P; Vihinen, Mauno

2014-11-11

305

Human Endogenous Retrovirus (HERVK9) Structural Polymorphism With Haplotypic HLA-A Allelic Associations  

PubMed Central

The frequency and HLA-A allelic associations of a HERVK9 DNA structural polymorphism located in close proximity to the highly polymorphic HLA-A gene within the major histocompatibility complex (MHC) genomic region were determined in Japanese, African Americans, and Australian Caucasians to better understand its human population evolutionary history. The HERVK9 insertion or deletion was detected as a 3? LTR or a solo LTR, respectively, by separate PCR assays. The average insertion frequency of the HERVK9.HG was significantly different (P < 1.083e?6) between the Japanese (0.59) and the African Americans (0.34) or Australian Caucasians (0.37). LD analysis predicted a highly significant (P < 1.0e?5) linkage between the HLA-A and HERVK9 alleles, probably as a result of hitchhiking (linkage). Evolutionary time estimates of the solo, 5? and 3? LTR nucleotide sequence divergences suggest that the HERVK9 was inserted 17.3 MYA with the first structural deletion occurring 15.1 MYA. The LTR/HLA-A haplotypes appear to have been formed mostly during the past 3.9 MY. The HERVK9 insertion and deletion, detected by a simple and economical PCR method, is an informative genetic and evolutionary marker for the study of HLA-A haplotype variations, human migration, the origins of contemporary populations, and the possibility of disease associations. PMID:18757922

Kulski, Jerzy K.; Shigenari, Atsuko; Shiina, Takashi; Ota, Masao; Hosomichi, Kazuyoshi; James, Ian; Inoko, Hidetoshi

2008-01-01

306

SNP prioritization using a Bayesian probability of association.  

PubMed

Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the P-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified 14 important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers' subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the P-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with P-values alone. PMID:23280596

Thompson, John R; Gögele, Martin; Weichenberger, Christian X; Modenese, Mirko; Attia, John; Barrett, Jennifer H; Boehnke, Michael; De Grandi, Alessandro; Domingues, Francisco S; Hicks, Andrew A; Marroni, Fabio; Pattaro, Cristian; Ruggeri, Fabrizio; Borsani, Giuseppe; Casari, Giorgio; Parmigiani, Giovanni; Pastore, Andrea; Pfeufer, Arne; Schwienbacher, Christine; Taliun, Daniel; Consortium, Ckdgen; Fox, Caroline S; Pramstaller, Peter P; Minelli, Cosetta

2013-02-01

307

SNP prioritization using a Bayesian probability of association  

PubMed Central

Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the p-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified fourteen important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers’ subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the p-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with p-values alone. PMID:23280596

Thompson, John R.; Gögele, Martin; Weichenberger, Christian X.; Modenese, Mirko; Attia, John; Barrett, Jennifer H; Boehnke, Michael; De Grandi, Alessandro; Domingues, Francisco S.; Hicks, Andrew A.; Marroni, Fabio; Pattaro, Cristian; Ruggeri, Fabrizio; Borsani, Giuseppe; Casari, Giorgio; Parmigiani, Giovanni; Pastore, Andrea; Pfeufer, Arne; Schwienbacher, Christine; Taliun, Daniel; Fox, Caroline S.; Pramstaller, Peter P.; Minelli, Cosetta

2013-01-01

308

CRP genotype and haplotype associations with serum C-reactive protein level and DAS28 in untreated early rheumatoid arthritis patients.  

PubMed

IntroductionSingle nucleotide polymorphisms (SNPs) in the CRP gene are implicated in the regulation of the constitutional C-reactive protein (CRP) expression and its response to pro-inflammatory stimuli. Previous reports suggest these effects may have an impact on clinical decision-making based on CRP, for example DAS28. We aimed to investigate the possible association between 7 CRP SNPs, their haplotypes, and the serum level of CRP as well as the DAS28 score in two cohorts of untreated active early rheumatoid arthritis (RA) patients followed during their initial treatment.MethodsOverall, 315 disease-modifying anti-rheumatic drugs and steroid naïve RA patients with disease duration <6 months were included from two randomized controlled trials (the CIMESTRA and OPERA trials). Seven CRP SNPs were investigated: rs11265257, rs1130864, rs1205, rs1800947, rs2808632, rs3093077 and rs876538. The genotype and haplotype associations to CRP and DAS28 levels were evaluated using linear regression analysis adjusted for age, sex and treatment.ResultsThe minor allele of rs1205 C¿>¿T was associated with decreased CRP levels at baseline (P =0.03), with the TT genotype having a 50% reduction in CRP from 16.7 to 8.4 mg/L (P =0.005) compared to homozygosity of the major allele, but no association was observed at year one (P =0.38). The common H2 haplotype, characterized by the T allele of rs1205, was associated with a 26% reduction in CRP at baseline (P =0.043), although no effect was observed at year one (P =0.466). No other SNP or haplotype was associated with CRP at baseline or year one (P ¿0.09). We observed no associations between SNPs or haplotypes and DAS28 scores at baseline or year one (P ¿0.10).Conclusion CRP genotype and haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score. This study shows that DAS28, the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.Trial registrationThe OPERA study is registered at clinicaltrials.gov (NCT00660647). The Cimestra study is not listed in a clinical trials registry due to inclusion of patients between October 1999 and October 2002. PMID:25359432

Ammitzbøll, Christian; Steffensen, Rudi; Bøgsted, Martin; Hørslev-Petersen, Kim; Hetland, Merete L; Junker, Peter; Johansen, Julia S; Pødenphant, Jan; Ostergaard, Mikkel; Ellingsen, Torkell; Stengaard-Pedersen, Kristian

2014-10-31

309

High throughput SNP discovery and genotyping in grapevine (Vitis vinifera L.) by combining a re-sequencing approach and SNPlex technology  

PubMed Central

Background Single-nucleotide polymorphisms (SNPs) are the most abundant type of DNA sequence polymorphisms. Their higher availability and stability when compared to simple sequence repeats (SSRs) provide enhanced possibilities for genetic and breeding applications such as cultivar identification, construction of genetic maps, the assessment of genetic diversity, the detection of genotype/phenotype associations, or marker-assisted breeding. In addition, the efficiency of these activities can be improved thanks to the ease with which SNP genotyping can be automated. Expressed sequence tags (EST) sequencing projects in grapevine are allowing for the in silico detection of multiple putative sequence polymorphisms within and among a reduced number of cultivars. In parallel, the sequence of the grapevine cultivar Pinot Noir is also providing thousands of polymorphisms present in this highly heterozygous genome. Still the general application of those SNPs requires further validation since their use could be restricted to those specific genotypes. Results In order to develop a large SNP set of wide application in grapevine we followed a systematic re-sequencing approach in a group of 11 grape genotypes corresponding to ancient unrelated cultivars as well as wild plants. Using this approach, we have sequenced 230 gene fragments, what represents the analysis of over 1 Mb of grape DNA sequence. This analysis has allowed the discovery of 1573 SNPs with an average of one SNP every 64 bp (one SNP every 47 bp in non-coding regions and every 69 bp in coding regions). Nucleotide diversity in grape (? = 0.0051) was found to be similar to values observed in highly polymorphic plant species such as maize. The average number of haplotypes per gene sequence was estimated as six, with three haplotypes representing over 83% of the analyzed sequences. Short-range linkage disequilibrium (LD) studies within the analyzed sequences indicate the existence of a rapid decay of LD within the selected grapevine genotypes. To validate the use of the detected polymorphisms in genetic mapping, cultivar identification and genetic diversity studies we have used the SNPlex™ genotyping technology in a sample of grapevine genotypes and segregating progenies. Conclusion These results provide accurate values for nucleotide diversity in coding sequences and a first estimate of short-range LD in grapevine. Using SNPlex™ genotyping we have shown the application of a set of discovered SNPs as molecular markers for cultivar identification, linkage mapping and genetic diversity studies. Thus, the combination a highly efficient re-sequencing approach and the SNPlex™ high throughput genotyping technology provide a powerful tool for grapevine genetic analysis. PMID:18021442

Lijavetzky, Diego; Cabezas, José Antonio; Ibáñez, Ana; Rodríguez, Virginia; Martínez-Zapater, José M

2007-01-01

310

A note on efficient computation of haplotypes via perfect phylogeny.  

PubMed

The problem of inferring haplotype phase from a population of genotypes has received a lot of attention recently. This is partly due to the observation that there are many regions on human genomic DNA where genetic recombination is rare (Helmuth, 2001; Daly et al., 2001; Stephens et al., 2001; Friss et al., 2001). A Haplotype Map project has been announced by NIH to identify and characterize populations in terms of these haplotypes. Recently, Gusfield introduced the perfect phylogeny haplotyping problem, as an algorithmic implication of the no-recombination in long blocks observation, together with the standard population-genetic assumption of infinite sites. Gusfield's solution based on matroid theory was followed by direct theta(nm2) solutions that use simpler techniques (Bafna et al., 2003; Eskin et al., 2003), and also bound the number of solutions to the PPH problem. In this short note, we address two questions that were left open. First, can the algorithms of Bafna et al. (2003) and Eskin et al. (2003) be sped-up to O(nm + m2) time, which would imply an O(nm) time-bound for the PPH problem? Second, if there are multiple solutions, can we find one that is most parsimonious in terms of the number of distinct haplotypes. We give reductions that suggests that the answer to both questions is "no." For the first problem, we show that computing the output of the first step (in either method) is equivalent to Boolean matrix multiplication. Therefore, the best bound we can presently achieve is O(nm(omega-1)), where omega < or = 2.52 is the exponent of matrix multiplication. Thus, any linear time solution to the PPH problem likely requires a different approach. For the second problem of computing a PPH solution that minimizes the number of distinct haplotypes, we show that the problem is NP-hard using a reduction from Vertex Cover (Garey and Johnson, 1979). PMID:15700406

Bafna, Vineet; Gusfield, Dan; Hannenhalli, Sridhar; Yooseph, Shibu

2004-01-01

311

The SNP rs3128965 of HLA-DPB1 as a Genetic Marker of the AERD Phenotype  

PubMed Central

Background Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population. Methods A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n?=?264), NC (n?=?238) and disease-control (aspirin tolerant asthma; ATA, n?=?387) groups. Results The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P?=?0.001, P?=?0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P?=?0.039, 0.037, and 0.004, respectively). Conclusions This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype. PMID:25536158

Kim, Seung-Hyun; Cho, Bo-Young; Choi, Hyunna; Shin, Eun-Soon; Ye, Young-Min; Lee, Jong-Eun; Park, Hae-Sim

2014-01-01

312

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

SciTech Connect

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.

Syrrou, M.; Georgiou, I.; Pagoulatos, G. [Univ. of Ioannina (Greece)] [and others] [Univ. of Ioannina (Greece); and others

1996-07-12

313

Haplotype exclusion: the solution to a problem in natural selection.  

PubMed

Antibody that possesses two identical paratopes (bivalent) is aggregated by antigen to trigger effector function. Antibody that possesses two different paratopes behaves as functionally monovalent. If these two antibodies interact with a given epitope, the monovalent antibody will block the aggregation of the bivalent antibody thereby inhibiting effector activation. We advance the hypothesis that haplotype exclusion is driven by the necessity to reduce the level of monovalent antibody. This assumption is compared to previous suggestions and quantitated. Further, several mechanisms of haplotype exclusion used by various species are analyzed in the light of this hypothesis. PMID:12160643

Langman, Rodney; Cohn, Melvin

2002-06-01

314

A custom correlation coefficient (CCC) approach for fast identification of multi-SNP association patterns in genome-wide SNPs data.  

PubMed

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

Climer, Sharlee; Yang, Wei; de las Fuentes, Lisa; Dávila-Román, Victor G; Gu, C Charles

2014-11-01

315

Linkage relationships and haplotype polymorphism among cichlid Mhc class II B loci.  

PubMed

The species flocks of cichlid fishes in the Great East African Lakes are paradigms of adaptive radiation and hence, of great interest to evolutionary biologists. Phylogenetic studies of these fishes have, however, been hampered by the lack of suitable polymorphic markers. The genes of the major histocompatibility complex hold the promise to provide, through their extensive polymorphism, a large number of such markers, but their use has been hampered by the complexity of the genetic system and the lack of definition of the individual loci. In this study we take the first substantial step to alleviate this problem. Using a combination of methods, including the typing of single sperm cells, gyno- or androgenetic individuals, and haploid embryos, as well as sequencing of class II B restriction fragments isolated from gels for Southern blots, we identify the previously characterized homology groups as distinct loci. At least 17 polymorphic class II B loci, all of which are presumably transcribed, have been found among the different species studied. Most of these loci are shared across the various cichlid species and genera. The number of loci per haplotype varies from individual to individual, ranging from 1 to 13. A total of 21 distinct haplotypes differing in the number of loci they carry has thus far been identified. All the polymorphic loci are part of the same cluster in which, however, distances between at least some of the loci (as indicated by recombination frequencies) are relatively large. Both the individual loci and the haplotypes can now be used to study phylogenetic relationships among the members of the species flocks and the mode in which speciation occurs during adaptive radiation. PMID:9649539

Málaga-Trillo, E; Zaleska-Rutczynska, Z; McAndrew, B; Vincek, V; Figueroa, F; Sültmann, H; Klein, J

1998-07-01

316

Linkage relationships and haplotype polymorphism among cichlid Mhc class II B loci.  

PubMed Central

The species flocks of cichlid fishes in the Great East African Lakes are paradigms of adaptive radiation and hence, of great interest to evolutionary biologists. Phylogenetic studies of these fishes have, however, been hampered by the lack of suitable polymorphic markers. The genes of the major histocompatibility complex hold the promise to provide, through their extensive polymorphism, a large number of such markers, but their use has been hampered by the complexity of the genetic system and the lack of definition of the individual loci. In this study we take the first substantial step to alleviate this problem. Using a combination of methods, including the typing of single sperm cells, gyno- or androgenetic individuals, and haploid embryos, as well as sequencing of class II B restriction fragments isolated from gels for Southern blots, we identify the previously characterized homology groups as distinct loci. At least 17 polymorphic class II B loci, all of which are presumably transcribed, have been found among the different species studied. Most of these loci are shared across the various cichlid species and genera. The number of loci per haplotype varies from individual to individual, ranging from 1 to 13. A total of 21 distinct haplotypes differing in the number of loci they carry has thus far been identified. All the polymorphic loci are part of the same cluster in which, however, distances between at least some of the loci (as indicated by recombination frequencies) are relatively large. Both the individual loci and the haplotypes can now be used to study phylogenetic relationships among the members of the species flocks and the mode in which speciation occurs during adaptive radiation. PMID:9649539

Málaga-Trillo, E; Zaleska-Rutczynska, Z; McAndrew, B; Vincek, V; Figueroa, F; Sültmann, H; Klein, J

1998-01-01

317

Analysis of hepatitis B virus drug-resistant mutant haplotypes by ultra-deep pyrosequencing.  

PubMed

Direct sequencing and reverse hybridization are currently the main methods for detecting drug-resistance mutations of hepatitis B virus (HBV). However, these methods do not enable haplotype analysis so they cannot be used to determine whether the mutations are co-located on the same viral genome. This limits the accurate identification of viral mutants that are resistant to drugs with a high genetic barrier. In our current study, ultra-deep pyrosequencing (UDPS) was used to detect HBV drug-resistance mutations in 25 entecavir-treated and five treatment-naive patients. Of the 25 entecavir-treated patients, 18 had experienced virological breakthrough and two exhibited reduced susceptibility to entecavir. The results obtained by UDPS were compared with those of direct sequencing, and the haplotypes of the drug-resistant HBV mutants were analysed. The average number of reads per patient covering the region in which drug-resistance mutations are located was 1735 (range 451-4526). UDPS detected additional drug-resistance mutations not detected by direct sequencing in 19 patients (mutation frequency range 1.1-23.8%). Entecavir-resistance mutations were found to be co-located on the same viral genome in all 20 patients displaying virological breakthrough or reduced susceptibility to entecavir. In conclusion, UDPS was not only sensitive and accurate in identifying drug-resistance mutations of HBV but also enabled haplotype analysis of the mutants. This method may offer significant advantages in explaining and predicting the responses of patients with HBV to antiviral therapy. PMID:22757653

Ko, S-Y; Oh, H-B; Park, C-W; Lee, H C; Lee, J-E

2012-10-01

318

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...

319

SNP Discovery through Next-Generation Sequencing and Its Applications  

PubMed Central

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

Kumar, Santosh; Banks, Travis W.; Cloutier, Sylvie

2012-01-01

320

Six Nations Polytechnic Aboriginal Teacher Education Program (SNP ATEP)  

E-print Network

Six Nations Polytechnic Aboriginal Teacher Education Program (SNP ATEP) Interim Practicum Report The Interim Report is intended to assist the Teacher Candidate and Associate Teacher in making judgments about demonstrated levels of teaching proficiency. Each Interim Report should be based on reasonable expectations

Ellis, Randy

321

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....

322

SNPs in forensic genetics: a review on SNP typing methodologies  

Microsoft Academic Search

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

Beatriz Sobrino; María Brión; Angel Carracedo

2005-01-01

323

SNP selection and multidimensional scaling to quantify population structure.  

PubMed

In the new era of large-scale collaborative Genome Wide Association Studies (GWAS), population stratification has become a critical issue that must be addressed. In order to build upon the methods developed to control the confounding effect of a structured population, it is extremely important to visualize and quantify that effect. In this work, we develop methodology for single nucleotide polymorphism (SNP) selection and subsequent population stratification visualization based on deviation from Hardy-Weinberg equilibrium in conjunction with non-metric multidimensional scaling (MDS); a distance-based multivariate technique. Through simulation, it is shown that SNP selection based on Hardy-Weinberg disequilibrium (HWD) is robust against confounding linkage disequilibrium patterns that have been problematic in past studies and methods as well as producing a differentiated SNP set. Non-metric MDS is shown to be a multivariate visualization tool preferable to principal components in conjunction with HWD SNP selection through theoretical and empirical study from HapMap samples. The proposed selection tool offers a simple and effective way to select appropriate substructure-informative markers for use in exploring the effect that population stratification may have in association studies. PMID:19194989

Miclaus, Kelci; Wolfinger, Russ; Czika, Wendy

2009-09-01

324

An HMM-based boundary-flexible model of human haplotype variation  

E-print Network

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 ...

Sheffi, Jonathan, 1981-

2004-01-01

325

Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10  

PubMed Central

Focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy are common causes of nephrotic syndrome. Variants in >20 genes, including genes critical for mitochondrial function, have been associated with these podocyte diseases. One such gene, PDSS2, is required for synthesis of the decaprenyl tail of coenzyme Q10 (Q10) in humans. The mouse gene Pdss2 is mutated in the kd/kd mouse model of collapsing glomerulopathy. We examined the hypothesis that human PDSS2 polymorphisms are associated with podocyte diseases. We genotyped 377 patients with primary FSGS or collapsing glomerulopathy, together with 900 controls, for 9 single-nucleotide polymorphisms in the PDSS2 gene in a case-control study. Subjects included 247 African American (AA) and 130 European American (EA) patients and 641 AA and 259 EA controls. Among EAs, a pair of proxy SNPs was significantly associated with podocyte disease, and patients homozygous for one PDSS2 haplotype had a strongly increased risk for podocyte disease. By contrast, the distribution of PDSS2 genotypes and haplotypes was similar in AA patients and controls. Thus a PDSS2 haplotype, which has a frequency of 13% in the EA control population and a homozygote frequency of 1.2%, is associated with a significantly increased risk for FSGS and collapsing glomerulopathy in EAs. Lymphoblastoid cell lines from FSGS patients had significantly less Q10 than cell lines from controls; contrary to expectation, this finding was independent of PDSS2 haplotype. These results suggest that FSGS patients have Q10 deficiency and that this deficiency is manifested in patient-derived lymphoblastoid cell lines. PMID:23926186

Winkler, Cheryl A.; Peng, Min; An, Ping; McKenzie, Louise M.; Kirk, Gregory D.; Shi, Yuchen; Xie, Letian X.; Marbois, Beth N.; Clarke, Catherine F.; Kopp, Jeffrey B.

2013-01-01

326

The Extended Tau Haplotype and the Age of Onset of Dementia in Down Syndrome  

Microsoft Academic Search

Background\\/Aims: Most people with Down syndrome (DS) develop Alzheimer’s disease (AD). The extended tau haplotype has been linked to AD. In this study, we examined the haplotype’s effect on the age of onset of AD in DS. Methods: People with DS were assessed for dementia. Genotyping was performed for the extended tau haplotype, APOE anda polymorphism in APP, attt5–8. Results:

Emma L. Jones; Marisa Margallo-Lana; Vee P. Prasher; Clive G. Ballard

2008-01-01

327

A SNP in the 5? flanking region of the myostatin-1b gene is associated with harvest traits in Atlantic salmon (Salmo salar)  

PubMed Central

Background Myostatin (MSTN) belongs to the transforming growth factor-? superfamily and is a potent negative regulator of skeletal muscle development and growth in mammals. Most teleost fish possess two MSTN paralogues. However, as a consequence of a recent whole genome-duplication event, salmonids have four: MSTN-1 (?1a and -1b) and MSTN-2 (?2a and -2b). Evidence suggests that teleost MSTN plays a role in the regulation of muscle growth. In the current study, the MSTN-1b gene was re-sequenced and screened for SNP markers in a commercial population of Atlantic salmon. After genotyping 4,800 progeny for the discovered SNPs, we investigated their association with eight harvest traits - four body-weight traits, two ratios of weight traits, flesh colour and fat percentage - using a mixed model association analysis. Results Three novel SNPs were discovered in the MSTN-1b gene of Atlantic salmon. One of the SNPs, located within the 5? flanking region (g.1086C?>?T), had a significant association with harvest traits (p?haplotype-based association analysis was consistent with this result because the two haplotypes that showed a significant association with body-weight traits, hap4 and hap5 (p??T locus. The alleles at g.1086C?>?T act in an additive manner and explain a small percentage of the genetic variation of these phenotypes. Conclusions The association analysis revealed that g.1086C?>?T had a significant association with all body-weight traits under study. Although the SNP explains a small percentage of the variance, our results indicate that a variation in the 5? flanking region of the myostatin gene is associated with the genetic regulation of growth in Atlantic salmon. PMID:24283985

2013-01-01

328

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 ...

329

High-Density SNP Genotyping of Tomato (Solanum lycopersicum L.) Reveals Patterns of Genetic Variation  

E-print Network

High-Density SNP Genotyping of Tomato (Solanum lycopersicum L.) Reveals Patterns of Genetic using a high-density single nucleotide polymorphism (SNP) array. 7,720 SNPs were genotyped Deynze A, Stoffel K, Douches DS, Zarka D, et al. (2012) High-Density SNP Genotyping of Tomato (Solanum

Douches, David S.

330

Development of an automated SNP analysis method using a paramagnetic beads handling robot  

Microsoft Academic Search

Biological and medical importance of thesingle nucleotide polymorphism (SNP) has led to development of a wide variety of methods for SNP typing. Aiming for establishing highly reliable and fully automated SNP typing, we have developed the adapter ligation method in combina- tion with the paramagnetic beads handling technology, Magtration1. The method utilizes sequence specific ligation between the fluorescently labeled adapter

Hiroko Hagiwara; Kazumi Sawakami-Kobayashi; Midori Yamamoto; Shoji Iwasaki; Mika Sugiura; Hatsumi Abe; Sumiko Kunihiro-Ohashi; Kumiko Takase; Noriko Yamane; Kaoru Kato; Renkon Son; Michihiro Nakamura; Osamu Segawa; Mamiko Yoshida; Masafumi Yohda; Hideji Tajima; Masato Kobori; Yousuke Takahama; Mitsuo Itakura; Masayuki Machida

2007-01-01

331

Strain screen and haplotype association mapping of wheel running in inbred mouse strains  

PubMed Central

Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (?8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity. PMID:20538847

Leamy, Larry; Pomp, Daniel; Turner, Michael J.; Fodor, Anthony A.; Knab, Amy; Bowen, Robert S.; Ferguson, David; Moore-Harrison, Trudy; Hamilton, Alicia

2010-01-01

332

Genetics of chloroquine-resistant malaria: a haplotypic view.  

PubMed

The development and rapid spread of chloroquine resistance (CQR) in Plasmodium falciparum have triggered the identification of several genetic target(s) in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76), are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria. PMID:24402147

Awasthi, Gauri; Das, Aparup

2013-12-01

333

CFTR mutation analysis and haplotype associations in CF patients?  

PubMed Central

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

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

2012-01-01

334

Nomenclature of mitochondrial DNA haplotypes for Oncorhynchus mykiss  

USGS Publications Warehouse

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.

Graziano, S.L.; Brown, K.H.; Nielsen, J.L.

2005-01-01

335

Nomenclature of mitochondrial DNA haplotypes for Oncorhynchus mykiss  

USGS Publications Warehouse

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.

Graziano, Sara L.; Brown, K.H.; Nielsen, Jennifer L.

2005-01-01

336

NOTE / NOTE Cytochrome-b haplotypes suggest an undescribed  

E-print Network

NOTE / NOTE Cytochrome-b haplotypes suggest an undescribed Peromyscus species from the Yukon M.K. Lucid and J.A. Cook Abstract: Peromyscus maniculatus (Wagner, 1845) and Peromyscus keeni Merriam, 1897 undescribed peromyscine species. Peromyscus arcticus is an available name. Re´sume´ : Peromyscus maniculatus

337

Large-Scale SNP Discovery through RNA Sequencing and SNP Genotyping by Targeted Enrichment Sequencing in Cassava (Manihot esculenta Crantz)  

PubMed Central

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

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

338

Large-Scale SNP Discovery through RNA Sequencing and SNP Genotyping by Targeted Enrichment Sequencing in Cassava (Manihot esculenta Crantz).  

PubMed

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

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

339

An approach to mapping haplotype-specific recombination sites in human MHC class III  

SciTech Connect

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.

Levo, A.; Westman, P.; Partanen, J. [Finnish Red Cross Blood Transfusion Service, Helsinki (Finland)

1996-12-31

340

Genetic Epidemiology 36 : 1721 (2012) Haploscope: A Tool for the Graphical Display of Haplotype  

E-print Network

Genetic Epidemiology 36 : 17­21 (2012) Haploscope: A Tool for the Graphical Display of Haplotype and inspection of haplotypes, is available for download at http://scheet.org/software. Genet. Epidemiol. 2011. 36 along a chromosome. Because haplotypes provide the basic representation of genetic information across

Rosenberg, Noah

341

Effect of 593C>T GPx1 SNP alone and in synergy with 47C>T SOD2 SNP on the outcome of critically ill patients.  

PubMed

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

Majolo, Fernanda; Oliveira Paludo, Francis Jackson de; Ponzoni, Aline; Graebin, Pietra; Dias, Fernando Suparregui; Alho, Clarice Sampaio

2015-02-01

342

Chloroplast DNA haplotype variation and population differentiation in Sorbus aucuparia L. (Rosaceae: Maloideae).  

PubMed

Intra-specific chloroplast DNA (cpDNA) variation was studied in Sorbus aucuparia L., an entomophilous, mid-or early successional tree producing fleshy fruits. Eight PCR-amplified fragments of the chloroplast genome were screened for restriction fragment length polymorphisms, using one or two 4 bp-cutter restriction endonucleases. cpDNA variation was investigated on two geographical scales: (1) among four regions in France and Belgium; and (2) within the Belgian region. A total of 150 individuals from six populations were analysed. Fourteen polymorphisms were detected in six of the cpDNA fragments. All polymorphisms probably resulted from insertions or deletions, and allowed the identification of 12 haplotypes. The level of genetic differentiation computed on the basis of haplotype frequencies was similar on the two geographical scales considered (G(STc) = 0.286 among regions, G(STc) = 0.259 among populations within the Belgian region). These values are much lower than those obtained in nine previously studied temperate tree species, which are all wind-pollinated, late-successional species producing dry fruits. These results might primarily be accounted for by the contrasting life history traits of S. aucuparia. In order to obtain insights into the relative contribution of pollen and seeds to gene flow, G(STc) was also compared with previously obtained G(ST) estimates based on allozyme data. PMID:10964230

Raspé, O; Saumitou-Laprade, P; Cuguen, J; Jacquemart, A L

2000-08-01

343

On Detecting Incomplete Soft or Hard Selective Sweeps Using Haplotype Structure  

PubMed Central

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

Ferrer-Admetlla, Anna; Liang, Mason; Korneliussen, Thorfinn; Nielsen, Rasmus

2014-01-01

344

Detecting Rare Haplotype-Environment Interaction with Logistic Bayesian LASSO  

PubMed Central

Two important contributors to missing heritability are believed to be rare variants and gene-environment interaction (GXE). Thus, detecting GXE where G is a rare haplotype variant (rHTV) is a pressing problem. Haplotype analysis is usually the natural second step to follow up on a genomic region that is implicated to be associated through single nucleotide variants (SNV) analysis. Further, rHTV can tag associated rare SNV and provide greater power to detect them than popular collapsing methods. Recently we proposed Logistic Bayesian LASSO (LBL) for detecting rHTV association with case-control data. LBL shrinks the unassociated (especially common) haplotypes towards zero so that an associated rHTV can be identified with greater power. Here we incorporate environmental factors and their interactions with haplotypes in LBL. As LBL is based on retrospective likelihood, this extension is not trivial. We model the joint distribution of haplotypes and covariates given the case-control status. We apply the approach (LBL-GXE) to the Michigan, Mayo, AREDS, Pennsylvania Cohort Study on Age-related Macular Degeneration (AMD). LBL-GXE detects interaction of a specific rHTV in CFH gene with smoking. To the best of our knowledge, this is the first time in the AMD literature that an interaction of smoking with a specific (rather than pooled) rHTV has been implicated. We also carry out simulations and find that LBL-GXE has reasonably good powers for detecting interactions with rHTV while keeping the type I error rates well-controlled. Thus, we conclude that LBL-GXE is a useful tool for uncovering missing heritability. PMID:24272913

Biswas, Swati; Xia, Shuang; Lin, Shili

2014-01-01

345

Detecting rare haplotype-environment interaction with logistic Bayesian LASSO.  

PubMed

Two important contributors to missing heritability are believed to be rare variants and gene-environment interaction (GXE). Thus, detecting GXE where G is a rare haplotype variant (rHTV) is a pressing problem. Haplotype analysis is usually the natural second step to follow up on a genomic region that is implicated to be associated through single nucleotide variants (SNV) analysis. Further, rHTV can tag associated rare SNV and provide greater power to detect them than popular collapsing methods. Recently we proposed Logistic Bayesian LASSO (LBL) for detecting rHTV association with case-control data. LBL shrinks the unassociated (especially common) haplotypes toward zero so that an associated rHTV can be identified with greater power. Here, we incorporate environmental factors and their interactions with haplotypes in LBL. As LBL is based on retrospective likelihood, this extension is not trivial. We model the joint distribution of haplotypes and covariates given the case-control status. We apply the approach (LBL-GXE) to the Michigan, Mayo, AREDS, Pennsylvania Cohort Study on Age-related Macular Degeneration (AMD). LBL-GXE detects interaction of a specific rHTV in CFH gene with smoking. To the best of our knowledge, this is the first time in the AMD literature that an interaction of smoking with a specific (rather than pooled) rHTV has been implicated. We also carry out simulations and find that LBL-GXE has reasonably good powers for detecting interactions with rHTV while keeping the type I error rates well controlled. Thus, we conclude that LBL-GXE is a useful tool for uncovering missing heritability. PMID:24272913

Biswas, Swati; Xia, Shuang; Lin, Shili

2014-01-01

346

Ancestral Asian source(s) of new world Y-chromosome founder haplotypes.  

PubMed Central

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

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

347

Frequent detection of parental consanguinity in children with developmental disorders by a combined CGH and SNP microarray  

PubMed Central

Background Genomic microarrays have been used as the first-tier cytogenetic diagnostic test for patients with developmental delay/intellectual disability, autism spectrum disorders and/or multiple congenital anomalies. The use of SNP arrays has revealed regions of homozygosity in the genome which can lead to identification of uniparental disomy and parental consanguinity in addition to copy number variations. Consanguinity is associated with an increased risk of birth defects and autosomal recessive disorders. However, the frequency of parental consanguinity in children with developmental disabilities is unknown, and consanguineous couples may not be identified during doctor’s visit or genetic counseling without microarray. Results We studied 607 proband pediatric patients referred for developmental disorders using a 4?×?180 K array containing both CGH and SNP probes. Using 720, 360, 180, and 90 Mb as the expected sizes of homozygosity for an estimated coefficient of inbreeding (F) 1/4, 1/8, 1/16, 1/32, parental consanguinity was detected in 21cases (3.46%). Conclusion Parental consanguinity is not uncommon in children with developmental problems in our study population, and can be identified by use of a combined CGH and SNP chromosome microarray. Identification of parental consanguinity in such cases can be important for further diagnostic testing. PMID:24053112

2013-01-01

348

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

PubMed

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

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

2014-11-01

349

Toll-like receptor 4 polymorphisms and their haplotypes modulate the risk of developing diabetic retinopathy in type 2 diabetes patients  

PubMed Central

Purpose Persistent inflammation and impaired neovascularization in type 2 diabetes mellitus (T2DM) patients may lead to development of macro- and microvascular complications. Diabetic retinopathy (DR) is one of the secondary microvascular complications of T2DM. Improper activation of the innate immune system may be an important contributor in the pathophysiology of DR. Toll-like receptor 4 (TLR4) is an important mediator of innate immunity, and genetic alterations in TLR4 support inflammation in the hyperglycemic condition. The present work was designed to investigate whether the TLR4 single nucleotide polymorphisms (SNPs) rs4986790, rs4986791, rs10759931, rs1927911, and rs1927914 are associated with DR in a north Indian population. Methods The study group of 698 individuals (128 DR, 250 T2DM, 320 controls) was genotyped by PCR-RFLP. Haplotype and linkage disequilibrium between SNPs were determined using Haploview software. Results Combined risk genotypes of TLR4 SNPs rs10759931 (odds ratio [OR] 1.50, p = 0.05) and rs1927914 (OR 1.48, p = 0.05) were found to be significantly associated with pathogenesis of DR. A total of 14 haplotypes with frequency >1% were obtained using Haploview software. Haplotypes ACATC (37.5%) and ACATT (14.8%) were the two most common haplotypes obtained. Conclusions Results of the present case-control study that included 698 north Indian subjects suggested that TLR4 SNPs rs10759931 and rs1927914 modulate the risk of DR in T2DM cases. Association analysis using haplotypes showed none of the haplotypes were associated with either susceptibility or resistance to DR in a north Indian population. PMID:24883015

Singh, Kanhaiya; Kant, Shri; Singh, Vivek Kumar; Agrawal, Neeraj K.; Gupta, Sanjeev K.

2014-01-01

350

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

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.

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

2014-01-01

351

Haplotype diversity of 16 Y-chromosomal STRs in three main ethnic populations (Malays, Chinese and Indians) in Malaysia.  

PubMed

We have analyzed 16 Y-STR loci (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385a/b, DYS393, DYS391, DYS439, DYS635 or Y-GATA C4, DYS392, Y-GATA H4, DYS437, DYS438 and DYS448) from the non-recombining region of the human Y-chromosome in 980 male individuals from three main ethnic populations in Malaysia (Malay, Chinese, Indian) using the AmpFlSTR((R)) Y-filertrade mark (Applied Biosystems, Foster City, CA). The observed 17-loci haplotypes and the individual allele frequencies for each locus were estimated, whilst the locus diversity, haplotype diversity and discrimination capacity were calculated in the three ethnic populations. Analysis of molecular variance indicated that 88.7% of the haplotypic variation is found within population and 11.3% is between populations (fixation index F(ST)=0.113, p=0.000). This study has revealed Y-chromosomes with null alleles at several Y-loci, namely DYS458, DYS392, DYS389I, DYS389II, DYS439, DYS448 and Y-GATA H4; and several occurrences of duplications at the highly polymorphic DYS385 loci. Some of these deleted loci were in regions of the Y(q) arm that have been implicated in the occurrence of male infertility. PMID:16457976

Chang, Yuet Meng; Perumal, Revathi; Keat, Phoon Yoong; Kuehn, Daniel L C

2007-03-22

352

Linkage disequilibrium and haplotype studies of chromosome 8p 11. 1-21. 1 markers and Werner syndrome  

SciTech Connect

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.

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

353

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

PubMed Central

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

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

354

Development of high-density SNP genotyping arrays for white spruce (Picea glauca) and transferability to subtropical and nordic congeners.  

PubMed

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

Pavy, Nathalie; Gagnon, France; Rigault, Philippe; Blais, Sylvie; Deschênes, 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

355

A novel SNP of the PNRC1 gene and its association with reproductive traits in Tsaiya ducks.  

PubMed

Proline-rich nuclear receptor coactivator (PNRC)1 is a member of a new family of nuclear receptor coactivators capable of potentiating the transcriptional activity of nuclear receptors. The objective was to investigate the relationship between PNRC1 genotypes of single nucleotide polymorphism (SNP) and reproductive traits in ducks. Brown Tsaiya ducks (N = 305) from two lines, a control line with no selection and the selected line, were used. Polymerase chain reaction-single strand polymorphism and DNA sequencing were done to screen polymorphisms of the PNRC1 gene. A novel SNP (G98T) in 3'-untranslated region of the PNRC1 gene was identified and resulted in two genotypes, GG and GT. The frequencies of genotype GG and allele G were higher in both lines investigated. Regarding egg weight at first egg (EWFE), based on SNP trait association analysis, ducks with the GG genotype had a 4.48 g per egg greater egg weight at first egg when compared with ducks of the GT genotype in the control line (P < 0.05). In addition, this SNP was associated with the hatchability rate (HR) in the selected line; ducks with the GT genotype had a 6.70% higher hatchability rate than those with the GG genotype (P < 0.05). Therefore, we inferred that the PNRC1 gene could be a candidate locus or linked to a major gene that influenced egg weight-related and hatchability traits in Tsaiya ducks. Further investigations on additional duck populations with larger sample sizes are needed to confirm these results. PMID:22494678

Chang, M-T; Cheng, Y-S; Huang, M-C

2012-07-01

356

Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649).  

PubMed

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

Knappskog, Stian; Gansmo, Liv B; Dibirova, Khadizha; Metspalu, Andres; Cybulski, Cezary; Peterlongo, Paolo; Aaltonen, Lauri; Vatten, Lars; Romundstad, Pål; 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; Lønning, Per E

2014-09-30

357

Haplotype structure at seven barley genes: relevance to gene pool bottlenecks, phylogeny of ear type and site of barley domestication.  

PubMed

Archaeological remains indicate that the origin of western agriculture occurred in a brief period about 10,500 years ago in a region of the Middle East known as the Fertile Crescent, where the wild progenitors of several key agricultural cereal species are endemic. Domestication entailed the appearance of agronomic traits such as seed size and threshability. For a representative sample of 20 domesticated barley (Hordeum vulgare) lines, including 13 two-rowed and 7 six-rowed varieties, we determined the haplotypes at seven loci-Adh2, Adh3, Amy1, Dhn9, GAPDH, PEPC and WAXY encompassing 5,616 bases per line-and compared them to the haplotypes at the same loci for 25 wild forms (Hordeum spontaneum) collected within and outside the Fertile Crescent. In comparisons of wild versus domesticated barley, the number of haplotypes (70 vs. 17), average nucleotide diversity, pi, (0.0077 vs. 0.0028), and Watterson's theta at silent sites (0.0104 vs. 0.0028) was reduced in domesticated lines. Two loci, Amy1 and PEPC, were monomorphic in domesticated lines; Amy1 and GAPDH produced significant values of Tajima's D. At GAPDH, pi was slightly higher in domesticated than wild forms, due to divergent high-frequency haplotypes; for the remaining six loci, 87% of nucleotide diversity has been lost in the domesticated forms. Bottlenecks acting on neutrally evolving loci either during the domestication process, during subsequent breeding, or both, are sufficient to account for reduced diversity and the results of Tajima's test, without the need to evoke selection at these loci. Phylogenetic networks data uncover distinct wild and domesticated barley genotypes and suggest that barley may have been domesticated in the Jordan valley. Because, based on AFLP data, the domesticated Turkish cultivars had a genetic basis as large as that present in large germplasm collections, all comparisons provided in this paper are of general value more than being restricted to the Turkish barley germplasm. PMID:16758198

Kilian, Benjamin; Ozkan, Hakan; Kohl, Jochen; von Haeseler, Arndt; Barale, Francesca; Deusch, Oliver; Brandolini, Andrea; Yucel, Cemal; Martin, William; Salamini, Francesco

2006-09-01

358

Protective Association of Tumor Necrosis Factor Superfamily 15 (TNFSF15) Polymorphic Haplotype with Ulcerative Colitis and Crohn's Disease in an Indian Population  

PubMed Central

Background Tumor necrosis factor superfamily (TNFSF) proteins are involved in the genesis of inflammatory bowel disease (IBD). We examined the association of seven single nucleotide polymorphisms (SNP) in the TNFSF15 gene with Crohn's disease (CD) and ulcerative colitis (UC) in the Indian population. Methods Seven SNPs in the TNFSF15 gene (rs10114470, rs3810936, rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487) were genotyped in 309 CD patients, 330 UC patients and 437 healthy controls using the Sequenom iPLEX MassArray platform. Disease associations were evaluated for allelotypes and for genotypes. Results The minor T alleles and the TT genotypes of rs10114470 and rs3810936 were significantly protectively associated with both CD and UC. The CC genotype of rs6478108, AA genotype of rs4263839, the AA genotype of rs6478109, the TT genotype of rs7848647 and the CC genotype of rs7869487 were all protectively associated with CD but not with UC. Two haplotype blocks could be discerned, one where SNPs rs10114470 and rs3810936 were in tight LD (D??=?0.8) and the other where rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487 were in tight LD (D? 0.92–1.00). The second block of haplotypes were not associated with CD or with UC. The first block of haplotypes was very significantly associated with both CD and UC. Conclusions Strong associations exist between TNFSF15 gene polymorphisms and IBD (both CD and UC) in the Indian population. PMID:25501099

Baskaran, Kirankumar; Pugazhendhi, Srinivasan; Ramakrishna, Balakrishnan S.

2014-01-01

359

openSNP--a crowdsourced web resource for personal genomics.  

PubMed

Genome-Wide Association Studies are widely used to correlate phenotypic traits with genetic variants. These studies usually compare the genetic variation between two groups to single out certain Single Nucleotide Polymorphisms (SNPs) that are linked to a phenotypic variation in one of the groups. However, it is necessary to have a large enough sample size to find statistically significant correlations. Direct-To-Consumer (DTC) genetic testing can supply additional data: DTC-companies offer the analysis of a large amount of SNPs for an individual at low cost without the need to consult a physician or geneticist. Over 100,000 people have already been genotyped through Direct-To-Consumer genetic testing companies. However, this data is not public for a variety of reasons and thus cannot be used in research. It seems reasonable to create a central open data repository for such data. Here we present the web platform openSNP, an open database which allows participants of Direct-To-Consumer genetic testing to publish their genetic data at no cost along with phenotypic information. Through this crowdsourced effort of collecting genetic and phenotypic information, openSNP has become a resource for a wide area of studies, including Genome-Wide Association Studies. openSNP is hosted at http://www.opensnp.org, and the code is released under MIT-license at http://github.com/gedankenstuecke/snpr. PMID:24647222

Greshake, Bastian; Bayer, Philipp E; Rausch, Helge; Reda, Julia

2014-01-01

360

Computational SNP analysis: current approaches and future prospects.  

PubMed

The computational approaches in determining disease-associated Non-synonymous single nucleotide polymorphisms (nsSNPs) have evolved very rapidly. Large number of deleterious and disease-associated nsSNP detection tools have been developed in last decade showing high prediction reliability. Despite of all these highly efficient tools, we still lack the accuracy level in determining the genotype-phenotype association of predicted nsSNPs. Furthermore, there are enormous questions that are yet to be computationally compiled before we might talk about the prediction accuracy. Earlier we have incorporated molecular dynamics simulation approaches to foster the accuracy level of computational nsSNP analysis roadmap, which further helped us to determine the changes in the protein phenotype associated with the computationally predicted disease-associated mutation. Here we have discussed on the present scenario of computational nsSNP characterization technique and some of the questions that are crucial for the proper understanding of pathogenicity level for any disease associated mutations. PMID:23852834

Kumar, Ambuj; Rajendran, Vidya; Sethumadhavan, Rao; Shukla, Priyank; Tiwari, Shalinee; Purohit, Rituraj

2014-03-01

361

Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations.  

PubMed

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 southern Han Chinese, 89 Southeast Asian Malays and 83 Tamil Indians. This resource provides population estimates of the frequencies of HLA alleles at these eight loci in the three population groups, particularly for HLA-DPA1 and HLA-DPB1 that were not assayed in HapMap. Comparing between population-specific reference panels and a cosmopolitan panel created from all four HapMap populations, we demonstrate that more accurate imputation is obtained with population-specific panels than with the cosmopolitan panel, especially for the Malays and Indians but even when imputing between northern and southern Han Chinese. As with SNP imputation, common HLA alleles were imputed with greater accuracy than low-frequency variants. PMID:24698974

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

362

Allele and haplotype diversity of X-chromosomal STRs in Ivory Coast.  

PubMed

Twenty-one X-chromosomal short tandem repeat (STR) loci, including the six clusters of linked markers DXS10148-DXS10135-DXS8378 (Xp22), DXS7132-DXS10079-DXS10074 (Xq12), DXS6801-DXS6809-DXS6789 (Xq21), DXS7424-DXS101 (Xq22), DXS10103-HPRTB-DXS10101 (Xq26), DXS8377-DXS10146-DXS10134-DXS7423 (Xq28) and the loci DXS6800, GATA172D05 and DXS10011 were typed in a population sample from Ivory Coast (n=125; 51 men and 74 women). Allele and haplotype frequencies as well as linkage disequilibrium data for kinship calculations are provided. On the whole, no significant differences in the genetic variability of X-STR markers were observed between Ivorians and other sub-Saharan African populations belonging to the Niger-Kordofanian linguistic group. PMID:21717153

Pasino, Serena; Caratti, Stefano; Del Pero, Massimiliano; Santovito, Alfredo; Torre, Carlo; Robino, Carlo

2011-09-01

363

WIDESPREAD AND STRUCTURED DISTRIBUTIONS OF BLOOD PARASITE HAPLOTYPES ACROSS A MIGRATORY DIVIDE OF THE SWAINSON'S THRUSH (CATHARUS USTULATUS)  

Microsoft Academic Search

We examined the phylogenetic distribution of cytochrome b haplotypes of the avian blood parasite genera Haemo- proteus and Plasmodium across the migratory divide of the Swainson's thrush (Catharus ustulatus) in British Columbia, Canada. From 87 host individuals, we identified 8 parasite haplotypes; 4 of Plasmodium and 4o fHaemoproteus. Six haplotypes were novel; 1 Haemoproteus haplotype was identical to H. majoris

L. M. E. Svensson; K. C. Ruegg; C. H. Sekercioglu; R. N. M. Sehgal

2007-01-01

364

Significant Impact of the MTHFR Polymorphisms and Haplotypes on Male Infertility Risk  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate and affects the activity of cellular cycles participating in nucleotide synthesis, DNA repair, genome stability, maintenance of methyl pool, and gene regulation. Genetically compromised MTHFR activity has been suggested to affect male fertility. The objective of the present study was to find the impact on infertility risk of c.203G>A, c.1298A>C, and c.1793G>A polymorphisms in the MTHFR gene. Methods PCR-RFLP and DNA sequencing were used to genotype the common SNPs in the MTHFR gene in 630 infertile and 250 fertile males. Chi-square test was applied for statistical comparison of genotype data. Linkage disequilibrium between the SNPs and the frequency of common haplotypes were assessed using Haploview software. Biochemical levels of total homocysteine (tHcy) and folic acid were measured. Meta-analysis on c.1298A>C polymorphism was performed using data from ten studies, comprising 2734 cases and 2737 controls. Results c.203G>A and c.1298A>C were found to be unrelated to infertility risk. c.1793G>A was protective against infertility (P?=?0.0008). c.677C>T and c.1793G>A were in significant LD (D’?=?0.9). Folic acid and tHcy level did not correlate with male infertility. Pooled estimate on c.1298A>C data from all published studies including our data showed no association of this polymorphism with male infertility (Odds ratio?=?1.035, P?=?0.56), azoospermia (Odds ratio?=?0.97, P?=?0.74), or oligoasthenoteratozoospermia (Odds ratio?=?0.92, p?=?0.29). Eight haplotypes with more than 1% frequency were detected, of which CCGA was protective against infertility (p?=?0.02), but the significance of the latter was not seen after applying Bonferroni correction. Conclusion Among MTHFR polymorphisms, c.203G>A and c.1298A>C do not affect infertility risk and c.1793G>A is protective against infertility. Haplotype analysis suggested that risk factors on the MTHFR locus do not extend too long on the DNA string. PMID:23874907

Gupta, Nishi; Sarkar, Saumya; David, Archana; Gangwar, Pravin Kumar; Gupta, Richa; Khanna, Gita; Sankhwar, Satya Narayan; Khanna, Anil; Rajender, Singh

2013-01-01

365

Origin of celiac disease: how old are predisposing haplotypes?  

PubMed

We recently presented the case of a first century AD young woman, found in the archaeological site of Cosa, showing clinical signs of malnutrition, such as short height, osteoporosis, dental enamel hypoplasia and cribra orbitalia, indirect sign of anemia, all strongly suggestive for celiac disease (CD). However, whether these findings were actually associated to CD was not shown based on genetic parameters. To investigate her human leukocyte antigen (HLA) class II polymorphism, we extracted DNA from a bone sample and a tooth and genotyped HLA using three HLA-tagging single nucleotide polymorphisms for DQ8, DQ2.2 and DQ2.5, specifically associated to CD. She displayed HLA DQ 2.5, the haplotype associated to the highest risk of CD. This is the first report showing the presence of a HLA haplotype compatible for CD in archaeological specimens. PMID:23066327

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

2012-10-01

366

Marker haplotype association with growth in German cystic fibrosis patients.  

PubMed

In 84 families with 101 children with cystic fibrosis (CF) and 103 unaffected siblings, the haplotype of CF chromosomes was determined with six restriction fragment length polymorphism (RFLP) markers that span the CF gene locus. Patient groups with different genotypes in the more distant flanking marker loci MET D, MET H, and D7S8 differed significantly from each other with respect to percentile height and weight, and percentage of weight for height. Patients homozygous 1-1 in met D (TaqI) and met H (TaqI) were thin and tall when homozygous 1-1 in J3.11 (MspI), and small when homozygous 2-2 in J3.11. Heterozygosity in 3.11 and met H and homozygosity 1-1 in met D segregated with the most severe growth retardation. In contrast, growth was normal in patients who were heterozygous in met D and/or had an uncommon KM.19/XV-2c haplotype. Most patients with pancreatic sufficiency and/or borderline sweat test values were carrying rare haplotypes on their CF chromosomes. Adult patients clustered in genotype groups with normal height percentile distributions. This association between haplotype and clinical severity of CF in the German population provides evidence for genetic microheterogeneity of the CF locus, either because of the existence of multiple alleles of the CF gene itself and/or because of the existence of closely linked polymorphic genes that control growth and development and hence modulate the clinical course and prognosis of CF. PMID:1968035

Tümmler, B; Aschendorff, A; Darnedde, T; Fryburg, K; Maass, G; Hundrieser, J

1990-02-01

367

Both a Nicotinic Single Nucleotide Polymorphism (SNP) and a Noradrenergic SNP Modulate Working Memory Performance when Attention is Manipulated  

PubMed Central

We investigated the relation between the two systems of visuospatial attention and working memory by examining the effect of normal variation in cholinergic and noradrenergic genes on working memory performance under attentional manipulation. We previously reported that working memory for location was impaired following large location precues, indicating the scale of visuospatial attention has a role in forming the mental representation of the target. In one of the first studies to compare effects of two single nucleotide polymorphisms (SNPs) on the same cognitive task, we investigated the neurotransmission systems underlying interactions between attention and memory. Based on our previous report that the CHRNA4 rs#1044396 C/T nicotinic receptor SNP affected visuospatial attention, but not working memory, and the DBH rs#1108580 G/A noradrenergic enzyme SNP affected working memory, but not attention, we predicted that both SNPs would modulate performance when the two systems interacted and working memory was manipulated by attention. We found the scale of visuospatial attention deployed around a target affected memory for location of that target. Memory performance was modulated by the two SNPs. CHRNA4 C/C homozygotes and DBH G allele carriers showed the best memory performance but also the greatest benefit of visuospatial attention on memory. Overall, however, the CHRNA4 SNP exerted a stronger effect than the DBH SNP on memory performance when visuospatial attention was manipulated. This evidence of an integrated cholinergic influence on working memory performance under attentional manipulation is consistent with the view that working memory and visuospatial attention are separate systems which can interact. PMID:19016604

Greenwood, Pamela M.; Sundararajan, Ramya; Lin, Ming-Kuan; Kumar, Reshma; Fryxell, Karl J.; Parasuraman, Raja

2010-01-01

368

Interferon-? (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-? receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations.  

PubMed

Pro-inflammatory cytokines IFN? and IFN? function through their cellular receptors IFN?R1 and IFN?R1, respectively to mediate immune processes during malaria infection. A total of 21 SNPs, 2 ins/del polymorphisms and a microsatellite repeat, selected on the basis of their reported association with infectious diseases including malaria in world populations, were analysed for association with Plasmodium falciparum malaria susceptibility in a case-control study with adult patients and ethnically-matched controls drawn from a disease meso- to hyperendemic and a nonendemic region of India. Among the five IFNG SNPs tested, an intron 3 and a 3'UTR SNP associated with disease in the endemic region. In addition, large (CA)n repeats of IFNG intron 1 associated with protection from severe malaria in the endemic region (severe vs. control, odds ratio=0.21, 95% CI=0.08-0.52, P=1.3×10(-4)). The TA11CAG haplotype (rs2069705 T/C, rs2430561 A/T, rs3138557 (CA)n, rs2069718 T/C, rs2069727 A/G, rs2069728 G/A) carrying a short CA11 repeat also exhibited very strong association with severe malaria, particularly in the endemic region (severe vs. control, OR=14.56, 95% CI=3.39-85.81, P=3×10(-5)). One SNP each from the IFNA8 and IFNA17 of IFNA gene cluster had a protective effect in the non-endemic region but not in the endemic region. A promoter and an intron 2 SNP of IFNAR1 were risk factors for disease and the IFNAR1 haplotype GCCAGG (rs2843710 C/G, rs2850015 C/T, +6993 C/T, rs2243594 A/G, rs1012335 G/C, rs2257167 G/C) carrying both the risk alleles strikingly associated with disease manifestation in the endemic region (severe vs. control, OR=27.14, 95% CI=3.12-1254, P=2×10(-5); non-severe vs. control, OR=61.87, 95% CI=10.08-2521, P=1×10(-8)). The data indicates dissimilar contribution of cytokine and cytokine receptor variants to disease in populations residing in areas of differential malaria endemicity. PMID:25445652

Kanchan, Kanika; Jha, Pankaj; Pati, Sudhanshu S; Mohanty, Sanjib; Mishra, Saroj K; Sharma, Surya K; Awasthi, Shally; Venkatesh, Vimala; Habib, Saman

2015-01-01

369

DNA marker haplotype association with pancreatic sufficiency in cystic fibrosis.  

PubMed Central

Patients with cystic fibrosis (CF) generally suffer from chronic obstructive lung disease, pancreatic insufficiency (PI), and a number of other exocrine malfunctions. Approximately 15% of CF patients are, however, pancreatic sufficient. To investigate whether the two clinical subgroups, PI and pancreatic sufficiency (PS), are caused by different CF mutant alleles, we have performed linkage disequilibrium and haplotype association analysis with three DNA markers that are tightly linked to the CF locus. The study showed that the allelic and haplotype distributions for these RFLPs are significantly different between the two groups. The data suggest that most of the CF-PI patients are probably descendants of a single mutational event at the CF locus and that the CF-PS patients resulted from multiple, different mutations. While final interpretation of these data awaits molecular cloning of the CF gene, the information on haplotype association in CF may be useful in genetic counseling and disease prognosis, in identifying the gene itself, and in defining the mutations. PMID:2567116

Kerem, B S; Buchanan, J A; Durie, P; Corey, M L; Levison, H; Rommens, J M; Buchwald, M; Tsui, L C

1989-01-01

370

An Optimal Algorithm for Perfect Phylogeny Haplotyping Ravi Vijaya Satya  

E-print Network

will play a crucial role in diagnosing and treat- ing diseases. The international HapMap project has been established to collect the SNP data. Phase-I of the HapMap project is now complete, which covers approximatelyMapConsortium, 2003]. Phase-II of the HapMap project, which will cover an additional 4.6 million SNPs, is underway

Mukherjee, Amar