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1

Could FIV zoonosis responsible of the breakdown of the pathocenosis which has reduced the European CCR5-Delta32 allele frequencies?  

PubMed Central

Background In Europe, the north-south downhill cline frequency of the chemokine receptor CCR5 allele with a 32-bp deletion (CCR5-?32) raises interesting questions for evolutionary biologists. We had suggested first that, in the past, the European colonizers, principally Romans, might have been instrumental of a progressively decrease of the frequencies southwards. Indeed, statistical analyses suggested strong negative correlations between the allele frequency and historical parameters including the colonization dates by Mediterranean civilisations. The gene flows from colonizers to native populations were extremely low but colonizers are responsible of the spread of several diseases suggesting that the dissemination of parasites in naive populations could have induced a breakdown rupture of the fragile pathocenosis changing the balance among diseases. The new equilibrium state has been reached through a negative selection of the null allele. Results Most of the human diseases are zoonoses and cat might have been instrumental in the decrease of the allele frequency, because its diffusion through Europe was a gradual process, due principally to Romans; and that several cat zoonoses could be transmitted to man. The possible implication of a feline lentivirus (FIV) which does not use CCR5 as co-receptor is discussed. This virus can infect primate cells in vitro and induces clinical signs in macaque. Moreover, most of the historical regions with null or low frequency of CCR5-?32 allele coincide with historical range of the wild felid species which harbor species-specific FIVs. Conclusion We proposed the hypothesis that the actual European CCR5 allelic frequencies are the result of a negative selection due to a disease spreading. A cat zoonosis, could be the most plausible hypothesis. Future studies could provide if CCR5 can play an antimicrobial role in FIV pathogenesis. Moreover, studies of ancient DNA could provide more evidences regarding the implications of zoonoses in the actual CCR5-?32 distribution.

Faure, Eric

2008-01-01

2

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.

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

3

The geographic spread of the CCR5 Delta32 HIV-resistance allele.  

PubMed

The Delta32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Delta32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Delta32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Delta32 allele, we implemented a spatially explicit model of the spread of Delta32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Delta32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Delta32 allele is consistent with previous reports of a strong selective advantage (>10%) for Delta32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Delta32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Delta32 allele and establish a general methodology for studying the geographic distribution of selected alleles. PMID:16216086

Novembre, John; Galvani, Alison P; Slatkin, Montgomery

2005-11-01

4

Distribution of the CCR5delta32 allele (gene variant CCR5) in Rond?nia, Western Amazonian region, Brazil  

PubMed Central

Since around 1723, on the occasion of its initial colonization by Europeans, Rondonia has received successive waves of immigrants. This has been further swelled by individuals from northeastern Brazil, who began entering at the beginning of the twentieth century. The ethnic composition varies across the state according to the various sites of settlement of each wave of immigrants. We analyzed the frequency of the CCR5?32 allele of the CCR5 chemokine receptor, which is considered a Caucasian marker, in five sample sets from the population. Four were collected in Porto Velho, the state capital and the site of several waves of migration. Of these, two, from the Hospital de Base were comprised of HB Mothers and HB Newborns presenting allele frequencies of 3.5% and 3.1%, respectively, a third from the peri-urban neighborhoods of Candelária/Bate-Estaca (1.8%), whereas a fourth, from the Research Center on Tropical Medicine/CEPEM (0.6%), was composed of malaria patients under treament. The fifth sample (3.4%) came from the inland Quilombola village of Pedras Negras. Two homozygous individuals (CCR5?32/CCR5?32) were detected among the HB Mother samples. The frequency of this allele was heterogeneous and higher where the European inflow was more pronounced. The presence of the allele in Pedras Negras revealed European miscegenation in a community largely comprising Quilombolas.

de Farias, Josileide Duarte; Santos, Marlene Guimaraes; de Franca, Andonai Krauze; Delani, Daniel; Tada, Mauro Shugiro; Casseb, Almeida Andrade; Simoes, Aguinaldo Luiz; Engracia, Vera

2012-01-01

5

Coregulation of HIV-1 dependency factors in individuals heterozygous to the CCR5-delta32 deletion  

PubMed Central

Background CCR5-delta32 heterozygous individuals are susceptible to HIV-1. However, it is not clear if there is a relevant protective effect against transmission and a beneficial effect in terms of HIV progression which cannot be attributed to CCR5 surface density alone. Therefore we investigated HIV-1 dependency factors (HDF) which might be differently regulated in CCR5 wild type (WT) and CCR5-delta32 heterozygous individuals. Methods We examined CD34+ hematopoietic progenitor cells derived from bone marrow samples from 19 healthy volunteers, 12 individuals with CCR5 WT and 7 with heterozygous CCR5-delta32 deletion. Samples were analyzed using a global gene expression oligonucleotide microarray (HG-U133plus 2.0, Affymetrix Inc.). Results A total of 205 genes were found with altered expression (3fold difference, present call rate of 75%, p?CCR5-delta32 heterozygotes. Conclusion The CCR5-delta32 deletion is associated with other HDFs in HIV-1 pathogenesis as a possible explanation for beneficial effects regarding the deletion leading to a variant expression profile in heterozygous carriers of this mutation.

2013-01-01

6

CCR5-Delta32: implications in SLE development.  

PubMed

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with strong genetic and environmental components. Previous studies have shown increased levels of several chemokines in active SLE. C-C chemokine receptor type 5 (CCR5) is involved in the recruitment of inflammatory cells into tissues, and mechanisms modulating CCR5 expression and function may interfere in SLE development, influencing the clinical course of the disease. The aim of this study was to evaluate the possible association between the CCR5?32 base-pair deletion polymorphism and SLE disease in a group of Portuguese patients. A total of 219 patients with SLE and 205 healthy individuals were studied. The frequency of CCR5/?32 heterozygotes was lower in patients with SLE than in controls (8% vs. 15% OR = 0.5162; P = 0.0319), suggesting a protective association between CCR5?32 allele and SLE. These results highlight the protective role of Th1 cells that express CCR5 in SLE pathogenesis. PMID:24164722

Carvalho, C; Calvisi, S L; Leal, B; Bettencourt, A; Marinho, A; Almeida, I; Farinha, F; Costa, P P; Silva, B M; Vasconcelos, C

2014-06-01

7

Coreceptor choice and T cell depletion by R5, X4, and R5X4 HIV-1 variants in CCR5-deficient (CCR5delta32) and normal human lymphoid tissue.  

PubMed

Coreceptor utilization by HIV-1 is an important determinant of pathogenesis. However, coreceptor selectivity is defined in vitro, while in vivo critical pathogenic events occur in lymphoid tissues. Using pharmacological inhibitors, we recently provided evidence that coreceptor selectivity by the R5X4 dual-tropic isolate 89.6 was more restricted in ex vivo infected lymphoid tissue than in vitro [S. Glushakova, Y. Yi, J. C. Grivel, A. Singh, D. Schols, E. De Clercq, R. G. Collman, and L. Margolis (1999). J. Clin. Invest. 104, R7-R11]. Here we extend those observations using CCR5-deficient (CCR5Delta32) lymphoid tissue as well as additional primary isolates. We definitively show that neither CCR5 nor secondary coreceptors used in vitro mediate 89.6 infection in lymphoid tissue. We also demonstrate that restricted coreceptor use in lymphoid tissue ex vivo compared with in vitro utilization occurs with other dual-tropic primary isolates and is not unique to 89.6. For all strains tested that are dual tropic in vitro, severe CD4 T cell depletion in lymphoid tissue correlated with preferential CXCR4 use in this ex vivo system. PMID:11277696

Malkevitch, N; McDermott, D H; Yi, Y; Grivel, J C; Schols, D; De Clercq, E; Murphy, P M; Glushakova, S; Collman, R G; Margolis, L

2001-03-15

8

Novel alleles of the chemokine-receptor gene CCR5.  

PubMed Central

The CCR5 gene encodes a cell-surface chemokine-receptor molecule that serves as a coreceptor for macrophage-tropic strains of HIV-1. Mutations in this gene may alter expression or function of the protein product, thereby altering chemokine binding/signaling or HIV-1 infection of cells that normally express CCR5 protein. Indeed, homozygotes for a 32-bp deletion allele of CCR5 (CCR5-delta 32), which causes a frameshift at amino acid 185, are relatively resistant to HIV-1 infection. Here we report the identification of 16 additional mutations in the coding region of the CCR5 gene, all but 3 of which are codon altering or "nonsynonymous." Most mutations were rare (found only once or twice in the sample); five were detected exclusively among African Americans, whereas eight were observed only in Caucasians. The mutations included 11 codon-altering nonsynonymous variants, one trinucleotide deletion, one chain-termination mutant, and three synonymous mutations. The high predominance of codon-altering alleles among CCR5 mutants (14/17 [81%], including CCR5-delta 32) is consistent with an adaptive accumulation of function-altering alleles for this gene, perhaps as a consequence of historic selective pressures.

Carrington, M; Kissner, T; Gerrard, B; Ivanov, S; O'Brien, S J; Dean, M

1997-01-01

9

Frequency of CCR5 Gene 32-bp deletion in Pakistani ethnic groups.  

PubMed

CCR5 is a G-protein-coupled chemokine receptor that is used as a co-factor by macrophage-tropic (M-tropic) isolates of human immunodeficiency virus-1 (HIV-1) to gain entry into host cells. A 32-bp deletion in the CCR5 gene (CCR5-Delta32) leads to the production of an altered gene product that prevents HIV-1 from entering the host cell. This study was carried out to determine prevalence of CCR5-Delta32 allele frequency in a large Pakistani population sample (n = 821) representing 10 ethnic groups. No individual was homozygous for the mutant allele and the frequency of the CCR5-Delta32 allele ranged from 0.62% to 3.57%. The CCR5-Delta32 allele frequency was generally lower in populations from southern Pakistan. The overall frequency of the CCR5-Delta32 allele in Pakistan was 2.31%, which is much lower than that found in European populations and similar to that in the Middle East. This is consistent with the historical records and genetic data that indicate a close genetic affinity among these populations. This study demonstrates that the Pakistani population is highly susceptible to M-tropic isolates of HIV-1 and public health measures need to be enforced with urgency if Pakistan is to avoid an HIV epidemic. PMID:12215252

Khaliq, S; Hameed, A; Ayub, Q; Mazhar, K; Mohyuddin, A; Mansoor, A; Mehdi, S Qasim

2002-01-01

10

Impact of CCR5delta32 Host Genetic Background and Disease Progression on HIV-1 Intrahost Evolutionary Processes: Efficient Hypothesis Testing through Hierarchical Phylogenetic Models  

PubMed Central

The interplay between C-C chemokine receptor type 5 (CCR5) host genetic background, disease progression, and intrahost HIV-1 evolutionary dynamics remains unclear because differences in viral evolution between hosts limit the ability to draw conclusions across hosts stratified into clinically relevant populations. Similar inference problems are proliferating across many measurably evolving pathogens for which intrahost sequence samples are readily available. To this end, we propose novel hierarchical phylogenetic models (HPMs) that incorporate fixed effects to test for differences in dynamics across host populations in a formal statistical framework employing stochastic search variable selection and model averaging. To clarify the role of CCR5 host genetic background and disease progression on viral evolutionary patterns, we obtain gp120 envelope sequences from clonal HIV-1 variants isolated at multiple time points in the course of infection from populations of HIV-1–infected individuals who only harbored CCR5-using HIV-1 variants at all time points. Presence or absence of a CCR5 wt/?32 genotype and progressive or long-term nonprogressive course of infection stratify the clinical populations in a two-way design. As compared with the standard approach of analyzing sequences from each patient independently, the HPM provides more efficient estimation of evolutionary parameters such as nucleotide substitution rates and dN/dS rate ratios, as shown by significant shrinkage of the estimator variance. The fixed effects also correct for nonindependence of data between populations and results in even further shrinkage of individual patient estimates. Model selection suggests an association between nucleotide substitution rate and disease progression, but a role for CCR5 genotype remains elusive. Given the absence of clear dN/dS differences between patient groups, delayed onset of AIDS symptoms appears to be solely associated with lower viral replication rates rather than with differences in selection on amino acid fixation.

Edo-Matas, Diana; Lemey, Philippe; Tom, Jennifer A.; Serna-Bolea, Celia; van den Blink, Agnes E.; van 't Wout, Angelique B.; Schuitemaker, Hanneke; Suchard, Marc A.

2011-01-01

11

Impact of CCR5delta32 host genetic background and disease progression on HIV-1 intrahost evolutionary processes: efficient hypothesis testing through hierarchical phylogenetic models.  

PubMed

The interplay between C-C chemokine receptor type 5 (CCR5) host genetic background, disease progression, and intrahost HIV-1 evolutionary dynamics remains unclear because differences in viral evolution between hosts limit the ability to draw conclusions across hosts stratified into clinically relevant populations. Similar inference problems are proliferating across many measurably evolving pathogens for which intrahost sequence samples are readily available. To this end, we propose novel hierarchical phylogenetic models (HPMs) that incorporate fixed effects to test for differences in dynamics across host populations in a formal statistical framework employing stochastic search variable selection and model averaging. To clarify the role of CCR5 host genetic background and disease progression on viral evolutionary patterns, we obtain gp120 envelope sequences from clonal HIV-1 variants isolated at multiple time points in the course of infection from populations of HIV-1-infected individuals who only harbored CCR5-using HIV-1 variants at all time points. Presence or absence of a CCR5 wt/?32 genotype and progressive or long-term nonprogressive course of infection stratify the clinical populations in a two-way design. As compared with the standard approach of analyzing sequences from each patient independently, the HPM provides more efficient estimation of evolutionary parameters such as nucleotide substitution rates and d(N)/d(S) rate ratios, as shown by significant shrinkage of the estimator variance. The fixed effects also correct for nonindependence of data between populations and results in even further shrinkage of individual patient estimates. Model selection suggests an association between nucleotide substitution rate and disease progression, but a role for CCR5 genotype remains elusive. Given the absence of clear d(N)/d(S) differences between patient groups, delayed onset of AIDS symptoms appears to be solely associated with lower viral replication rates rather than with differences in selection on amino acid fixation. PMID:21135151

Edo-Matas, Diana; Lemey, Philippe; Tom, Jennifer A; Serna-Bolea, Cèlia; van den Blink, Agnes E; van 't Wout, Angélique B; Schuitemaker, Hanneke; Suchard, Marc A

2011-05-01

12

Distribution of HIV-1 resistant polymorphisms among HIV infected patients in Georgia.  

PubMed

Host genetic factors are believed to play an important role in the pathogenesis and natural history of HIV disease along with determining the rate and severity of HIV epidemic in a particular country. CCR5, CCR2 and SDF1 genes are known to influence the susceptibility to HIV-1 infection and to be involved in the rate of disease progression. Unlike CCR5 Delta32 mutation, mutations in CCR2-64I and SDF1-3A do not provide full protection against HIV-1 acquisition, however, they are believed to delay the onset of AIDS defining illness. The objectives of this study were to evaluate the prevalence of host genetic factors among HIV infected patients in Georgia in order to define the correlations between CCR5Delta32, CCR-64I and SDF1-3A genotypes and HIV disease progression in our country. 120 HIV infected individuals were enrolled in the study. Mutations were detected by the polymerase chain reaction/restriction fragment length polymorphism method. We have studied the DNA polymorphisms at the loci that encode these proteins in 120 HIV infected individuals. As expected, no CCR5 homozygous 32 base pair mutation was found among HIV infected persons, however 6 heterozygous patients produced allele frequency 2.5%. Allele frequency of CCR2 and SDF1 allele was equal to 10.75% and 32% respectively. The overall frequency of CCR2 and CCR5 mutations is comparable to their frequency among European populations. However, to our knowledge, the frequency of SDF1-3A allele frequency in Georgians is higher than has been reported in European countries. We found a delay in the progression of HIV infection among persons who were between heterozygous for the CCR5 Delta32 mutation. In order to explore the impact of host genetic factors on the HIV epidemic in Georgia, host genetic studies involving different groups would be of interest. PMID:19124913

Karchava, M; Nelson, Kenrad E; Gochitashvili, N; Dvali, N; Tsertsvadze, T

2008-12-01

13

Angiotensin-converting enzyme deletion allele is beneficial for the longevity of Europeans.  

PubMed

The human angiotensin converting enzyme (ACE) gene is one of the most investigated candidate genes for cardiovascular diseases (CVD), but the understanding of its role among the elderly is vague. Therefore, this study focuses at: (a) testing the association of ACE polymorphism with CVD risk factors among the elderly, and (b) detecting the possible unequal distribution of ACE genotypes between senescent and younger segments of the European populations. The association of ACE I/D polymorphism with CVD health status [hypertension (HT), obesity, dislypidemia] in 301 very old subjects (88.2 ± 5 years; F/M = 221/80) was tested by means of logistic regression analysis. The meta-analysis of D allele frequency in general vs. elderly (80+ years) groups was conducted using all publicly available data for European populations comprising both age cohorts. Multiple multinomial logistic regression revealed that within this elderly sample, age (younger olds, 80-90 years), female sex (OR = 3.13, 95% CI = 1.59-6.19), and elevated triglycerides (OR = 2.53, 95% CI = 1.29-4.95) were positively associated with HT, while ACE polymorphism was not. It was also established that the DD genotype was twice as high in 80+ cohort compared to general population of Croatia (p < 0.00001). This trend was confirmed by the meta-analysis that showed higher D allele frequencies in olds from nine of ten considered European populations (OR = 1.19, 95% CI = 1.08-1.31). The data in elderly cohort do not confirm previously reported role of ACE DD genotype to the development of HT. Moreover, meta-analysis indicated that ACE D allele has some selective advantage that contributes to longevity in majority of European populations. PMID:21614448

Zajc Petranovi?, Matea; Skari?-Juri?, Tatjana; Smolej Naran?i?, Nina; Tomas, Zeljka; Kraja?i?, Petra; Mili?i?, Jasna; Barbali?, Maja; Tomek-Roksandi?, Spomenka

2012-06-01

14

Diverging trends between heterozygosity and allelic richness during postglacial colonization in the European beech.  

PubMed Central

Variation at 12 polymorphic isozyme loci was studied in the European beech on the basis of an extensive sample of 389 populations distributed throughout the species range. Special emphasis was given to the analysis of the pattern of geographic variation on the basis of two contrasting measures of genetic diversity, gene diversity (H) and allelic richness, and to their relationship. Measures of allelic richness were corrected for variation in sample size by using the rarefaction method. As expected, maximum allelic richness was found in the southeastern part of the range (southern Italy and the Balkans), where beech was confined during the last ice age. Surprisingly, H was lower in refugia than in recently colonized regions, resulting in a negative correlation between the two diversity measures. The decrease of allelic richness and the simultaneous increase of H during postglacial recolonization was attributed to several processes that differentially affect the two diversity parameters, such as bottlenecks due to long-distance founding events, selection during population establishment, and increased gene flow at low population densities.

Comps, B; Gomory, D; Letouzey, J; Thiebaut, B; Petit, R J

2001-01-01

15

Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European.  

PubMed

Ancient genomic sequences have started to reveal the origin and the demographic impact of farmers from the Neolithic period spreading into Europe. The adoption of farming, stock breeding and sedentary societies during the Neolithic may have resulted in adaptive changes in genes associated with immunity and diet. However, the limited data available from earlier hunter-gatherers preclude an understanding of the selective processes associated with this crucial transition to agriculture in recent human evolution. Here we sequence an approximately 7,000-year-old Mesolithic skeleton discovered at the La Braña-Arintero site in León, Spain, to retrieve a complete pre-agricultural European human genome. Analysis of this genome in the context of other ancient samples suggests the existence of a common ancient genomic signature across western and central Eurasia from the Upper Paleolithic to the Mesolithic. The La Braña individual carries ancestral alleles in several skin pigmentation genes, suggesting that the light skin of modern Europeans was not yet ubiquitous in Mesolithic times. Moreover, we provide evidence that a significant number of derived, putatively adaptive variants associated with pathogen resistance in modern Europeans were already present in this hunter-gatherer. PMID:24463515

Olalde, Iñigo; Allentoft, Morten E; Sánchez-Quinto, Federico; Santpere, Gabriel; Chiang, Charleston W K; DeGiorgio, Michael; Prado-Martinez, Javier; Rodríguez, Juan Antonio; Rasmussen, Simon; Quilez, Javier; Ramírez, Oscar; Marigorta, Urko M; Fernández-Callejo, Marcos; Prada, María Encina; Encinas, Julio Manuel Vidal; Nielsen, Rasmus; Netea, Mihai G; Novembre, John; Sturm, Richard A; Sabeti, Pardis; Marquès-Bonet, Tomàs; Navarro, Arcadi; Willerslev, Eske; Lalueza-Fox, Carles

2014-03-13

16

HMW and LMW glutenin alleles among putative tetraploid and hexaploid European spelt wheat (Triticum spelta L.) progenitors.  

PubMed

The allelic compositions of high- and low-molecular-weight subunits of glutenins (HMW-GS and LMW-GS) among European spelt ( Triticum spelta L.) and related hexaploid and tetraploid Triticum species were investigated by one- and two-dimensional polyacrylamide-gel electrophoresis (PAGE) and capillary electrophoresis (CE). A total of seven novel glutenin alleles (designated A1a*, B1d*, B1g*, B1f*, B1j*, D1a* at Glu-1 and A3h at the Glu-3 loci, respectively) in European spelt wheat were detected by SDS-PAGE, which were confirmed further by employing A-PAGE and CE methods. Particularly, two HMW-GS alleles, Glu-B1d* coding the subunits 6.1 and 22.1, and Glu-B1f* coding the subunits 13 and 22*, were found to occur in European spelt with frequencies of 32.34% and 5.11%, respectively. These two alleles were present in cultivated emmer (Triticum dicoccum), but they were not observed in bread wheat (Triticum aestivum L.). The allele Glu-B1g* coding for 13* and 19* subunits found in spelt wheat was also detected in club wheat (Triticum compactum L.). Additionally, two alleles coding for LMW-GS, Glu-A3h and Glu-B3d, occurred with high frequencies in spelt, club and cultivated emmer wheat, whereas these were not found or present with very low frequencies in bread wheat. Our results strongly support the secondary origin hypothesis, namely European spelt wheat originated from hybridization between cultivated emmer and club wheat. This is also confirmed experimentally by the artificial synthesis of spelt through crossing between old European emmer wheat, T. dicoccum and club wheat, T. compactum. PMID:13679994

Yan, Y; Hsam, S L K; Yu, J Z; Jiang, Y; Ohtsuka, I; Zeller, F J

2003-11-01

17

Frequency of CCR5 variants among rural populations with low HIV-1 prevalence in Cameroon.  

PubMed

Among rural populations in Cameroon, HIV-1 prevalence is low and the genetic diversity broad. An unusual population-level genetic background may modulate this pattern of HIV infection. We examined HIV-1 prevalence, CCR5Delta32 and CCR5 promoter -2459 G genotype frequency among 1390 rural inhabitants. No individual was identified with the CCR5Delta32 allele, but homozygotes for the CCR5 promoter variant -2459G (27.5%) were relatively common. A seroprevalence of 3.1% of HIV-1 was reported. PMID:17301575

Torimiro, Judith N; Wolfe, Nathan D; Thomas, Alero; Martin, Maureen P; Mpoudi-Ngole, Eitel; Tamoufe, Ubald; Birx, Deborah L; Carrington, Mary; Burke, Donald S; Carr, Jean K

2007-02-19

18

Simultaneous purifying selection on the ancestral MC1R allele and positive selection on the melanoma-risk allele V60L in south Europeans.  

PubMed

In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1R alleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe. Furthermore, we show that purifying and positive selection act simultaneously on MC1R. Thus, at least in Spain, regions at opposite ends of the incident UV-B radiation distribution show significantly different frequencies for the melanoma-risk allele V60L (a mutation also associated to red hair and fair skin and even blonde hair), with higher frequency of V60L at those regions of lower incident UV-B radiation. Besides, using the 1000G south European data, we show that the V60L haplogroup is also characterized by an extended haplotype homozygosity (EHH) pattern indicative of positive selection. We, thus, provide evidence for an adaptive value of human skin depigmentation in Europe and illustrate how an adaptive process can simultaneously help to maintain a disease-risk allele. In addition, our data support the hypothesis proposed by Jablonski and Chaplin (Human skin pigmentation as an adaptation to UVB radiation. Proc Natl Acad Sci U S A. 2010;107:8962-8968), which posits that habitation of middle latitudes involved the evolution of partially depigmented phenotypes that are still capable of suitable tanning. PMID:24045876

Martínez-Cadenas, Conrado; López, Saioa; Ribas, Gloria; Flores, Carlos; García, Oscar; Sevilla, Arrate; Smith-Zubiaga, Isabel; Ibarrola-Villaba, Maider; Pino-Yanes, Maria del Mar; Gardeazabal, Jesús; Boyano, Dolores; García de Galdeano, Alicia; Izagirre, Neskuts; de la Rúa, Concepción; Alonso, Santos

2013-12-01

19

Characterization of the HLA-C*07:01:01G allele group in European and African-American cohorts  

PubMed Central

The HLA-C*07:01:01G allele group consists of three nonsynonymous alleles, C*07:01:01, C*07:06 and C*07:18, plus C*07:01:02, which is synonymous to C*07:01:01. All of these alleles have identical exons 2, 3 and 4, but differ in exons 5 or 6. Therefore routine sequence-based typing (SBT) of exons 2 and 3 is unable to resolve these subtypes, resulting in ambiguous typing results in population and disease cohort studies. In the present study, we fully characterized C*07:01:01G subtypes in European and African Americans and examined their relative frequency distributions. In European Americans C*07:01:01G is predominantly represented by C*07:01:01 (94.4%), whereas C*07:01:02 (1.1%) and C*07:18 (4.5%) were detected relatively infrequently. In African Americans C*07:18 (42.4%) showed a high frequency similar to that of C*07:01:01 (44.7%) whereas C*07:06 was detected at a low frequency (4.7%). C*07:06 was found exclusively on B*44:03 carrying haplotypes in both ethnic groups, but C*07:18 showed multiple linkage relationships with HLA-B. These results demonstrate that C*07:01:01G as defined by routine SBT is a heterogeneous group of alleles, especially among individuals of African origin. If C*07:01:01G subtypes prove to bear divergent functional significance, it would be necessary to include these subtypes in routine HLA-C typing for clinical transplantation and disease association studies.

Deng, Zhihui; Gao, Xiaojiang; Kirk, Greg; Wolinsky, Steven; Carrington, Mary

2012-01-01

20

The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent.  

PubMed

Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22-28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India. PMID:24244186

Basu Mallick, Chandana; Iliescu, Florin Mircea; Möls, Märt; Hill, Sarah; Tamang, Rakesh; Chaubey, Gyaneshwer; Goto, Rie; Ho, Simon Y W; Gallego Romero, Irene; Crivellaro, Federica; Hudjashov, Georgi; Rai, Niraj; Metspalu, Mait; Mascie-Taylor, C G Nicholas; Pitchappan, Ramasamy; Singh, Lalji; Mirazon-Lahr, Marta; Thangaraj, Kumarasamy; Villems, Richard; Kivisild, Toomas

2013-11-01

21

Transplantation of selected or transgenic blood stem cells - a future treatment for HIV/AIDS?  

PubMed Central

Interaction with the chemokine receptor, CCR5, is a necessary precondition for maintaining HIV-1 infection. Individuals with the CCR5-delta32 deletion who lack this receptor are highly resistant to infection by the most common forms of HIV-1. We recently reported on the successful transplantation in an HIV-1-positive patient of allogeneic stem cells homozygous for the CCR5-delta32 allele, which stopped viral replication for more than 27 months without antiretroviral therapy. Here, we report on the results of a meeting regarding the potential implications and future directions of stem cell-targeted HIV treatments. The meeting drew together an international panel of hematologists, immunologists, HIV specialists and representatives from bone marrow donor registries. The meeting came to an agreement to support further attempts to use CCR5-delta32 deleted stem cells, for example, prescreened cord blood stem cells, to treat probable HIV-1-positive patients with malignancies. Furthermore, improvement of HIV-1 therapy that interferes with the entry mechanism seems to be a promising approach in HIV-1-infected patients with no matching CCR5-delta32 deleted donor.

2009-01-01

22

Analysis of Allele and Haplotype Diversity Across 25 Genomic Regions in Three Eastern European Populations  

Microsoft Academic Search

Objective: Individual population history is the main reason for the variability of linkage disequilibrium (LD) patterns and haplotype frequencies among populations. Such diversity may influence the transferability of tag SNPs from one population to another. Our goal was to compare patterns of pairwise LD and allele and haplotype frequencies in Estonian and Russian populations, to estimate the genetic variation between

Andrey Khrunin; Evelin Mihailov; Tiit Nikopensius; Kaarel Krjutškov; Svetlana Limborska; Andres Metspalu

2009-01-01

23

Identification of functionally variant MDR1 alleles among European Americans and African Americans  

Microsoft Academic Search

MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring

Richard B. Kim; Brenda F. Leake; Edna F. Choo; George K. Dresser; Samir V. Kubba; Ute I. Schwarz; Amanda Taylor; Hong-Guang Xie; Joel McKinsey; Sheng Zhou; Lu-Bin Lan; John D. Schuetz; Erin G. Schuetz; Grant R. Wilkinson

2001-01-01

24

Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans  

PubMed Central

We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1?03:01, HLA-DRB1?08:01, and HLA-DQA1?01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).

Morris, David L.; Taylor, Kimberly E.; Fernando, Michelle M.A.; Nititham, Joanne; Alarcon-Riquelme, Marta E.; Barcellos, Lisa F.; Behrens, Timothy W.; Cotsapas, Chris; Gaffney, Patrick M.; Graham, Robert R.; Pons-Estel, Bernardo A.; Gregersen, Peter K.; Harley, John B.; Hauser, Stephen L.; Hom, Geoffrey; Langefeld, Carl D.; Noble, Janelle A.; Rioux, John D.; Seldin, Michael F.; Criswell, Lindsey A.; Vyse, Timothy J.

2012-01-01

25

Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.  

PubMed

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations. PMID:23568192

Li, M; Luo, X-J; Rietschel, M; Lewis, C M; Mattheisen, M; Müller-Myhsok, B; Jamain, S; Leboyer, M; Landén, M; Thompson, P M; Cichon, S; Nöthen, M M; Schulze, T G; Sullivan, P F; Bergen, S E; Donohoe, G; Morris, D W; Hargreaves, A; Gill, M; Corvin, A; Hultman, C; Toga, A W; Shi, L; Lin, Q; Shi, H; Gan, L; Meyer-Lindenberg, A; Czamara, D; Henry, C; Etain, B; Bis, J C; Ikram, M A; Fornage, M; Debette, S; Launer, L J; Seshadri, S; Erk, S; Walter, H; Heinz, A; Bellivier, F; Stein, J L; Medland, S E; Arias Vasquez, A; Hibar, D P; Franke, B; Martin, N G; Wright, M J; Su, B

2014-04-01

26

Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility  

PubMed Central

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64 888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P = 6.32 × 10?5, odds ratio (OR) = 1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10?6). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.

Li, M; Luo, X-j; Rietschel, M; Lewis, CM; Mattheisen, M; Muller-Myhsok, B; Jamain, S; Leboyer, M; Landen, M; Thompson, PM; Cichon, S; Nothen, MM; Schulze, TG; Sullivan, PF; Bergen, SE; Donohoe, G; Morris, DW; Hargreaves, A; Gill, M; Corvin, A; Hultman, C; Toga, AW; Shi, L; Lin, Q; Shi, H; Gan, L; Meyer-Lindenberg, A; Czamara, D; Henry, C; Etain, B; Bis, JC; Ikram, MA; Fornage, M; Debette, S; Launer, LJ; Seshadri, S; Erk, S; Walter, H; Heinz, A; Bellivier, F; Stein, JL; Medland, SE; Vasquez, A Arias; Hibar, DP; Franke, B; Martin, NG; Wright, MJ; Su, B

2014-01-01

27

Allelic proportions of 16 STR loci-including the new European Standard Set (ESS) loci-in a Swiss population sample.  

PubMed

Allele frequencies and forensically relevant population statistics of 16 STR loci, including the new European Standard Set (ESS) loci, were estimated from 668 unrelated individuals of Caucasian appearance living in different parts of Switzerland. The samples were amplified with a combination of the following three kits: AmpFlSTR® NGM SElect™, PowerPlex® ESI17 and PowerPlex® ESX 17. All loci were highly polymorphic and no significant departure from Hardy-Weinberg equilibrium and linkage equilibrium was detected after correction for sampling. PMID:24305954

Gehrig, Christian; Balitzki, Beate; Kratzer, Adelgunde; Cossu, Christian; Malik, Naseem; Castella, Vincent

2014-05-01

28

Influence of the CXCL1 rs4074 A Allele on Alcohol Induced Cirrhosis and HCC in Patients of European Descent  

PubMed Central

Background and Aims CXCL1 (CXC chemokine-ligand-1) is a ligand for CXC chemokine receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. In the present study, we investigated the influence of the CXCL1 rs4074 polymorphism on the occurrence of alcohol induced liver cirrhosis and hepatocellular carcinoma (HCC). Methods The study involved 458 patients with alcoholic cirrhosis (170 with HCC), 115 alcoholics without liver disease and 342 healthy controls. All subjects were genotyped for the CXCL1 rs4074 polymorphism and CXCL1 serum levels of 132 patients were measured. In vitro CXCL1 secretion in TLR-transfected cell lines were studied by ELISA. Results Distribution of the CXCL1 genotypes (GG/GA/AA) was 159/219/80 in patients with alcoholic cirrhosis, 52/44/19 in alcoholic controls and 158/140/44 in healthy controls. Patients with alcohol-induced cirrhosis were significantly more often carriers of the CXCL1 rs4074 A allele (65.3%) than alcoholics without liver disease (54.8%, OR=1.55; 95%CI=1.025-2.350; p=0.04) and healthy controls (53.8%, OR=1.62; 95%CI=1.212-2.151; p=0.001). Accordingly, the frequency of the CXCL1 rs4074 A allele was significantly higher in the cirrhotic patients than in the subjects without cirrhosis (41.4% vs. 33.9%, OR=1.38, 95% CI:1.14–1.66, p=0.001). Furthermore cirrhotic carriers of the CXCL1 rs4074 A allele had significantly higher CXCL1 serum levels than carriers of the GG genotype. In contrast to sera from healthy controls, sera from patients with alcoholic cirrhosis induced CXCL1 secretion in TLR2- (p=0.016) and TLR4- (p=0.008) transfected HEK293 cells. This finding indicates that sera from patients with alcoholic cirrhosis contain soluble ligands that can induce CXCL1 production via stimulation of TLRs. Conclusion The enhanced CXCL1 serum levels in carriers of the rs4074 A allele together with their increased frequency in patients with alcohol induced cirrhosis suggest the CXCL1 rs4074 A allele as a genetic risk factor for alcoholic cirrhosis.

Lutz, Philipp; Langhans, Bettina; Wolter, Franziska; Eisenhardt, Marianne; Kramer, Benjamin; Kokordelis, Pavlos; Glassner, Andreas; Muller, Tobias; Rosendahl, Jonas; Fischer, Janett; Berg, Thomas; Grunhage, Frank; Leifeld, Ludger; Soyka, Michael; Nattermann, Jacob; Sauerbruch, Tilman; Stickel, Felix; Spengler, Ulrich

2013-01-01

29

The CCR5 deletion mutation fails to protect against multiple sclerosis.  

PubMed

Recent advances in the understanding and identification of chemokines and their receptors have provided evidence for their consideration as candidate loci with respect to genetic susceptibility/resistance to MS. Increased levels of the chemokine, macrophage inflammatory protein (MIP)-1 alpha, have been demonstrated in the cerebrospinal fluid of both patients with MS and mice with EAE, and anti-MIP-1 alpha antibodies have been shown to prevent EAE. Recently, a common deletion mutation in the gene for the major receptor for MIP-1 alpha, chemokine receptor 5 (CCR5) has been described. Homozygotes for the mutation fail to express this receptor. Moreover, homozygotes are highly protected against HIV infection this has potential implications for the cell entry of infectious agents in other multifactorial disease where a viral component may be involved. In view of these aspects, a group of 120 unrelated Australian relapsing remitting MS and 168 unrelated control subjects were screened for the CCR5 delta 32 mutation. There was no significant difference in the allele frequency of CCR5 delta 32 gene between the MS patients (0.1125) and the control population (0.0921). The presence of two CCR5 delta 32 homozygotes in the MS patients indicates that the absence of CCR5 is not protective against MS. These data suggest that CCR5 is not an essential component in MS expression, though this may be due to redundancy in the chemokine system where different chemokine receptors may substitute for CCR5 when it is absent. PMID:9438209

Bennetts, B H; Teutsch, S M; Buhler, M M; Heard, R N; Stewart, G J

1997-11-01

30

The HLA class I and class II allele frequencies studied at the DNA level in the Svanetian population (Upper Caucasus) and their relationships to Western European populations.  

PubMed

The Caucasus and the Iberian peninsula have been connected from a linguistic (Basque and Kvartelian languages), toponimic and historic perspectives. They also represent places (e.g. Dmanisi in Georgia and Atapuerca in Northern Spain) where the oldest hominoid remains in Europe are being discovered and studied. These circumstances prompted us to study the genetic background of the Svans (living on the southern slopes of the Greater Caucasus in the Republic of Georgia) in comparison with Basques from the semi-isolated Arratia valley as well with other Northern Spanish and Western European populations. DRB1*1101-DQA1*0501-DQB1*0301 and DRB1*1301-DQA1*0103-DQB1*0603 haplotypes were found in Svans at the highest frequency. The second most frequent three-locus haplotypes in this population were DRB1*0701-DQA1*0201-DQB1*0201 and DRB1*1301-DQA1*0103-DQB1*0602. Furthermore, the following 5-locus extended haplotypes were not found in other populations: A3-B8-DRB1*11-DQA1*0501-DQB1*0301, A2-B8-DRB1*13-DQA1*0103-DQB1*0603, A2-B40-DRB1*14-DQA1*0104-DQB1*0501, A2-B51-DRB1*08-DQA1*0401-DQB1*0402, A3-B7-DRB1*03-DQA1*0501-DQB1*0201 and A24-B39-DRB1*08-DQA1*0401-DQB1*0402. Other haplotypes present in Svans were also frequently observed in Northern Spain and in other Western European countries. However, haplotypes reported as characteristic for Basques were not found in the Svans. A dendrogram using HLA class II alleles places the closest genetic distance observed between Svans and Czechs, whereas Slovenes and other Mediterranean populations (Jews, Hungarians, Frenchmen, Sardinians and Greeks) have the greatest genetic distance. When both HLA class I and class II alleles from 17 populations were compared, the smallest genetic distances were with Rumanians, Czechs and Armenians. Northern Spanish populations were placed closer to each other and clearly separated from Svans. In conclusion, the Svan population shows considerable polymorphism. These observations suggest a mixture of alleles in Svans from geographically distinct areas, and probably do not support a common ancestor for these Caucasian inhabitants and people from Northern Spain. PMID:11782273

Sánchez-Velasco, P; Leyva-Cobián, F

2001-10-01

31

One mutation in the galactocerebrosidase gene is responsible for a majority of mutant alleles in Northern European patients with infantile Krabbe disease  

SciTech Connect

Globoid cell leukodystrophy (GCL) or Krabbe disease is an autosomal recessive disorder resulting from a deficiency of galactocerebrosidase (GALC) activity. The typical human patient presents with symptoms of spasticity, developmental delay and irritability by 6 months of age. Older patients, including adults, are also diagnosed with this disorder. While patients from all ethnic groups are included within the more than 230 patients diagnosed in this laboratory, many trace their ancestry to Northern Europe. Patients are easy to diagnose by their low GALC activity. However, carriers are difficult to identify due to a large overlap in the {open_quotes}control{close_quotes} and carrier ranges. With our cloning of the GALC gene we have undertaken a study to identify mutations causing GCL in some of our families. We have identified a C to T transition at position {open_quotes}502{close_quotes} (counting form the A of the initiation codon) in about 65% of the mutant alleles in patients with Northern European ancestry. Identification of an intron 32 nucleotides downstream from the site of the mutation permits amplification of genomic DNA samples and rapid cycle sequencing. This mutation was found primarily in classic infantile patients, however it was found in the heterozygous state in a juvenile patient and in an African-American patient. This mutation changes the codon for arginine to one for cysteine, and computer analysis predicts a significant change in the secondary structure of this multi-subunit enzyme. A G to A transition at position {open_quotes}694{close_quotes} was found in the homozygous state in another infantile patient from a consanguineous mating. We are in the process of looking for this mutation in other patients. It is hoped that a few mutations will be found to be responsible for infantile Krabbe disease so that carrier identification can be improved for some families.

Rafi, M.A.; Luzi, P.; Hershberger, M. [Jefferson Medical College, Philadelphia, PA (United States)] [and others

1994-09-01

32

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

PubMed

Fragile X syndrome, the most common form of inherited mental retardation, is caused by expansion of a (CGG)(n) repeat located in the FMR1 gene. The molecular factors involved in the mutation process from stable (CGG)(n) alleles towards unstable alleles are largely unknown, although family transmission studies and population studies have suggested that loss of AGG interruptions in the (CGG)(n) repeat is essential. We have analysed the AGG interspersion pattern of the FMR1 (CGG)(n) repeat and the haplotype distribution of closely located microsatellite markers DXS548 and FRAXAC1, in three circumarctic populations: Norwegians, Nenets and Saami. The data confirm the conservation, reported in all human populations studied so far, of an AGG interruption for each 9-10 CGG and support the stabilising effect of AGG interruptions. The data also indicate the existence of chromosomes of Asian origin in the Saami and Nenets population, thereby confirming a genetic relationship between Northern Europe and Asia. DXS548-FRAXAC1 haplotype frequencies were compared between 24 Norwegian fragile X males and 119 normal males. Significant linkage disequilibrium were found between the fragile X mutation and haplotype 6-4 and between normal (CGG)(n) alleles and haplotype 7-3. PMID:11571563

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

2001-09-01

33

Genetic parameters and allele frequencies of five new European Standard Set STR loci (D10S1248, D22S1045, D2S441, D1S1656, D12S391) in the population of Romania  

PubMed Central

Aim To establish allele frequencies and genetic parameters for 5 new European Standard Set short tandem repeat (STR) loci in the population of Romania and to compare them with those in other populations. Methods DNA was isolated using QIAamp 96 DNA Swab BioRobot Kit and Chelex 100 methods. Polymerase chain reaction amplification was done using Investigator ESSplexPlus Kit (D1S1656, D2S441, D2S1338, D3S1358, D8S1179, D10S1248, D12S391, D16S539, D18S51, D19S433, D21S11, D22S1045, FGA, TH01, and vWA). For DNA typing, Applied Biosystems 3500/3500xL Genetic Analyzer was used. Statistical analysis was done using Powerstats, GDA, and Arlequin software. Results Power of discrimination and polymorphism information content was highest for two new ESS loci, D1S1656 and D12S391. Comparison of allele frequencies for 5 new ESS loci in Romanian population with previously published population data showed significant differences for all compared populations, with the exception of Hungary. Geographically more distant populations, such as Spain, Sweden, United Kingdom, Germany, and Portugal differed more than closer populations. Conclusion New ESS STR loci are very useful for the analysis of forensic samples (persons or traces) due to their characteristics (shortness and high polymorphism). In comparisons with other common STR markers, they have a higher power of discrimination and also higher polymorphism information content, and could be used in any national DNA database.

Stanciu, Florin; Vladu, Simona; Cutar, Veronica; Cocioaba, Daniela; Iancu, Florentina; Cotolea, Adnana; Stoian, Ionel Marius

2013-01-01

34

HLA alleles and drug hypersensitivity reactions.  

PubMed

The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions. PMID:22136512

Profaizer, T; Eckels, D

2012-04-01

35

[Population study of the Udmurt population: analysis of ten polymorphic DNA loci of the nuclear genome].  

PubMed

Genetic structure of Southern and Northern ethnographic groups of the Udmurt population from six regions of the Republic of Udmurtia has been studied. All the samples were examined using ten polymorphic DNA loci: VNTR/PAH, VNTR/ApoB, VNTR/DAT1, VNTR/eNOS, ACE, CCR5delta32, KM19, IVS6a, THOI, and FABP2. Allelic and genotype frequencies were estimated for each of the six populations. The average heterozygosity for these ten polymorphic loci varied from 0.47 in Udmurts from Glazovskii region to 0.53 in Udmurts from Malopuginskii region. The level of genetic variation (F(ST)) between populations of Udmurts was 0.0048. Ethnographic subdivision of the population into Northern and Southern Udmurts is in good agreement with the values of genetic distances and phylogenetic analysis. PMID:17633563

Bermisheva, M A; Petrova, N V; Zinchenko, R A; Timkovskaia, E E; Malyshev, P Iu; Gavrilina, S G; Ginter, E K; Kusnutdinova, E K

2007-05-01

36

Allele coding in genomic evaluation  

PubMed Central

Background Genomic data are used in animal breeding to assist genetic evaluation. Several models to estimate genomic breeding values have been studied. In general, two approaches have been used. One approach estimates the marker effects first and then, genomic breeding values are obtained by summing marker effects. In the second approach, genomic breeding values are estimated directly using an equivalent model with a genomic relationship matrix. Allele coding is the method chosen to assign values to the regression coefficients in the statistical model. A common allele coding is zero for the homozygous genotype of the first allele, one for the heterozygote, and two for the homozygous genotype for the other allele. Another common allele coding changes these regression coefficients by subtracting a value from each marker such that the mean of regression coefficients is zero within each marker. We call this centered allele coding. This study considered effects of different allele coding methods on inference. Both marker-based and equivalent models were considered, and restricted maximum likelihood and Bayesian methods were used in inference. Results Theoretical derivations showed that parameter estimates and estimated marker effects in marker-based models are the same irrespective of the allele coding, provided that the model has a fixed general mean. For the equivalent models, the same results hold, even though different allele coding methods lead to different genomic relationship matrices. Calculated genomic breeding values are independent of allele coding when the estimate of the general mean is included into the values. Reliabilities of estimated genomic breeding values calculated using elements of the inverse of the coefficient matrix depend on the allele coding because different allele coding methods imply different models. Finally, allele coding affects the mixing of Markov chain Monte Carlo algorithms, with the centered coding being the best. Conclusions Different allele coding methods lead to the same inference in the marker-based and equivalent models when a fixed general mean is included in the model. However, reliabilities of genomic breeding values are affected by the allele coding method used. The centered coding has some numerical advantages when Markov chain Monte Carlo methods are used.

2011-01-01

37

A Risk Allele for Nicotine Dependence in CHRNA5 Is a Protective Allele for Cocaine Dependence  

PubMed Central

Background A non-synonymous coding polymorphism, rs16969968, of the CHRNA5 gene which encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence (20). The goal of the present study is to examine the association of this variant with cocaine dependence. Methods Genetic association analysis in two, independent samples of unrelated cases and controls; 1.) 504 European-American participating in the Family Study on Cocaine Dependence (FSCD); 2.) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholsim (COGA). Results In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (OR = 0.67 per allele, p = 0.0045, assuming an additive genetic model), but in the reverse direction compared to that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD. Conclusion The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.

Grucza, Richard A; Wang, Jen C.; Stitzel, Jerry A.; Hinrichs, Anthony L.; Saccone, Scott F.; Saccone, Nancy L.; Bucholz, Kathleen K.; Cloninger, C. Robert; Neuman, Rosalind J.; Budde, John P.; Fox, Louis; Bertelsen, Sarah; Kramer, John; Hesselbrock, Victor; Tischfield, Jay; Nurnberger, John. I.; Almasy, Laura; Porjesz, Bernice; Kuperman, Samuel; Schuckit, Marc A.; Edenberg, Howard J.; Rice, John P.; Goate, Alison M.; Bierut, Laura J.

2008-01-01

38

Allelic association between marker loci  

PubMed Central

Allelic association has proven useful to refine the location of major genes prior to positional cloning, but it is of uncertain value for genome scans in complex inheritance. We have extended kinship theory to give information content for linkage and allelic association. Application to pairs of closely linked markers as a surrogate for marker × oligogene pairs indicates that association is largely determined by regional founders, with little effect of subsequent demography. Sub-Saharan Africa has the least allelic association, consistent with settlement of other regions by small numbers of founders. Recent speculation about substantial advantages of isolates over large populations, of constant size over expansion, and of F1 hybrids over incrosses is not supported by theory or data. On the contrary, fewer affected cases, less opportunity for replication, and more stochastic variation tend to make isolates less informative for allelic association, as they are for linkage.

Lonjou, C.; Collins, A.; Morton, N. E.

1999-01-01

39

Type 2 Diabetes Risk Alleles Demonstrate Extreme Directional Differentiation among Human Populations, Compared to Other Diseases  

PubMed Central

Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed disparity in T2D incidence rates across ethnic populations.

Chen, Rong; Corona, Erik; Sikora, Martin; Dudley, Joel T.; Morgan, Alex A.; Moreno-Estrada, Andres; Nilsen, Geoffrey B.; Ruau, David; Lincoln, Stephen E.; Bustamante, Carlos D.; Butte, Atul J.

2012-01-01

40

Invasive Allele Spread under Preemptive Competition  

NASA Astrophysics Data System (ADS)

We study a discrete spatial model for invasive allele spread in which two alleles compete preemptively, initially only the "residents" (weaker competitors) being present. We find that the spread of the advantageous mutation is well described by homogeneous nucleation; in particular, in large systems the time-dependent global density of the resident allele is well approximated by Avrami's law.

Yasi, J. A.; Korniss, G.; Caraco, T.

41

Human acetylator polymorphism: estimate of allele frequency in Libya and details of global distribution.  

PubMed Central

Acetylator phenotyping by means of a sulphadimidine tests revealed 65% of Libyan Arabs to be slow acetylators. Hence the frequency of the allele controlling slow acetylation (As) is estimated as q = 0.81 +/- 0.05. This estimate is similar to those previously recorded in European and adjacent Middle Eastern populations.

Karim, A K; Elfellah, M S; Evans, D A

1981-01-01

42

DLA-DRB1, DQA1, and DQB1 alleles and haplotypes in North American Gray Wolves.  

PubMed

The canine major histocompatibility complex contains highly polymorphic genes, many of which are critical in regulating immune response. Since domestic dogs evolved from Gray Wolves (Canis lupus), common DLA class II alleles should exist. Sequencing was used to characterize 175 Gray Wolves for DLA class II alleles, and data from 1856 dogs, covering 85 different breeds of mostly European origin, were available for comparison. Within wolves, 28 new alleles were identified, all occurring in at least 2 individuals. Three DLA-DRB1, 8 DLA-DQA1, and 6 DLA-DQB1 alleles also identified in dogs were present. Twenty-eight haplotypes were identified, of which 2 three-locus haplotypes, and many DLA-DQA1/DQB1 haplotypes, are also found in dogs. The wolves studied had relatively few dog DLA alleles and may therefore represent a remnant population descended from Asian wolves. The single European wolf included carried a haplotype found in both these North American wolves and in many dog breeds. Furthermore, one wolf DQB1 allele has been found in Shih Tzu, a breed of Asian origin. These data suggest that the wolf ancestors of Asian and European dogs may have had different gene pools, currently reflected in the DLA alleles present in dog breeds. PMID:17611255

Kennedy, Lorna J; Angles, John M; Barnes, Annette; Carmichael, Lindsey E; Radford, Alan D; Ollier, William E R; Happ, George M

2007-01-01

43

Genetically Determined Amerindian Ancestry Correlates with Increased Frequency of Risk Alleles for Systemic Lupus Erythematosus  

PubMed Central

Objectives To analyze if genetically determined Amerindian ancestry predicts the increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus. Methods Single nucleotide polymorphisms within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo normal healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation of the presence of risk alleles with ancestry was done using linear regression. Results A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, PDCD1, ITGAM, and IRF5 were associated with lupus in a Hispanic-Mestizo cohort enriched for European and Amerindian ancestry. In addition, two SNPs within the MHC region, previously associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression we predict an average increase of 2.34 risk alleles when comparing a lupus patient with 100% Amerindian ancestry to an SLE patient with 0% American Indian Ancestry (p<0.0001). SLE patients with 43% more Amerindian ancestry are predicted to carry one additional risk allele. Conclusion Amerindian ancestry increased the number of risk alleles for lupus.

Sanchez, E; Webb, R; Rasmussen, A.; Kelly, J.A; Riba, L.; Kaufman, K.M.; Garcia-de la Torre, I.; Moctezuma, J.F.; Maradiaga-Cecena, M.A.; Cardiel, M.; Acevedo, E.; Cucho-Venegas, M.; Garcia, M.A.; Gamron, S.; Pons-Estel, B.A.; Vasconcelos, C.; Martin, J.; Tusie-Luna, T.; Harley, J.B.; Richardson, B.; Sawalha, A.H.; Alarcon-Riquelme, M.E.

2011-01-01

44

An historical perspective on "The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus".  

PubMed

Human population genetics is a completely different science today compared to two decades ago, at least at the empiric level. Our paper [Chang (Hum Genet 98:91-101, 1996a)] demonstrated that three different alleles were common when one considered many populations although other low frequency alleles occurred. Because previous work had been largely done on European subjects, our findings involved 36 distinct populations and showed that East Asian populations had nearly lost the 7-repeat allele, and that Native American populations had the highest frequencies of that allele globally, was a significant early empiric demonstration of the potential magnitude of population variation at important genes. There are thousands of loci tested on many of the same populations and the gene frequency pattern seen for the DRD4 7-repeat allele is seen at other loci, arguing that this pattern commonly reflects the pattern of divergence of populations and accumulated random genetic drift. PMID:24162668

Kidd, Kenneth K; Pakstis, Andrew J; Yun, Libing

2014-04-01

45

Distribution of HLA-A alleles in eight ethnic groups from Pakistan.  

PubMed

The extreme polymorphism found at some loci of the HLA system has made it an invaluable tool for population genetic analyses. In this study eight diverse ethnic groups from Pakistan were analyzed at the HLA-A locus using sequence specific primers for polymerase chain reaction (PCR-SSP) and then further typed to the allele level using a two-stage sequence specific oligonucleotide probe (SSOP) strategy. Four of these ethnic groups (Burusho, Hazara, Kalash, Pathan) were from the north and four (Baloch, Brahui, Sindhi and Parsi) were from the south of Pakistan. Nine alleles were identified as unique to a particular ethnic group within Pakistan. Maximum variation was seen in the HLA-A*02 allele family for which 11 alleles were detected in the eight Pakistani ethnic groups. The alleles that showed significant variation between the Pakistani ethnic groups include A*0101, A*0206, A*0209, A*0207, A*0217, A*1101, A*2402/09 N/11 N, A*2902, A*3301 and A*3001. A phylogenetic tree based on DA distances for HLA-A allele frequencies separated the Pakistani populations from other world populations and also separated the only Dravidian speaking population of Pakistan, the Brahui, from the remaining Indo-European speaking ethnic groups of Pakistan. PMID:12753666

Mohyuddin, A; Williams, F; Mansoor, A; Mehdi, S Q; Middleton, D

2003-04-01

46

Transferrin polymorphism and genetic differentiation in Cervus elaphus L. (European red deer) populations  

Microsoft Academic Search

A study of transferrin in 11 different European populations of Cervus elaphus as well as in one Cervus elephus × Cervus nippon hybrid population has revealed a polymorphism of this protein. Genetic analysis suggests that it is controlled by one gene locus with three codominant alleles. The allele frequencies allow a clear discrimination not only between the hybrid population and

Sven Herzog; Christine Mushövel; Hans H Hattemer; Alexander Herzog

1991-01-01

47

Allele-specific gene expression uncovered  

Microsoft Academic Search

Genetic variation in populations can result in variation in levels of gene expression but the extent to which this occurs has been unclear. In this article, recent studies of allele-specific expression among autosomal non-imprinted genes are reviewed. These new data provide evidence that differential expression is relatively common and that allelic differences are heritable and can be highly context specific.

Julian C. Knight

2004-01-01

48

Allelic Diversity and Recombination in Campylobacter jejuni  

PubMed Central

The allelic diversity and population structure of Campylobacter jejuni were studied by multilocus nucleotide sequence analysis. Sequences from seven housekeeping genes were obtained from 32 C. jejuni isolates isolated from enteritis patients in Germany, Hungary, Thailand, and the United States. Also included was strain NCTC 11168, the complete genomic sequence of which has recently been published. For all loci analyzed, multiple strains carried identical alleles. The frequency of synonymous and nonsynonymous sequence polymorphisms was low. The number of unique alleles per locus ranged from 9 to 15. These alleles occurred in 31 different combinations (sequence types), so that all but two pairs of strains could be distinguished from each other. Sequences were analyzed for evidence of recombination by the homoplasy test and split decomposition. These analyses showed that intraspecific recombination is frequent in C. jejuni and has generated extensive diversity of allelic profiles from a small number of polymorphic nucleotides.

Suerbaum, Sebastian; Lohrengel, Marc; Sonnevend, Agnes; Ruberg, Florian; Kist, Manfred

2001-01-01

49

S-Allele characterization in self-incompatible pear (Pyrus communis L.)  

Microsoft Academic Search

Gametophytic self-incompatibility, a natural mechanism occurring in pear and other fruit-tree species, is usually controlled by the S-locus with allelic variants ( S1, S2, Sn). Recently, biochemical and molecular tools have determined the S-genotype of cultivars in various species. The present study determined the S-locus composition of ten European pear cultivars via S-PCR molecular assay, thereby obviating time-consuming fieldwork whose

Silvia Zuccherelli; Paola Tassinari; Wim Broothaerts; Stefano Tartarini; Luca Dondini; Silviero Sansavini

2002-01-01

50

Bovine Polledness - An Autosomal Dominant Trait with Allelic Heterogeneity  

PubMed Central

The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a ?381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations.

Medugorac, Ivica; Seichter, Doris; Graf, Alexander; Russ, Ingolf; Blum, Helmut; Gopel, Karl Heinrich; Rothammer, Sophie; Forster, Martin; Krebs, Stefan

2012-01-01

51

Nucleation and Spread of an Invasive Allele  

NASA Astrophysics Data System (ADS)

We analyze a prototypical discrete spatial model for the spread of an invasive allele when individuals compete preemptively for common limiting resources. Initially, the population is genetically monomorphic with the resident allele at high density. The invasive allele is introduced through rare, but recurrent, mutation. The mutant allele is the better competitor (has an individual-level advantage) but its spread is limited by the local availability of resources. We find that each successful introduction of the mutant leads to strong spatial clustering. Spatial patterns in simulation resemble nucleation and subsequent growth, articulately described by Avrami's law in sufficiently large systemsootnotetextG. Korniss and T. Caraco, J. Theor. Biol. (in press, 2004); http://www.rpi.edu/ korniss/Research/JTB04.pdf.

Korniss, Gyorgy; Caraco, Thomas

2005-03-01

52

Alleles of the Human Mu Opioid Receptor, Diagnostic Methods using said Alleles, and Methods of Treatment Based Thereon.  

National Technical Information Service (NTIS)

Provided herein are variant alleles of a gene encoding a mu opioid receptor, along with cloning vectors for replicating such variant alleles, expressing vectors for expressing the variant alleles to produce variant mu opioid receptors, and antibodies to s...

K. S. LaForge M. J. Kreek

2006-01-01

53

Allele-specific silencing of the dominant disease allele in sialuria by RNA interference  

PubMed Central

Dominant disease alleles are attractive therapeutic targets for allele-specific gene silencing by small interfering RNA (siRNA). Sialuria is a dominant disorder caused by missense mutations in the allosteric site of GNE, coding for the rate-limiting enzyme of sialic acid biosynthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase. The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes excessive production of free sialic acid. For this study we employed synthetic siRNAs specifically targeting the dominant GNE mutation c.797G>A (p.R266Q) in sialuria fibroblasts. We demonstrated successful siRNA-mediated down-regulation of the mutant allele by allele-specific real-time PCR. Importantly, mutant allele-specific silencing resulted in a significant decrease of free sialic acid, to within the normal range. Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing demonstrating specificity of this effect. These findings indicate that allele-specific silencing of a mutated allele is a viable therapeutic strategy for autosomal dominant diseases, including sialuria.—Klootwijk, R. D., Savelkoul, P. J. M., Ciccone, C., Manoli, I., Caplen, N. J., Krasnewich, D. M., Gahl, W. A., Huizing, M. Allele-specific silencing of the dominant disease allele in sialuria by RNA interference.

Klootwijk, Riko D.; Savelkoul, Paul J. M.; Ciccone, Carla; Manoli, Irini; Caplen, Natasha J.; Krasnewich, Donna M.; Gahl, William A.; Huizing, Marjan

2008-01-01

54

Demographic history and rare allele sharing among human populations.  

PubMed

High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2-4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ?1,000 sequenced chromosomes per population, whereas ?2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence. PMID:21730125

Gravel, Simon; Henn, Brenna M; Gutenkunst, Ryan N; Indap, Amit R; Marth, Gabor T; Clark, Andrew G; Yu, Fuli; Gibbs, Richard A; Bustamante, Carlos D

2011-07-19

55

Demographic history and rare allele sharing among human populations  

PubMed Central

High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2–4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ?1,000 sequenced chromosomes per population, whereas ?2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.

Gravel, Simon; Henn, Brenna M.; Gutenkunst, Ryan N.; Indap, Amit R.; Marth, Gabor T.; Clark, Andrew G.; Yu, Fuli; Gibbs, Richard A.; Bustamante, Carlos D.; Altshuler, David L.; Durbin, Richard M.; Abecasis, Goncalo R.; Bentley, David R.; Chakravarti, Aravinda; Clark, Andrew G.; Collins, Francis S.; De La Vega, Francisco M.; Donnelly, Peter; Egholm, Michael; Flicek, Paul; Gabriel, Stacey B.; Gibbs, Richard A.; Knoppers, Bartha M.; Lander, Eric S.; Lehrach, Hans; Mardis, Elaine R.; McVean, Gil A.; Nickerson, Debbie A.; Peltonen, Leena; Schafer, Alan J.; Sherry, Stephen T.; Wang, Jun; Wilson, Richard K.; Gibbs, Richard A.; Deiros, David; Metzker, Mike; Muzny, Donna; Reid, Jeff; Wheeler, David; Wang, Jun; Li, Jingxiang; Jian, Min; Li, Guoqing; Li, Ruiqiang; Liang, Huiqing; Tian, Geng; Wang, Bo; Wang, Jian; Wang, Wei; Yang, Huanming; Zhang, Xiuqing; Zheng, Huisong; Lander, Eric S.; Altshuler, David L.; Ambrogio, Lauren; Bloom, Toby; Cibulskis, Kristian; Fennell, Tim J.; Gabriel, Stacey B.; Jaffe, David B.; Shefler, Erica; Sougnez, Carrie L.; Bentley, David R.; Gormley, Niall; Humphray, Sean; Kingsbury, Zoya; Koko-Gonzales, Paula; Stone, Jennifer; McKernan, Kevin J.; Costa, Gina L.; Ichikawa, Jeffry K.; Lee, Clarence C.; Sudbrak, Ralf; Lehrach, Hans; Borodina, Tatiana A.; Dahl, Andreas; Davydov, Alexey N.; Marquardt, Peter; Mertes, Florian; Nietfeld, Wilfiried; Rosenstiel, Philip; Schreiber, Stefan; Soldatov, Aleksey V.; Timmermann, Bernd; Tolzmann, Marius; Egholm, Michael; Affourtit, Jason; Ashworth, Dana; Attiya, Said; Bachorski, Melissa; Buglione, Eli; Burke, Adam; Caprio, Amanda; Celone, Christopher; Clark, Shauna; Conners, David; Desany, Brian; Gu, Lisa; Guccione, Lorri; Kao, Kalvin; Kebbel, Andrew; Knowlton, Jennifer; Labrecque, Matthew; McDade, Louise; Mealmaker, Craig; Minderman, Melissa; Nawrocki, Anne; Niazi, Faheem; Pareja, Kristen; Ramenani, Ravi; Riches, David; Song, Wanmin; Turcotte, Cynthia; Wang, Shally; Mardis, Elaine R.; Wilson, Richard K.; Dooling, David; Fulton, Lucinda; Fulton, Robert; Weinstock, George; Durbin, Richard M.; Burton, John; Carter, David M.; Churcher, Carol; Coffey, Alison; Cox, Anthony; Palotie, Aarno; Quail, Michael; Skelly, Tom; Stalker, James; Swerdlow, Harold P.; Turner, Daniel; De Witte, Anniek; Giles, Shane; Gibbs, Richard A.; Wheeler, David; Bainbridge, Matthew; Challis, Danny; Sabo, Aniko; Yu, Fuli; Yu, Jin; Wang, Jun; Fang, Xiaodong; Guo, Xiaosen; Li, Ruiqiang; Li, Yingrui; Luo, Ruibang; Tai, Shuaishuai; Wu, Honglong; Zheng, Hancheng; Zheng, Xiaole; Zhou, Yan; Li, Guoqing; Wang, Jian; Yang, Huanming; Marth, Gabor T.; Garrison, Erik P.; Huang, Weichun; Indap, Amit; Kural, Deniz; Lee, Wan-Ping; Leong, Wen Fung; Quinlan, Aaron R.; Stewart, Chip; Stromberg, Michael P.; Ward, Alistair N.; Wu, Jiantao; Lee, Charles; Mills, Ryan E.; Shi, Xinghua; Daly, Mark J.; DePristo, Mark A.; Altshuler, David L.; Ball, Aaron D.; Banks, Eric; Bloom, Toby; Browning, Brian L.; Cibulskis, Kristian; Fennell, Tim J.; Garimella, Kiran V.; Grossman, Sharon R.; Handsaker, Robert E.; Hanna, Matt; Hartl, Chris; Jaffe, David B.; Kernytsky, Andrew M.; Korn, Joshua M.; Li, Heng; Maguire, Jared R.; McCarroll, Steven A.; McKenna, Aaron; Nemesh, James C.; Philippakis, Anthony A.; Poplin, Ryan E.; Price, Alkes; Rivas, Manuel A.; Sabeti, Pardis C.; Schaffner, Stephen F.; Shefler, Erica; Shlyakhter, Ilya A.; Cooper, David N.; Ball, Edward V.; Mort, Matthew; Phillips, Andrew D.; Stenson, Peter D.; Sebat, Jonathan; Makarov, Vladimir; Ye, Kenny; Yoon, Seungtai C.; Bustamante, Carlos D.; Clark, Andrew G.; Boyko, Adam; Degenhardt, Jeremiah; Gravel, Simon; Gutenkunst, Ryan N.; Kaganovich, Mark; Keinan, Alon; Lacroute, Phil; Ma, Xin; Reynolds, Andy; Clarke, Laura; Flicek, Paul; Cunningham, Fiona; Herrero, Javier; Keenen, Stephen; Kulesha, Eugene; Leinonen, Rasko; McLaren, William M.; Radhakrishnan, Rajesh; Smith, Richard E.; Zalunin, Vadim; Zheng-Bradley, Xiangqun; Korbel, Jan O.; Stutz, Adrian M.; Humphray, Sean; Bauer, Markus; Cheetham, R. Keira; Cox, Tony; Eberle, Michael; James, Terena; Kahn, Scott; Murray, Lisa; Chakravarti, Aravinda; Ye, Kai; De La Vega, Francisco M.; Fu, Yutao; Hyland, Fiona C. L.; Manning, Jonathan M.; McLaughlin, Stephen F.; Peckham, Heather E.; Sakarya, Onur; Sun, Yongming A.; Tsung, Eric F.; Batzer, Mark A.; Konkel, Miriam K.; Walker, Jerilyn A.; Sudbrak, Ralf; Albrecht, Marcus W.; Amstislavskiy, Vyacheslav S.; Herwig, Ralf; Parkhomchuk, Dimitri V.; Sherry, Stephen T.; Agarwala, Richa; Khouri, Hoda M.; Morgulis, Aleksandr O.; Paschall, Justin E.; Phan, Lon D.; Rotmistrovsky, Kirill E.; Sanders, Robert D.; Shumway, Martin F.

2011-01-01

56

MICROSATELLITE MARKERS REVEAL DIFFERENTIATION OF SOUTHEASTERN AND WESTERN EUROPEAN SHEEP BREEDS  

Microsoft Academic Search

Summary Fifty-seven European, particularly Mediterranean, and Middle Eastern sheep breeds from 15 countries were typed with 31 microsatellite markers. Principle component and Bayesian model-based clustering analysis based on allele frequencies revealed a clear distinction between Western European breeds on the one hand and Southeastern European and Middle Eastern breeds on the other hand. Abstract Thirty-one microsatellite markers covering 22 chromosomes,

Peter Christina; Dalamitra Stella; Perez Trinidad

57

Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture.  

PubMed

The T(-13910) variant located in the enhancer element of the lactase (LCT) gene correlates perfectly with lactase persistence (LP) in Eurasian populations whereas the variant is almost nonexistent among Sub-Saharan African populations, showing high prevalence of LP. Here, we report identification of two new mutations among Saudis, also known for the high prevalence of LP. We confirmed the absence of the European T(-13910) and established two new mutations found as a compound allele: T/G(-13915) within the -13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/C(-3712), -3712 bp from the LCT gene. The compound allele is driven to a high prevalence among Middle East population(s). Our functional analyses in vitro showed that both SNPs of the compound allele, located 10 kb apart, are required for the enhancer effect, most probably mediated through the binding of the hepatic nuclear factor 1 alpha (HNF1 alpha). High selection coefficient (s) approximately 0.04 for LP phenotype was found for both T(-13910) and the compound allele. The European T(-13910) and the earlier identified East African G(-13907) LP allele share the same ancestral background and most likely the same history, probably related to the same cattle domestication event. In contrast, the compound Arab allele shows a different, highly divergent ancestral haplotype, suggesting that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption. These results support the convergent evolution of the LP in diverse populations, most probably reflecting different histories of adaptation to milk culture. PMID:18179885

Enattah, Nabil Sabri; Jensen, Tine G K; Nielsen, Mette; Lewinski, Rikke; Kuokkanen, Mikko; Rasinpera, Heli; El-Shanti, Hatem; Seo, Jeong Kee; Alifrangis, Michael; Khalil, Insaf F; Natah, Abdrazak; Ali, Ahmed; Natah, Sirajedin; Comas, David; Mehdi, S Qasim; Groop, Leif; Vestergaard, Else Marie; Imtiaz, Faiqa; Rashed, Mohamed S; Meyer, Brian; Troelsen, Jesper; Peltonen, Leena

2008-01-01

58

Overcoming Allelic Specificity by Immunization with Five Allelic Forms of Plasmodium falciparum Apical Membrane Antigen 1  

PubMed Central

Apical membrane antigen 1 (AMA1) is a leading vaccine candidate, but the allelic polymorphism is a stumbling block for vaccine development. We previously showed that a global set of AMA1 haplotypes could be grouped into six genetic populations. Using this information, six recombinant AMA1 proteins representing each population were produced. Rabbits were immunized with either a single recombinant AMA1 protein or mixtures of recombinant AMA1 proteins (mixtures of 4, 5, or 6 AMA1 proteins). Antibody levels were measured by enzyme-linked immunosorbent assay (ELISA), and purified IgG from each rabbit was used for growth inhibition assay (GIA) with 12 different clones of parasites (a total of 108 immunogen-parasite combinations). Levels of antibodies to all six AMA1 proteins were similar when the antibodies were tested against homologous antigens. When the percent inhibitions in GIA were plotted against the number of ELISA units measured with homologous AMA1, all data points followed a sigmoid curve, regardless of the immunogen. In homologous combinations, there were no differences in the percent inhibition between the single-allele and allele mixture groups. However, all allele mixture groups showed significantly higher percent inhibition than the single-allele groups in heterologous combinations. The 5-allele-mixture group showed significantly higher inhibition to heterologous parasites than the 4-allele-mixture group. On the other hand, there was no difference between the 5- and 6-allele-mixture groups. These data indicate that mixtures with a limited number of alleles may cover a majority of the parasite population. In addition, using the data from 72 immunogen-parasite combinations, we mathematically identified 13 amino acid polymorphic sites which significantly impact GIA activities. These results could be a foundation for the rational design of a future AMA1 vaccine.

Herrera, Raul; Diouf, Ababacar; Zhou, Hong; Mu, Jianbing; Hu, Zonghui; MacDonald, Nicholas J.; Reiter, Karine; Nguyen, Vu; Shimp, Richard L.; Singh, Kavita; Narum, David L.; Long, Carole A.; Miller, Louis H.

2013-01-01

59

The optimal measure of allelic association  

PubMed Central

Allelic association between pairs of loci is derived in terms of the association probability ? as a function of recombination ?, effective population size N, linear systematic pressure v, and time t, predicting both ?rt, the decrease of association from founders and ?ct, the increase by genetic drift, with ?t = ?rt + ?ct. These results conform to the Malecot equation, with time replaced by distance on the genetic map, or on the physical map if recombination in the region is uniform. Earlier evidence suggested that ? is less sensitive to variations in marker allele frequencies than alternative metrics for which there is no probability theory. This robustness is confirmed for six alternatives in eight samples. In none of these 48 tests was the residual variance as small as for ?. Overall, efficiency was less than 80% for all alternatives, and less than 30% for two of them. Efficiency of alternatives did not increase when information was estimated simultaneously. The swept radius within which substantial values of ? are conserved lies between 385 and 893 kb, but deviation of parameters between measures is enormously significant. The large effort now being devoted to allelic association has little value unless the ? metric with the strongest theoretical basis and least sensitivity to marker allele frequencies is used for mapping of marker association and localization of disease loci.

Morton, N. E.; Zhang, W.; Taillon-Miller, P.; Ennis, S.; Kwok, P.-Y.; Collins, A.

2001-01-01

60

The optimal measure of allelic association.  

PubMed

Allelic association between pairs of loci is derived in terms of the association probability rho as a function of recombination theta, effective population size N, linear systematic pressure v, and time t, predicting both rho(rt), the decrease of association from founders and rho(ct), the increase by genetic drift, with rho(t) = rho(rt) + rho(ct). These results conform to the Malecot equation, with time replaced by distance on the genetic map, or on the physical map if recombination in the region is uniform. Earlier evidence suggested that rho is less sensitive to variations in marker allele frequencies than alternative metrics for which there is no probability theory. This robustness is confirmed for six alternatives in eight samples. In none of these 48 tests was the residual variance as small as for rho. Overall, efficiency was less than 80% for all alternatives, and less than 30% for two of them. Efficiency of alternatives did not increase when information was estimated simultaneously. The swept radius within which substantial values of rho are conserved lies between 385 and 893 kb, but deviation of parameters between measures is enormously significant. The large effort now being devoted to allelic association has little value unless the rho metric with the strongest theoretical basis and least sensitivity to marker allele frequencies is used for mapping of marker association and localization of disease loci. PMID:11309498

Morton, N E; Zhang, W; Taillon-Miller, P; Ennis, S; Kwok, P Y; Collins, A

2001-04-24

61

Mutator alleles of yeast DNA polymerase ?  

Microsoft Academic Search

The yeast REV3 gene encodes the catalytic subunit of DNA polymerase zeta (pol ?), a B family polymerase that performs mutagenic DNA synthesis in cells. To probe pol ? mutagenic functions, we generated six mutator alleles of REV3 with amino acid replacements for Leu979, a highly conserved residue inferred to be at the pol ? active site. Replacing Leu979 with

Ayako N. Sakamoto; Jana E. Stone; Grace E. Kissling; Scott D. McCulloch; Youri I. Pavlov; Thomas A. Kunkel

2007-01-01

62

Haras rare alleles in breast cancer susceptibility  

Microsoft Academic Search

Over the last several years, evidence has accumulated to support the idea that rare Ha-ras polymorphisms are associated with inherited susceptibility to certain human cancers. A recent epidemiologic study conducted at our institution found a significant association specifically with breast cancer, although the mechanism underlying this relationship remains unclear. We have proposed that rare Ha-ras alleles are markers of a

Kathleen Conway; Sharon Edmiston; Daniel B. Fried; Barbara S. Hulka; Peter A. Garrett; Edison T. Liu

1995-01-01

63

APOE2 allele increased in tardive dyskinesia.  

PubMed

Ninety-seven inpatients with tardive dyskinesia (average AIMS score = 13), the majority of whom were schizophrenic, were studied. Forty patients were Caucasian, and 57 were African-American. The APOE genotypes of these patients were compared to previously published genotypes of controls and with previously published studies of APOE genotypes in patients with schizophrenia. There were no significant differences in APOE allele frequencies comparing the African-American tardive dyskinesia population and the African-American control groups. In contrast, significant (< 0.05) P values were obtained comparing the Caucasian tardive dyskinesia population to the Caucasian controls, when comparing allele frequencies and genotypic frequencies. This study suggests that Caucasians bearing an APOE2 allele are at increased risk of developing tardive dyskinesia, whereas African-Americans are not. APOE genotype-specific risks of both tardive dyskinesia and Alzheimer's disease that vary across populations could be due to recruitment of patients or controls or could be due to modifying effects of differing genetic or environmental backgrounds. The mechanism by which the APOE2 allele increases risk of tardive dyskinesia is not known. Further information about the mechanisms of increased risk of tardive dyskinesia could result in stratification of prescribing practices weighing the costs of medications against the relative risk of side effects. PMID:16261623

Halford, Jonathan; Mazeika, Gandis; Slifer, Susan; Speer, Marcy; Saunders, Ann M; Strittmatter, Warren J; Morgenlander, Joel C

2006-04-01

64

Population stratification and spurious allelic association  

Microsoft Academic Search

3-8 Considerable effort is being expended in attempts to detect genetic loci contributing to complex diseases. 9 Association and linkage studies comprise the two dominant strategies: association studies aim to find disease-predisposing alleles at the population level; and linkage studies focus on familial segregation. Although both strategies have compelling strengths, association analyses are more widely done and likely to spread

Lon R Cardon

65

Expression of human PTPN22 alleles.  

PubMed

Considering the female predominance in most of the autoimmune disorders that associate with the PTPN22 Trp620 variant and the complexity by which this variant influences immunologic tolerance, the objective of this study was to ascertain if the allele-specific expression of the disease-associated Arg620Trp polymorphism is affected by cis-acting or sex-specific trans-acting factor/s (e.g. sex-hormones). The use of the allele-specific transcript quantification of the Arg620Trp encoding 1858T polymorphism revealed no difference in the expression of the 1858C- and T-alleles in non-stimulated peripheral blood mononuclear cells (PBMCs) from non-pregnant female subjects, male subjects or pregnant female subjects in first or third trimester (P=0.70), respectively. While the transcription of PTPN22 in anti-CD3/anti-CD28 stimulated PBMCs increased fourfold (P<0.0001) and 13-fold (P<0.0001) after 48 and 72 h of activation, respectively, the expression of PTPN22 1858C- and T-alleles increased to the same extent (P=0.64). The present result essentially excludes such phenomena as a partial explanation for the female predominance in most of the autoimmune disorders that associate with the PTPN22 Trp620 variant. PMID:17230194

Nielsen, C; Barington, T; Husby, S; Lillevang, S T

2007-03-01

66

Evolutionary Dynamics of Sporophytic Self-Incompatibility Alleles in Plants  

PubMed Central

The stationary frequency distribution and allelic dynamics in finite populations are analyzed through stochastic simulations in three models of single-locus, multi-allelic sporophytic self-incompatibility. The models differ in the dominance relationships among alleles. In one model, alleles act codominantly in both pollen and style (SSIcod), in the second, alleles form a dominance hierarchy in pollen and style (SSIdom). In the third model, alleles interact codominantly in the style and form a dominance hierarchy in the pollen (SSIdomcod). The SSIcod model behaves similarly to the model of gametophytic self-incompatibility, but the selection intensity is stronger. With dominance, dominant alleles invade the population more easily than recessive alleles and have a lower frequency at equilibrium. In the SSIdom model, recessive alleles have both a higher allele frequency and higher expected life span. In the SSIdomcod model, however, loss due to drift occurs more easily for pollen-recessive than for pollen-dominant alleles, and therefore, dominant alleles have a higher expected life span than the more recessive alleles. The process of allelic turnover in the SSIdomcod and SSIdom models is closely approximated by a random walk on a dominance ladder. Implications of the results for experimental studies of sporophytic self-incompatibility in natural populations are discussed.

Schierup, M. H.; Vekemans, X.; Christiansen, F. B.

1997-01-01

67

Pharmacogenetic landscape of clopidogrel in north Indians suggest distinct interpopulation differences in allele frequencies.  

PubMed

Aim: Clopidogrel, a widely used antiplatelet drug, exhibits high interindividual variability; more than 80% of which could be explained by genetic polymorphisms. We built an allele frequency map of variants affecting clopidogrel response in north Indians. Materials & methods: We mined a cross-sectional population-scale genome-wide dataset of 2128 Indo-Europeans residing in north India for presence of variants associated with pharmacogenetics of clopidogrel. Results: Our analysis reveals significant differences in population-scale allele frequencies between Indians and the global population. Indians had a higher allele frequency for variants in the CYP2C9*2, CYP2C9*3 and P2RY1 genes whereas lower frequency for the ABCB1, CYP1A2, CYP2C19*2C, CYP3A5 and PON1 genes compared with the global population. Furthermore, from our study we proposed a model to explain the higher prevalence of clopidogrel metabolizers in north Indians. Conclusion: This is the largest population-scale genetic epidemiology study that provides a high-resolution map of variants associated with clopidogrel response that could be potentially valuable to clinicians to rationally plan appropriate dosage for therapy in resource poor conditions based on population level allele frequencies. Original submitted 29 August 2013; Revision submitted 2 December 2013. PMID:24798721

Giri, Anil K; Khan, Nazir M; Basu, Analabha; Tandon, Nikhil; Scaria, Vinod; Bharadwaj, Dwaipayan

2014-04-01

68

Ethnic Variation in Allele Distribution of the Androgen Receptor (AR) (CAG)n Repeat  

PubMed Central

The androgen receptor (AR) is important in reproductive organ development, as well as tissue homeostasis of the pancreas, liver, and skeletal muscle in adulthood. The trinucleotide (CAG)n repeat polymorphism in exon 1 of the AR gene is thought to regulate AR activity, with longer alleles conferring reduced receptor activity. Therefore, the evaluation of the allelic distribution of the AR (CAG)n repeat in various ethnic groups is crucial in understanding the interindividual variability in AR activity. We evaluated ethnic variation of this AR polymorphism by genotyping individuals from the multiethnic Hyperglycemia and Adverse Pregnancy Outcome study cohort. We genotyped 4421 Caucasian mothers and 3365 offspring of European ancestry; 1494 Thai mothers and 1742 offspring; 1119 Afro-Caribbean mothers and 1142 offspring; and 780 Hispanic mothers and 770 offspring of Mexican ancestry from Bellflower, California. The distributions of (CAG)n alleles among all 4 ethnic groups are significantly different (P < .0001). Pairwise tests confirmed significant differences between each pair of ethnicities tested (P < 10?28). The relative AR (CAG)n repeat length in the different groups was as follows: Afro-Caribbean (shortest repeat lengths and greatest predicted AR activity) < Caucasian < Hispanic < Thai (longest repeat length and lowest predicted AR activity). Significant interethnic differences in the allele frequencies of the AR exon 1 (CAG)n polymorphism exist. Our results suggest that there may be potential ethnic differences in androgenic pathway activity and androgen sensitivity.

Ackerman, Christine M.; Lowe, Lynn P.; Lee, Hoon; Hayes, M. Geoffrey; Dyer, Alan R.; Metzger, Boyd E.; Lowe, William L.; Urbanek, Margrit

2013-01-01

69

HIV-1 disease-influencing effects associated with ZNRD1, HCP5 and HLA-C alleles are attributable mainly to either HLA-A10 or HLA-B*57 alleles.  

PubMed

A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis. PMID:18982067

Catano, Gabriel; Kulkarni, Hemant; He, Weijing; Marconi, Vincent C; Agan, Brian K; Landrum, Michael; Anderson, Stephanie; Delmar, Judith; Telles, Vanessa; Song, Li; Castiblanco, John; Clark, Robert A; Dolan, Matthew J; Ahuja, Sunil K

2008-01-01

70

Allele-specific silencing of the dominant disease allele in sialuria by RNA interference  

Microsoft Academic Search

Dominant disease alleles are attractive therapeutic targets for allele-specific gene silencing by small interfering RNA (siRNA). Sialuria is a dominant disorder caused by missense mutations in the allosteric site of GNE, coding for the rate-limiting enzyme of sialic acid biosynthesis, UDP-GlcNAc 2-epimerase\\/ManNAc kinase. The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes excessive production of free

Riko D. Klootwijk; Paul J. M. Savelkoul; Carla Ciccone; Irini Manoli; Natasha J. Caplen; Donna M. Krasnewich; William A. Gahl; Marjan Huizing

2008-01-01

71

Allelic or NonAllelic? Complementation Studies with Bacteriophage T4 rII Mutations  

Microsoft Academic Search

An easy-to-perform exercise to demonstrate complementation is presented. Complementation tests are used to determine whether mutations affecting the same phenotype are within the same gene (allelic) or in different genes (non-allelic). In this exercise, mutations in the rII locus of bacteriophage T4 are studied. Host E. coli bacteria are co-infected with different T4 mutant phage. If two mutations are in

Susan J. Karcher

72

Use of allele scores as instrumental variables for Mendelian randomization  

PubMed Central

Background An allele score is a single variable summarizing multiple genetic variants associated with a risk factor. It is calculated as the total number of risk factor-increasing alleles for an individual (unweighted score), or the sum of weights for each allele corresponding to estimated genetic effect sizes (weighted score). An allele score can be used in a Mendelian randomization analysis to estimate the causal effect of the risk factor on an outcome. Methods Data were simulated to investigate the use of allele scores in Mendelian randomization where conventional instrumental variable techniques using multiple genetic variants demonstrate ‘weak instrument’ bias. The robustness of estimates using the allele score to misspecification (for example non-linearity, effect modification) and to violations of the instrumental variable assumptions was assessed. Results Causal estimates using a correctly specified allele score were unbiased with appropriate coverage levels. The estimates were generally robust to misspecification of the allele score, but not to instrumental variable violations, even if the majority of variants in the allele score were valid instruments. Using a weighted rather than an unweighted allele score increased power, but the increase was small when genetic variants had similar effect sizes. Naive use of the data under analysis to choose which variants to include in an allele score, or for deriving weights, resulted in substantial biases. Conclusions Allele scores enable valid causal estimates with large numbers of genetic variants. The stringency of criteria for genetic variants in Mendelian randomization should be maintained for all variants in an allele score.

Burgess, Stephen; Thompson, Simon G

2013-01-01

73

Genetic susceptibility associated with rare HRAS1 variable number of tandem repeats alleles in Spanish non-small cell lung cancer patients.  

PubMed

The highly polymorphic HRAS1 variable number of tandem repeats (VNTR), which maps 1 kb downstream from the human H-ras1 gene, has been described as an inherited predisposing factor in many human cancers. Here, we investigated the association between the presence of rare HRAS1 minisatellite alleles and lung cancer in the population studied. Four hundred sixty-six HRAS1 VNTR alleles from 233 lung cancer patients and 892 alleles from 446 unaffected controls were typed using PCR-long agarose gel electrophoresis assay of peripheral blood lymphocyte DNA. Rare alleles were differentiated from common alleles (a1, a2, a3, and a4) by shifts in electrophoretic mobility. Odds ratio was calculated to evaluate increased risk of lung cancer associated to the presence of rare HRAS1 alleles. A higher percentage of rare HRAS1 VNTR alleles in lung cancer patients than in unaffected controls (32.7 versus 21.9%) was confirmed. The presence of rare alleles was associated with an increased risk of lung cancer (odds ratio = 1.68; P < or = 0.0001), indicating a genetic predisposition to lung cancer. No differences based on other clinicopathological variables were observed. Furthermore, a meta-analysis showed a higher distribution of rare alleles in our study of Caucasian Spaniards than was found in other studies of American and Northern European Caucasian populations. We conclude that the presence of rare HRAS1 VNTR alleles may be an inherited predisposing factor in lung cancer. This presence can be easily determined from peripheral blood samples by PCR-based methods. Furthermore, interracial variations in allele frequencies and variations between Caucasian subpopulations suggest that genetic variations may be involved in susceptibility to lung oncogenesis, especially in certain ethnic populations. PMID:10430091

Rosell, R; Calvo, R; Sánchez, J J; Maurel, J; Guillot, M; Monzó, M; Núñez, L; Barnadas, A

1999-07-01

74

Allelic association in the FRAX region.  

PubMed

The sex chromosomes enable direct determination of haplotypes, and the analysis of 8 microsatellite markers from the FRAX region on Xq27-q28 contributes 7219 independent haplotypes from our study in Wessex. Allelic association increases with frequency of alleles, and is less for trinucleotide than dinucleotide repeats. The estimate of epsilon, the exponential decline of association with distance in kb, is 0.0023. The swept radius 1/epsilon estimates the distance at which disequilibrium falls to e(-1) approximately .37 of its initial value. The current study estimates the swept radius of association to be 433 kb, which is surprisingly close to estimates for SNPs, and suggests that a marker density of 1/100 kb should be powerful in regions such as FRAX. An explanation for these results is offered, and some speculations made about what will be found when SNPs are subjected to an equally intensive study in multiple regions. PMID:11281215

Ennis, S; Collins, A; Murray, A; Macpherson, J N; Morton, N E

2000-11-01

75

Near fixation of 374l allele frequencies of the skin pigmentation gene SLC45A2 in Africa.  

PubMed

The L374F polymorphism of the SLC45A2 gene, encoding the membrane-associated transporter protein that plays an important role in melanin synthesis, has been suggested to be associated with skin color in human populations. In this study, the detailed distribution of the 374f and 374l alleles has been investigated in 2,581 unrelated subjects from 36 North, East, West, and Central African populations. We found once more the highly significant (p < 0.001) correlation coefficient (r = 0.957) cline of 374f frequencies with degrees of latitude in European and North African populations. Almost all the African populations located below 16° of latitude are fixed for the 374l allele. Peul, Toucouleur, and Soninké populations have 374l allele frequencies of 0.06, 0.03, and 0.03, respectively. PMID:23660638

Lucotte, Gérard; Yuasa, Isao

2013-10-01

76

Allelic frequencies and statistical data obtained from 12 codis STR loci in an admixed population of the Brazilian Amazon  

PubMed Central

The allelic frequencies of 12 short tandem repeat loci were obtained from a sample of 307 unrelated individuals living in Macapá, a city in the northern Amazon region, Brazil. These loci are the most commonly used in forensics and paternity testing. Based on the allele frequency obtained for the population of Macapá, we estimated an interethnic admixture for the three parental groups (European, Native American and African) of, respectively, 46%, 35% and 19%. Comparing these allele frequencies with those of other Brazilian populations and of the Iberian Peninsula population, no significant distances were observed. The interpopulation genetic distances (FST coefficients) to the present database ranged from FST = 0.0016 between Macapá and Belém to FST = 0.0036 between Macapá and the Iberian Peninsula.

da Costa Francez, Pablo Abdon; Rodrigues, Elzemar Martins Ribeiro; Frazao, Gleycianne Furtado; dos Reis Borges, Nathalia Danielly; dos Santos, Sidney Emanuel Batista

2011-01-01

77

Allelic frequencies and statistical data obtained from 12 codis STR loci in an admixed population of the Brazilian Amazon.  

PubMed

The allelic frequencies of 12 short tandem repeat loci were obtained from a sample of 307 unrelated individuals living in Macapá, a city in the northern Amazon region, Brazil. These loci are the most commonly used in forensics and paternity testing. Based on the allele frequency obtained for the population of Macapá, we estimated an interethnic admixture for the three parental groups (European, Native American and African) of, respectively, 46%, 35% and 19%. Comparing these allele frequencies with those of other Brazilian populations and of the Iberian Peninsula population, no significant distances were observed. The interpopulation genetic distances (F(ST) coefficients) to the present database ranged from F(ST) = 0.0016 between Macapá and Belém to F(ST) = 0.0036 between Macapá and the Iberian Peninsula. PMID:21637540

da Costa Francez, Pablo Abdon; Rodrigues, Elzemar Martins Ribeiro; Frazão, Gleycianne Furtado; Dos Reis Borges, Nathalia Danielly; Dos Santos, Sidney Emanuel Batista

2011-01-01

78

Allele frequencies of gene polymorphisms related to economic traits in Bos taurus and Bos indicus cattle breeds.  

PubMed

Allele frequencies of 10 representative polymorphisms for beef and milk traits were investigated for a total of 240 animals from Bos taurus and Bos indicus breeds, including two Japanese groups (Japanese Black and Japanese Brown), two East Asian groups (Korean and Mongolian), three European groups (Holstein, Angus and Hereford) and a Bos indicus group in South Asia (Myanmar, Laos and Cambodia). The Japanese Black revealed unique genetic construction in GH, FASN and SREBP-1 and the other Asian populations show intermediate frequencies between European and Japanese populations. The Bos indicus group showed low favorable allele frequencies in most of the genes. The study showed the variability and distribution of 10 genes affecting economic traits among world representative cattle breeds. The genetic information would contribute to elucidating the genetic background for worldwide cattle breeds and the possibility of improvement using the markers. PMID:22111625

Kaneda, Makoto; Lin, Bang Zhong; Sasazaki, Shinji; Oyama, Kenji; Mannen, Hideyuki

2011-12-01

79

HLA-DRB1 Alleles Are Associated with the Susceptibility to Sporadic Parkinson's Disease in Chinese Han Population  

PubMed Central

Immune disorders may play an important role in the pathogenesis of Parkinson's disease (PD). Recently, polymorphisms in the HLA-DR region have been found to be associated with sporadic PD in European ancestry populations. However, polymorphisms in the HLA complex are highly variable with ethnic and geographic origin. To explore the relationships between polymorphisms of the HLA-DR region and sporadic PD in Chinese Han population, we genotyped 567 sporadic PD patients and 746 healthy controls in two independent series for the HLA-DRB1 locus with Polymerase chain reaction-sequence based typing(PCR-SBT). The ?2 test was used to evaluate the distribution of allele frequencies between the patients and healthy controls. The impact of HLA-DRB1 alleles on PD risk was estimated by unconditional logistic regression. We found a significant higher frequency of HLA-DRB1*0301 in sporadic PD patients than in healthy controls and a positive association, which was independent of onset age, between HLA-DRB1*0301 and PD risk. Conversely, a lower frequency of HLA-DRB1*0406 was found in sporadic PD patients than in healthy controls, with a negative association between HLA-DRB1*0406 and PD risk. Furthermore, a meta-analysis involving 195205 individuals was conducted to summarize the frequencies of these two alleles in populations from various ethnic regions, we found a higher frequency of HLA-DRB1*0301, but a lower frequency of HLA-DRB1*0406 in European ancestry populations than that in Asians, this was consistent with the higher prevalence of sporadic PD in European ancestry populations. Based on these results, we speculate that HLA-DRB1 alleles are associated with the susceptibility to sporadic PD in Chinese Han population, among them HLA-DRB1*0301 is a risk allele while the effect of HLA-DRB1*0406 deserves debate.

Sun, Congcong; Wei, Lei; Luo, Feifei; Li, Yi; Li, Jiaobiao; Zhu, Feiqi; Kang, Ping; Xu, Rensi; Xiao, LuLu; Liu, Zhuolin; Xu, Pingyi

2012-01-01

80

Evaluation of Allele-Specific Somatic Changes of Genome-Wide Association Study Susceptibility Alleles in Human Colorectal Cancers  

PubMed Central

Background Tumors frequently exhibit loss of tumor suppressor genes or allelic gains of activated oncogenes. A significant proportion of cancer susceptibility loci in the mouse show somatic losses or gains consistent with the presence of a tumor susceptibility or resistance allele. Thus, allele-specific somatic gains or losses at loci may demarcate the presence of resistance or susceptibility alleles. The goal of this study was to determine if previously mapped susceptibility loci for colorectal cancer show evidence of allele-specific somatic events in colon tumors. Methods We performed quantitative genotyping of 16 single nucleotide polymorphisms (SNPs) showing statistically significant association with colorectal cancer in published genome-wide association studies (GWAS). We genotyped 194 paired normal and colorectal tumor DNA samples and 296 paired validation samples to investigate these SNPs for allele-specific somatic gains and losses. We combined analysis of our data with published data for seven of these SNPs. Results No statistically significant evidence for allele-specific somatic selection was observed for the tested polymorphisms in the discovery set. The rs6983267 variant, which has shown preferential loss of the non-risk T allele and relative gain of the risk G allele in previous studies, favored relative gain of the G allele in the combined discovery and validation samples (corrected p-value?=?0.03). When we combined our data with published allele-specific imbalance data for this SNP, the G allele of rs6983267 showed statistically significant evidence of relative retention (p-value?=?2.06×10?4). Conclusions Our results suggest that the majority of variants identified as colon cancer susceptibility alleles through GWAS do not exhibit somatic allele-specific imbalance in colon tumors. Our data confirm previously published results showing allele-specific imbalance for rs6983267. These results indicate that allele-specific imbalance of cancer susceptibility alleles may not be a common phenomenon in colon cancer.

Gerber, Madelyn M.; Hampel, Heather; Schulz, Nathan P.; Fernandez, Soledad; Wei, Lai; Zhou, Xiao-Ping; de la Chapelle, Albert; Toland, Amanda Ewart

2012-01-01

81

Comprehensive phenotype of the p.Arg420his allelic form of spinocerebellar ataxia type 13.  

PubMed

The p.Arg420His allelic form of spinocerebellar ataxia type 13 has been reported in a large Filipino kindred, as well as three European index cases, one with an affected offspring. Haplotype analysis has confirmed independent mutational events. All individuals share adult-onset, predominantly cerebellar signs and a slowly progressive course. However, a comprehensive phenotypic description has yet to be published on SCA13(p.Arg420His). In this study, we present the results of a detailed neurological clinical and diagnostic testing on 21 mutation-positive members of a four-generation Filipino family to further define this disease, aiding diagnosis and prognosis. PMID:23912307

Subramony, S H; Advincula, Joel; Perlman, Susan; Rosales, Raymond L; Lee, Lillian V; Ashizawa, Tetsuo; Waters, Michael F

2013-12-01

82

SIBLING family genes and bone mineral density: Association and allele-specific expression in humans.  

PubMed

Osteoporosis is a common complex disorder with reduced bone mineral density (BMD) and increased susceptibility to fracture. Peak BMD is one of the primary determinants of osteoporotic fracture risk, and is under substantial genetic control. Extracellular matrix, a major component of the bone, influences BMD by regulating mineral deposition and maintaining cellular activity. It contains several SIBLING family proteins, null mutations of which cause mineralization defects in humans. In this study, we tested 59 single-nucleotide polymorphisms (SNPs) located in the 5 SIBLING family genes (DSPP, DMP1, IBSP, MEPE and SPP1) for association with normal variation in peak BMD in healthy men and women. We measured femoral neck (FN) and lumbar spine (LS) areal BMD by dual energy x-ray absorptiometry (DXA) in 1692 premenopausal European-American women, 512 premenopausal African-American women and 715 European-American men. SNPs were tested for association with FN and LS-BMD in the 3 subsamples. In the European-American women, we observed association (p?0.005) with LS-BMD for SNPs in DSPP, IBSP and MEPE, and for FN-BMD with SNPs in DMP1 and IBSP. Allele-specific regulation of gene expression (ASE) is an important mechanism in which an allele giving rise to modest influence in transcript abundance might result in a predisposition to disease. To identify whether there was ASE of SIBLING family genes at these SNPs, we examined 52 human bone samples obtained from the femoral neck during surgical hip replacement (27 female, 25 male; 44 European-American and 8 African-American). We observed unidirectional ASE for the IBSP gene, with lower expression of the G allele compared to the A allele for SNP rs17013181. Our data suggest that SNPs within the SIBLING genes may contribute to normal variation of peak BMD. Further studies are necessary to identify the functional variants and to determine the mechanisms underlying the differences in ASE and how these differences relate to the pathophysiology of osteoporosis. PMID:24747200

Alam, Imranul; Padgett, Leah R; Ichikawa, Shoji; Alkhouli, Mohammed; Koller, Daniel L; Lai, Dongbing; Peacock, Munro; Xuei, Xiaoling; Foroud, Tatiana; Edenberg, Howard J; Econs, Michael J

2014-07-01

83

Mutant maize variety containing the glt1-1 allele  

DOEpatents

A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating.

Nelson, Oliver E. (Cross Plains, WI); Pan, David (Madison, WI)

1994-01-01

84

Mutant maize variety containing the glt1-1 allele  

DOEpatents

A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating. 2 figs.

Nelson, O.E.; Pan, D.

1994-07-19

85

Common allele on chromosome 9 associated with coronary heart disease  

US Patent & Trademark Office Database

Disclosed are methods and compositions for determining whether a person carries an allele associated with increased risk for coronary atherosclerosis by determining whether the person has had RA-CHR9 allele, such as by determining whether the person has an RA-CHR9 allele-associated single nucleotide polymorphism (SNP).

2011-02-08

86

Leveraging Information Across HLA Alleles\\/Supertypes Improves Epitope Prediction  

Microsoft Academic Search

We present a model for predicting HLA class I restricted CTL epitopes. In contrast to almost all other work in this area, we train a single model on epitopes from all HLA alleles and supertypes, yet re- tain the ability to make epitope predictions for specific HLA alleles. We are therefore able to leverage data across all HLA alleles and\\/or

David Heckerman; Carl Myers Kadie; Jennifer Listgarten

2006-01-01

87

A Newly Characterized HLA DQbeta Allele Associated with Pemphigus Vulgaris  

Microsoft Academic Search

The inheritance of particular alleles of major histocompatibility complex class II genes increases the risk for various human autoimmune diseases; however, only a small percentage of individuals having an allele associated with susceptibility develop disease. The identification of allelic variants more precisely correlated with disease susceptibility would greatly facilitate clinical screening and diagnosis. Oligonucleotide-primed gene amplification in vitro was used

Animesh A. Sinha; Chaim Brautbar; Fanny Szafer; Adam Friedmann; Eli Tzfoni; John A. Todd; Lawrence Steinman; Hugh O. McDevitt

1988-01-01

88

Kappa chain monoallelic demethylation and the establishment of allelic exclusion.  

PubMed

Allelic exclusion in kappa light-chain synthesis is thought to result from a feedback mechanism by which the expression of a functional kappa light chain on the surface of the B cell leads to an intracellular signal that down-regulates the V(D)J recombinase, thus precluding rearrangement of the other allele. Whereas such a feedback mechanism clearly plays a role in the maintenance of allelic exclusion, here we provide evidence suggesting that the initial establishment of allelic exclusion involves differential availability of the two kappa alleles for rearrangement. Analysis of kappa+ B-cell populations and of individual kappa+ B cells that have rearranged only one allele demonstrates that in these cells, critical sites on the rearranged allele are unmethylated, whereas the nonrearranged allele remains methylated. This pattern is apparently generated by demethylation that is initiated at the small pre-B cell stage, on a single allele, in a process that occurs prior to rearrangement and requires the presence in cis of both the intronic and 3' kappa enhancers. Taken together with data demonstrating that undermethylation is required for rearrangement, these results indicate that demethylation may actually underly the process of allelic exclusion by directing the initial choice of a single kappa allele for rearrangement. PMID:9637682

Mostoslavsky, R; Singh, N; Kirillov, A; Pelanda, R; Cedar, H; Chess, A; Bergman, Y

1998-06-15

89

Allelic genealogies in sporophytic self-incompatibility systems in plants.  

PubMed Central

Expectations for the time scale and structure of allelic genealogies in finite populations are formed under three models of sporophytic self-incompatibility. The models differ in the dominance interactions among the alleles that determine the self-incompatibility phenotype: In the SSIcod model, alleles act codominantly in both pollen and style, in the SSIdom model, alleles form a dominance hierarchy, and in SSIdomcod, alleles are codominant in the style and show a dominance hierarchy in the pollen. Coalescence times of alleles rarely differ more than threefold from those under gametophytic self-incompatibility, and transspecific polymorphism is therefore expected to be equally common. The previously reported directional turnover process of alleles in the SSIdomcod model results in coalescence times lower and substitution rates higher than those in the other models. The SSIdom model assumes strong asymmetries in allelic action, and the most recessive extant allele is likely to be the most recent common ancestor. Despite these asymmetries, the expected shape of the allele genealogies does not deviate markedly from the shape of a neutral gene genealogy. The application of the results to sequence surveys of alleles, including interspecific comparisons, is discussed.

Schierup, M H; Vekemans, X; Christiansen, F B

1998-01-01

90

Demography can favour female-advantageous alleles.  

PubMed

When female fecundity is relatively independent of male abundance, while male reproduction is proportional to female abundance, females have a larger effect on population dynamics than males (i.e. female demographic dominance). This population dynamic phenomenon might not appear to influence evolution, because male and female genomes still contribute equally much to the next generation. However, here we examine two evolutionary scenarios to provide a proof of principle that spatial structure can make female demographic dominance matter. Our two simulation models combine dispersal evolution with local adaptation subjected to intralocus sexual conflict and environmentally driven sex ratio biases, respectively. Both models have equilibria where one environment (without being intrinsically poorer) has so few reproductive females that trait evolution becomes disproportionately determined by those environments where females survive better (intralocus sexual conflict model), or where daughters are overproduced (environmental sex determination model). Surprisingly, however, the two facts that selection favours alleles that benefit females, and population growth is improved when female fitness is high, together do not imply that all measures of population performance are improved. The sex-specificity of the source-sink dynamics predicts that populations can evolve to fail to persist in habitats where alleles do poorly when expressed in females. PMID:25056617

Harts, Anna M F; Schwanz, Lisa E; Kokko, Hanna

2014-09-01

91

Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere's disease.  

PubMed

Toll-like receptors trigger the innate immune response by activating various cell types such us macrophages and lymphocytes. We genotyped SNV of TLR3, TRL7, TLR8 and TLR10 in 863 Spanish and 150 Italian patients with Meniere's disease (MD) and 1,013 controls by using Taqman assays. Real-Time qPCR was used to measure the expression level of TLR10 in peripheral blood leukocytes. The overall dataset showed that the C allele and the CC genotype of rs11096955 in TLR10 gene were more commonly observed in controls than patients (corrected p = 1 × 10(-3), OR = 0.68 [95 % confidence interval, 0.54-0.84] for CC genotype; corrected p = 1.5 × 10(-5), OR = 0.75 [0.66-0.85] for allele C). Moreover, the CC genotype was more frequent in patients with uni- (19 %) than bilateral sensorineural hearing loss (SNHL) (13 %). Logistic regression demonstrated that the time since the onset of MD, Tumarkin crises, hearing stage and rs11096955 were independent factors influencing the risk of bilateral SNHL. In addition, rs11096955 influenced hearing loss progression in patients with bilateral MD. No change in expression of TLR10 was observed according to CC, CA or AA genotypes. Our data suggest that allelic variants of TLR10 gene may influence the susceptibility and time-course of hearing loss of MD in the European population. PMID:23370977

Requena, Teresa; Gazquez, Irene; Moreno, Antonia; Batuecas, Angel; Aran, Ismael; Soto-Varela, Andres; Santos-Perez, Sofia; Perez, Nicolas; Perez-Garrigues, Herminio; Lopez-Nevot, Alicia; Martin, Eduardo; Sanz, Ricardo; Perez, Paz; Trinidad, Gabriel; Alarcon-Riquelme, Marta E; Teggi, Roberto; Zagato, Laura; Lopez-Nevot, Miguel A; Lopez-Escamez, Jose A

2013-05-01

92

DRB1 alleles in polymyalgia rheumatica and rheumatoid arthritis in southern France.  

PubMed

To investigate the association of HLA-DRB1 alleles with polymyalgia rheumatica (PMR) and rheumatoid arthritis (RA), 55 patients with PMR without giant cell arteritis, 203 patients with RA and 230 controls, all from the European population of Marseille, were HLA-DRB1 genotyped by PCR-SSO. HLA-DRB1*01 was significantly increased in both the PMR and RA groups compared to controls (35% versus 17%, P(c) < 0.05, and 41% versus 17%, P(c) < 0.001, respectively). HLA-DRB1*04 was significantly increased in the RA group compared to controls (48% versus 23%, P(c) < 0.001) but not in the PMR group. HLA-DRB1*04 subtype frequencies were significantly different between PMR patients and RA patients. Shared epitope-positive HLA-DRB1*04 alleles (DRB1*0401, 0404, 0405, 0408) were significantly overrepresented in RA patients compared to PMR patients and shared epitope-negative HLA-DRB1*04 alleles were overrepresented in PMR patients compared to RA patients. In conclusion, in the Mediterranean population studied, HLA-DRB1*01 is associated with RA and PMR whereas HLA-DRB1*04 is associated with RA only. PMID:11251689

Reviron, D; Foutrier, C; Guis, S; Mercier, P; Roudier, J

2001-02-01

93

Allelic Interactions Heritably Alter the Activity of a Metastable Maize Pl Allele  

PubMed Central

The maize pl locus encodes a transcriptional activator of anthocyanin biosynthetic genes. The Pl-Rhoades (Pl-Rh) allele confers robust purple anthocyanin pigment in several tissues. Spontaneous derivatives of Pl-Rh, termed Pl'-mahogany (Pl'-mah), arise that confer reduced pigment and are meiotically heritable. These derivatives influence other Pl-Rh alleles such that only Pl'-mah alleles are transmitted from a Pl-Rh/Pl'-mah heterozygote. Genetic crosses establish that chromosomal segregation distortion does not explain this exclusive transmission and suggest that Pl-Rh invariably changes to Pl'-mah when exposed to Pl'-mah. Such behavior is a hallmark of paramutation. Cosegregation experiments demonstrate that this paramutagenic activity is genetically linked to the pl locus. By visually quantifying pl action through successive crosses, we find that phenotypic expression is inversely related to paramutagenic strength. In addition, the paramutagenic state is metastable; reversion to a nonparamutagenic Pl-Rh state can occur. The behavior of Pl-Rh is unique, yet it shares characteristics with paramutation at two other maize loci, b and r. Previous analysis of b and r paramutation revealed extensive differences and led to suggestions of distinct molecular mechanisms. Consideration of the common features of all three systems reinvigorates the interpretation that the mechanistic processes of these three allelic interactions are similar.

Hollick, J. B.; Patterson, G. I.; Coe-Jr., E. H.; Cone, K. C.; Chandler, V. L.

1995-01-01

94

Ten Novel HLA-DRB1 Alleles and One Novel DRB3 Allele.  

National Technical Information Service (NTIS)

Ten novel HLA-DRB1 and one DRB3 alleles are described. Eight of the variants are single-nucleotide substitutions, four resulting in an amino acid change (DRB1*1145, *1148, *0828 and *1514) and four with silent substitutions (DRB1*040504, *130103, *160502 ...

A. M. Lazaro J. Ng J. R. Moraes M. E. Moraes N. K. Steiner

2006-01-01

95

DQB1*06:02 allele specific expression varies by allelic dosage, not narcolepsy status  

PubMed Central

The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single allele HLA associations. In this study, we explored genome wide expression in peripheral white blood cells of 50 narcolepsy versus 47 controls (half of whom were DQB1*06:02 positive) and found the largest differences between the groups to be in the signal from HLA probes. Further studies of HLA-DQ expression (mRNA and protein in a subset) in 125 controls and 147 narcolepsy cases did not reveal any difference, a result we explain by the lack of proper control of allelic diversity in Affymetrix HLA probes. Rather, a clear effect of DQB1*06:02 allelic dosage on DQB1*06:02 mRNA levels (1.65 fold) and protein (1.59 fold) could be demonstrated independent of the disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes.

lachmi, Karin Weiner; Lin, Ling; Kornum, Birgitte Rahbek; Rico, Tom; Lo, Betty; Aran, Adi; Mignot, Emmanuel

2012-01-01

96

Allele-specific disparity in breast cancer  

PubMed Central

Background In a cancer cell the number of copies of a locus may vary due to amplification and deletion and these variations are denoted as copy number alterations (CNAs). We focus on the disparity of CNAs in tumour samples, which were compared to those in blood in order to identify the directional loss of heterozygosity. Methods We propose a numerical algorithm and apply it to data from the Illumina 109K-SNP array on 112 samples from breast cancer patients. B-allele frequency (BAF) and log R ratio (LRR) of Illumina were used to estimate Euclidian distances. For each locus, we compared genotypes in blood and tumour for subset of samples being heterozygous in blood. We identified loci showing preferential disparity from heterozygous toward either the A/B-allele homozygous (allelic disparity). The chi-squared and Cochran-Armitage trend tests were used to examine whether there is an association between high levels of disparity in single nucleotide polymorphisms (SNPs) and molecular, clinical and tumour-related parameters. To identify pathways and network functions over-represented within the resulting gene sets, we used Ingenuity Pathway Analysis (IPA). Results To identify loci with a high level of disparity, we selected SNPs 1) with a substantial degree of disparity and 2) with substantial frequency (at least 50% of the samples heterozygous for the respective locus). We report the overall difference in disparity in high-grade tumours compared to low-grade tumours (p-value < 0.001) and significant associations between disparity in multiple single loci and clinical parameters. The most significantly associated network functions within the genes represented in the loci of disparity were identified, including lipid metabolism, small-molecule biochemistry, and nervous system development and function. No evidence for over-representation of directional disparity in a list of stem cell genes was obtained, however genes appeared to be more often altered by deletion than by amplification. Conclusions Our data suggest that directional loss and amplification exist in breast cancer. These are highly associated with grade, which may indicate that they are enforced with increasing number of cell divisions. Whether there is selective pressure for some loci to be preferentially amplified or deleted remains to be confirmed.

2011-01-01

97

Detection of Borrelia burgdorferi Sensu Stricto ospC Alleles Associated with Human Lyme Borreliosis Worldwide in Non-Human-Biting Tick Ixodes affinis and Rodent Hosts in Southeastern United States  

PubMed Central

Comparative analysis of ospC genes from 127 Borrelia burgdorferi sensu stricto strains collected in European and North American regions where Lyme disease is endemic and where it is not endemic revealed a close relatedness of geographically distinct populations. ospC alleles A, B, and L were detected on both continents in vectors and hosts, including humans. Six ospC alleles, A, B, L, Q, R, and V, were prevalent in Europe; 4 of them were detected in samples of human origin. Ten ospC alleles, A, B, D, E3, F, G, H, H3, I3, and M, were identified in the far-western United States. Four ospC alleles, B, G, H, and L, were abundant in the southeastern United States. Here we present the first expanded analysis of ospC alleles of B. burgdorferi strains from the southeastern United States with respect to their relatedness to strains from other North American and European localities. We demonstrate that ospC genotypes commonly associated with human Lyme disease in European and North American regions where the disease is endemic were detected in B. burgdorferi strains isolated from the non-human-biting tick Ixodes affinis and rodent hosts in the southeastern United States. We discovered that some ospC alleles previously known only from Europe are widely distributed in the southeastern United States, a finding that confirms the hypothesis of transoceanic migration of Borrelia species.

Golovchenko, Maryna; Honig, Vaclav; Mallatova, Nadja; Krbkova, Lenka; Mikulasek, Peter; Fedorova, Natalia; Belfiore, Natalia M.; Grubhoffer, Libor; Lane, Robert S.; Oliver, James H.

2013-01-01

98

Detection of Borrelia burgdorferi sensu stricto ospC alleles associated with human lyme borreliosis worldwide in non-human-biting tick Ixodes affinis and rodent hosts in Southeastern United States.  

PubMed

Comparative analysis of ospC genes from 127 Borrelia burgdorferi sensu stricto strains collected in European and North American regions where Lyme disease is endemic and where it is not endemic revealed a close relatedness of geographically distinct populations. ospC alleles A, B, and L were detected on both continents in vectors and hosts, including humans. Six ospC alleles, A, B, L, Q, R, and V, were prevalent in Europe; 4 of them were detected in samples of human origin. Ten ospC alleles, A, B, D, E3, F, G, H, H3, I3, and M, were identified in the far-western United States. Four ospC alleles, B, G, H, and L, were abundant in the southeastern United States. Here we present the first expanded analysis of ospC alleles of B. burgdorferi strains from the southeastern United States with respect to their relatedness to strains from other North American and European localities. We demonstrate that ospC genotypes commonly associated with human Lyme disease in European and North American regions where the disease is endemic were detected in B. burgdorferi strains isolated from the non-human-biting tick Ixodes affinis and rodent hosts in the southeastern United States. We discovered that some ospC alleles previously known only from Europe are widely distributed in the southeastern United States, a finding that confirms the hypothesis of transoceanic migration of Borrelia species. PMID:23263953

Rudenko, Nataliia; Golovchenko, Maryna; Hönig, Václav; Mallátová, Nadja; Krbková, Lenka; Mikulásek, Peter; Fedorova, Natalia; Belfiore, Natalia M; Grubhoffer, Libor; Lane, Robert S; Oliver, James H

2013-03-01

99

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

100

B Cell Development under the Condition of Allelic Inclusion  

Microsoft Academic Search

Mice whose IgH alleles are engineered to encode two distinct antibody heavy (H) chains generate a normal-sized B cell compartment in which most cells stably express the two heavy chains. This demonstrates that “toxicity” of bi-allelic H chain expression and cell- autonomous mechanisms of silencing in-frame IgH gene rearrangements do not significantly contribute to allelic exclusion at the IgH locus.

Eiichiro Sonoda; Yael Pewzner-Jung; Stephan Schwers; Shinsuke Taki; Steffen Jung; Dan Eilat; Klaus Rajewsky

1997-01-01

101

Characterisation of novel S- alleles from cherry ( Prunus avium L.)  

Microsoft Academic Search

In plant populations exhibiting gametophytic self-incompatibility, individuals harbouring rare S alleles are likely to have a reproductive advantage over individuals having more common alleles. Consequently, determination\\u000a of the self-incompatibility haplotype of individuals is essential for genetic studies and the development of informed management\\u000a strategies. This study characterises six new S alleles identified in wild cherry (Prunus avium L.). Investigations to

S. P. Vaughan; R. I. Boškovi?; A. Gisbert-Climent; K. Russell; K. R. Tobutt

2008-01-01

102

A Japanese-specific allele in the GALNT11 gene  

Microsoft Academic Search

In this study, five single nucleotide polymorphisms (SNPs) in the ABCC4, FBN1, CEP152, ZNF804B, and GALNT11 genes were investigated to assess allele frequencies in 14 different populations by a novel pentaplex PCR method. All SNPs were polymorphic in East Asians, whereas mutant alleles were absent or rare in non-East Asians. The frequencies of a mutant allele in FBN1 (rs140598) showed

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

2010-01-01

103

Four novel PEPD alleles causing prolidase deficiency  

SciTech Connect

Mutations at the PEPD locus cause prolidase (an enzyme specific for proline- and hydroxyproline-terminated dipeptides) deficiency (McKusick 170100), a rare autosomal recessive disorder characterized by iminodipeptiduria, skin ulcers, mental retardation, and recurrent infections. Four PEPD mutations from five severely affected individuals were characterized by analysis of reverse-transcribed, PCR-amplified (RT-PCR) cDNA. The authors used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragments spanning all or part of exons 13-15 in three of the probands. Direct sequencing of the mutant cDNAs showed a G[yields]A, 1342 substitution (G448R) in two patients and a 3-bp deletion ([Delta]E452 or [Delta]E453) in another. In the other two probands the amplified products were of reduced size. Direct sequencing of these mutant cDNAs revealed a deletion of exon 5 in one patient and of exon 7 in the other. Intronic sequences flanking exons 5 and 7 were identified using inverse PCR followed by direct sequencing. Conventional PCR and direct sequencing then established the intron-exon borders of the mutant genomic DNA revealing two splice acceptor mutations: a G[yields]C substitution at position -1 of intron 4 and an A[yields]G substitution at position -2 of intron 6. The results indicate that the severe form of prolidase deficiency is caused by multiple PEPD alleles. In this report the authors attempt to begin the process of describing these alleles and cataloging their phenotype expression. 31 refs., 8 figs., 2 tabs.

Ledoux, P.; Scriver, C.; Hechtman, P. (McGill Univ., Montreal (Canada))

1994-06-01

104

Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease  

PubMed Central

Background: There is evidence that iron may play a role in the pathology of Alzheimer's disease (AD). There may be genetic factors that contribute to iron deposition resulting in tissue damage thus exacerbating AD. Methods: We have genotyped 269 healthy elderly controls, 191 cases with definite or probable AD, and 69 with mild cognitive impairment (MCI) from the OPTIMA cohort. Results: We have examined the interaction between the C2 variant of the transferrin (TF) gene and the C282Y allele of the haemochromatosis (HFE) gene as risk factors for developing AD. Our results showed that each of the two variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. The interaction was significant by logistic regression (p = 0.014) and by synergy factor analysis (p = 0.015, synergy factor = 5.1). Further, carriers of these two alleles plus apolipoprotein E ?4 (APOE4) were at still higher risk of AD: of the 14 tri-carriers of the three variants, identified in this study, 12 had AD and two MCI. Conclusion: We suggest that the combination of TF C2 and HFE C282Y may lead to an excess of redox-active iron and the induction of oxidative stress in neurones, which is exacerbated in carriers of APOE4. Since 4% of Northern Europeans carry the two iron-related variants and since iron overload is a treatable condition, these results merit replication.

Robson, K; Lehmann, D; Wimhurst, V; Livesey, K; Combrinck, M; Merryweather-Clar..., A; Warden, D; Smith, A

2004-01-01

105

Mutated tumor alleles are expressed according to their DNA frequency  

PubMed Central

The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

Castle, John C.; Loewer, Martin; Boegel, Sebastian; Tadmor, Arbel D.; Boisguerin, Valesca; de Graaf, Jos; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Tureci, Ozlem; Sahin, Ugur

2014-01-01

106

Parental Analysis of Introgressive Hybridization between African and European Honeybees Using Nuclear DNA Rflps  

PubMed Central

African honeybees, introduced into Brazil 33 years ago, have spread through most of South and Central America and have largely replaced the extant European bees. Due to a paucity of genetic markers, genetic interactions between European and African bees are not well understood. Three restriction fragment length polymorphisms (RFLPs), detected with random, nuclear DNA probes, are described. The polymorphisms are specific to bees of European descent, possibly specific to certain European races. Each European marker was found present at a high frequency in U.S. colonies but absent in South African bees. Previous mitochondrial DNA studies of neotropical bees have revealed negligible maternal gene flow from managed European apiaries into feral African populations. The findings reported here with nuclear DNA show paternal gene flow between the two but suggest asymmetries in levels of introgressive hybridization. Managed colonies in southern Mexico, derived from European maternal lines, showed diminished levels of the European nuclear markers, reflecting significant hybridization with African drones. The European alleles were present only at low frequencies in feral swarms from the same area. The swarms were of African maternal descent. In Venezuelan colonies, also derived from African maternal lines, the European markers were almost totally absent. The results point to limited paternal introgression from European colonies into the African honeybee populations. These findings dispute other views regarding modes of Africanization.

Hall, H. G.

1990-01-01

107

European Biodiesel Board  

NSDL National Science Digital Library

The European Biodiesel Board (EBB), a nonprofit organization, works to promote biodiesel use in the European Union (EU). The EBB website offers downloadable articles regarding biodiesel in the EU, downloadable reports from EU member states, a list of upcoming events, an EBB email information service, and basic statistical tables representing biodiesel production by country.

1969-12-31

108

European auxiliary propulsion, 1972  

NASA Technical Reports Server (NTRS)

The chemical and electric auxiliary propulsion technology of the United Kingdom, France, and West Germany is discussed in detail, and the propulsion technology achievements of Italy, India, Japan, and Russia are reviewed. A comparison is presented of Shell 405 catalyst and a European spontaneous hydrazine catalyst called CNESRO I. Finally, conclusions are drawn regarding future trends in European auxiliary propulsion technology development.

Holcomb, L. B.

1972-01-01

109

European logistics beyond 2000  

Microsoft Academic Search

European companies are facing new challenges in the next millennium. Seven trends in international logistics are outlined. These are supply chain management, globalisation of the supply chain, virtual enterprises, e-business, green logistics, strategic partnerships and new management principles. The implications for European companies are discussed and illustrated by examples from advanced companies. Asserts that it is employees and not the

Tage Skjoett-Larsen

2000-01-01

110

European Commission: Public Opinion  

NSDL National Science Digital Library

Some Scout Report readers might be wondering "How do Europeans feel about the euro?" or even "What do Europeans think about the effectiveness of different energy policies?" All of the answers to these questions (and many more) can be found on the European Commission's Public Opinion site. The site contains the results from surveys conducted with Europeans on their attitudes towards alcohol, the role of the European Union in formulating security policy, and a number of other topics. Visitors will definitely want to make their way to the Eurobarometer Interactive Search System, which allows them to choose a subject or country which is of interest to them. Visitors should also take a look at their very fine "Qualitative Studies" section, which includes reports such as "The Future of Europe" and "Integrating Gender Mainstreaming into Employment Policies". Needless to say, summaries of the reports are available in a wide range of languages, including Dutch, German, Italian, and French.

111

European Geography Test  

NSDL National Science Digital Library

European Geography Test is a collection of challenging Web-based geography exams that survey students' knowledge of European topography, European urban geography, and general map skills. Currently, this site hosts seven tests, which are available in English, Swedish, Spanish, and Dutch. Tests are divided into three different learning levels, and the focus and objectives for each test are clearly stated. The tests employ interactive maps, photographic images, pull-down menus, radio buttons, and fill-in forms to ask students a series of multiple choice, true or false, and matching questions. The questions included in European Geography Test were developed as part of an inter-university project for DGXXII of the European Commission by a consortium of instructors in the UK, Sweden, Belgium, Spain, and The Netherlands. Note: users must register at the site to take the free tests; registration requires name, email address, age, and country of residence.

112

HLA-A?3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans  

PubMed Central

BACKGROUND Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B?1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS The HLA-A?3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5×10?8). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A?3101 allele (P = 1.1×10?6). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS–TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS The presence of the HLA-A?3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.)

McCormack, Mark; Alfirevic, Ana; Bourgeois, Stephane; Farrell, John J.; Kasperaviciute, Dalia; Carrington, Mary; Sills, Graeme J.; Marson, Tony; Jia, Xiaoming; de Bakker, Paul I.W.; Chinthapalli, Krishna; Molokhia, Mariam; Johnson, Michael R.; O'Connor, Gerard D.; Chaila, Elijah; Alhusaini, Saud; Shianna, Kevin V.; Radtke, Rodney A.; Heinzen, Erin L.; Walley, Nicole; Pandolfo, Massimo; Pichler, Werner; Park, B. Kevin; Depondt, Chantal; Sisodiya, Sanjay M.; Goldstein, David B.; Deloukas, Panos; Delanty, Norman; Cavalleri, Gianpiero L.; Pirmohamed, Munir

2011-01-01

113

The human leucocyte antigen DQB1*0602 allele is associated with electroencephelograph differences in individuals with obstructive sleep apnoea syndrome.  

PubMed

Human leucocyte antigen (HLA) DQB1*0602 allele, a well-known genetic risk factor for narcolepsy, has been associated with sleep parameters in healthy subjects. We aimed to assess the association of this allele with daytime sleepiness and altered sleep electroencephalogram characteristics in the general population and in patients with obstructive sleep apnoea syndrome (OSAS). Eight hundred and ninety-four individuals from the Epidemiologic Study of Sleep were genotyped for the HLA DQB1*0602 allele. Full-night polysomnography was performed, and daytime sleepiness was analysed according to the Epworth Sleepiness Scale. HLA-DQB1*0602 allele-positive and -negative subjects in the general population, as well as in patients with OSAS, exhibited similar sleep parameters and levels of daytime sleepiness. However, spectral analysis showed that allele-positive individuals with OSAS exhibited higher theta power during sleep Stage 1 (P < 0.05) in occipital derivations, and lower delta power during sleep Stages 1 and 2 (P < 0.01) compared with individuals negative for the allele, even after correction for potential confounders as age, sex, body mass index and European ancestry. No significant differences in the electroencephalogram variables were found in individuals without OSAS. The data highlight the HLA-DQB1*0602 as a potential genetic factor influencing sleep physiology in individuals diagnosed with OSAS. PMID:23136848

Manzotte, Thais; Guindalini, Camila; Mazzotti, Diego R; Palombini, Luciana; de Souza, Altay L; Poyares, Dalva; Bittencourt, Lia R A; Tufik, Sergio

2013-04-01

114

Mutator alleles of yeast DNA polymerase ?  

PubMed Central

The yeast REV3 gene encodes the catalytic subunit of DNA polymerase zeta (pol ?), a B family polymerase that performs mutagenic DNA synthesis in cells. To probe pol ? mutagenic functions, we generated six mutator alleles of REV3 with amino acid replacements for Leu979, a highly conserved residue inferred to be at the pol ? active site. Replacing Leu979 with Gly, Val, Asn, Lys, Met or Phe resulted in yeast strains with elevated UV-induced mutant frequencies. While four of these strains had reduced survival following UV irradiation, the rev3-L979F and rev3-L979M strains had normal survival, suggesting retention of pol ? catalytic activity. UV mutagenesis in the rev3-L979F background was increased when photoproduct bypass by pol ? was eliminated by deletion of RAD30. The rev3-L979F mutation had little to no effect on mutagenesis in an ogg1? background, which cannot repair 8-oxo-guanine in DNA. UV-induced can1 mutants from rev3-L979F and rad30?rev3-L979F strains primarily contained base substitutions and complex mutations, suggesting error-prone bypass of UV photoproducts by L979F pol ?. Spontaneous mutation rates in rev3-L979F and rev3-L979M strains are elevated by about 2-fold overall and by 2- to 8-fold for C to G transversions and complex mutations, both of which are known to be generated by wild-type pol ? in vitro. These results indicate that Rev3p-Leu979 replacements reduce the fidelity of DNA synthesis by yeast pol ? in vivo. In conjunction with earlier studies, the data establish that the conserved amino acid at the active site location occupied by Leu979 is critical for the fidelity of all four yeast B family polymerases. Reduced fidelity with retention of robust polymerase activity suggests that the homologous rev3-L979F allele may be useful for analyzing pol ? functions in mammals, where REV3 deletion is lethal.

Sakamoto, Ayako N.; Stone, Jana E.; Kissling, Grace E.; McCulloch, Scott D.; Pavlov, Youri I.; Kunkel, Thomas A.

2007-01-01

115

Mutator alleles of yeast DNA polymerase zeta.  

PubMed

The yeast REV3 gene encodes the catalytic subunit of DNA polymerase zeta (pol zeta), a B family polymerase that performs mutagenic DNA synthesis in cells. To probe pol zeta mutagenic functions, we generated six mutator alleles of REV3 with amino acid replacements for Leu979, a highly conserved residue inferred to be at the pol zeta active site. Replacing Leu979 with Gly, Val, Asn, Lys, Met or Phe resulted in yeast strains with elevated UV-induced mutant frequencies. While four of these strains had reduced survival following UV irradiation, the rev3-L979F and rev3-L979M strains had normal survival, suggesting retention of pol zeta catalytic activity. UV mutagenesis in the rev3-L979F background was increased when photoproduct bypass by pol eta was eliminated by deletion of RAD30. The rev3-L979F mutation had little to no effect on mutagenesis in an ogg1Delta background, which cannot repair 8-oxo-guanine in DNA. UV-induced can1 mutants from rev3-L979F and rad30Deltarev3-L979F strains primarily contained base substitutions and complex mutations, suggesting error-prone bypass of UV photoproducts by L979F pol zeta. Spontaneous mutation rates in rev3-L979F and rev3-L979M strains are elevated by about two-fold overall and by two- to eight-fold for C to G transversions and complex mutations, both of which are known to be generated by wild-type pol zetain vitro. These results indicate that Rev3p-Leu979 replacements reduce the fidelity of DNA synthesis by yeast pol zetain vivo. In conjunction with earlier studies, the data establish that the conserved amino acid at the active site location occupied by Leu979 is critical for the fidelity of all four yeast B family polymerases. Reduced fidelity with retention of robust polymerase activity suggests that the homologous rev3-L979F allele may be useful for analyzing pol zeta functions in mammals, where REV3 deletion is lethal. PMID:17715002

Sakamoto, Ayako N; Stone, Jana E; Kissling, Grace E; McCulloch, Scott D; Pavlov, Youri I; Kunkel, Thomas A

2007-12-01

116

Divergent patterns of allelic diversity from similar origins: the case of oilseed rape (Brassica napus L.) in China and Australia.  

PubMed

Oilseed rape (Brassica napus) in Australia and China have similar origins, with introductions from Europe, Canada, and Japan in the mid 20th century, and there has been some interchange of germplasm between China and Australia since that time. Allelic diversity of 72 B. napus genotypes representing contemporary germplasm in Australia and China, including samples from India, Europe, and Canada, was characterized by 55 polymorphic simple sequence repeat (SSR) markers spanning the entire B. napus genome. Hierarchical clustering and two-dimensional multidimensional scaling identified a Chinese group (China-1) that was separated from "mixed group" of Australian, Chinese (China-2), European, and Canadian lines. A small group from India was distinctly separated from all other B. napus genotypes. Chinese genotypes, especially in the China-1 group, have inherited unique alleles from interspecific crossing, primarily with B. rapa, and the China-2 group has many alleles in common with Australian genotypes. The concept of "private alleles" is introduced to describe both the greater genetic diversity and the genetic distinctiveness of Chinese germplasm, compared with Australian germplasm, after 50 years of breeding from similar origins. PMID:18356934

Chen, S; Nelson, M N; Ghamkhar, K; Fu, T; Cowling, W A

2008-01-01

117

Admixture Mapping of an Allele Affecting Interleukin 6 Soluble Receptor and Interleukin 6 Levels  

PubMed Central

Circulating levels of inflammatory markers can predict cardiovascular disease risk. To identify genes influencing the levels of these markers, we genotyped 1,343 single-nucleotide polymorphisms (SNPs) in 1,184 African Americans from the Health, Aging and Body Composition (Health ABC) Study. Using admixture mapping, we found a significant association of interleukin 6 soluble receptor (IL-6 SR) with European ancestry on chromosome 1 (LOD 4.59), in a region that includes the gene for this receptor (IL-6R). Genotyping 19 SNPs showed that the effect is largely explained by an allele at 4% frequency in West Africans and at 35% frequency in European Americans, first described as associated with IL-6 SR in a Japanese cohort. We replicate this association (P?1.0×10-12) and also demonstrate a new association with circulating levels of a different molecule, IL-6 (P<3.4×10-5). After replication in 1,674 European Americans from Health ABC, the combined result is even more significant: P?1.0×10-12 for IL-6 SR, and P<2.0×10-9 for IL-6. These results also serve as an important proof of principle, showing that admixture mapping can not only coarsely localize but can also fine map a phenotypically important variant.

Reich, David; Patterson, Nick; Ramesh, Vijaya; De Jager, Philip L.; McDonald, Gavin J.; Tandon, Arti; Choy, Edwin; Hu, Donglei; Tamraz, Bani; Pawlikowska, Ludmila; Wassel-Fyr, Christina; Huntsman, Scott; Waliszewska, Alicja; Rossin, Elizabeth; Li, Rongling; Garcia, Melissa; Reiner, Alexander; Ferrell, Robert; Cummings, Steve; Kwok, Pui-Yan; Harris, Tamara; Zmuda, Joseph M.; Ziv, Elad

2007-01-01

118

Segregating YKU80 and TLC1 Alleles Underlying Natural Variation in Telomere Properties in Wild Yeast  

PubMed Central

In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres (<150 bp), whereas American isolates had telomeres approximately three times as long (>400 bp). Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect (TPE). Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci (QTLs) were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations (American-YKU70 and European-YKU80) resulting in very short telomeres.

Liti, Gianni; Haricharan, Svasti; Cubillos, Francisco A.; Tierney, Anna L.; Sharp, Sarah; Bertuch, Alison A.; Parts, Leopold; Bailes, Elizabeth; Louis, Edward J.

2009-01-01

119

Asynchronous replication and allelic exclusion in the immune system  

Microsoft Academic Search

The development of mature B cells involves a series of molecular decisions which culminate in the expression of a single light-chain and heavy-chain antigen receptor on the cell surface. There are two alleles for each receptor locus, so the ultimate choice of one receptor type must involve a process of allelic exclusion. One way to do this is with a

Raul Mostoslavsky; Nandita Singh; Toyoaki Tenzen; Maya Goldmit; Chana Gabay; Sharon Elizur; Peimin Qi; Benjamin E. Reubinoff; Andrew Chess; Howard Cedar; Yehudit Bergman

2001-01-01

120

Trans allele methylation and paramutation-like effects in mice  

PubMed Central

In mammals, imprinted genes have parent-of-origin–specific patterns of DNA methylation that cause allele-specific expression. At Rasgrf1 (encoding RAS protein-specific guanine nucleotide-releasing factor 1), a repeated DNA element is needed to establish methylation and expression of the active paternal allele1. At Igf2r (encoding insulin-like growth factor 2 receptor), a sequence called region 2 is needed for methylation of the active maternal allele2,3. Here we show that replacing the Rasgrf1 repeats on the paternal allele with region 2 allows both methylation and expression of the paternal copy of Rasgrf1, indicating that sequences that control methylation can function ectopically. Paternal transmission of the mutated allele also induced methylation and expression in trans of the normally unmethylated and silent wild-type maternal allele. Once activated, the wild-type maternal Rasgrf1 allele maintained its activated state in the next generation independently of the paternal allele. These results recapitulate in mice several features in common with paramutation described in plants4.

Herman, Herry; Lu, Michael; Anggraini, Melly; Sikora, Aimee; Chang, Yanjie; Yoon, Bong June; Soloway, Paul D

2009-01-01

121

Observations Suggesting Allelism of the Achondroplasia and Hypochondroplasia Genes  

Microsoft Academic Search

It is argued that there are at least two alleles at the achondroplasia locus: one responsible for classic achondroplasia and one responsible for hypochondroplasia. Homozygosity for the achondroplasia gene produces a lethal skeletal dysplasia; homozygosity for hypochondroplasia has not been described. We report here a child considered to be a genetic compound for the achondroplasia and hypochondroplasia alleles.

Victor A. McKusick; Thaddeus E. Kelly; John P. Dorst

1973-01-01

122

Identification of the MICA*070 allele by sequencing and phasing  

PubMed Central

A novel MICA allele, MICA*070, was defined by sequencing. The new allele differs from the MICA*008:04 sequence in exon 2, encoding a C instead of G corresponding to cDNA nucleotide position 183. This nucleotide substitution is predicted to encode serine instead of arginine at residue 38 of the ?1 domain of the MICA molecule.

Moran, D.; Morishima, S.; Malkki, M.; Petersdorf, E. W.

2013-01-01

123

Rescue of Progeria in Trichothiodystrophy by Homozygous Lethal Xpd Alleles  

PubMed Central

Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of “null” alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

Andressoo, Jaan-Olle; Jans, Judith; de Wit, Jan; Coin, Frederic; Hoogstraten, Deborah; van de Ven, Marieke; Toussaint, Wendy; Huijmans, Jan; Thio, H. Bing; van Leeuwen, Wibeke J; de Boer, Jan; Egly, Jean-Marc; Hoeijmakers, Jan H. J; van der Horst, Gijsbertus T. J; Mitchell, James R

2006-01-01

124

Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution  

PubMed Central

Background Cytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated. We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese?+?Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models. Results Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at ?29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity?allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices.

2014-01-01

125

Statistical Studies on Protein Polymorphism in Natural Populations. III. Distribution of Allele Frequencies and the Number of Alleles per Locus  

PubMed Central

With the aim of understanding the mechanism of maintenance of protein polymorphism, we have studied the properties of allele frequency distribution and the number of alleles per locus, using gene-frequency data from a wide range of organisms (mammals, birds, reptiles, amphibians, Drosophila and non-Drosophila invertebrates) in which 20 or more loci with at least 100 genes were sampled. The observed distribution of allele frequencies was U-shaped in all of the 138 populations (mostly species or subspecies) examined and generally agreed with the theoretical distribution expected under the mutation-drift hypothesis, though there was a significant excess of rare alleles (gene frequency, 0 ? 0.05) in about a quarter of the populations. The agreement between the mutation-drift theory and observed data was quite satisfactory for the numbers of polymorphic (gene frequency, 0.05 ? 0.95) and monomorphic (0.95 ? 1.0) alleles.—The observed pattern of allele-frequency distribution was incompatible with the prediction from the overdominance hypothesis. The observed correlations of the numbers of rare alleles, polymorphic alleles and monomorphic alleles with heterozygosity were of the order of magnitude that was expected under the mutation-drift hypothesis. Our results did not support the view that intracistronic recombination is an important source of genetic variation. The total number of alleles per locus was positively correlated with molecular weight in most of the species examined, and the magnitude of the correlation was consistent with the theoretical prediction from mutation-drift hypothesis. The correlation between molecular weight and the number of alleles was generally higher than the correlation between molecular weight and heterozygosity, as expected.

Chakraborty, Ranajit; Fuerst, Paul A.; Nei, Masatoshi

1980-01-01

126

European Population Genetic Substructure: Further Definition of Ancestry Informative Markers for Distinguishing among Diverse European Ethnic Groups  

PubMed Central

The definition of European population genetic substructure and its application to understanding complex phenotypes is becoming increasingly important. In the current study using over 4,000 subjects genotyped for 300,000 single-nucleotide polymorphisms (SNPs), we provide further insight into relationships among European population groups and identify sets of SNP ancestry informative markers (AIMs) for application in genetic studies. In general, the graphical description of these principal components analyses (PCA) of diverse European subjects showed a strong correspondence to the geographical relationships of specific countries or regions of origin. Clearer separation of different ethnic and regional populations was observed when northern and southern European groups were considered separately and the PCA results were influenced by the inclusion or exclusion of different self-identified population groups including Ashkenazi Jewish, Sardinian, and Orcadian ethnic groups. SNP AIM sets were identified that could distinguish the regional and ethnic population groups. Moreover, the studies demonstrated that most allele frequency differences between different European groups could be controlled effectively in analyses using these AIM sets. The European substructure AIMs should be widely applicable to ongoing studies to confirm and delineate specific disease susceptibility candidate regions without the necessity of performing additional genome-wide SNP studies in additional subject sets.

Tian, Chao; Kosoy, Roman; Nassir, Rami; Lee, Annette; Villoslada, Pablo; Klareskog, Lars; Hammarstrom, Lennart; Garchon, Henri-Jean; Pulver, Ann E; Ransom, Michael; Gregersen, Peter K; Seldin, Michael F

2009-01-01

127

Whole transcriptome RNA-Seq allelic expression in human brain  

PubMed Central

Background Measuring allelic RNA expression ratios is a powerful approach for detecting cis-acting regulatory variants, RNA editing, loss of heterozygosity in cancer, copy number variation, and allele-specific epigenetic gene silencing. Whole transcriptome RNA sequencing (RNA-Seq) has emerged as a genome-wide tool for identifying allelic expression imbalance (AEI), but numerous factors bias allelic RNA ratio measurements. Here, we compare RNA-Seq allelic ratios measured in nine different human brain regions with a highly sensitive and accurate SNaPshot measure of allelic RNA ratios, identifying factors affecting reliable allelic ratio measurement. Accounting for these factors, we subsequently surveyed the variability of RNA editing across brain regions and across individuals. Results We find that RNA-Seq allelic ratios from standard alignment methods correlate poorly with SNaPshot, but applying alternative alignment strategies and correcting for observed biases significantly improves correlations. Deploying these methods on a transcriptome-wide basis in nine brain regions from a single individual, we identified genes with AEI across all regions (SLC1A3, NHP2L1) and many others with region-specific AEI. In dorsolateral prefrontal cortex (DLPFC) tissues from 14 individuals, we found evidence for frequent regulatory variants affecting RNA expression in tens to hundreds of genes, depending on stringency for assigning AEI. Further, we find that the extent and variability of RNA editing is similar across brain regions and across individuals. Conclusions These results identify critical factors affecting allelic ratios measured by RNA-Seq and provide a foundation for using this technology to screen allelic RNA expression on a transcriptome-wide basis. Using this technology as a screening tool reveals tens to hundreds of genes harboring frequent functional variants affecting RNA expression in the human brain. With respect to RNA editing, the similarities within and between individuals leads us to conclude that this post-transcriptional process is under heavy regulatory influence to maintain an optimal degree of editing for normal biological function.

2013-01-01

128

Frequency of FCGR3B Alleles in Thai Blood Donors  

PubMed Central

Background Human neutrophil antigens (HNAs) are involved in autoimmune and alloimmune neutropenia and transfusion-related acute lung injury. The HNA-1 system is important in immunogenetics, and allele frequencies have been described in different populations. This study investigated the frequency of FCGR3B alleles encoding HNA-1a, HNA-1b, and HNA-1c among Thai blood donors and compared these frequencies with those previously reported for other populations. Methods Eight hundred DNA samples obtained from unrelated healthy blood donors at the National Blood Centre, Thai Red Cross Society, Bangkok, and the Blood Bank, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, were included. Samples were simultaneously typed for each FCGR3B allele using an in-house polymerase chain reaction with sequence-specific primer (PCR-SSP) technique. Results The frequencies of FCGR3B*1, FCGR3B*2, and FCGR3B*3 alleles in central Thai blood donors were 0.548, 0.452, and 0.004, respectively; only FCGR3B*1 and FCGR3B*2 alleles were found in northern Thai blood donors (0.68 and 0.32, respectively). Compared with other Asian populations, central Thais had higher frequencies of the FCGR3B*2 allele (P<0.001), while the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in northern Thais were similar to those previously reported in Taiwanese and Japanese populations. In contrast, the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in the northern Thai population were statistically different from those observed in central Thai, Korean, German, and Turkish populations. Conclusions FCGR3B allele frequencies were significantly different between central and northern Thai blood donors. Our in-house PCR-SSP method is a simple, cost-effective, and convenient method for FCGR3B allele detection.

Kaset, Chollanot; Leetrakool, Nipapan; Intharanut, Kamphon

2013-01-01

129

Population Dynamics of Sex-Determining Alleles in Honey Bees and Self-Incompatibility Alleles in Plants  

PubMed Central

Mathematical theories of the population dynamics of sex-determining alleles in honey bees are developed. It is shown that in an infinitely large population the equilibrium frequency of a sex allele is 1/n, where n is the number of alleles in the population, and the asymptotic rate of approach to this equilibrium is 2/(3n) per generation. Formulae for the distribution of allele frequencies and the effective and actual numbers of alleles that can be maintained in a finite population are derived by taking into account the population size and mutation rate. It is shown that the allele frequencies in a finite population may deviate considerably from 1/n. Using these results, available data on the number of sex alleles in honey bee populations are discussed. It is also shown that the number of self-incompatibility alleles in plants can be studied in a much simpler way by the method used in this paper. A brief discussion about general overdominant selection is presented.

Yokoyama, Shozo; Nei, Masatoshi

1979-01-01

130

The European Fusion Programme  

SciTech Connect

The long-term objective of the European fusion programme is the harnessing of the power of fusion to help meet mankind's future energy needs.This paper describes the current research programme, the unique organisational character of the fusion programme, and European and world-wide co-operation. The future evolution of the programme as part of the European Research Area and the developments currently taking place in preparation for the possible construction of ITER, the next major step towards the realisation of fusion power, are discussed.

Antidormi, R.; Bartlett, D.; Bruhns, H. [European Commission (Belgium)

2004-03-15

131

MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus  

PubMed Central

We previously reported that the G allele of rs3853839 at 3?untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P?=?6.5×10?10, odds ratio (OR) (95%CI)?=?1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta?=?7.5×10?11, OR?=?1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3?UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2?=?0.255, P?=?0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3?UTR segment bearing the C allele (P?=?0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta?=?2.0×10?19, OR?=?1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.

Sakurai, Daisuke; Kaufman, Kenneth M.; Edberg, Jeffrey C.; Kimberly, Robert P.; Kamen, Diane L.; Gilkeson, Gary S.; Jacob, Chaim O.; Scofield, R. Hal; Langefeld, Carl D.; Kelly, Jennifer A.; Ramsey-Goldman, Rosalind; Petri, Michelle A.; Reveille, John D.; Vila, Luis M.; Alarcon, Graciela S.; Vyse, Timothy J.; Pons-Estel, Bernardo A.; Freedman, Barry I.; Gaffney, Patrick M.; Sivils, Kathy Moser; James, Judith A.; Gregersen, Peter K.; Anaya, Juan-Manuel; Niewold, Timothy B.; Merrill, Joan T.; Criswell, Lindsey A.; Stevens, Anne M.; Boackle, Susan A.; Cantor, Rita M.; Chen, Weiling; Grossman, Jeniffer M.; Hahn, Bevra H.; Harley, John B.; Alarc?n-Riquelme, Marta E.; Brown, Elizabeth E.; Tsao, Betty P.

2013-01-01

132

CHARACTERIZATION OF ALLOZYME NULL AND LOW ACTIVITY ALLELES FROM TWO NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER  

Microsoft Academic Search

Null and low enzyme activity alleles recovered from two natural populations were analyzed for a number of genetic and biochemical properties. Analysis of 58 mutations at 14 loci showed that all but one allele were genetically viable and fertile, four alleles were associated with chromosome rearrangements, 28 alleles retained some enzyme activity, 13 alleles formed an active heterodimer with active

BARBARA DICKSON BURKHART; ELIZABETH MONTGOMERY; CHARLES H. LANGLEY; ROBERT A. VOELKER

133

Assignment of SNP allelic configuration in polyploids using competitive allele-specific PCR: application to citrus triploid progeny  

PubMed Central

Background Polyploidy is a major component of eukaryote evolution. Estimation of allele copy numbers for molecular markers has long been considered a challenge for polyploid species, while this process is essential for most genetic research. With the increasing availability and whole-genome coverage of single nucleotide polymorphism (SNP) markers, it is essential to implement a versatile SNP genotyping method to assign allelic configuration efficiently in polyploids. Scope This work evaluates the usefulness of the KASPar method, based on competitive allele-specific PCR, for the assignment of SNP allelic configuration. Citrus was chosen as a model because of its economic importance, the ongoing worldwide polyploidy manipulation projects for cultivar and rootstock breeding, and the increasing availability of SNP markers. Conclusions Fifteen SNP markers were successfully designed that produced clear allele signals that were in agreement with previous genotyping results at the diploid level. The analysis of DNA mixes between two haploid lines (Clementine and pummelo) at 13 different ratios revealed a very high correlation (average = 0·9796; s.d. = 0·0094) between the allele ratio and two parameters [? angle = tan?1 (y/x) and y? = y/(x + y)] derived from the two normalized allele signals (x and y) provided by KASPar. Separated cluster analysis and analysis of variance (ANOVA) from mixed DNA simulating triploid and tetraploid hybrids provided 99·71 % correct allelic configuration. Moreover, triploid populations arising from 2n gametes and interploid crosses were easily genotyped and provided useful genetic information. This work demonstrates that the KASPar SNP genotyping technique is an efficient way to assign heterozygous allelic configurations within polyploid populations. This method is accurate, simple and cost-effective. Moreover, it may be useful for quantitative studies, such as relative allele-specific expression analysis and bulk segregant analysis.

Cuenca, Jose; Aleza, Pablo; Navarro, Luis; Ollitrault, Patrick

2013-01-01

134

Ethics and European security  

SciTech Connect

The alliance between the United States and her NATO partners has been strained severely in the last few years. American perceptions of European disloyalty and European impressions of American assertiveness and lack of judgment have played a large part in generating tensions between the allies and emphasising the new peace movements. This book is an attempt to develop a broader understanding of the problem of European security based on Christian ethics. There are disagreements and differences of emphasis among the contributors but they have in common the view that an exclusive preoccupation with the military dimension is damagingly one-sided. Instead the contributors argue that moral and theological concerns are a vital part of the politics and mechanics of European security and must be incorporated in any effort to devise new policies for security in Europe and the West.

Paskins, B.

1986-01-01

135

European Judicial Network  

NSDL National Science Digital Library

As a part of the European Commission, the European Judicial Network is primarily concerned with providing information about community law, European law, and various aspects of civil and commercial law. The homepage is well-organized, and visitors can start by clicking on the topic page sections, which cover everything from bringing a case to court to alternative dispute resolutions. On the right-side of the homepage, visitors can click on the flags of member states to learn more about each nation's legal system. The site will certainly be of interest to those with a legal background, but the main stated objective of the site is "to make life easier for people facing litigation of whatever kind where there is a transnational element." Not surprisingly, all of this information is available in the twenty official languages of the European Union.

2007-01-01

136

HLA class II allele frequencies in the Lebanese population.  

PubMed

Human leukocyte antigens (HLA) allele determination is becoming an increasingly important aspect in the field of transplantation as well as in the area of HLA association with a number of diseases. Through Lebanon's history, this country, situated at a crossroads between Europe, Asia and Africa, has been a host for various populations of different ethnicities. The aim of our study is to determine whether allele polymorphisms in the Lebanese population present a distinguishing feature. Although data on HLA phenotypic polymorphisms in Lebanon have been reported in the literature, our study is the first to examine frequencies of HLA polymorphisms in the country at the molecular level. Allele frequencies of the Lebanese population were analyzed and compared with those of other populations. HLA class II genotyping of DRB1* and DQB1* loci by PCR-sequence-specific primer (SSP) was performed on 191 unrelated Lebanese subjects of both sexes and of different regions and sects in Lebanon. The study revealed that DRB1*1101, DRB1*0401 and DRB1*0301 were the three most common DRB1* alleles observed (respective allele frequencies of 0.302, 0.164 and 0.096). In the DQB locus allele group, DQB1*0301 (allele frequency of 0.384) was highly predominant followed by the DQB1* 0501, DQB1*0201 and DQB1*0302 with respective allele frequencies of 0.199, 0.195 and 0.103. These results confirm previous serological studies and show the high prevalence of DRB1*1101 and DQB1*0301 in Lebanon, which could be explained by the high frequency of consanguineous marriages in the population. The presence of other common alleles is consistent with historical data showing that the Lebanese population is an admixture of various ethnicities. PMID:12835080

Samaha, Hanady; Rahal, Elias A; Abou-Jaoude, Maroun; Younes, Mazen; Dacchache, Jocelyn; Hakime, Noha

2003-07-01

137

Jon C. Herron Software: AlleleA1  

NSDL National Science Digital Library

AlleleA1 is an interactive software simulation of evolution at a single locus in an ideal population of imaginary organisms. The locus of interest has 2 alleles: A1 and A2. The user enters values for parameters controlling selection, mutation, migration, genetic drift, and inbreeding. As the simulation runs, the software plots a graph showing the frequency of allele A1 over time. This webpage has application programs for both Mac and Windows systems, as well as a tutorial (pdf version) to guide the user through the program.

Herron, Jon C.

2010-02-16

138

Haplotype Homozygosity and Derived Alleles in the Human Genome  

PubMed Central

Haplotype-based techniques are being used to estimate the relative age of alleles—particularly in screening loci for signals of recent positive selection—but does this approach capture even coarse age differences? Using simulations and empirical data from the International HapMap Project, we show that a simple pairwise metric of haplotype homozygosity gives significantly higher mean values for human single-nucleotide–polymorphism alleles that appear to be derived than for those that appear to be ancestral, as determined by comparison with the chimpanzee genome. Our results support the use of haplotype-based techniques, such as extended haplotypic homozygosity, to assess the age of alleles.

Fry, Andrew E.; Trafford, Clare J.; Kimber, Martin A.; Chan, Man-Suen; Rockett, Kirk A.; Kwiatkowski, Dominic P.

2006-01-01

139

Analysis of maize brittle-1 alleles and a defective Suppressor-mutator-induced mutable allele.  

PubMed Central

A mutant allele of the maize brittle-1 (bt1) locus, brittle-1-mutable (bt1-m), was shown genetically and molecularly to result from the insertion of a defective Suppressor-mutator (dSpm) transposable element. An Spm-hybridizing restriction enzyme fragment, which cosegregates with the bt1-m allele and is absent from wild-type revertants of bt1-m, was identified and cloned. Non-Spm portions of it were used as probes to identify wild-type (Bt1) cDNAs in an endosperm library. The 4.3-kb bt1-m genomic clone contains a 3.3-kb dSpm, which is inserted in an exon and is composed of Spm termini flanking non-Spm sequences. RNA gel blot analyses, using a cloned Bt1 cDNA probe, indicated that Bt1 mRNA is present in the endosperm of developing kernels and is absent from embryo or leaf tissues. Several transcripts are produced by bt1-m. The deduced translation product from a 1.7-kb Bt1 cDNA clone has an apparent plastid transit peptide at its amino terminus and sequence similarity to several mitochondrial inner-envelope translocator proteins, suggesting a possible role in amyloplast membrane transport.

Sullivan, T D; Strelow, L I; Illingworth, C A; Phillips, R L; Nelson, O E

1991-01-01

140

Performance of HLA allele prediction methods in African Americans for class II genes HLA-DRB1, -DQB1, and –DPB1  

PubMed Central

Background The expense of human leukocyte antigen (HLA) allele genotyping has motivated the development of imputation methods that use dense single nucleotide polymorphism (SNP) genotype data and the region’s haplotype structure, but the performance of these methods in admixed populations (such as African Americans) has not been adequately evaluated. We compared genotype-based—derived from both genome-wide genotyping and targeted sequencing—imputation results to existing allele data for HLA–DRB1, ?DQB1, and –DPB1. Results In European Americans, the newly-developed HLA Genotype Imputation with Attribute Bagging (HIBAG) method outperformed HLA*IMP:02. In African Americans, HLA*IMP:02 performed marginally better than HIBAG pre-built models, but HIBAG models constructed using a portion of our African American sample with both SNP genotyping and four-digit HLA class II allele typing had consistently higher accuracy than HLA*IMP:02. However, HIBAG was significantly less accurate in individuals heterozygous for local ancestry (p??0.04). Accuracy improved in models with equal numbers of African and European chromosomes. Variants added by targeted sequencing and SNP imputation further improved both imputation accuracy and the proportion of high quality calls. Conclusion Combining the HIBAG approach with local ancestry and dense variant data can produce highly-accurate HLA class II allele imputation in African Americans.

2014-01-01

141

Genetic Epidemiology of Glioblastoma Multiforme: Confirmatory and New Findings from Analyses of Human Leukocyte Antigen Alleles and Motifs  

PubMed Central

Background Human leukocyte antigen (HLA) class I genes mediate cytotoxic T-lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM). Methodology/Principal Findings As an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio?=?0.41, p?=?0.04 by univariate analysis). Other alleles (A*29, A*30, A*31 and A*33) within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio?=?2.71, p?=?0.02). Conclusions/Significance HLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations.

Song, Wei; Ruder, Avima M.; Hu, Liangyuan; Li, Yufeng; Ni, Rong; Shao, Wenshuo; Kaslow, Richard A.; Butler, MaryAnn; Tang, Jianming

2009-01-01

142

Replication of a rare protective allele in the noradrenaline transporter gene and ADHD.  

PubMed

Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect. PMID:18937296

Xu, X; Hawi, Z; Brookes, K J; Anney, R; Bellgrove, M; Franke, B; Barry, E; Chen, W; Kuntsi, J; Banaschewski, T; Buitelaar, J; Ebstein, R; Fitzgerald, M; Miranda, A; Oades, R D; Roeyers, H; Rothenberger, A; Sergeant, J; Sonuga-Barke, E; Steinhausen, H-C; Faraone, S V; Gill, M; Asherson, P

2008-12-01

143

Replication of a rare protective allele in the noradrenaline transporter gene and ADHD  

PubMed Central

Objective Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Method Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Results Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P=0.0001; average odds ratio=0.33; for SNP rs3785143 P=0.008; average odds ratio=1.3). Conclusions The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

Xu, X; Hawi, Z; Brookes, KJ; Anney, R; Bellgrove, M; Franke, B; Barry, E; Chen, W; Kuntsi, J; Banaschewski, T; Buitelaar, J; Ebstein, R; Fitzgerald, M; Miranda, A; Oades, RD; Roeyers, H; Rothenberger, A; Sergeant, J; Sonuga-Barke, E; Steinhausen, H-C; Faraone, SV; Gill, M

2008-01-01

144

CYP2A7 polymorphic alleles confound the genotyping of CYP2A6*4A allele  

Microsoft Academic Search

Human cytochrome P450 (CYP) 2A6 metabolizes nicotine to cotinine. Genetic polymorphisms of CYP2A6 contribute to the interindividual variability of nicotine metabolism. We encountered some subjects possessing two copies of the CYP2A6 gene, although they were genotyped as heterozygotes of the CYP2A6*4A allele (entire CYP2A6 gene deleted allele). From the subjects, we found CYP2A7 polymorphic alleles (CYP2A7*1B, CYP2A7*1C, and CYP2A7*1D) in

T Fukami; M Nakajima; H Sakai; H L McLeod; T Yokoi

2006-01-01

145

Ig? allelic inclusion is a consequence of receptor editing  

PubMed Central

The discovery of lymphocytes bearing two light chains in mice carrying self-reactive antibody transgenes has challenged the “one lymphocyte–one antibody” rule. However, the extent and nature of allelically included cells in normal mice is unknown. We show that 10% of mature B cells coexpress both Ig? alleles. These cells are not the result of failure in allelic exclusion per se, but arise through receptor editing. We find that under physiological conditions, editing occurs both by deletion and by inclusion with equal probability. In addition, we demonstrate that B lymphocytes carrying two B-cell receptors are recruited to germinal center reactions, and thus fully participate in humoral immune responses. Our data measure the scope of allelic inclusion and provide a mechanism whereby autoreactive B cells might “escape” central tolerance.

Casellas, Rafael; Zhang, Qingzhao; Zheng, Nai-Ying; Mathias, Melissa D.; Smith, Kenneth; Wilson, Patrick C.

2007-01-01

146

The Selective Value of Alleles Underlying Polygenic Traits  

PubMed Central

To define the genetic and ecological circumstances that are conductive to evolution via genetic drift at the allelic level, the selection coefficient for a constituent allele of arbitrary effect is derived for a polygenic character exposed to stabilizing selection. Under virtually all possible conditions, alleles within the class for which the absolute value of the average effect is <10-2 phenotypic standard deviations are neutral with respect to each other. In addition, when the mean phenotype is at the optimum and the genetic variance is in selection-drift-mutation equilibrium, a considerable amount of neutral evolution is expected in the class of alleles with intermediate effects on the phenotype. These results help clarify how molecular evolution via genetic drift may occur at a locus despite intense selection and provide a potential mechanistic explanation for the neutral theory of molecular evolution.

Lynch, Michael

1984-01-01

147

European Education, European Citizenship? On the Role of Education in Constructing Europeanness.  

ERIC Educational Resources Information Center

Focuses on the role of the European Union (EU) education programs in fostering a sense of European citizenship. Addresses the five meanings given to the concept of European citizenship: (1) recognition of European heritage; (2) EU loyalty; (3) right of free movement; (4) political participation; and (5) active citizenship. (CMK)

Ollikainen, Aaro

2000-01-01

148

Distribution of HLA-B alleles in Mexican Amerindian populations  

Microsoft Academic Search

In the present study we analyzed by PCR-SSO technique the HLA-B gene frequencies in 281 healthy individuals from four Mexican Amerindian populations (66 Mayos, 90 Mazatecans, 72 Nahuas and 53 Teenek). The most frequent alleles in all studied populations were HLA-B35, HLA-B39, and HLA-B40; however, some differences were observed between populations. The HLA-B35 allele was the most frequent in three

Gilberto Vargas-Alarcón; Guadalupe Hernández-Pacheco; Joaquín Zuñiga; José Manuel Rodríguez-Pérez; Nonanzit Pérez-Hernández; Carlos Rangel; Cynthia Villarreal-Garza; Jorge Martínez-Laso; Julio Granados; Antonio Arnaiz-Villena

2003-01-01

149

DRD4 dopamine receptor allelic diversity in various primate species  

SciTech Connect

The DRD4 dopamine receptor is uniquely characterized by a 48 bp repeating segment within the coding region, located in exon III. Different DRD4 alleles are produced by the presence of additional 48 bp repeats, each of which adds 16 amino acids to the length of the 3rd intracytoplasmic loop of the receptor. The DRD4 receptor is therefore an intriguing candidate gene for behaviors which are influenced by dopamine function. In several human populations, DRD4 alleles with 2-8 and 10 repeats have previously been identified, and the 4 and 7 repeat alleles are the most abundant. We have determined DRD4 genotypes in the following nonhuman primate species: chimpanzee N=2, pygmy chimpanzee N=2, gorilla N=4, siamang N=2, Gelada baboon N=1, gibbon N=1, orangutan (Bornean and Sumatran) N=62, spider monkey N=4, owl monkey N=1, Colobus monkey N=1, Patas monkey N=1, ruffed lemur N=1, rhesus macaque N=8, and vervet monkey N=28. The degree of DRD4 polymorphism and which DRD4 alleles were present both showed considerable variation across primate species. In contrast to the human, rhesus macaque monkeys were monomorphic. The 4 and 7 repeat allels, highly abundant in the human, may not be present in certain other primates. For example, the four spider monkeys we studied showed the 7, 8 and 9 repeat length alleles and the only gibbon we analyzed was homozygous for the 9 repeat allele (thus far not observed in the human). Genotyping of other primate species and sequencing of the individual DRD4 repeat alleles in different species may help us determine the ancestral DRD4 repeat length and identify connections between DRD4 genotype and phenotype.

Adamson, M.; Higley, D. [NIAAA, Rockville, MD (United States); O`Brien, S. [NCI, Frederick, MD (United States)] [and others

1994-09-01

150

Allele-specific copy number analysis of tumors  

PubMed Central

We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of “ASCAT profiles” (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in near-triploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development.

Van Loo, Peter; Nordgard, Silje H.; Lingjaerde, Ole Christian; Russnes, Hege G.; Rye, Inga H.; Sun, Wei; Weigman, Victor J.; Marynen, Peter; Zetterberg, Anders; Naume, Bj?rn; Perou, Charles M.; Kristensen, Vessela N.

2010-01-01

151

Allele-specific Silencing of Mutant Myh6 Allele in Mice Suppresses Hypertrophic Cardiomyopathy  

PubMed Central

Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Here we demonstrate that expression of the HCM cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNAi cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC403/+ mice had neither hypertrophy or myocardial fibrosis, the pathologic manifestations of HCM for at least 6 months. As inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allelic-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.

Jiang, Jianming; Wakimoto, Hiroko; Seidman, J. G.; Seidman, Christine E.

2014-01-01

152

European Forest Institute: Research  

NSDL National Science Digital Library

This European Forest Institute (EFI) is "An independent non-governmental organization conducting European forest research." This website provides information about EFI's mission, research goals, strategies and programs. Site users can view information about on-going and completed projects in any of the four EFI research programs which include: Forest Ecology and Management, Forest Products Markets and Socio-Economics, Policy Analysis, and Forest Resources and Information. EFI also provides a search engine for locating specific research projects as well as information about how to propose an EFI project.

153

Distribution of BoLA-DRB3 Allelic Frequencies and Identification of Two New Alleles in Iranian Buffalo Breed  

PubMed Central

The role of the major histocompatibility complex (MHC) in the immune response makes it an attractive candidate gene for associations with disease resistance and susceptibility. This study describes genetic variability in the BoLA-DRB3 in Iranian buffaloes. Heminested PCR-RFLP method was used to identify the frequency of BoLA-DRB3 alleles. The BoLA-DRB3 locus is highly polymorphic in the study herd (12 alleles). Almost 63.50% of the alleles were accounted for by four alleles (BoLA-DRB3.2 ?48, ?20, ?21, and obe) in Iranian buffalo. The DRB3.2 ?48 allele frequency (24.20%) was higher than the others. The frequencies of the DRB3.2 ?20 and DRB3.2 ?21 are 14.52 and 14.00, respectively, and obe and gbb have a new pattern. Significant distinctions have been found between Iranian buffalo and other cattle breed studied. In the Iranian buffaloes studied alleles associated with resistance to various diseases are found.

Mosafer, J.; Heydarpour, M.; Manshad, E.; Russell, G.; Sulimova, G. E.

2012-01-01

154

Mass allele detection (MAD) of rare 5-HT1A structural variants with allele-specific amplification and electrochemiluminescent detection.  

PubMed

A strategy is described that exploits allele-specific amplification (ASA-PCR) and electrochemiluminescence (ECL) detection technology to rapidly and cheaply screen large numbers of DNAs arranged in pooled matrices in order to identify individual nucleotide sequence variants. To demonstrate this strategy, a large genomic DNA collection was screened for two nucleotide variants in the 5-HT1A serotonin receptor gene and individual heterozygotes were identified. Conversion of two SSCP variants to allele-specific PCR polymorphisms was accomplished, and PCR product capture and ECL detection were enabled by the covalent addition of biotin to allele-specific PCR primers and ruthenium to the nonspecific PCR primer. A two-level DNA pooling strategy was used to reduce the number of individual PCR reactions required. Pooling experiments established that ASA-PCR with ECL detection is sufficiently sensitive to reproducibly detect a single specific allele in the presence of a 40-fold excess of genomic DNA from individuals negative for the specific allele. The detection sensitivity of the ECL device and the design of the pooled DNA arrays reduced the number of PCRs required to detect the rare individuals with the variant sequences by approximately 90%. This strategy is called mass allele detection (MAD). PMID:8829630

Bergen, A; Wang, C Y; Nakhai, B; Goldman, D

1996-01-01

155

A comparison of adjustment methods to test the robustness of an STR DNA database comprised of 24 European populations  

Microsoft Academic Search

An aim of the European Network of Forensic Science Institutes (ENFSI) is to produce a DNA database of second generation multiplex (SGM) STR profiles that is representative of the resident cosmopolitan populations. To achieve this, data were collected from 24 different populations. All of the data were combined to form one database of 5700 profiles from which allele proportions were

Peter Gill; Lindsey Foreman; John S Buckleton; Christopher M Triggs; Heather Allen

2003-01-01

156

Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y.  

PubMed

Pigmentation is a polygenic trait encompassing some of the most visible phenotypic variation observed in humans. Here we present direct estimates of selection acting on functional alleles in three key genes known to be involved in human pigmentation pathways--HERC2, SLC45A2, and TYR--using allele frequency estimates from Eneolithic, Bronze Age, and modern Eastern European samples and forward simulations. Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2-10% per generation. Our results provide direct evidence that strong selection favoring lighter skin, hair, and eye pigmentation has been operating in European populations over the last 5,000 y. PMID:24616518

Wilde, Sandra; Timpson, Adrian; Kirsanow, Karola; Kaiser, Elke; Kayser, Manfred; Unterländer, Martina; Hollfelder, Nina; Potekhina, Inna D; Schier, Wolfram; Thomas, Mark G; Burger, Joachim

2014-04-01

157

Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y  

PubMed Central

Pigmentation is a polygenic trait encompassing some of the most visible phenotypic variation observed in humans. Here we present direct estimates of selection acting on functional alleles in three key genes known to be involved in human pigmentation pathways—HERC2, SLC45A2, and TYR—using allele frequency estimates from Eneolithic, Bronze Age, and modern Eastern European samples and forward simulations. Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2–10% per generation. Our results provide direct evidence that strong selection favoring lighter skin, hair, and eye pigmentation has been operating in European populations over the last 5,000 y.

Wilde, Sandra; Timpson, Adrian; Kirsanow, Karola; Kaiser, Elke; Kayser, Manfred; Unterlander, Martina; Hollfelder, Nina; Potekhina, Inna D.; Schier, Wolfram; Thomas, Mark G.; Burger, Joachim

2014-01-01

158

Extensive genetic diversity in the HLA class II region of Africans, with a focally predominant allele, DRB1*1304.  

PubMed Central

Molecular HLA class II typing of greater than 1700 individuals from The Gambia in West Africa and Malawi in South-Central Africa revealed a striking diversity of HLA DRB-DQB haplotypes as defined by restriction fragment length polymorphism (RFLP); this diversity is twice as extensive as that found in northern Europeans. Despite this diversity, sequence and PCR/oligonucleotide analysis showed that the recently described variant DRB1*1304 is the commonest DRB1 allele in The Gambia. The sequence, geographical distribution, and RFLP association of this allele, together with homozygosity test results, suggest that DRB1*1304 may have arisen from DRB1*1102 and have reached its remarkably high frequency as a result of recent directional selection. The prevalence of this unusual allele has implications for trials of subunit vaccines in this area. The extensive and distinctive HLA class II region polymorphism in sub-Saharan Africans is consistent with evidence from other genetic loci implying an African origin of modern Homo sapiens.

Hill, A V; Allsopp, C E; Kwiatkowski, D; Taylor, T E; Yates, S N; Anstey, N M; Wirima, J J; Brewster, D R; McMichael, A J; Molyneux, M E

1992-01-01

159

European respiratory nurses association.  

PubMed

A new overarching organisation, the European Respiratory Nurses Association (ERNA), hopes to become a must-join group for nursing organisations across Europe. The aim of ERNA is to give nurses with an interest in respiratory care a greater voice and, ultimately, to improve the care of patients living with respiratory conditions. PMID:24902058

Randhawa, Gurpreet; Fletcher, Monica

2014-06-01

160

Liberalizing European steel trade  

Microsoft Academic Search

This paper constructs a simple model of the steel sector in Europe distinguishing eight western and two eastern European regions. It models the production of steel and also the various trade restrictions extant in 1992. It uses this model first to calculate the output and welfare effects of rationalizing the sector to remove the excess capacity experienced in 1992 and

L. Alan Winters

1995-01-01

161

Gifted European American Woman.  

ERIC Educational Resources Information Center

This article describes factors affecting the achievement of 15 highly accomplished European American women in the fields of business, higher education, and law and government. Findings indicate participants tended to attribute their success to external factors while simultaneously employing proactive strategies to overcome potential barriers.…

Kitano, Margie K.; Perkins, Carol O.

2000-01-01

162

Efficiency in European banking  

Microsoft Academic Search

This paper extends the established literature on modelling the cost characteristics of banking markets by applying the flexible Fourier functional form and stochastic cost frontier methodologies to estimate scale economies, X-inefficiencies and technical change for a large sample of European banks between 1989 and 1997. The results reveal that scale economies are widespread for smallest banks and those in the

Y. Altunba?; E. P. M. Gardener; P. Molyneux; B. Moore

2001-01-01

163

Eastern European Cinema.  

ERIC Educational Resources Information Center

Presents a structure for a course that highlights the best cinemas of Eastern European countries, in order to acquaint students with cinematic traditions of the region. Discusses course activities, coursework and evaluation, and resources. Advocates structuring the course around the film of experience of Eastern Europe, and presents and discusses…

Iordanova, Dina

1999-01-01

164

European Bioinformatics Institute  

NSDL National Science Digital Library

Some interesting research projects are described on this website from the European Bioinformatics Institute. The site offers a number of data resources on topics such as genomes, macromolecular structures, protein families, and structure analysis. Taxonomy and ontology databases are also linked here, as well as databases of research literature.

2013-06-11

165

Future European Security Framework.  

National Technical Information Service (NTIS)

The issue of European security has undergone a radical change. The threat of a large-scale military confrontation has faded; in its place are a combination of opportunities and risks. The opportunities arise if Central and Eastern Europe make the transiti...

G. D. Keuning

1993-01-01

166

European Music Year 1985.  

ERIC Educational Resources Information Center

Articles concerning music are included in this newsletter dedicated to cultural venture to be jointly carried out by the Council of Europe and the European communities. Many events will mark Music Year 1985, including concerts, dance performances, operas, publications, recordings, festivals, exhibitions, competitions, and conferences on musical…

Alexanderson, Thomas; And Others

1984-01-01

167

European inflation dynamics  

Microsoft Academic Search

We provide evidence on the fit of the New Phillips Curve (NPC) for the Euro area over the period 1970–1998, and use it as a tool to compare the characteristics of European inflation dynamics with those observed in the U.S. We also analyze the factors underlying inflation inertia by examining the cyclical behavior of marginal costs, as well as that

Jordi Gal??; Mark Gertler; J. David López-Salido

2001-01-01

168

Slovenian population data for five new European Standard Set Short tandem repeat loci and SE33 locus  

PubMed Central

Aim To establish the allele distribution and statistical parameters of forensic interest for the D10S1248, D22S1045, D2S441, D1S1656, D12S391, and SE33 loci in Slovenian population and to compare allele frequencies with those from other populations. Methods We analyzed blood and buccal swab samples from 333 unrelated, healthy Slovenian individuals. All samples were genotyped using the AmpFlSTR NGM Kit to obtain the allele frequency data for the loci D10S1248, D22S1045, D2S441, D1S1656, and D12S391. Samples from 113 individuals were also analyzed using the PowerPlex ESX 17 system to obtain the allele frequency data for the SE33 locus. Allele frequencies and statistical parameters of forensic interest were determined and frequency profiles compared between Slovenian and other European Caucasian populations using the Arlequin software, version 3.5.1.3. Results The investigated short tandem repeat (STR) loci in Slovenian population had a great discriminating potential with a combined discrimination power of 0.99999998. The highest discrimination power and polymorphism information content were observed for the SE33 locus, followed by loci D1S1656, D12S391, D10S1248, D2S441, and D22S1045. When Slovenian allele frequency distribution was compared with other European populations, deviations were found only for Spanish and Italian population for D2S441 and D12S391. Conclusion Slovenian population does not differ significantly from other European populations in terms of allele frequency distributions for the six analyzed STR loci. Based on forensic efficiency values, SE33 may be considered the most informative locus, which makes it especially useful in forensic investigations.

Zupanic Pajnic, Irena; Podovsovnik Axelsson, Eva; Balazic, Joze

2014-01-01

169

Detecting imbalanced expression of SNP alleles by minisequencing on microarrays  

PubMed Central

Background Each of the human genes or transcriptional units is likely to contain single nucleotide polymorphisms that may give rise to sequence variation between individuals and tissues on the level of RNA. Based on recent studies, differential expression of the two alleles of heterozygous coding single nucleotide polymorphisms (SNPs) may be frequent for human genes. Methods with high accuracy to be used in a high throughput setting are needed for systematic surveys of expressed sequence variation. In this study we evaluated two formats of multiplexed, microarray based minisequencing for quantitative detection of imbalanced expression of SNP alleles. We used a panel of ten SNPs located in five genes known to be expressed in two endothelial cell lines as our model system. Results The accuracy and sensitivity of quantitative detection of allelic imbalance was assessed for each SNP by constructing regression lines using a dilution series of mixed samples from individuals of different genotype. Accurate quantification of SNP alleles by both assay formats was evidenced for by R2 values > 0.95 for the majority of the regression lines. According to a two sample t-test, we were able to distinguish 1–9% of a minority SNP allele from a homozygous genotype, with larger variation between SNPs than between assay formats. Six of the SNPs, heterozygous in either of the two cell lines, were genotyped in RNA extracted from the endothelial cells. The coefficient of variation between the fluorescent signals from five parallel reactions was similar for cDNA and genomic DNA. The fluorescence signal intensity ratios measured in the cDNA samples were compared to those in genomic DNA to determine the relative expression levels of the two alleles of each SNP. Four of the six SNPs tested displayed a higher than 1.4-fold difference in allelic ratios between cDNA and genomic DNA. The results were verified by allele-specific oligonucleotide hybridisation and minisequencing in a microtiter plate format. Conclusions We conclude that microarray based minisequencing is an accurate and accessible tool for multiplexed screening for imbalanced allelic expression in multiple samples and tissues in parallel.

Liljedahl, Ulrika; Fredriksson, Mona; Dahlgren, Andreas; Syvanen, Ann-Christine

2004-01-01

170

Allele-Dependent Barley Grain ?-Amylase Activity1  

PubMed Central

The wild ancestor of cultivated barley, Hordeum vulgare subsp. spontaneum (K. Koch) A. & Gr. (H. spontaneum), is a source of wide genetic diversity, including traits that are important for malting quality. A high ?-amylase trait was previously identified in H. spontaneum strains from Israel, and transferred into the backcross progeny of a cross with the domesticated barley cv Adorra. We have used Southern-blot analysis and ?-amy1 gene characterization to demonstrate that the high ?-amylase trait in the backcross line is co-inherited with the ?-amy1 gene from the H. spontaneum parent. We have analyzed the ?-amy1 gene organization in various domesticated and wild-type barley strains and identified three distinct ?-amy1 alleles. Two of these ?-amy1 alleles were present in modern barley, one of which was specifically found in good malting barley cultivars. The third allele, linked with high grain ?-amylase activity, was found only in a H. spontaneum strain from the Judean foothills in Israel. The sequences of three isolated ?-amy1 alleles are compared. The involvement of specific intron III sequences, in particular a 126-bp palindromic insertion, in the allele-dependent expression of ?-amylase activity in barley grain is proposed.

Erkkila, Maria J.; Leah, Robert; Ahokas, Hannu; Cameron-Mills, Verena

1998-01-01

171

The European Dimension in Education.  

ERIC Educational Resources Information Center

This paper addresses concerns about a European dimension in education that has been created by the enlargement of the European Union (EU) (the inclusion of Austria, Finland, and Sweden) and the gradual transformations of institutions into a future federal state. Sections of the paper include: (1) "Introduction"; (2) "Defining the European

Council of Europe, Strasbourg (France). Directorate of Education, Culture and Sport, Documentation Section.

172

Agriculture and European Union Enlargement  

Microsoft Academic Search

Potential accession of a number of eastern and central European countries into the European Union (EU) seems destined to lead to further reforms of the Common Agricultural Policy (CAP). The financial costs of absorbing these countries may be extreme. This report documents the modeling framework (European Simulation Model, ESIM) used to analyze the 1992 CAP reform and discusses possible effects

Timothy E. Josling; David R. Kelch; Peter S. Liapis; Stefan Tangermann

1998-01-01

173

A phylogeny for the principal alleles of the human phosphoglucomutase-1 locus.  

PubMed Central

The results of phosphoglucomutase-1 (PGM1) typings by starch gel electrophoresis and subtypings by isoelectric focusing are presented for a sample of Japanese. A distinction made on the basis of isoelectric focusing (termed "+" and "-") is nonrandomly associated with each of the products of the four most common electrophoretic alleles (PGM1(1), PGM1(2), PGM1(3), and PGM1(7). The isoelectric trait cosegregates with the allele; the degree of nonrandomness of the association varies from allele to allele. Thus, the four alleles become eight. On the basis of these facts plus the additive nature of the pI differences between allele products and the geographical distribution of the alleles, an allele phylogeny can be constructed. This postulates that the eight alleles may be explained by three nucleotide substitutions involving the stem allele plus four intragenic recombinations between these substitutions. The potential of intragenic recombination as a cause of mutation has been insufficiently appreciated. Images

Takahashi, N; Neel, J V; Satoh, C; Nishizaki, J; Masunari, N

1982-01-01

174

The distribution of the HLA-DQ? alleles and genotypes in the Finnish population as determined by the use of DNA amplification and allele specific oligonucleotides  

Microsoft Academic Search

Summary Allele and genotype frequencies for the HLA-130a locus were determined for use in forensic analyses and paternity tests in Finland. The polymerase chain reaction (PCR) and the reverse dot blot format were employed to detect 6 different HLA-DQa alleles. All 6 HLA-DQa alleles were detected among the 112 unrelated individuals with allele frequencies ranging from 5.8% to 32.6%. The

A. Sajantilala; M. Ström; B. Budowle; P. J. Tienari; C. Ehnholm; L. Peltonen

1991-01-01

175

Distribution of a pseudodeficiency allele among Tay-Sachs carriers  

SciTech Connect

Recently Triggs-Raine et al. (1992) identified a new mutation in the gene coding for the [alpha]-subunit of [beta]-hexosaminidase A (hex A), the enzyme whose deficiency causes Tay-Sachs disease. This mutation, a C[sub 739]-to-T transition in exon 7, results in an altered enzyme that is active (albeit at reduced levels) in cells but that has essentially no activity in serum. This so-called pseudodeficient allele was first detected in compound heterozygotes who also carried a Tay-Sachs disease allele and therefore had no detectable hex A in their serum but who were in good health. Carriers of this apparently benign mutation are generally indistinguishable from carriers of a lethal mutation by means of routine enzyme-based screening tests, because the product of the pseudodeficient allele is not detectable in serum and has decreased activity in cells. This suggests that some individuals who have been classified as Tay-Sachs carriers are actually carriers of the pseudodeficient allele and are not at risk to have a child affected with Tay-Sachs disease. The pseudodeficient allele may also be responsible for some inconclusive diagnoses, where leukocyte values fall below the normal range but are still above the carrier range. The fact that there are now two mutant alleles (the psuedodeficient and the adult) that are indistinguishable from the lethal infantile mutations by means of enzyme assay yet that are phenotypically very different and that together may account for as much as 12% of enzyme-defined carriers on the basis of the data here suggests that DNA analysis should be part of a comprehensive screening program. It will be particularly useful to identify the mutations in couples at risk, before they undergo prenatal diagnosis. DNA analysis will also resolve some inconclusive diagnoses.

Tomczak, J.; Grebner, E.E. (Thomas Jefferson Univ., Philadelphia, PA (United States)); Boogen, C. (Univ. of Essen Medical School (Germany))

1993-08-01

176

The Inheritance of Resistance Alleles in Multiple Sclerosis  

PubMed Central

Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10-bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complex–associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex–associated susceptibility.

Herrera, Blanca M; DeLuca, Gabriele C; Lincoln, Matthew R; Orton, Sarah M; Chao, Michael J; Sadovnick, A. Dessa; Ebers, George C

2007-01-01

177

CCR5 as a Natural and Modulated Target for Inhibition of HIV  

PubMed Central

Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection—this without detrimental effects to the host—and transplantation of CCR5-delta32 stem cells in a patient with HIV (“Berlin patient”) achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase I/II trials by engineering HIV-resistant hematopoietic cells.

Burke, Bryan P.; Boyd, Maureen P.; Impey, Helen; Breton, Louis R.; Bartlett, Jeffrey S.; Symonds, Geoff P.; Hutter, Gero

2013-01-01

178

CCR5 as a natural and modulated target for inhibition of HIV.  

PubMed

Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection-this without detrimental effects to the host-and transplantation of CCR5-delta32 stem cells in a patient with HIV ("Berlin patient") achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase I/II trials by engineering HIV-resistant hematopoietic cells. PMID:24381033

Burke, Bryan P; Boyd, Maureen P; Impey, Helen; Breton, Louis R; Bartlett, Jeffrey S; Symonds, Geoff P; Hütter, Gero

2014-01-01

179

Alternative Fitness Models with the Same Allele Frequency Dynamics  

PubMed Central

For any set of one- or two-locus genotypic fitnesses there are alternative sets, usually frequency-dependent and often with quite different biological meanings, that give rise to the same equations for change of allele or haplotype frequencies. Therefore, it is not possible to distinguish among alternative fitness models from allele or haplotype frequency trajectories or equilibrium distributions. For a single locus and for two loci when linkage equilibrium can be assumed, a simple procedure generates some of the alternative fitness sets.

Denniston, C.; Crow, J. F.

1990-01-01

180

Presence of the functional CASPASE-12 allele in Indian subpopulations.  

PubMed

Most humans lack a functional CASP12 gene, with the nonfunctional variant (CASP12p1), found in 100% of the Caucasian and east Asian population, and in approximately 80% of people of African descent. However, 20% of Africans carry an intact allele of CASP12, which produces a full-length pro-enzyme and increases the risk of sepsis. We examined CASP12 allele distribution in persons from central and southern Asia and found that CASP12 was significantly present in members of the Dravidian language group, particularly in persons from the Indian state of Tamil Nadu. PMID:22471600

Yavari, M; Brinkley, G; Klapstein, K D; Hartwig, W C; Rao, R; Hermel, E

2012-10-01

181

Autoimmunity risk alleles: hotspots in B cell regulatory signaling pathways  

PubMed Central

Autoimmunity is the consequence of the combination of genetic predisposition and environmental effects, such as infection, injury, and constitution of the gut microbiome. In this edition of the JCI, Dai et al. describe the use of knockin technology to test the mechanism of action of a polymorphism in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) (LYP) that is associated with susceptibility to multiple autoimmune diseases. The function of this allele, and that of a disproportionate number of autoimmune disease risk alleles, suggests that inhibitory signaling pathways that maintain B lymphocyte immune tolerance may represent an Achilles’ heel in the prevention of autoimmunity.

Cambier, John C.

2013-01-01

182

TLR1 polymorphisms in Europeans and spontaneous pregnancy loss.  

PubMed

Toll-like receptors (TLRs) are critical components of the pathogen recognition by the host innate immune system. Recently it has been shown that TLR1 is under evolutionary pressure in Europeans. This involves the positive selection of the nonsynonymous TLR1 1805G variant in Europeans, although this is associated with poor TLR1 response and unfavorable prognosis in various infections. In terms of natural selection, differential fertility is another mechanism, independent of infection susceptibility, that may explain the polymorphism pattern observed for TLR1. To test this hypothesis, we assessed the correlation of two TLR1 SNPs (T1805G and G239C) with spontaneous pregnancy loss in a case-control study that included 132 spontaneous pregnancy loss patients and 142 control volunteers. Similar allele frequencies of T1805G were observed between cases and controls, but GG genotype tended to be associated with pregnancy loss (OR 1.91; 95%CI 1.03, 3.53). No differences were observed for the TLR1 G239C SNP. Our findings showed slight differences in the distribution of T1805G variants in women with pregnancy loss, but these were not indicative of a protective effect of the TLR1 1805G allele for this fertility disorder. Although our hypothesis was not proven, potential effects of TLR1 polymorphisms on pregnancy outcome have been suggested, and future studies in larger cohorts are warranted. PMID:22200569

Cri?an, Tania O; Farca?, Marius F; Trifa, Adrian P; Plantinga, Theo S; Militaru, Mariela S; Pop, Ioan V; Netea, Mihai G; Popp, Radu A

2012-02-15

183

European Space Agency  

NSDL National Science Digital Library

This is the home page of the European Space Agency (ESA), the European equivalent to NASA, formed of 16 member countries. Users can access information on ESA's activities, including such topics as Earth observation, human spaceflight, and various aspects of space science. The educational section includes exercises for high school and college students and a teachers' section with projects, classroom tools, and training information. The kids' section includes lab activities, games, and news articles written for younger students. A multimedia gallery is provided that contains imagery of Mars, Earth, and other objects in the solar system, artists' conceptions of spacecraft, and others. There is also a media center which provides press releases, information notes, and information on ESA television broadcasts. Miscellaneous services include an events calendar, list of publications, and a "frequently asked questions" section. The site can be translated into a variety of languages.

184

European Environment Agency (EEA)  

NSDL National Science Digital Library

The European Environment Agency (EEA) Website contains a huge selection of online environmental information, data, and reports pertaining to all fifteen EU states, as well as Iceland, Lichtenstein, and Norway. Information is organized by themes, and the site employs a powerful multilingual search feature. Themes include environmental issues, sectors and activities, information related to specific media, regions, and actions for environmental improvement. The site also contains EEA publications and reports, as well as a data service providing access to data sets covering at least all EU member states. Finally, the European Environment Information and Observation Network (EIONET) provides a network which "facilitates co-operation and flow of data and information between EIONET partners and with the EEA." The EEA Website is a large, research-oriented repository of information.

185

The European Nucleotide Archive  

PubMed Central

The European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena) is Europe’s primary nucleotide-sequence repository. The ENA consists of three main databases: the Sequence Read Archive (SRA), the Trace Archive and EMBL-Bank. The objective of ENA is to support and promote the use of nucleotide sequencing as an experimental research platform by providing data submission, archive, search and download services. In this article, we outline these services and describe major changes and improvements introduced during 2010. These include extended EMBL-Bank and SRA-data submission services, extended ENA Browser functionality, support for submitting data to the European Genome-phenome Archive (EGA) through SRA, and the launch of a new sequence similarity search service.

Leinonen, Rasko; Akhtar, Ruth; Birney, Ewan; Bower, Lawrence; Cerdeno-Tarraga, Ana; Cheng, Ying; Cleland, Iain; Faruque, Nadeem; Goodgame, Neil; Gibson, Richard; Hoad, Gemma; Jang, Mikyung; Pakseresht, Nima; Plaister, Sheila; Radhakrishnan, Rajesh; Reddy, Kethi; Sobhany, Siamak; Ten Hoopen, Petra; Vaughan, Robert; Zalunin, Vadim; Cochrane, Guy

2011-01-01

186

Clonal Ordering of 17p and 5q Allelic Losses in Barrett Dysplasia and Adenocarcinoma  

NASA Astrophysics Data System (ADS)

Both 17p and 5q allelic losses appear to be involved in the pathogenesis or progression of many human solid tumors. In colon carcinogenesis, there is strong evidence that the targets of the 17p and 5q allelic losses are TP53, the gene encoding p53, and APC, respectively. It is widely accepted that 5q allelic losses precede 17p allelic losses in the progression to colonic carcinoma. The data, however, supporting this proposed order are largely based on the prevalence of 17p and 5q allelic losses in adenomas and unrelated adenocarcinomas from different patients. We investigated the order in which 17p and 5q allelic losses developed during neoplastic progression in Barrett esophagus by evaluating multiple aneuploid cell populations from the same patient. Using DNA content flow cytometric cell sorting and polymerase chain reaction, 38 aneuploid cell populations from 14 patients with Barrett esophagus who had high grade dysplasia, cancer or both were evaluated for 17p and 5q allelic losses. 17p allelic losses preceded 5q allelic losses in 7 patients, both 17p and 5q allelic losses were present in all aneuploid populations of 4 patients, and only 17p (without 5q) allelic losses were present in the aneuploid populations of 3 patients. In no patient did we find that a 5q allelic loss preceded a 17p allelic loss. Our data suggest that 17p allelic losses typically occur before 5q allelic losses during neoplastic progression in Barrett esophagus.

Blount, Patricia L.; Meltzer, Stephen J.; Yin, Jing; Huang, Ying; Krasna, Mark J.; Reid, Brian J.

1993-04-01

187

Telemedicine and European law.  

PubMed

A Directive of the European Union was first published in 2000, which dealt with telemedicine as part of its provisions. This E-Commerce Directive, as it became known, was subjected to further study which revealed some problems relative to the practice of telemedicine. Among the subjects discussed in this paper are those of privacy, data protection, free movement of services, the impact of electronic communication and ethical issues. PMID:15074761

Callens, Stefaan

2003-01-01

188

European bounty for taxonomists  

Microsoft Academic Search

Non-professional taxonomists have been responsible for describing more than half of the animal species discovered in Europe from 1998 to 2007 (see also Nature 467, 788; 2010). The extraordinary current rate of description of new species makes Europe an unexpected frontier for biodiversity exploration. The Fauna Europaea database (http:\\/\\/www.faunaeur.org), released in 2004, lists more than 125,000 European species of multicellular

Benoît Fontaine; Achterberg van C; M. A. Alonso-Zarazaga; R. Araujo; M. Asche; H. Aspöck; U. Aspöck; P. Audisio; B. Aukema; N. Bailly; M. Balsamo; R. A. Bank; C. Belfiore; W. Bogdanowicz; G. Boxshall; D. Burckhardt; P. Chylarecki; L. Deharveng; A. Dubois; H. Enghoff; R. Fochetti; C. Fontaine; O. Gargominy; M. S. Gomez Lopez; D. Goujet; M. S. Harvey; K.-G. Heller; Helsdingen van Peter; H. Hoch; Jong de Y; O. Karsholt; W. Los; W. Magowski; J. A. Massard; S. J. McInnes; L. F. Mendes; E. Mey; V. Michelsen; A. Minelli; J. M. Nieto Nafria; Nieukerken van E. J; Th. Pape; Prins De W; M. Ramos; C. Ricci; C. Roselaar; E. Rota; H. Segers; T. Timm; Tol van J; Ph. Bouchet

2010-01-01

189

ERPA: European Research Papers Archive  

NSDL National Science Digital Library

ERPA, the European Research Papers Archive, provides a common interface for searching a database of online working papers relevant to European integration. Contributors to the archive include the Robert Schuman Centre of the Academy of European Law at the European University Institute, the Max Planck Institute for the Study of Societies, the Jean Monnet Working Papers Series at Harvard Law School, and the European Communities Studies Association-Austria. Users can select either a short form to search recent additions to the archive or a long form to either or to also access the many advanced search options, including full-text searches.

190

Nine new tetranucleotide microsatellite DNA markers for the European mudminnow Umbra krameri  

Microsoft Academic Search

We have isolated eight polymorphic and one monomorphic perfect tetra-nucleotide microsatellite markers for the rare European\\u000a mudminnow Umbra krameri from genomic libraries enriched for (GACA)n and (GATA)n repeat sequences. A total of 36 individuals from two different populations (Slovakia and Hungary) were tested for these loci.\\u000a The number of alleles per locus ranged from six to twelve with expected heterozygosities

Kathrin A. Winkler; Steven Weiss

2009-01-01

191

Allozymic and morphometric evidence for two stocks of the European anchovy Engraulis encrasicolus in Adriatic waters  

Microsoft Academic Search

Allozyme electrophoresis and morphometric analyses were used to investigate the stock structure of European anchovies (Engraulis encrasicolus L.) captured by Italian vessels in the Adriatic Sea. Twenty four putative enzyme loci were studied, all of which exhibited genotypic proportions in accordance with Hardy-Weinberg predictions. Two loci, IDHP-2* (isocitrate dehydrogenase, 1.1.1.42) and G3PDH-2* (glycerol-3-phosphate dehydrogenase, 1.1.1.8), showed significant allele-frequency differences among

D. G. Bembo; G. R. Carvalho; N. Cingolani; E. Arneri; G. Giannetti; T. J. Pitcher

1996-01-01

192

Distribution of Mytilus taxa in European coastal areas as inferred from molecular markers  

NASA Astrophysics Data System (ADS)

The genetic constitution of mussels ( Mytilus spp.) was studied by means of three nuclear (Me 15/16, EF-bis, ITS) and one mtDNA (ND2-COIII) marker on a large European scale. In addition to a sharp cline between Atlantic and Mediterranean M. galloprovincialis, we observed a clear genetic distinction between the Black Sea and Mediterranean populations and a higher incidence of M. trossulus than reported so far in northern European populations. The frequency of M. galloprovincialis nuclear alleles was high along the Iberian Peninsula and decreased abruptly along the French coasts with a high frequency of M. edulis alleles in the Bay of Biscay, The Netherlands, Germany, Iceland, Barents and White Seas, and with little evidence of introgression between the two taxa. M. trossulus alleles were observed in the Baltic Sea and Danish Straits as expected. In addition, occurrence of M. trossulus alleles in cold waters of Iceland, Barents Sea and White Sea is reported for the first time.

Kijewski, T.; ?mietanka, B.; Zbawicka, M.; Gosling, E.; Hummel, H.; Wenne, R.

2011-02-01

193

Protective effect of the AT137RQ and ARQK176 PrP alleles against classical scrapie in Sarda breed sheep  

PubMed Central

The susceptibility of sheep to scrapie is under the control of the host’s prion protein (PrP) gene and is also influenced by the strain of the agent. PrP polymorphisms at codons 136 (A/V), 154 (R/H) and 171 (Q/R/H) are the main determinants of susceptibility/resistance of sheep to classical scrapie. They are combined in four main variants of the wild-type ARQ allele: VRQ, AHQ, ARH and ARR. Breeding programmes have been undertaken on this basis in the European Union and the USA to increase the frequency of the resistant ARR allele in sheep populations. Herein, we report the results of a multi-flock study showing the protective effect of polymorphisms other than those at codons 136, 154 and 171 in Sarda breed sheep. All ARQ/ARQ affected sheep (n = 154) and 378 negative ARQ/ARQ controls from four scrapie outbreaks were submitted to sequencing of the PrP gene. The distribution of variations other than those at the standard three codons, between scrapie cases and negative controls, was statistically different in all flocks. In particular, the AT137RQ and ARQK176 alleles showed a clear protective effect. This is the first study demonstrating a protective influence of alleles other than ARR under field conditions. If further investigations in other sheep breeds and with other scrapie sources confirm these findings, the availability of various protective alleles in breeding programmes of sheep for scrapie resistance could be useful in breeds with a low frequency of the ARR allele and would allow maintaining a wider variability of the PrP gene.

Vaccari, Gabriele; Scavia, Gaia; Sala, Marcello; Cosseddu, Gianmario; Chiappini, Barbara; Conte, Michela; Esposito, Elena; Lorenzetti, Raniero; Perfetti, Gabriella; Marconi, Paola; Scholl, Francesco; Barbaro, Katia; Bella, Antonino; Nonno, Romolo; Agrimi, Umberto

2009-01-01

194

Microsatellite Variation in Honey Bee (Apis Mellifera L.) Populations: Hierarchical Genetic Structure and Test of the Infinite Allele and Stepwise Mutation Models  

PubMed Central

Samples from nine populations belonging to three African (intermissa, scutellata and capensis) and four European (mellifera, ligustica, carnica and cecropia) Apis mellifera subspecies were scored for seven microsatellite loci. A large amount of genetic variation (between seven and 30 alleles per locus) was detected. Average heterozygosity and average number of alleles were significantly higher in African than in European subspecies, in agreement with larger effective population sizes in Africa. Microsatellite analyses confirmed that A. mellifera evolved in three distinct and deeply differentiated lineages previously detected by morphological and mitochondrial DNA studies. Dendrogram analysis of workers from a given population indicated that super-sisters cluster together when using a sufficient number of microsatellite data whereas half-sisters do not. An index of classification was derived to summarize the clustering of different taxonomic levels in large phylogenetic trees based on individual genotypes. Finally, individual population X loci data were used to test the adequacy of the two alternative mutation models, the infinite allele model (IAM) and the stepwise mutation models. The better fit overall of the IAM probably results from the majority of the microsatellites used including repeats of two or three different length motifs (compound microsatellites).

Estoup, A.; Garnery, L.; Solignac, M.; Cornuet, J. M.

1995-01-01

195

Unusual FGA and D19S433 off-ladder alleles and other allelic variants at the STR loci D8S1132, vWA, D18S51 and ACTBP2 (SE33)  

Microsoft Academic Search

A very short FGA allele *14 and a long D19S433 allele *19.2 were detected and sequenced, as well as the new D8S1132 alleles *12.1, *14 and *15.1. Further new sequence data (vWA allele *18.3, D18S51 allele *11.2, SE33 alleles *24.2, *32, *34 and *37, including the rare variant allele *13.2) are described.

E. M. Dauber; G. Dorner; S. Wenda; E. M. Schwartz-Jungl; B. Glock; W. Bär; W. R. Mayr

2008-01-01

196

Allelic variation in a fatty-acyl reductase gene causes divergence in moth sex pheromones.  

PubMed

Pheromone-based behaviours are crucial in animals from insects to mammals, and reproductive isolation is often based on pheromone differences. However, the genetic mechanisms by which pheromone signals change during the evolution of new species are largely unknown. In the sexual communication system of moths (Insecta: Lepidoptera), females emit a species-specific pheromone blend that attracts males over long distances. The European corn borer, Ostrinia nubilalis, consists of two sex pheromone races, Z and E, that use different ratios of the cis and trans isomers of acetate pheromone components. This subtle difference leads to strong reproductive isolation in the field between the two races, which could represent a first step in speciation. Female sex pheromone production and male behavioural response are under the control of different major genes, but the identity of these genes is unknown. Here we show that allelic variation in a fatty-acyl reductase gene essential for pheromone biosynthesis accounts for the phenotypic variation in female pheromone production, leading to race-specific signals. Both the cis and trans isomers of the pheromone precursors are produced by both races, but the precursors are differentially reduced to yield opposite ratios in the final pheromone blend as a result of the substrate specificity of the enzymes encoded by the Z and E alleles. This is the first functional characterization of a gene contributing to intraspecific behavioural reproductive isolation in moths, highlighting the importance of evolutionary diversification in a lepidopteran-specific family of reductases. Accumulation of substitutions in the coding region of a single biosynthetic enzyme can produce pheromone differences resulting in reproductive isolation, with speciation as a potential end result. PMID:20592730

Lassance, Jean-Marc; Groot, Astrid T; Liénard, Marjorie A; Antony, Binu; Borgwardt, Christin; Andersson, Fredrik; Hedenström, Erik; Heckel, David G; Löfstedt, Christer

2010-07-22

197

A cis-eQTL of HLA-DRB1 and a frameshift mutation of MICA contribute to the pattern of association of HLA alleles with cervical cancer.  

PubMed

The association of classic human leukocyte antigen (HLA) alleles with risk of cervical cancer has been extensively studied, and a protective effect has consistently been found for DRB1*1301, DQA1*0103, and/or DQB1*0603 (these three alleles are in perfect linkage disequilibrium [LD] and often occur on the same haplotype in Europeans), while reports have differed widely with respect to the effect of HLA-B*07, DRB1*1501, and/or DQB1*0602 (the last two alleles are also in perfect LD in Europeans). It is not clear whether the reported HLA alleles are responsible for the differences in cervical cancer susceptibility, or if functional variants at other locations within the major histocompatibility complex (MHC) region may explain the effect. In order to assess the relative contribution of both classic HLA alleles and single-nucleotide polymorphisms (SNPs) within the MHC region to cervical cancer susceptibility, we have imputed classic HLA alleles in 1034 cervical cancer patients and 3948 controls in a Swedish population for an integrated analysis. We found that the protective haplotype DRB1*1301-DQA1*0103-DQB1*0603 has a direct effect on cervical cancer and always occurs together with the C allele of a HLA-DRB1 cis-eQTL (rs9272143), which increases the expression of HLA-DRB1. The haplotype rs9272143C-DRB1*1301-DQA1*0103-DQB1*0603 conferred the strongest protection against cervical cancer (odds ratio [OR] = 0.41, 95% confidence interval [CI] = 0.32-0.52, P = 6.2 × 10(-13) ). On the other hand, the associations with HLA-B*0702 and DRB1*1501-DQB1*0602 are attributable to the joint effects of both the HLA-DRB1 cis-eQTL (rs9272143) and a frameshift mutation (G inserion of rs67841474, also known as A5.1) of the MHC class I polypeptide-related sequence A gene (MICA). Variation in LD between the classic HLA loci, rs9272143 and rs67841474 between populations may explain the different associations of HLA-B*07 and DRB1*1501-DQB1*0602 with cervical cancer between studies. The mechanism suggested may also explain similar inconsistent results for other HLA-associated diseases. PMID:24520070

Chen, Dan; Gyllensten, Ulf

2014-04-01

198

Prognostic Value of Allelic Imbalance in Prostate Biopsy.  

National Technical Information Service (NTIS)

Purpose: The novel Concept that is being tested in this project is that allelic imbalance (Al) in tissue obtained at prostate biopsy can serve as a sensitive and independent marker for staging and predicting disease recurrence in prostate cancer. Scope: T...

J. K. Griffith

2006-01-01

199

Prognostic Value of Allelic Imbalance in Prostate Biopsy.  

National Technical Information Service (NTIS)

The novel concept that is being tested in this project is that allelic imbalance (AI) in tissue obtained at prostate biopsy can serve as a sensitive and independent marker for staging and predicting disease recurrence in prostate cancer. The two aims of t...

J. K. Griffith

2005-01-01

200

Apolipoprotein e alleles in cuban patients with mild cognitive impairment.  

PubMed

Background: Apolipoprotein E (ApoE) ?4 genotype is the most clearly documented risk factor for Alzheimer's disease (AD). Epidemiological studies demonstrate an accelerated rate of progression to dementia and AD in patients with mild cognitive impairment (MCI). We assessed the ApoE allele and genotypes frequencies in Cuban patients with MCI. Methods: We performed ApoE genotyping of 74 Cuban patients more than 65 years old. Cognitive assessments included the Mini-Mental State Examination (MMSE) and a cognitive battery for evaluating memory, attention, perception, and executive function. Results: Cognitive impairments were characterized by amnesia and executive deficits in patients with MCI. The Apo ?4 allele frequency was 0.196 in patients with MCI, 10-fold higher than that in the controls. Patients carrying the ?4 allele exhibited poorer performance in MMSE and tests assessing executive function and short-term memory than noncarriers. Conclusions: The patients exhibited amnestic MCI multiple domains. Cognitive performance was worse in patients who carried the ApoE ?4 allele. PMID:24370622

Suárez, Viana Manrique; Fernández, Yuriem; López, Elena Del Carmen Ruiz; Clarke, David Higginson; Bobes, Maria Antonieta; Riverón, Ana Maria; López-Cánovas, Lilia

2014-05-01

201

The clinical spectrum of complete FBN1 allele deletions  

Microsoft Academic Search

The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a

Yvonne Hilhorst-Hofstee; Ben CJ Hamel; Joke BGM Verheij; Marry EB Rijlaarsdam; Jan M Cobben; Cindy Giroth; Claudia AL Ruivenkamp; Kerstin BM Hansson; Janneke Timmermans; Henriette A Moll; Martijn H Breuning; Gerard Pals

2011-01-01

202

A measure of population subdivision based on microsatellite allele frequencies  

Microsoft Academic Search

Microsatellite loci, loci that vary in the number of repeats of a simple DNA sequence, are becoming commonly used in the analysis of natural populations. Microsatellite loci are often highly polymorphic and relatively easy to survey and hence offer the hope of greater understanding of population structure. The question is how to make the best use of allele frequencies at

Montgomery Slatkin

1995-01-01

203

Experimental evolution of a novel sexually antagonistic allele.  

PubMed

Evolutionary conflict permeates biological systems. In sexually reproducing organisms, sex-specific optima mean that the same allele can have sexually antagonistic expression, i.e. beneficial in one sex and detrimental in the other, a phenomenon known as intralocus sexual conflict. Intralocus sexual conflict is emerging as a potentially fundamental factor for the genetic architecture of fitness, with important consequences for evolutionary processes. However, no study to date has directly experimentally tested the evolutionary fate of a sexually antagonistic allele. Using genetic constructs to manipulate female fecundity and male mating success, we engineered a novel sexually antagonistic allele (SAA) in Drosophila melanogaster. The SAA is nearly twice as costly to females as it is beneficial to males, but the harmful effects to females are recessive and X-linked, and thus are rarely expressed when SAA occurs at low frequency. We experimentally show how the evolutionary dynamics of the novel SAA are qualitatively consistent with the predictions of population genetic models: SAA frequency decreases when common, but increases when rare, converging toward an equilibrium frequency of ?8%. Furthermore, we show that persistence of the SAA requires the mating advantage it provides to males: the SAA frequency declines towards extinction when the male advantage is experimentally abolished. Our results empirically demonstrate the dynamics underlying the evolutionary fate of a sexually antagonistic allele, validating a central assumption of intralocus sexual conflict theory: that variation in fitness-related traits within populations can be maintained via sex-linked sexually antagonistic loci. PMID:22956914

Dean, Rebecca; Perry, Jennifer C; Pizzari, Tommaso; Mank, Judith E; Wigby, Stuart

2012-01-01

204

Autoimmune Disease Classification by Inverse Association with SNP Alleles  

Microsoft Academic Search

With multiple genome-wide association studies (GWAS) performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction of allele-specific disease associations for SNPs. In this work, we refine the notion of a genetic

Marina Sirota; Marc A. Schaub; Serafim Batzoglou; William H. Robinson; Atul J. Butte

2009-01-01

205

Rescue of Progeria in Trichothiodystrophy by Homozygous Lethal Xpd Alleles  

Microsoft Academic Search

Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive

Jaan-Olle Andressoo; Judith Jans; Jan de Wit; Frederic Coin; Deborah Hoogstraten; Marieke van de Ven; Wendy Toussaint; Jan Huijmans; H. Bing Thio; Wibeke J. van Leeuwen; Jan de Boer; Jean-Marc Egly; Jan H. J. Hoeijmakers; James R. Mitchell

2006-01-01

206

Systematic underestimation of the age of selected alleles  

PubMed Central

A common interpretation of genome-wide selection scans is that the dispersal of anatomically modern humans out of Africa and into diverse environments led to a number of genetic adaptations. If so, patterns of polymorphism from non-African individuals should show the signature of adaptations dating to 40,000–100,000 Kya, coinciding with the main exodus from Africa. However, scans of polymorphism data from a few populations have yielded conflicting results about the chronology of local, population-specific adaptations. In particular, a number of papers report very recent ages for selected alleles in humans, which postdate the development of agriculture 10 Kya, and suggest that adaptive differences among human populations are much more recent. I present an analysis of simulations suggesting a downward bias in methods commonly used to estimate the age of selected alleles. These findings indicate that an estimate of a time to the most recent common ancestor (tMRCA) obtained using standard methods (used as a proxy for the age of an allele) of less than 10 Kya is consistent with an allele that actually became selected before the onset of agriculture and potentially as early as 50 Kya. These findings suggest that the genomic scans for selection may be consistent with selective pressures tied to the Out of Africa expansion of modern human populations.

Kelley, Joanna L.

2012-01-01

207

Estimating the age of alleles by use of intraallelic variability  

SciTech Connect

A method is presented for estimating the age of an allele by use of its frequency and the extent of variation among different copies. The method uses the joint distribution of the number of copies in a population sample and the coalescence times of the intraallelic gene genealogy conditioned on the number of copies. The linear birth-death process is used to approximate the dynamics of a rare allele in a finite population. A maximum-likelihood estimate of the age of the allele is obtained by Monte Carlo integration over the coalescence times. The method is applied to two alleles at the cystic fibrosis (CFTR) locus, {Delta}F508 and G542X, for which intraallelic variability at three intronic microsatellite loci has been examined. Our results indicate that G542X is somewhat older than {Delta}F508. Although absolute estimates depend on the mutation rates at the microsatellite loci, our results support the hypothesis that {Delta}F508 arose <500 generations ({approx}10,000 years) ago. 32 refs., 4 figs.

Slatkin, M.; Rannala, B. [Univ of California, Berkeley, CA (United States)

1997-02-01

208

Multifragment alleles in DNA fingerprints of the parrot, Amazona ventralis  

USGS Publications Warehouse

Human DNA probes that identify variable numbers of tandem repeat loci are being used to generate DNA fingerprints in many animal and plant species. In most species the majority of the sc rable autoradiographic bands of the DNA fingerprint represent alleles from numerous unlinked loci. This study was initiated to use DNA fingerprints to determine the amount of band-sharing among captive Hispaniolan parrots (Amazona ventralis) with known genetic relationships. This would form the data base to examine DNA fingerprints of the closely related and endangered Puerto Rican parrot (A. vittata) and to estimate the degree of inbreeding in the relic population. We found by segregation analysis of the bands scored in the DNA fingerprints of the Hispaniolan parrots that there may be as few as two to five loci identified by the human 33.15 probe. Furthermore, at one locus we identified seven alleles, one of which is represented by as many as 19 cosegregating bands. It is unknown how common multiband alleles might be in natural populations, and their existence will cause problems in the assessment of relatedness by band-sharing analysis. We believe, therefore, that a pedigree analysis should be included in all DNA fingerprinting studies, where possible, in order to estimate the number of loci identified by a minisatellite DNA probe and to examine the nature of their alleles.

Brock, M.K; White, B.N.

1991-01-01

209

Competitive enzymatic reaction to control allele-specific extensions  

PubMed Central

Here, we present a novel method for SNP genotyping based on protease-mediated allele-specific primer extension (PrASE), where the two allele-specific extension primers only differ in their 3?-positions. As reported previously [Ahmadian,A., Gharizadeh,B., O'Meara,D., Odeberg,J. and Lundeberg,J. (2001), Nucleic Acids Res., 29, e121], the kinetics of perfectly matched primer extension is faster than mismatched primer extension. In this study, we have utilized this difference in kinetics by adding protease, a protein-degrading enzyme, to discriminate between the extension reactions. The competition between the polymerase activity and the enzymatic degradation yields extension of the perfectly matched primer, while the slower extension of mismatched primer is eliminated. To allow multiplex and simultaneous detection of the investigated single nucleotide polymorphisms (SNPs), each extension primer was given a unique signature tag sequence on its 5? end, complementary to a tag on a generic array. A multiplex nested PCR with 13 SNPs was performed in a total of 36 individuals and their alleles were scored. To demonstrate the improvements in scoring SNPs by PrASE, we also genotyped the individuals without inclusion of protease in the extension. We conclude that the developed assay is highly allele-specific, with excellent multiplex SNP capabilities.

Hultin, Emilie; Kaller, Max; Ahmadian, Afshin; Lundeberg, Joakim

2005-01-01

210

Allelic diversity of the population of Phytophthora infestans in China  

Microsoft Academic Search

Introduction of resistance genes from wild Solanum species into potato cultivars is considered the most promising and environmentally safe approach to achieve late blight resistance. An R-gene stacking breeding program using cisgenesis is planning to trial its products in China. To adapt this approach to local conditions, we propose to assess the allelic diversity of known avirulent genes of P.

Y. Li; S. Huang; Lee van der T; G. J. T. Kessel; E. Jacobsen; R. Zhang; G. Jin; C. Lan; Z. Zhao; S. Kamoun

2009-01-01

211

The Maintenance of Single-Locus Polymorphism. IV. Models with Mutation from Existing Alleles  

PubMed Central

The ability of viability selection to maintain allelic polymorphism is investigated using a constructionist approach. In extensions to the models we have previously proposed, a population is bombarded with a series of mutations whose fitnesses in conjunction with other alleles are functions of the corresponding fitnesses with a particular allele, the parent allele, already in the population. Allele frequencies are iterated simultaneously, thus allowing alleles to be driven to extinction by selection. Such models allow very high levels of polymorphism to evolve: up to 38 alleles in one case. Alleles that are lethal as homozygotes can evolve to surprisingly high frequencies. The joint evolution of allele frequencies and viabilities highlights the necessity to consider more than the current morphology of a population. Comparisons are made with the neutral theory of evolution and it is suggested that failure to reject neutrality using the Ewens-Watterson test cannot be regarded as evidence for the neutral theory.

Spencer, H. G.; Marks, R. W.

1992-01-01

212

The HLA-DRB1 Shared Epitope Is Associated With Susceptibility to Rheumatoid Arthritis in African Americans Through European Genetic Admixture  

PubMed Central

Objective To determine whether shared epitope (SE)–containing HLA–DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population. Methods In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti–cyclic citrullinated peptide (anti-CCP) antibodies and HLA–DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry. Results The frequency of SE-containing HLA–DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA–DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody–positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody–negative RA (P = 0.01, by chi-square test). Conclusion HLA–DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which ~50–70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.

Hughes, Laura B.; Morrison, Dahliann; Kelley, James M.; Padilla, Miguel A.; Vaughan, L. Kelly; Westfall, Andrew O.; Dwivedi, Harshit; Mikuls, Ted R.; Holers, V. Michael; Parrish, Lezlie A.; Alarcon, Graciela S.; Conn, Doyt L.; Jonas, Beth L.; Callahan, Leigh F.; Smith, Edwin A.; Gilkeson, Gary S.; Howard, George; Moreland, Larry W.; Patterson, Nick; Reich, David; Bridges, S. Louis

2009-01-01

213

Tri-allelic pattern at the TPOX locus: a familial study.  

PubMed

Alleles at the TPOX STR locus have 6-14 different numbers of a four-nucleotide (AATG) repeat motif arranged in tandem. Although tri-allelic genotypes are generally rare, the TPOX tri-allelic pattern has a higher frequency, varying widely among populations. Despite this, there are few accurate reports to disclose the nature of the TPOX third allele. In this work we present data obtained from 45 individuals belonging to the same pedigree, in which there are cases of tri-allelic TPOX genotypes. The subjects were apparently healthy with a normal biological development. We noticed six tri-allelic cases in this family, and all of them were women. Karyotype analysis showed no occurrence of partial 2p trisomy. All the tri-allelic cases had the genotype 8-10-11, probably due to three copies of the TPOX STR sequence in all cells (Type 2 tri-allelic pattern). Based on previous data we assumed the allele 10 as the TPOX third allele. The pedigree analyses show evidences that the TPOX extra-allele was the allele10, it is placed far from the main TPOX locus, and that there is a potential linkage of the TPOX extra-allele-10 with Xq. This was the first study that included a large pedigree analysis in order to understand the nature TPOX tri-allelic pattern. PMID:24144843

Picanço, Juliane Bentes; Raimann, Paulo Eduardo; Paskulin, Giorgio Adriano; Alvarez, Luís; Amorim, António; Batista Dos Santos, Sidney Emanuel; Alho, Clarice Sampaio

2014-02-10

214

Report of the European DNA profiling group (EDNAP): an investigation of the complex STR loci D21S11 and HUMFIBRA (FGA)  

Microsoft Academic Search

This paper describes a collaborative exercise which was intended to demonstrate whether uniformity of DNA profiling results could be achieved between European laboratories using two complex short tandem repeat (STR) loci. The loci D21S11 and HUMFIBRA (FGA) were chosen because they are commonly used by different European laboratories. D21S11 has approximately 14 common alleles (f>0.001), whereas HUMFIBRA has 19 common

Peter Gill; E d'Aloja; J Andersen; B Dupuy; M Jangblad; V Johnsson; A. D Kloosterman; A Kratzer; M. V Lareu; M Meldegaard; C Phillips; H Pfitzinger; S Rand; M Sabatier; R Scheithauer; H Schmitter; P Schneider; M. C Vide

1997-01-01

215

Comprehensive typing of DQB1 alleles by PCR-RFLP.  

PubMed

The protocols represented in this report can resolve all 22 DQB1 alleles. The second exon of DQB1 was subjected to PCR using two group-specific primers to obtain DQB1 group 1 (DQ5 and DQ6) and group 2 (DQ2, DQ3, DQ4) specific amplified products, respectively. Three endonucleases, ApaI, BssHII and NciI, can provide typing of DQ5 and DQ6 based on easy-to-read uncleaved, cleaved and a combination of uncleaved/cleaved patterns. Similarly, two endonucleases, FokI and BgII can define the specificities DQ2, DQ3 and DQ4. Moreover, all 13 group 1 DQB1 alleles and all but one of their 78 possible heterozygotes can be unambiguously resolved using an extended panel of 10 endonucleases. The remaining pair of heterozygotes, DQB1*05031/0603 and 05032/0608, can however be resolved by double digestion with BsmFI and SfaNI. RsaI splits the previously unresolved alleles DQB1*0602 and 0603 in the amplified products of the modified primer SDQ-01. Fnu4HI can resolve DQB1*0606 from 0605. DQB1*0603, 0607 and 0608 can be resolved by SfaNI and the new endonuclease BsmFI. The comprehensive typing of group 2 DQB1 alleles can be achieved using five endonucleases. All 9 group 2 DQB1 alleles and all but one pair (DQB1*0301/0302 from DQB1*03032/0304) of 36 possible heterozygotes can be resolved. Thus, PCR-RFLP remains a simple, inexpensive and reliable method for DQB1 typing. The PCR-RFLP can be used for comprehensive DQB1 typing either independently or to complement the PCR-SSP and PCR-SSOP methods. PMID:7916168

Sengar, D P; Goldstein, R

1994-04-01

216

Testing allele homogeneity: the problem of nested hypotheses  

PubMed Central

Background The evaluation of associations between genotypes and diseases in a case-control framework plays an important role in genetic epidemiology. This paper focuses on the evaluation of the homogeneity of both genotypic and allelic frequencies. The traditional test that is used to check allelic homogeneity is known to be valid only under Hardy-Weinberg equilibrium, a property that may not hold in practice. Results We first describe the flaws of the traditional (chi-squared) tests for both allelic and genotypic homogeneity. Besides the known problem of the allelic procedure, we show that whenever these tests are used, an incoherence may arise: sometimes the genotypic homogeneity hypothesis is not rejected, but the allelic hypothesis is. As we argue, this is logically impossible. Some methods that were recently proposed implicitly rely on the idea that this does not happen. In an attempt to correct this incoherence, we describe an alternative frequentist approach that is appropriate even when Hardy-Weinberg equilibrium does not hold. It is then shown that the problem remains and is intrinsic of frequentist procedures. Finally, we introduce the Full Bayesian Significance Test to test both hypotheses and prove that the incoherence cannot happen with these new tests. To illustrate this, all five tests are applied to real and simulated datasets. Using the celebrated power analysis, we show that the Bayesian method is comparable to the frequentist one and has the advantage of being coherent. Conclusions Contrary to more traditional approaches, the Full Bayesian Significance Test for association studies provides a simple, coherent and powerful tool for detecting associations.

2012-01-01

217

Nomenclature for alleles of the thiopurine methyltransferase gene  

PubMed Central

The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors’ articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G > A) from TPMT*24 to TPMT*30 and position 611 (T > C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.

Appell, Malin L.; Berg, Jonathan; Duley, John; Evans, William E.; Kennedy, Martin A.; Lennard, Lynne; Marinaki, Tony; McLeod, Howard L.; Relling, Mary V.; Schaeffeler, Elke; Schwab, Matthias; Weinshilboum, Richard; Yeoh, Allen E.J.; McDonagh, Ellen M.; Hebert, Joan M.; Klein, Teri E.; Coulthard, Sally A.

2013-01-01

218

Nomenclature for alleles of the thiopurine methyltransferase gene.  

PubMed

The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors' articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G>A) from TPMT*24 to TPMT*30 and position 611 (T>C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. PMID:23407052

Appell, Malin L; Berg, Jonathan; Duley, John; Evans, William E; Kennedy, Martin A; Lennard, Lynne; Marinaki, Tony; McLeod, Howard L; Relling, Mary V; Schaeffeler, Elke; Schwab, Matthias; Weinshilboum, Richard; Yeoh, Allen E J; McDonagh, Ellen M; Hebert, Joan M; Klein, Teri E; Coulthard, Sally A

2013-04-01

219

Genetic variation in the major histocompatibility complex of the European brown hare (Lepus europaeus) across distinct phylogeographic areas.  

PubMed

The major histocompatibility complex is one of the best studied systems in vertebrates providing evidence for the long-term action of selection. Here, we examined the intra- and inter-population genetic diversity of the MHC class II DRB locus in European brown hare (Lepus europaeus) and correlated the results with genetic variability already estimated from the MHC DQA locus and from maternally (mitochondrial DNA (mtDNA)) and biparentally (allozymes, microsatellites) inherited loci. L. europaeus showed remarkable genetic polymorphism in both DQA and DRB1 loci. The Anatolian populations exhibited the highest genetic polymorphism for both loci. Balancing selection has established increased variability in the European populations despite the founder effects after the last glaciation. Different evolutionary rates were traced for DRB1 and DQA loci, as evidenced by the higher number of common DRB1 than DQA alleles and the greater differences between DRB1 alleles with common origin in comparison with DQA alleles. The high number of rare alleles with low frequencies detected implies that frequency-dependent selection drives MHC evolution in the brown hare through the advantage of rare alleles. Both loci were under the influence of positive selection within the peptide-binding region. The functional polymorphism, recorded as amino acid substitutions within the binding pockets, fell also within distinct geographic patterns, yet it was much narrower than the genetic polymorphism. We hypothesize that certain structural and functional characteristics of the binding pockets set limitations to the actual shape of genetic polymorphism in MHC. PMID:24743946

Koutsogiannouli, Evagelia A; Moutou, Katerina A; Stamatis, Costas; Walter, Lutz; Mamuris, Zissis

2014-06-01

220

Cystic fibrosis allele frequency, sex ratio anomalies and fertility: a new theory for the dissemination of mutant alleles  

Microsoft Academic Search

The observation that mothers of cystic fibrosis patients come from sibships that are larger than those of the fathers is explained by a decrease in sex ratio with increasing size of parental sibships. This feature also provides the basis for a new theory for the dissemination of the major mutant allele, deduced to have arisen 2700–5000 years ago, in accordance

Dorian J. Pritchard

1991-01-01

221

Consistent Association of Type 2 Diabetes Risk Variants Found in Europeans in Diverse Racial and Ethnic Groups  

PubMed Central

It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10?4) and similar in all populations (odds ratios 1.09–1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; Phet?=?3.8×10?4). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding “synthetic associations” of rare mutations in T2D.

Waters, Kevin M.; Stram, Daniel O.; Hassanein, Mohamed T.; Le Marchand, Loic; Wilkens, Lynne R.; Maskarinec, Gertraud; Monroe, Kristine R.; Kolonel, Laurence N.; Altshuler, David; Henderson, Brian E.; Haiman, Christopher A.

2010-01-01

222

European Pulsar Timing Array  

NASA Astrophysics Data System (ADS)

The European Pulsar Timing Array is a collaboration that has recently been formed between the five major radio observatories in Europe: Jodrell Bank, Effelsberg, Westerbork, Nançay and Sardinia. Together we work towards detecting gravitational waves. We combine the individual strengths of all the different observatories to obtain improved results. We give a short introduction on the partners, goals and instrumentation of this collaboration. Besides gravitational wave detection, the EPTA collaboration is sharing data to optimize timing on, for example, millisecond binary pulsars. We present some recent results of combining datasets of the four telescopes now in use for the EPTA.

Janssen, G. H.; Stappers, B. W.; Kramer, M.; Purver, M.; Jessner, A.; Cognard, I.

2008-02-01

223

European Museum Guide  

NSDL National Science Digital Library

Museum Media Publishers publishes this guide to the major museums in twelve European countries. The current edition describes some 1500 exhibitions planned between May 1997 and May 1998. Museums and exhibitions are listed alphabetically by country and city. Each entry describes the museum's collection, visiting information, and a description of their exhibitions through May 1998. When possible, a hyperlink to the museum's web site is also provided. Users can also view a chronological index of all the exhibitions in each country or search the site by museum or exhibition.

224

European Space Agency: Rosetta  

NSDL National Science Digital Library

Rosetta is the European Space Agency's comet exploration spacecraft. Materials presented here describe the space craft and its mission, which is to rendezvous with and orbit Comet 67 P/Churyumov-Gerasimenko, and soft-land an instrument package on the comet's nucleus. En route to the comet, it will perform fly-bys of two asteroids, Steins and Lutetia. Topics include a mission summary, background science, information on the orbiter and lander, and a mission schedule. An image gallery is also provided that contains pictures of the spacecraft, imagery taken by the spacecraft, pictures of the launch, and others.

225

Maximizing allele detection: Effects of analytical threshold and DNA levels on rates of allele and locus drop-out.  

PubMed

Interpretation of DNA evidence depends upon the ability of the analyst to accurately compare the DNA profile obtained from an item of evidence and the DNA profile of a standard. This interpretation becomes progressively more difficult as the number of 'drop-out' and 'drop-in' events increase. Analytical thresholds (AT) are typically selected to ensure the false detection of noise is minimized. However, there exists a tradeoff between the erroneous labeling of noise as alleles and the false non-detection of alleles (i.e. drop-out). In this study, the effect ATs had on both types of error was characterized. Various ATs were tested, where three relied upon the analysis of baseline signals obtained from 31 negative samples. The fourth AT was determined by utilizing the relationship between RFU signal and DNA input. The other ATs were the commonly employed 50, 150 and 200 RFU thresholds. Receiver Operating Characteristic (ROC) plots showed that although high ATs completely negated the false labeling of noise, DNA analyzed with ATs derived using analysis of the baseline signal exhibited the lowest rates of drop-out and the lowest total error rates. In another experiment, the effect small changes in ATs had on drop-out was examined. This study showed that as the AT increased from ?10 to 60 RFU, the number of heterozygous loci exhibiting the loss of one allele increased. Between ATs of 60 and 150 RFU, the frequency of allelic drop-out remained constant at 0.27 (±0.02) and began to decrease when ATs of 150 RFU or greater were utilized. In contrast, the frequency of heterozygous loci exhibiting the loss of both alleles consistently increased with AT. In summary, for samples amplified with less than 0.5ng of DNA, ATs derived from baseline analysis of negatives were shown to decrease the frequency of drop-out by a factor of 100 without significantly increasing rates of erroneous noise detection. PMID:22796031

Rakay, Christine A; Bregu, Joli; Grgicak, Catherine M

2012-12-01

226

European Industrial Relations Observatory Online  

NSDL National Science Digital Library

The European Industrial Relations Observatory Online (EIROnline) was developed by the European Foundation for the Improvement of Living and Working Conditions, an autonomous body created by the European Community. The aim of the site is to "initiate, collect, store, disseminate and provide access to information and analysis on developments in industrial relations" in the 15 European Union member states and Norway. Visitors will find the latest industrial relations news and feature articles arranged by country. There is also a bimonthly publication called the EIRObserver summarizing the news and items over the past two months.

227

Attenuated APC alleles produce functional protein from internal translation initiation  

PubMed Central

Some truncating mutations of the APC tumor suppressor gene are associated with an attenuated phenotype of familial adenomatous polyposis coli (AAPC). This work demonstrates that APC alleles with 5? mutations produce APC protein that down-regulates ?-catenin, inhibits ?-catenin/T cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrate that cap-independent translation is initiated internally at an AUG at codon 184 of APC. Furthermore, APC coding sequence between AAPC mutations and AUG 184 permits internal ribosome entry in a bicistronic vector. These data suggest that AAPC alleles in vivo may produce functional APC by internal initiation and establish a functional correlation between 5? APC mutations and their associated clinical phenotype.

Heppner Goss, Kathleen; Trzepacz, Chris; Tuohy, Therese M. F.; Groden, Joanna

2002-01-01

228

The Fixation of Locally Beneficial Alleles in a Metapopulation  

PubMed Central

Extinction, recolonization, and local adaption are common in natural spatially structured populations. Understanding their effect upon genetic variation is important for systems such as genetically modified organism management or avoidance of drug resistance. Theoretical studies on the effect of extinction and recolonization upon genetic variance started appearing in the 1970s, but the role of local adaption still has no good theoretical basis. Here we develop a model of a haploid species in a metapopulation in which a locally adapted beneficial allele is introduced. We study the effect of different spatial patterns of local adaption, and different metapopulation dynamics, upon the fixation probability of the beneficial allele. Controlling for the average selection pressure, we find that a small area of positive selection can significantly increase the global probability of fixation. However, local adaption becomes less important as extinction rate increases. Deme extinction and recolonization have a spatial smoothing effect that effectively reduces spatial variation in fitness.

Vuilleumier, Severine; Yearsley, Jon M.; Perrin, Nicolas

2008-01-01

229

Inferring Selection Intensity and Allele Age from Multilocus Haplotype Structure  

PubMed Central

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

Chen, Hua; Slatkin, Montgomery

2013-01-01

230

Teratogenic Alleles in Autism and Other Neurodevelopmental Disorders  

Microsoft Academic Search

\\u000a Genes for neurodevelopmental disorders have proven difficult to find. In the case of autism, even though a number of genes\\u000a associated with the disorder have been identified, the cause of the disorder is far from clear. We discuss here a new category\\u000a of genetic contribution to human disorders, i.e., gene variants (alleles) that act in mothers during pregnancy to contribute

William G. Johnson; Madhura Sreenath; Steven Buyske; Edward S. Stenroos

231

Model-Free Analysis and Permutation Tests for Allelic Associations  

Microsoft Academic Search

In this short report, we address some practical problems in performing likelihood-based allelic association analysis of case-control data. Model-free statistics are proposed and their properties assessed by simulation, and procedures based on permutation tests are described for marker-marker as well as marker-disease associations. A memory-efficient algorithm is developed which enables several highly polymorphic markers to be analysed.

Jing Hua Zhao; David Curtis; Pak Chung Sham

2000-01-01

232

Somatic Allelic Deletion of nm23 in Human Cancer  

Microsoft Academic Search

Tumor progression to the metastatic phenotype is accompanied in certain cell types by reduced expression of the nm2i gene. We have localized human nm23-Hl to chromosome 17 by somatic cell hybrid analysis. Regional localization in the CEPH database and in situ hybrid ization is reported. Somatic allelic deletion of nm23-HI was observed in human breast, renal, colorectal, and lung carcinoma

Alvaro Leone; O. Wesley McBride; Ainsley Weston; Mary G. Wang; Patrick Anglard; Craig S. Cropp; John R. Goepel; Rosette Lidereau; Robert Callahan; W. Marston Linehan; Robert C. Rees; Curtis C. Harris; Lance A. Liotta; Patricia S. Steeg

233

Argyrophilic grain disease is associated with apolipoprotein E ?2 allele  

Microsoft Academic Search

Argyrophilic grain disease (AGD) is a distinct degenerative disorder of the human brain associated with the formation of\\u000a abnormally phosphorylated tau protein. AGD-related cytoskeletal changes are known to affect specific subsets of nerve cells\\u000a and oligodendrocytes. Here we demonstrate a remarkable association between the apolipoprotein E (ApoE) ?2 allele and AGD.\\u000a Individuals afflicted with AGD (n = 48) reveal a

Estifanos Ghebremedhin; Christian Schultz; Giovannina Botez; Udo Rüb; Irena Sassin; Eva Braak; Heiko Braak

1998-01-01

234

Allelic imbalance and biochemical outcome after radical prostatectomy  

Microsoft Academic Search

Objective:To compare the incidence of allelic imbalance (AI) in men with rapid disease progression with those who remained disease free after radical prostatectomy, with the aim of identifying genetic markers to predict prognosis and guide further treatment.Patients and methods:Tumour and normal DNA were extracted from two matched groups of 31 men with extracapsular node-negative (pT3N0) prostate cancer who had undergone

S R J Bott; J R W Masters; M C Parkinson; R S Kirby; M Feneley; J Hooper; M Williamson; SRJ Bott

2006-01-01

235

ALLELE-SPECIFIC EXPRESSION OF APC IN ADENOMATOUS POLYPOSIS FAMILIES  

PubMed Central

Backgound & Aims Germline mutations of the APC gene are the pathogenic cause of most cases of familial adenomatous polyposis (FAP) and a lesser proportion of attenuated FAP (AFAP). Systematic analysis of APC at the RNA level may provide insight into the pathogenicity of identified mutations and uncover the molecular basis of FAP/AFAP in families without identifiable mutations. Here, we analyzed the prevalence of imbalances in the allelic expression of APC in polyposis families with germline mutations in the gene and without detectable mutations in APC or and MUTYH. Methods Allele-specific expression (ASE) was determined by single nucleotide primer extension using an exon 11 polymorphism as an allele-specific marker. In total, 52 APC-mutation-positive (36 families) and 24 APC/MUTYH-mutation-negative (23 families) informative patients were analyzed. Seventy-six controls were also included. Results Of the APC-mutation-positive families, most of those in which the mutation was located before the last exon of the gene (12 of 14) showed ASE imbalance, which is consistent with a mechanism of nonsense-mediated decay (NMD). Of the APC/MUTYH mutation-negative families, two (9%) showed ASE imbalance as a hallmark of the putative pathogenic cause of the disease. Normal allele expression was restored after treatment of short-term cultured lymphocytes with puromycin, supporting the NMD hypothesis. Conclusions ASE analysis may be an indicator of pathogenicity for some cases of FAP and AFAP in which APC mutations are not found. ASE might also be useful for prioritizing the order in which different areas of APC should be tested. Our results underline the importance of RNA-level studies in molecular diagnosis of FAP.

Castellsague, Ester; Gonzalez, Sara; Guino, Elisabet; Stevens, Kristen N.; Borras, Ester; Raymond, Victoria M.; Lazaro, Conxi; Blanco, Ignacio; Gruber, Stephen B.; Capella, Gabriel

2010-01-01

236

Prediction of bone density from vitamin D receptor alleles  

Microsoft Academic Search

BONE density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women1,2 suffer osteoporotic fractures as a result of low bone density2, which is under strong genetic control3-6 acting through effects on bone turnover7,8. Here we show that common allelic variants in the gene encoding the vitamin D receptor9 can be used

Nigel A. Morrison; Jian Cheng Qi; Akifumi Tokita; Paul J. Kelly; Linda Crofts; Tuan V. Nguyen; Philip N. Sambrook; John A. Eisman

1994-01-01

237

Human leptin locus (LEP) alleles and BMI in Samoans  

Microsoft Academic Search

Objectives: Because of their location in known candidate gene regions for obesity the associations between six microsatellite markers (D2S2170, D2S144, D2S1268, D2S1788, D2S1348 and a tetranucleotide repeat in the 3? UTR of the LEP locus) and body mass index (BMI) were studied in adult Samoans.Design: The study was designed to detect differences in the proportion of alleles at the six

ST McGarvey; W Forrest; G Sun; D Smelser; J Tufa; S Viali; R Deka

2002-01-01

238

Expanding Allelic Diversity of Helicobacter pylori vacA  

Microsoft Academic Search

The diversity of the gene encoding the vacuolating cytotoxin (vacA )o fHelicobacter pylori was analyzed in 98 isolates obtained from different geographic locations. The studies focused on variation in the previously defined s and m regions of vacA, as determined by PCR and direct sequencing. Phylogenetic analysis revealed the existence of four distinct types of s-region alleles: aside from the

LEEN-JAN VAN DOORN; C EU FIGUEIREDO; RICARDO SANNA; SALVADOR PENA; PETER MIDOLO; ENDERS K. W. NG; JOHN C. ATHERTON; MARTIN J. BLASER; WIM G. V. QUINT

1998-01-01

239

Inferring selection intensity and allele age from multilocus haplotype structure.  

PubMed

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

Chen, Hua; Slatkin, Montgomery

2013-08-01

240

Allelic Variants of Complement Genes Associated with Dense Deposit Disease  

PubMed Central

The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies.

Abrera-Abeleda, Maria Asuncion; Nishimura, Carla; Frees, Kathy; Jones, Michael; Maga, Tara; Katz, Louis M.; Zhang, Yuzhou

2011-01-01

241

A survey of FRAXE allele sizes in three populations  

SciTech Connect

FRAXE is a fragile site located at Xq27-8, which contains polymorphic triplet GCC repeats associated with a CpG island. Similar to FRAXA, expansion of the GCC repeats results in an abnormal methylation of the CpG island and is associated with a mild mental retardation syndrome (FRAXE-MR). We surveyed the GCC repeat alleles of FRAXE from 3 populations. A total of 665 X chromosomes including 416 from a New York Euro-American sample (259 normal and 157 with FRAXA mutations), 157 from a Chinese sample (144 normal and 13 FRAXA), and 92 from a Finnish sample (56 normal and 36 FRAXA) were analyzed by polymerase chain reaction. Twenty-seven alleles, ranging from 4 to 39 GCC repeats, were observed. The modal repeat number was 16 in the New York and Finnish samples and accounted for 24% of all the chromosomes tested (162/665). The modal repeat number in the Chinese sample was 18. A founder effect for FRAXA was suggested among the Finnish FRAXA samples in that 75% had the FRAXE 16 repeat allele versus only 30% of controls. Sequencing of the FRAXE region showed no imperfections within the GCC repeat region, such as those commonly seen in FRAXA. The smaller size and limited range of repeats and the lack of imperfections suggests the molecular mechanisms underlying FRAXE triplet mutations may be different from those underlying FRAXA. 27 refs., 4 figs., 1 tab.

Zhong, N.; Ju, W.; Curley, D. [New York State Institute for Basic Research for Developmental Disabilities, Staten Island, NY (United States)] [and others] [New York State Institute for Basic Research for Developmental Disabilities, Staten Island, NY (United States); and others

1996-08-09

242

Tracing pastoralist migrations to southern Africa with lactase persistence alleles.  

PubMed

Although southern African Khoisan populations are often assumed to have remained largely isolated during prehistory, there is growing evidence for a migration of pastoralists from eastern Africa some 2,000 years ago, prior to the arrival of Bantu-speaking populations in southern Africa. Eastern Africa harbors distinctive lactase persistence (LP) alleles, and therefore LP alleles in southern African populations may be derived from this eastern African pastoralist migration. We sequenced the lactase enhancer region in 457 individuals from 18 Khoisan and seven Bantu-speaking groups from Botswana, Namibia, and Zambia and additionally genotyped four short tandem repeat (STR) loci that flank the lactase enhancer region. We found nine single-nucleotide polymorphisms, of which the most frequent is -14010(?)C, which was previously found to be associated with LP in Kenya and Tanzania and to exhibit a strong signal of positive selection. This allele occurs in significantly higher frequency in pastoralist groups and in Khoe-speaking groups in our study, supporting the hypothesis of a migration of eastern African pastoralists that was primarily associated with Khoe speakers. Moreover, we find a signal of ongoing positive selection in all three pastoralist groups in our study, as well as (surprisingly) in two foraging groups. PMID:24704073

Macholdt, Enrico; Lede, Vera; Barbieri, Chiara; Mpoloka, Sununguko W; Chen, Hua; Slatkin, Montgomery; Pakendorf, Brigitte; Stoneking, Mark

2014-04-14

243

Novel Reporter Alleles of GSK-3? and GSK-3?  

PubMed Central

Glycogen Synthase Kinase 3 (GSK-3) is a key player in development, physiology and disease. Because of this, GSK-3 inhibitors are increasingly being explored for a variety of applications. In addition most analyses focus on GSK-3? and overlook the closely related protein GSK-3?. Here, we describe novel GSK-3? and GSK-3? mouse alleles that allow us to visualise expression of their respective mRNAs by tracking ?-galactosidase activity. We used these new lacZ alleles to compare expression in the palate and cranial sutures and found that there was indeed differential expression. Furthermore, both are loss of function alleles and can be used to generate homozygous mutant mice; in addition, excision of the lacZ cassette from GSK-3? creates a Cre-dependent tissue-specific knockout. As expected, GSK3? mutants were viable, while GSK3? mutants died after birth with a complete cleft palate. We also assessed the GSK-3? mutants for cranial and sternal phenotypes and found that they were essentially normal. Finally, we observed gestational lethality in compound GSK-3??/?; GSK3?+/? mutants, suggesting that GSK-3 dosage is critical during embryonic development.

Barrell, William B.; Szabo-Rogers, Heather L.; Liu, Karen J.

2012-01-01

244

Functional characterization of 32 CYP2C9 allelic variants.  

PubMed

Genetic variations in cytochrome P450 2C9 (CYP2C9) contribute to interindividual variability in the metabolism of clinically used drugs such as warfarin and tolbutamide. We functionally characterized 32 types of allelic variant CYP2C9 proteins. Recombinant CYP2C9 proteins generated using a heterologous expression system are useful for comparing functional changes in CYP2C9 variant proteins expressed from low-frequency alleles. Wild-type CYP2C9 and its 31 variants were found to be transiently expressed in COS-7 cells, and the enzymatic activity of the CYP2C9 variants was characterized using S-warfarin as a representative substrate. Among the 32 types of CYP2C9 allelic variants tested, CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33 and CYP2C9.35 exhibited no enzyme activity, and 12 types showed significantly decreased enzyme activity. In vitro analysis of CYP2C9 variant proteins should be useful for predicting CYP2C9 phenotypes and for application to personalized drug therapy. PMID:23752738

Niinuma, Y; Saito, T; Takahashi, M; Tsukada, C; Ito, Mi; Hirasawa, N; Hiratsuka, M

2014-04-01

245

Tests and estimates of allelic association in complex inheritance  

PubMed Central

Family-based procedures such as the transmission disequilibrium test (TDT) were motivated by concern that sample-based methods to map disease genes by allelic association are not robust to population stratification, migration, and admixture. Other factors to consider in designing a study of allelic association are specification of gene action in a weakly parametric model, efficiency, diagnostic reliability for hypernormal individuals, interest in linkage and imprinting, and sibship composition. Family-based samples lend themselves to the TDT despite its inefficiency compared with cases and unrelated normal controls. The TDT has an efficiency of 1/2 for parent-offspring pairs and 2/3 for father-mother-child trios. Against cases and hypernormal controls, the efficiency is only 1/6 on the null hypothesis. Although dependent on marker gene frequency and other factors, efficiency for hypernormal controls is always greater than for random controls. Efficiency of the TDT is increased in multiplex families and by inclusion of normal sibs, approaching a case-control design with normal but not hypernormal controls. Isolated cases favor unrelated controls, and only in exceptional populations would avoidance of stratification justify a family-based design to map disease genes by allelic association.

Morton, N. E.; Collins, A.

1998-01-01

246

Paternal alleles enhance female reproductive success in tropical pythons.  

PubMed

The conventional view that female reproductive success is unlikely to benefit from multiple mating has come under strong challenge in recent years. In the present study, we demonstrate that the time wild-caught reproductive female water pythons (Liasis fuscus) spent in the laboratory prior to oviposition affected both hatching success and the number of male microsatellite alleles detected in the broods. A negative correlation between time in captivity and number of male alleles observed in the broods suggests that reduced hatching success was most likely not caused by environmental factors such as non-optimal temperatures, but rather by restricted mating opportunities. Maternal nutritional status and mean hatchling mass did not affect brood viability. However, our results revealed a positive correlation between number of male microsatellite alleles observed in the broods and hatching success, suggesting that increased paternal genetic variability enhanced female reproductive success. As microsatellite loci are unlikely to be direct targets of selection, we suggest that variability at these loci may cosegregate with other polymorphic genes directly linked to fitness. PMID:15836649

Madsen, Thomas; Ujvari, Beata; Olsson, Mats; Shine, Richard

2005-05-01

247

Allelic frequencies of 20 visible phenotype variants in the korean population.  

PubMed

The prediction of externally visible characteristics from DNA has been studied for forensic genetics over the last few years. Externally visible characteristics include hair, skin, and eye color, height, and facial morphology, which have high heritability. Recent studies using genome-wide association analysis have identified genes and variations that correlate with human visible phenotypes and developed phenotype prediction programs. However, most prediction models were constructed and validated based on genotype and phenotype information on Europeans. Therefore, we need to validate prediction models in diverse ethnic populations. In this study, we selected potentially useful variations for forensic science that are associated with hair and eye color, iris pattern, and facial morphology, based on previous studies, and analyzed their frequencies in 1,920 Koreans. Among 20 single nucleotide polymorphisms (SNPs), 10 SNPs were polymorphic, 6 SNPs were very rare (minor allele frequency < 0.005), and 4 SNPs were monomorphic in the Korean population. Even though the usability of these SNPs should be verified by an association study in Koreans, this study provides 10 potential SNP markers for forensic science for externally visible characteristics in the Korean population. PMID:23843775

Lim, Ji Eun; Oh, Bermseok

2013-06-01

248

Allelic Frequencies of 20 Visible Phenotype Variants in the Korean Population  

PubMed Central

The prediction of externally visible characteristics from DNA has been studied for forensic genetics over the last few years. Externally visible characteristics include hair, skin, and eye color, height, and facial morphology, which have high heritability. Recent studies using genome-wide association analysis have identified genes and variations that correlate with human visible phenotypes and developed phenotype prediction programs. However, most prediction models were constructed and validated based on genotype and phenotype information on Europeans. Therefore, we need to validate prediction models in diverse ethnic populations. In this study, we selected potentially useful variations for forensic science that are associated with hair and eye color, iris pattern, and facial morphology, based on previous studies, and analyzed their frequencies in 1,920 Koreans. Among 20 single nucleotide polymorphisms (SNPs), 10 SNPs were polymorphic, 6 SNPs were very rare (minor allele frequency < 0.005), and 4 SNPs were monomorphic in the Korean population. Even though the usability of these SNPs should be verified by an association study in Koreans, this study provides 10 potential SNP markers for forensic science for externally visible characteristics in the Korean population.

Lim, Ji Eun

2013-01-01

249

High frequency of HLA-A?0103 allele in a Somali population  

Microsoft Academic Search

We report the existence of class I HLA allele A?0103 in an ethnic group (Somali) where this allele has not been reported. This allele was discovered in a study to examine the relationship between HLA alleles and humoral antibody response to measles vaccine among recent immigrants from Somalia to Olmsted County, Minnesota. We initially used polymerase chain reaction–sequence-specific primers (PCR-SSP)

Gregory A Poland; Youvraj Sohni; Michael Domanico; Cindy M Kroning; Steven R DeGoey; Mouhammed Jimale; Robert M Jacobson; S Breanndan Moore

2001-01-01

250

Allele-specific detection of single mRNA molecules in situ  

PubMed Central

We describe a method for fluorescent in situ identification of individual mRNA molecules, allowing quantitative and accurate measurements of allele-specific transcripts that differ by only a few nucleotides, in single cells. By using a combination of allele-specific and non-allele-specific probe libraries, we achieve over 95% detection accuracy. We investigate the allele-specific stochastic expression of the pluripotency factor Nanog in murine embryonic stem cells.

Hansen, Clinton H.; van Oudenaarden, Alexander

2013-01-01

251

European project ISAWARE  

NASA Astrophysics Data System (ADS)

As air traffic is increasing, the probability of encountering 'surveillance' alerts during flight is also increasing. In order to ensure safety, new on board systems need to be developed to provide the crew with a better 'situation awareness' (SA) about its external environment and potential hazards. In addition, the means to manage the data generated by these new systems needs to be build up. Despite the tremendous amount of information, crew workload must not increase. This is where the ISAWARE project comes in with the Integrated Situation Awareness System (ISAS) concept. ISAWARE (Increasing Safety through collision Avoidance WARning intEgration) is a project partly funded by the European Community, executed by a well balanced composition of several European aerospace companies (airframers, a helicopter manufacturer, avionics suppliers, airlines), one research laboratory and one university. The overall objective of the ISAWARE project is to conduct research into the potential improvements to flight safety that can be achieved by providing the pilot with complete predictive situation awareness during all phases of the flight. The Integrated Situational Awareness System (ISAS) merges data from different safety systems concerning terrain, traffic, weather and other. The system ensures the alerts consistency, prioritises alerts and anticipates threats along a predicted trajectory earlier than current systems can provide. The second main axis of the research is the development of synthetic vision displays (PFD, ND and HUD) to enhance the Human-Machine Interface (HMI). The key focus of the project is the development of a ground-based demonstrator rig which is interfaced to a dynamic flight simulator. This rig is used for the evaluation of the ISAWARE concept by a representative range of active airline crews.

Kaiser, Jochen; Smietanski, Guillaume; Kubbat, Wolfgang

2001-08-01

252

European Schoolnet: Enabling School Networking  

ERIC Educational Resources Information Center

School networking is increasingly important in a globalised world, where schools themselves can be actors on an international stage. This article builds on the activities and experience of the longest established European initiative in this area, European Schoolnet (EUN), a network of 31 Ministries of Education. First, we offer an introduction…

Scimeca, Santi; Dumitru, Petru; Durando, Marc; Gilleran, Anne; Joyce, Alexa; Vuorikari, Riina

2009-01-01

253

A Quasi-equilibrium theory of the distribution of rare alleles in a subdivided population  

Microsoft Academic Search

The conditional average frequency of rare alleles has been shown in simulations to provide a simple and robust estimator of the number of individuals exchanged between local populations in an island model (Nm). This statistic is defined as the average frequency of an allele in those samples in which the allele is present. Here, we show that the conditional average

N H Barton; M Slatkin

1986-01-01

254

Allele-Specific Enzymatic Amplification of beta -globin Genomic DNA for Diagnosis of Sickle Cell Anemia  

Microsoft Academic Search

A rapid nonradioactive approach to the diagnosis of sickle cell anemia is described based on an allele-specific polymerase chain reaction (ASPCR). This method allows direct detection of the normal or the sickle cell beta -globin allele in genomic DNA without additional steps of probe hybridization, ligation, or restriction enzyme cleavage. Two allele-specific oligonucleotide primers, one specific for the sickle cell

Dan Y. Wu; Luis Ugozzoli; Bijay K. Pal; R. Bruce Wallace

1989-01-01

255

The NOTCH Locus of DROSOPHILA HYDEI: Alleles, Phenotypes and Functional Organization  

PubMed Central

The Notch (N) locus of Drosophila hydei and a series of its alleles and phenotypes are described. Some models are discussed to explain the opposite effects of some alleles on the structure of the wing, the neomorphic action of NAx over typical N alleles and the interaction with the mutation Costal-nick (Cnk).

Van Breugel, F. M. A.; Langhout, B. Van Zijll

1983-01-01

256

HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in the Serbian population.  

PubMed

This study provides the first published detailed analysis of five loci polymorphisms as well as reports of two, three and five loci haplotype frequencies in the Serbian population in a sample of 1992 volunteer bone marrow donors recruited from different part of the country. Typing was performed by PCR SSO method combined with PCR SSP techniques to resolve ambiguities. In total, 16 HLA-A, 28 HLA-B, 14 HLA-C, 13 HLA-DRB1 and 5 HLA-DQB1 allelic groups were identified. The most frequent in allele groups are HLA-A(?)02 (29.5%), HLA-A(?)01 (14.2%), HLA-B(?)35 (13.1%), HLA-B(?)51 (12.8%), HLA-C(?)07 (24.8%), HLA-DRB1(?)11 (16.9%), HLA-DRB1(?)13 (13.2%), HLA-DQB1(?)03 (33.3%) and DQB1(?)05 (33.0%). The most frequent three- and five-loci haplotypes were A(?)01-B(?)08-DRB1(?)03 (5.9%) and A(?)02-B(?)18-DRB1(?)11 (1.9%), A(?)01-B(?)08-C(?)07-DRB1(?)03-DQB1(?)02 (6.6%) followed by A(?)02-B(?)18-C(?)07-DRB1(?)11-DQB1(?)03 (2.5%), then A(?)33-B(?)14-C(?)08-DRB1(?)01-DQB1(?)05 and A(?)02-B(?)35-C(?)04-DRB1(?)16-DQB1(?)05 (2.2% both), respectively. The results of cluster analysis showed that the Serbian population is closely related to the populations living in central Balkan and neighboring European regions. The level of allelic diversity found in this study are relevant to facilitate searching for unrelated matched donor and provide a healthy control population from our region that should be useful in the future disease association study. PMID:24374041

Andric, Zorana; Popadic, Dusan; Jovanovic, Barbara; Jaglicic, Ivana; Bojic, Svetlana; Simonovic, Ruzica

2014-03-01

257

HLA-B*40 Allele Plays a Role in the Development of Acute Leukemia in Mexican Population: A Case-Control Study  

PubMed Central

Among oncohematological diseases, acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are characterized by the uncontrolled production and accumulation of blasts that can lead to death. Although the physiopathology of these diseases is multifactorial, a genetic factor seems to be at play. Several studies worldwide have shown association of ALL and AML with several alleles of the major histocompatibility complex (MHC). Objective. To determine gene frequencies of HLA-B alleles in Mexicans (individuals with Native American genetic background admixed with European descent) with ALL and AML. Methods. We compared the HLA-B alleles in 213 patients with ALL and 85 patients with AML to those present in 731 umbilical cord blood (UCB) samples as a control group; this was done by means of the PCR-SSP technique. Results. We found an increased frequency of the HLA-B*40 allele in ALL patients as compared to the control group (14.5% versus 9.84%, P = 0.003, OR = 1.67); this was particularly evident in a subgroup of young (less than 18?years old) ALL patients (P = 0.002, OR = 1.76); likewise, a decreased frequency of HLA-B*40 allele in AML patients was observed as compared to the control group (4.70% versus 9.84%, P = 0.02, OR = 0.42). Conclusions. These results might suggest opposing effects of the HLA-B*40 in the genetic susceptibility to develop ALL or AML and offer the possibility to study further the molecular mechanisms of cell differentiation within the bone marrow lineage.

Fernandez-Torres, Javier; Flores-Jimenez, Denhi; Arroyo-Perez, Antonio; Granados, Julio; Lopez-Reyes, Alberto

2013-01-01

258

Conditional Allele Mouse Planner (CAMP): software to facilitate the planning and design of breeding strategies involving mice with conditional alleles  

Microsoft Academic Search

Transgenic and conditional knockout mouse models play an important role in biomedical research and their use has grown exponentially\\u000a in the last 5–10 years. Generating conditional knockouts often requires breeding multiple alleles onto the background of a\\u000a single mouse or group of mice. Breeding these mice depends on parental genotype, litter size, transmission frequency, and\\u000a the number of breeding rounds. Therefore,

Jason D. Hoffert; Trairak Pisitkun; R. Lance Miller

259

Novel Method for Analysis of Allele Specific Expression in Triploid Oryzias latipes Reveals Consistent Pattern of Allele Exclusion  

PubMed Central

Assessing allele-specific gene expression (ASE) on a large scale continues to be a technically challenging problem. Certain biological phenomena, such as X chromosome inactivation and parental imprinting, affect ASE most drastically by completely shutting down the expression of a whole set of alleles. Other more subtle effects on ASE are likely to be much more complex and dependent on the genetic environment and are perhaps more important to understand since they may be responsible for a significant amount of biological diversity. Tools to assess ASE in a diploid biological system are becoming more reliable. Non-diploid systems are, however, not uncommon. In humans full or partial polyploid states are regularly found in both healthy (meiotic cells, polynucleated cell types) and diseased tissues (trisomies, non-disjunction events, cancerous tissues). In this work we have studied ASE in the medaka fish model system. We have developed a method for determining ASE in polyploid organisms from RNAseq data and we have implemented this method in a software tool set. As a biological model system we have used nuclear transplantation to experimentally produce artificial triploid medaka composed of three different haplomes. We measured ASE in RNA isolated from the livers of two adult, triploid medaka fish that showed a high degree of similarity. The majority of genes examined (82%) shared expression more or less evenly among the three alleles in both triploids. The rest of the genes (18%) displayed a wide range of ASE levels. Interestingly the majority of genes (78%) displayed generally consistent ASE levels in both triploid individuals. A large contingent of these genes had the same allele entirely suppressed in both triploids. When viewed in a chromosomal context, it is revealed that these genes are from large sections of 4 chromosomes and may be indicative of some broad scale suppression of gene expression.

Garcia, Tzintzuni I.; Matos, Isa; Shen, Yingjia; Pabuwal, Vagmita; Coelho, Maria Manuela; Wakamatsu, Yuko; Schartl, Manfred; Walter, Ronald B.

2014-01-01

260

German role in the European energy market.  

National Technical Information Service (NTIS)

The paper evaluates the role of the united Germany in the European energy market. Following fields are emphasized: The European dimension; contrasting patterns of energy demand; the electricity crunch; the institutional issues; European implications. 7 ta...

O. Noreng

1990-01-01

261

European Science Notes. Volume 41, Number 9.  

National Technical Information Service (NTIS)

European Science Notes is a monthly publication with brief articles on recent developments in European scientific research. Partial contents: Review of selected papers presented at the European Conference of the International Society for Research on Aggre...

C. J. Fox

1987-01-01

262

Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population  

PubMed Central

Characterization of allelic variants of the TPMT gene (TPMT) responsible for changes in TPMT activity, and elucidation of the mechanism by which these alleles act, are required because of the clinical importance of this polymorphism for patients receiving thiopurine drugs.We defined the mutational and allelic spectrum of TPMT in a group of 191 Europeans. Using PCR–SSCP, we screened for mutation the entire coding sequence, the exon-intron boundaries, the promoter region and the 3?-flanking region of the gene. Six mutations were detected throughout the ten exons and seven TPMT alleles were characterized. Four of them, TPMT*2, *3A, *3C and *7, harbouring the known mutations, G238C, G460A, A719G or T681G, were nonfunctional and accounted for 0.5, 5.7, 0.8 and 0.3% of the allele totality, respectively.Within the promoter region, six alleles corresponding to a variable number of tandem repeats (VNTR), were identified. VNTR*V4 and *V5a which harbour four or five repeats of a 17–18?bp unit, were the most frequent (55% and 34%, respectively). The other VNTR alleles, having from five to eight repeats, were rarer.The TPMT phenotype was correctly predicted by genotyping for 87% of individuals. A clear negative correlation between the total number of repeats from both alleles and the TPMT activity level was observed, indicating that VNTRs contribute to interindividual variations of TPMT activity. Therefore, additional analysis of the promoter region of TPMT can improve the phenotype prediction rate by genotyping.

Spire-Vayron de la Moureyre, Catherine; Debuysere, Herve; Mastain, Bruno; Vinner, Elizabeth; Marez, Delphine; Lo Guidice, Jean-Marc; Chevalier, Dany; Brique, Serge; Motte, Kokou; Colombel, Jean-Frederic; Turck, Dominique; Noel, Christian; Flipo, Rene-Marc; Pol, Annie; Lhermitte, Michel; Lafitte, Jean-Jacques; Libersa, Christian; Broly, Franck

1998-01-01

263

A family with two female compound heterozygous for the FMR1 premutation alleles  

PubMed Central

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation (FMR1) gene have been linked to various types of clinical involvement ranging from mood and anxiety disorders to immunological disorders and executive function deficits. Carrier females typically have a premutation allele and a normal allele (<55 CGG repeats). Although rare, 7 cases of females that carry two expanded alleles (compound heterozygous premutation) have been reported. Here we report on four members of a family including two compound heterozygous premutation sisters with similar CGG allele sizes, affected with different levels of clinical severity.

Basuta, Kirin; Lozano, Reymundo; Schneider, Andrea; Yrigollen, Carolyn M.; Hessl, David; Hagerman, Randi J.; Tassone, Flora

2014-01-01

264

Distribution of (CGG)n and FMR-1 associated microsatellite alleles in a normal Chilean population.  

PubMed

We report on the allele distribution in a normal Chilean population at 2 microsatellite loci neighbouring the FRAXA locus and at the CGG repeat in the 5' end of the FMR-1 gene, which causes the fragile X syndrome. The most common CGG repeat allele was 30 (41.7%), with 29 being second most common (30.2%). This distribution was similar from that seen in Caucasians but different from that observed in Chinese controls, where the most common allele was 29 repeats. Four alleles of FRAXAC1 and 6 of DXS548 were observed in the Chilean sample. A striking linkage disequilibrium of FMR-1 alleles with FRAXAC1 alleles was observed. In 90% of the 30 CGG repeat alleles only 31% of the 29 CGG repeat alleles had the FRAXAC1 154 bp allele. This result is in agreement with the suggestion that slippage between CGG repeat alleles 29 and 30 and between 152 and 154 FRAXAC1 alleles is very rare. This study suggests a founder chromosome effect in the Chilean population. PMID:9475597

Jara, L; Aspillaga, M; Avendaño, I; Obreque, V; Blanco, R; Valenzuela, C Y

1998-01-23

265

Geographical structure and differential natural selection among North European populations  

PubMed Central

Population structure can provide novel insight into the human past, and recognizing and correcting for such stratification is a practical concern in gene mapping by many association methodologies. We investigate these patterns, primarily through principal component (PC) analysis of whole genome SNP polymorphism, in 2099 individuals from populations of Northern European origin (Ireland, United Kingdom, Netherlands, Denmark, Sweden, Finland, Australia, and HapMap European-American). The major trends (PC1 and PC2) demonstrate an ability to detect geographic substructure, even over a small area like the British Isles, and this information can then be applied to finely dissect the ancestry of the European-Australian and European-American samples. They simultaneously point to the importance of considering population stratification in what might be considered a small homogeneous region. There is evidence from FST-based analysis of genic and nongenic SNPs that differential positive selection has operated across these populations despite their short divergence time and relatively similar geographic and environmental range. The pressure appears to have been focused on genes involved in immunity, perhaps reflecting response to infectious disease epidemic. Such an event may explain a striking selective sweep centered on the rs2508049-G allele, close to the HLA-G gene on chromosome 6. Evidence of the sweep extends over a 8-Mb/3.5-cM region. Overall, the results illustrate the power of dense genotype and sample data to explore regional population variation, the events that have crafted it, and their implications in both explaining disease prevalence and mapping these genes by association.

McEvoy, Brian P.; Montgomery, Grant W.; McRae, Allan F.; Ripatti, Samuli; Perola, Markus; Spector, Tim D.; Cherkas, Lynn; Ahmadi, Kourosh R.; Boomsma, Dorret; Willemsen, Gonneke; Hottenga, Jouke J.; Pedersen, Nancy L.; Magnusson, Patrik K.E.; Kyvik, Kirsten Ohm; Christensen, Kaare; Kaprio, Jaakko; Heikkila, Kauko; Palotie, Aarno; Widen, Elisabeth; Muilu, Juha; Syvanen, Ann-Christine; Liljedahl, Ulrika; Hardiman, Orla; Cronin, Simon; Peltonen, Leena; Martin, Nicholas G.; Visscher, Peter M.

2009-01-01

266

European Southern Observatory  

NSDL National Science Digital Library

The European Southern Observatory (ESO) is an intergovernmental organization comprised of 14 member countries. Its headquarters are in Germany, but they have three observatories in Chile as well. Their website is loaded with information and visitors shouldn't miss going on the "Virtual Tours", on the far right side of the homepage. The tours are of the three observatories in Chile, and offer almost 360 degree views of beautiful, yet sparse landscapes. The tour of La Silla has two particularly beautiful views, "La Silla Moonlight" and "La Silla Sunset". Visitors interested in seeing a panning of an artist's 3D rendering of the Orion Nebula must go to the "Video" link on the left hand menu on the homepage. There are over 1400 videos to choose from, so for those not into the Orion Nebula, never fear, there are plenty of other video choices. Finally, visitors must go to the "Top 100 Images" link on the right side of the homepage to see amazing and gorgeous images taken from the ESO's various observatories.

267

Analysis of elite variety tag SNPs reveals an important allele in upland rice  

PubMed Central

Elite crop varieties usually fix alleles that occur at low frequencies within non-elite gene pools. Dissecting these alleles for desirable agronomic traits can be accomplished by comparing the genomes of elite varieties with those from non-elite populations. Here we deep-sequence six elite rice varieties and use two large control panels to identify elite variety tag single-nucleotide polymorphism alleles (ETASs). Guided by this preliminary analysis, we comprehensively characterize one protein-altering ETAS in the 9-cis-epoxycarotenoid dioxygenase gene of the IRAT104 upland rice variety. This allele displays a drastic frequency difference between upland and irrigated rice, and a selective sweep is observed around this allele. Functional analysis indicates that in upland rice, this allele is associated with significantly higher abscisic acid levels and denser lateral roots, suggesting its association with upland rice suitability. This report provides a potential strategy to mine rare, agronomically important alleles.

Lyu, Jun; Zhang, Shilai; Dong, Yang; He, Weiming; Zhang, Jing; Deng, Xianneng; Zhang, Yesheng; Li, Xin; Li, Baoye; Huang, Wangqi; Wan, Wenting; Yu, Yang; Li, Qiong; Li, Jun; Liu, Xin; Wang, Bo; Tao, Dayun; Zhang, Gengyun; Wang, Jun; Xu, Xun; Hu, Fengyi; Wang, Wen

2013-01-01

268

Effects of the APOE ?2 allele on mortality and cognitive function in the oldest old.  

PubMed

Some studies indicate that the APOE ?2 allele may have a protective effect on mortality and mental health among the elderly adults. We investigated the effect of the APOE ?2 allele on cognitive function and mortality in 1651 members of the virtually extinct Danish 1905 birth cohort. We found no protective effect of the APOE ?2 allele on mortality compared with the APOE ?3 allele. The point estimates indicated an increased protection against cognitive decline over time for persons with the APOE ?2 allele. Cognitive score did not significantly modify the mortality risk of the various APOE genotypes. We did not find a protective effect of the APOE ?2 allele on mortality among the oldest old, but in agreement with our previous findings, we found a 22% increased mortality risk for APOE ?4 carriers. The APOE ?2 allele may be protective on cognitive decline among the oldest old. PMID:23051975

Lindahl-Jacobsen, Rune; Tan, Qihua; Mengel-From, Jonas; Christensen, Kaare; Nebel, Almut; Christiansen, Lene

2013-04-01

269

Prostate Cancer Risk Alleles and Their Associations with Other Malignancies  

PubMed Central

Objectives Prostate cancer (CaP) has been associated with other common malignancies. Recently, numerous single nucleotide polymorphisms (SNPs) have been associated with CaP susceptibility; however, it is unknown whether these risk alleles are responsible for the relationship between CaP and other malignancies. Methods We have genotyped 1121 CaP patients for 36 risk alleles known to be significantly associated with CaP susceptibility and determined their relationships to other malignancies in CaP probands and in their first-degree relatives. Results The most common other malignancies in CaP probands were non-melanoma skin cancer (13.6%), leukemia (7.3%), melanoma (3.9%), non-Hodgkin’s lymphoma (0.7%), colorectal cancer (0.6%), and multiple myeloma (0.3%). Among probands, there was a significantly increased frequency of leukemia in carriers of SNP rs2736098 (5p15, P=0.03) and melanoma in carriers of either SNP rs1512268 (8p21, P=0.006) or SNP rs5759167 (22q13, P=0.02). Multiple myeloma was more common in carriers of SNP rs9364554 (6q25, P=0.02). Probands who were carriers of SNP rs16901979 (8q24) were significantly more likely to report a family history of melanoma (P=0.03), while probands with family histories of multiple myeloma and non-Hodgkin’s disease were significantly more likely to be carriers of SNPs rs12621278 (2q31, P=0.04) and rs6465657 (7q21, P=0.02), respectively. Conclusions Certain alleles associated with CaP susceptibility may be associated with increased or decreased risk of other malignancies in CaP probands and their first-degree relatives. Further studies are warranted to examine the underlying mechanisms of these SNPs in CaP and other malignancies.

Cooper, Phillip R.; McGuire, Barry B.; Helfand, Brian T.; Loeb, Stacy; Hu, Qiaoyan; Catalona, William J.

2011-01-01

270

Immunogenicity of single versus mixed allele vaccines of Plasmodium vivax Duffy binding protein region II.  

PubMed

The Duffy binding protein (DBP) of Plasmodium vivax is vital for host erythrocyte invasion. DBP region II (DBPII) contains critical residues for receptor recognition and anti-DBPII antibodies have been shown to inhibit erythrocyte binding and invasion, thereby making the molecule an attractive vaccine candidate against P. vivax blood stages. Similar to other blood-stage antigens, allelic variation within the DBPII and associated strain-specific immunity is a major challenge for development of a broadly effective vaccine against P. vivax malaria. We hypothesized that immunization with a vaccine composed of multiple DBP alleles or a modified epitope DBP (DEKnull) will be more effective in producing a broadly reactive and inhibitory antibody response to diverse DBPII alleles than a single allele vaccine. In this study, we compared single, naturally occurring DBPII allele immunizations (Sal1, 7.18, P) and DEKnull with a combination of (Sal1, 7.18, P) alleles. Quantitative analysis by ELISA demonstrated that the multiple allele vaccine tend to be more immunogenic than any of the single allele vaccines when tested for reactivity against a panel of DBPII allelic variants whereas DEKnull was less immunogenic than the mixed-allele vaccine but similar in reactivity to the single allele vaccines. Further analysis for functional efficacy by in vitro erythrocyte-binding inhibition assays demonstrated that the multiple allele immunization produced a stronger strain-neutralizing response than the other vaccination strategies even though inhibition remained biased toward some alleles. Overall, there was no correlation between antibody titer and functional inhibition. These data suggest that a multiple allele vaccine may enhance immunogenicity of a DBPII vaccine but further investigation is required to optimize this vaccine strategy to achieve broader coverage against global P. vivax strains. PMID:23916294

Ntumngia, Francis B; Schloegel, Jesse; McHenry, Amy M; Barnes, Samantha J; George, Miriam T; Kennedy, Sandra; Adams, John H

2013-09-13

271

MHC associations with clinical and autoantibody manifestations in European SLE.  

PubMed

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies. PMID:24598797

Morris, D L; Fernando, M M A; Taylor, K E; Chung, S A; Nititham, J; Alarcón-Riquelme, M E; Barcellos, L F; Behrens, T W; Cotsapas, C; Gaffney, P M; Graham, R R; Pons-Estel, B A; Gregersen, P K; Harley, J B; Hauser, S L; Hom, G; Langefeld, C D; Noble, J A; Rioux, J D; Seldin, M F; Vyse, T J; Criswell, L A

2014-04-01

272

A Sequencing-Based Survey of Functional APAF1 Alleles in a Large Sample of Individuals with Affective Illness and Population Controls  

PubMed Central

Rare apoptosis-promoting functional variants in the apoptosis protease activating factor 1 (APAF1) gene were recently reported to co-segregate with major depression in male members of families from Utah. In order to estimate the impact of these variants on risk for major depressive disorder (MDD) in the general population, we surveyed the frequency of the APAF1 putative MDD risk alleles using re-sequencing in a large sample of northern European and European-American subjects, including a large number of males with MDD. The E777K and N782T APAF1 variants previously described by Harlan et al. [Harlan et al. (2006) Mol Psychiatry 11(1):76–85] were found at low frequencies in affected individuals and population controls. The C450W and Q465R variants were not detected in any of the 632 subjects sequenced. These results show that the APAF1 variants associated with risk for MDD in the Utah pedigrees are very rare in Northern European and European-American populations. In addition, the E777K and N782T variants were found at low frequencies both in patients and population controls, suggesting that these variants have limited impact on risk for MDD.

Amin, Zenab; Kanarek, Katarzyna; Krupitsky, Evgeny; Walderhaug, Espen; Ilomaki, Risto; Blumberg, Hilary; Price, Lawrence H.; Bhagwagar, Zubin; Carpenter, Linda L.; Tyrka, Audrey R.; Magnusson, Andres; Landr?, Nils Inge; Zvartau, Edwin; Gelernter, Joel; Epperson, C. Neill; Rasanen, Pirkko; Siironen, Jari; Lappalainen, Jaakko

2013-01-01

273

European Solar Engineering School Homepage  

NSDL National Science Digital Library

The European Solar Engineering School (ESES) provides courses in advanced solar energy engineering for well qualified master's level engineering students. The following are offered: advanced solar thermal engineering, advanced photovoltaic engineering, applied solar energy engineering, and utilization of solar energy.

2007-02-12

274

Relative efficiency of European airports  

Microsoft Academic Search

Using data envelopment analysis, efficiency ratios for European airports are determined. It appears that most airports are operating under increasing returns to scale. This is also reflected in the most productive scale size determined for the airports.

Eric Pels; Peter Nijkamp; Piet Rietveld

2001-01-01

275

European oil product supply modelling.  

National Technical Information Service (NTIS)

Over the last few years, trends in European oil product consumption (in terms of level as structure and quality) has important implications of the refining industry. In this context, the purpose of this thesis consists in building a mathematical programmi...

V. Saint-Antonin

1998-01-01

276

European Union: US Hegemonic Competitor.  

National Technical Information Service (NTIS)

Since World War II, Europe has evolved from the Westphalian intentional system into a consociational, supranational state system opting to trade sovereignty for collective economic, political and military security. Intergovernmentalism in the European Com...

R. L. Kellar

2001-01-01

277

Public Accountability in the European Union: Is the European Parliament able to hold the European Council accountable?  

Microsoft Academic Search

The European Council occupies a central role in European politics. Yet it is not officially accountable to any public or parliamentary body for the decisions it makes on behalf of European citizens. National parliaments are only entitled to exert control over their own Heads of Government or State. The European Parliament, as a supranational institution, is the only parliamentary body

Marianne van de Steeg

2009-01-01

278

North European Transect  

NASA Astrophysics Data System (ADS)

A nearly continuous, 3600 km long, NE-running North European Transect (NET) is combined from the existing deep seismic reflection data sets in the Baltic Sea (BABEL, 1600 km), Northern Finland (FIRE 4-4A, 580 km) and Barents Sea (1-AR, 1440 km;). The reflective image of the deep crust is highly dependent on the thickness of the sedimentary cover. The cover is few hundred meters in the Baltic sea, few tens of meters in the land areas and few kilometers in the Barents Sea area. In the Barents Sea area, the seismic image is dominated by the layered structure of the sedimentary basins and the middle and lower crust are poorly imaged. Therefore the Moho boundary in the Barents Sea has been determined from wide-angle reflections. Geologically the transect covers the transition from Phanerozoic Europe to Precambrian Europe and back to the Phanerozoic Barents Sea Shelf. It displays how Northern Europe grew around Baltica in several tectonic episodes involving the formation and destruction of Columbia/Hudsonland, Rodinia and Pangea supercontinents. The paleo plateboundaries are traversed by subvertical transparent zones suggesting transpressional and trantensional environments. The BABEL lines image how the core of Baltica was formed by sequential accretion of microcontinents and arc terranes at the old continental margin during the Svecofennian Orogeny ~1.9-1.8 Ga .When Baltica joined the Columbia supercontinent, new terranes were added to its southern edge in the Sveocbaltic Orogeny (~1.8 Ga). During the dispersal of the Columbia, the Baltic Sea failed rift was formed, rapakivi granitoids were intruded and sedimentary basins were developed. An extended plate margin structure has been imposed on the Rodinian (Sveconorwegian) and Pangean additions (Variscan-Caledonian). Major crustal thinning takes place along a series of subvertical faults across the Trans-European Suture Zone marking the transition from Phanerozoic to Proterozoic Europe. The FIRE lines in Northen Finland image a collage of older continental fragments and intervening basins that have been welded together in Svecofennian and Lapland-Kola orogenies. The Lapland-Kola orogen record the collision of Baltica and Laurentia during the compilation of the Columbia supercontinent. The collisional structures were overprinted by extension associated with the dispersal of Columbia. The Russian Arctic line 1-AR focuses on the Phanerozoic sedimentary cover of the Barents Sea Basin. The line images the transition from Paleoproterozoic Baltica to Neoproterozoic Barentsia. As part of the Rodinia supercontinent formation, Baltica collided with Barentsia resulting in Timanide orogeny. During the break-up of Rodinia an aborted rift was formed within the Barentsia. Later peripheral tectonic events modified the interior parts of Barentsia that acted first as a back arc basin and later as a foreland basin to the Uralian and Caledonian orogen during the formation of the Pangea supercontinent.

Korja, Annakaisa; Heikkinen, Pekka J.; Roslov, Yuri; Ivanova, Nina; Verba, Marc; Sakoulina, Tamara

2010-05-01

279

Allelic loss and linkage studies in prostate cancer  

SciTech Connect

Prostate cancer is the most common malignancy in U.S. males. Many examples of familial aggregation have been reported, and segregration analysis suggests that an autosomal dominant gene with a penetrance of 88% by age 85 accounts for 9% of all cases. Because many dominant cancer predisposition syndromes are related to germline mutations in tumor suppressor genes, we analyzed a series of sporadic and hereditary tumors for allelic loss. High grade sporadic, paraffin-embedded, primary prostate tumors were obtained from the archival collection in the Department of Pathology at Yale and hereditary tumors from three families were obtained by an advertisement in the New York Times and from referrals by urologists. PCR analysis showed loss in 4/7 informative sporadic prostate tumors with NEFL (8p21), in 8/22 informative tumors with D10S169 (10q26-qter), in 2/8 informative tumors with D10S108 (10q) and in 4/23 informative tumors with D10S89 (10p) in agreement with previous studies. PYGM on chromosome 11 and D9S127 on chromosome 9 showed no loss. Linkage analysis with NEFL in 3 prostate cancer families gave strongly negative results for close linkage (Z=-2.1 at {theta}=0.01) but LOD scores were very dependent on parameters, e.g. gene frequency, phenocopy rate, and penetrance. Linkage analysis with chromosome 10 markers and systematic analysis of the genome for other area of allelic loss are underway.

Johnson, D.R.; Bale, A.E.; Lytton, B. [Yale Univ. School of Medicine, New Haven, CT (United States)] [and others

1994-09-01

280

Measuring and Testing Genetic Differentiation with Ordered versus Unordered Alleles  

PubMed Central

Estimates and variances of diversity and differentiation measures in subdivided populations are proposed that can be applied to haplotypes (ordered alleles such as DNA sequences, which may contain a record of their own histories). Hence, two measures of differentiation can be compared for a single data set: one (G(ST)) that makes use only of the allelic frequencies and the other (N(ST)) for which similarities between the haplotypes are taken into account in addition. Tests are proposed to compare N(ST) and G(ST) with zero and with each other. The difference between N(ST) and G(ST) can be caused by several factors, including sampling artefacts, unequal effect of mutation rates and phylogeographic structure. The method presented is applied to a published data set where a nuclear DNA sequence had been determined from individuals of a grasshopper distributed in 24 regions of Europe. Additional insights into the genetic subdivision of these populations are obtained by progressively combining related haplotypes and reanalyzing the data each time.

Pons, O.; Petit, R. J.

1996-01-01

281

Genomic landscape of human allele-specific DNA methylation.  

PubMed

DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species. PMID:22523239

Fang, Fang; Hodges, Emily; Molaro, Antoine; Dean, Matthew; Hannon, Gregory J; Smith, Andrew D

2012-05-01

282

Association of MICA and MICB alleles with symptomatic dengue infection.  

PubMed

Dengue viruses (DV) are one of the most important arthropod-borne viral diseases in the developing world. DV can cause syndromes that are either self-limiting or severe. Allelic variants of human leukocyte antigen (HLA) genes have been demonstrated to be associated with disease susceptibility. Here we report the association of nonclassical HLA class I MICA-MICB genes with disease outcome during DV infection. A sequencing-based typing method and genotyping of MICA and MICB in a well-characterized group of Cuban individuals with dengue hemorrhagic fever (DHF), dengue fever (DF), or asymptomatic dengue infection (ADI) was performed. Statistical analysis revealed a tendency for MICA*008 and MICB*008 to associate with susceptibility to illness when symptomatic versus asymptomatic cases (odds ratio [OR] = 2.1, p(v) = 0.03, and OR = 10.4, p = 0.0096, respectively) were compared. Surprisingly, a stronger association of both allelic forms was observed for the DF patients compared with the ADI group (MICA*008, OR = 5.2, p = 0.0001; and MICB*008, OR = 13.2, p = 0.0025) rather than the severe cases. Major histocompatibility class I-related gene-related natural killer cells and/or ?? and ?? T-cell activation might regulate the development of symptomatic DF and DHF. PMID:21762746

García, Gissel; del Puerto, Florencia; Pérez, Ana B; Sierra, Beatriz; Aguirre, Eglys; Kikuchi, Mihoko; Sánchez, Lizet; Hirayama, Kenji; Guzmán, María G

2011-10-01

283

Characterization of ROP18 alleles in human toxoplasmosis.  

PubMed

The role of the virulent gene ROP18 polymorphisms is not known in human toxoplasmosis. A total of 320 clinical samples were analyzed. In samples positive for ROP18 gene, we determined by an allele specific PCR, if patients got the upstream insertion positive ROP18 sequence Toxoplasma strain (mouse avirulent strain) or the upstream insertion negative ROP18 sequence Toxoplasma strain (mouse virulent strain). We designed an ELISA assay for antibodies against ROP18 derived peptides from the three major clonal lineages of Toxoplasma. 20 clinical samples were of quality for ROP18 allele analysis. In patients with ocular toxoplasmosis, a higher inflammatory reaction on eye was associated to a PCR negative result for the upstream region of ROP18. 23.3%, 33% and 16.6% of serums from individuals with ocular toxoplasmosis were positive for type I, type II and type III ROP18 derived peptides, respectively but this assay was affected by cross reaction. The absence of Toxoplasma ROP18 promoter insertion sequence in ocular toxoplasmosis was correlated with severe ocular inflammatory response. Determination of antibodies against ROP18 protein was not useful for serotyping in human toxoplasmosis. PMID:24177250

Sánchez, Víctor; de-la-Torre, Alejandra; Gómez-Marín, Jorge Enrique

2014-04-01

284

An allele of the crm gene blocks cyanobacterial circadian rhythms  

PubMed Central

The SasA-RpaA two-component system constitutes a key output pathway of the cyanobacterial Kai circadian oscillator. To date, rhythm of phycobilisome associated (rpaA) is the only gene other than kaiA, kaiB, and kaiC, which encode the oscillator itself, whose mutation causes completely arrhythmic gene expression. Here we report a unique transposon insertion allele in a small ORF located immediately upstream of rpaA in Synechococcus elongatus PCC 7942 termed crm (for circadian rhythmicity modulator), which results in arrhythmic promoter activity but does not affect steady-state levels of RpaA. The crm ORF complements the defect when expressed in trans, but only if it can be translated, suggesting that crm encodes a small protein. The crm1 insertion allele phenotypes are distinct from those of an rpaA null; crm1 mutants are able to grow in a light:dark cycle and have no detectable oscillations of KaiC phosphorylation, whereas low-amplitude KaiC phosphorylation rhythms persist in the absence of RpaA. Levels of phosphorylated RpaA in vivo measured over time are significantly altered compared with WT in the crm1 mutant as well as in the absence of KaiC. Taken together, these results are consistent with the hypothesis that the Crm polypeptide modulates a circadian-specific activity of RpaA.

Boyd, Joseph S.; Bordowitz, Juliana R.; Bree, Anna C.; Golden, Susan S.

2013-01-01

285

Allele frequency of CODIS 13 in Indonesian population.  

PubMed

Since the first application of DNA technology in 1985 in forensic cases, and the acceptance of this technology in 1988 at court, the DNA typing is widely used in personal identification, parentage cases and tracing the source of biological samples found in the crime scene. The FBI on 1990 had recommended the forensic labs to used 13 loci of Short Tandem Repeats (STR), known as CODIS 13, as the loci of choice for forensic use. The research on the population DNA database on these loci is extremely important for calculating the Paternity Index as well as Matching Probability for forensic application of DNA technology. As many as 402 unrelated persons, consisted of 322 from western part of Indonesia and 80 from eastern part of Indonesia, were chosen as the respondents of this research, after signing the informed consent. The peripheral blood sample was taken using sterile lancets and dropped onto FTA classic cards. The DNA was extracted by FTA purification solution (3x) and TE(-1) (2x), and amplified by PCR mix, either Cofiler or Profiler Plus (Perkin Elmers), followed by sequencing using ABI Prism type 3100 Avant Genetic Analyzer. The analysis showed that the alleles frequencies of Indonesian is specific, different with the other Asian populations with some specific alleles and microvariant were found. PMID:19261522

Untoro, Evi; Atmadja, Djaja Surya; Pu, Chang-En; Wu, Fang-Chi

2009-04-01

286

Prevalence of CYP2C9 and VKORC1 alleles in the Argentine population and implications for prescribing dosages of anticoagulants.  

PubMed

Dicumarinic oral anticoagulants have a narrow therapeutic range and a great individual variability in response, which makes calculation of the correct dose difficult and critical. Genetic factors involved in this variability include polymorphisms of genes that encode the metabolic enzyme CYP2C9 and the target enzyme vitamin K epoxide reductase complex 1 (VKORC1); these polymorphisms can be associated with reduced enzymatic expression. We examined the frequency of the most relevant variants encoding CYP2C9 (alleles *1, *2 and *3) and VKORC1 (SNP -1639A>G) in the Argentinian population. Molecular typing was performed by PCR-RFLP on a randomly selected sample of 101 healthy volunteers from the Hospital Italiano de Buenos Aires gene bank. Fifty-seven subjects were identified as homozygous for CYP2C9*1 and 14 for *2, while 24 and 5 were heterozygous for *2 and *3 alleles; one individual was a composite heterozygote (*2/*3). When we examined VKORC1, 21 subjects were AA homozygous, 60 were AG heterozygotes and 20 were GG homozygotes. This is the first analysis of genotypic frequencies for CYP2C9 and VKORC1 performed in an Argentinian population. These allele prevalences are similar to what is known for Caucasian population, reflecting the European ancestor of our patient population, coming mostly from Buenos Aires city and surroundings. Knowledge of this prevalence information is instrumental for cost-effective pharmacogenomic testing in patients undergoing oral anticoagulation treatment. PMID:22290467

Scibona, P; Redal, M A; Garfi, L G; Arbelbide, J; Argibay, P F; Belloso, W H

2012-01-01

287

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry  

PubMed Central

A coding variant in ADH1B (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by DSM-IV criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio of 0.34, 95% confidence interval 0.24, 0.48) for alcohol dependence, with genome-wide significance (6.6 × 10?10). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24 hour period (lifetime), with p = 3×10?13. We also tested the effects of this allele on the development of alcoholism in adolescents and young adults and demonstrated a significant protective effect. This variant has the strongest effect on risk for alcohol dependence of any tested in European populations.

Bierut, Laura Jean; Goate, Alison M; Breslau, Naomi; Johnson, Eric O; Bertelsen, Sarah; Fox, Louis; Agrawal, Arpana; Bucholz, Kathleen K; Grucza, Richard; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John; Porjesz, Bernice; Saccone, Nancy L; Schuckit, Marc; Tischfield, Jay; Wang, Jen C; Foroud, Tatiana; Rice, John P; Edenberg, Howard J

2011-01-01

288

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.  

PubMed

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations. PMID:21968928

Bierut, L J; Goate, A M; Breslau, N; Johnson, E O; Bertelsen, S; Fox, L; Agrawal, A; Bucholz, K K; Grucza, R; Hesselbrock, V; Kramer, J; Kuperman, S; Nurnberger, J; Porjesz, B; Saccone, N L; Schuckit, M; Tischfield, J; Wang, J C; Foroud, T; Rice, J P; Edenberg, H J

2012-04-01

289

Caucasian and Asian specific rheumatoid arthritis risk loci reveal limited replication and apparent allelic heterogeneity in north Indians.  

PubMed

Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for allelic/locus heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker.Of the 44 European specific index SNPs, neither index nor surrogate SNPs were present for nine SNPs in the genotyping array. Of the remaining 35, associations were replicated at seven genes namely PTPN22 (rs1217407, p?=?3×10(-3)); IL2-21 (rs13119723, p?=?0.008); HLA-DRB1 (rs660895, p?=?2.56×10(-5); rs6457617, p?=?1.6×10(-09); rs13192471, p?=?6.7×10(-16)); TNFA1P3 (rs9321637, p?=?0.03); CCL21 (rs13293020, p?=?0.01); IL2RA (rs2104286, p?=?1.9×10(-4)) and ZEB1 (rs2793108, p?=?0.006). Of the three Asian specific loci tested, rs2977227 in PADI4 showed modest association (p<0.02). Further, of the 140 SNPs (in LE with index/surrogate variant) tested, association was observed at 11 additional genes: PTPRC, AFF3, CD28, CTLA4, PXK, ANKRD55, TAGAP, CCR6, BLK, CD40 and IL2RB. This study indicates limited replication of European and Asian index SNPs and apparent allelic heterogeneity in RA etiology among north Indians warranting independent GWAS in this population. However, replicated associations of HLA-DRB1, PTPN22 (which confer ?50% of the heritable risk to RA) and IL2RA suggest that cross-ethnicity fine mapping of such loci is apposite for identification of causal variants. PMID:22355377

Prasad, Pushplata; Kumar, Ashok; Gupta, Rajiva; Juyal, Ramesh C; Thelma, B K

2012-01-01

290

Caucasian and Asian Specific Rheumatoid Arthritis Risk Loci Reveal Limited Replication and Apparent Allelic Heterogeneity in North Indians  

PubMed Central

Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for allelic/locus heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker. Of the 44 European specific index SNPs, neither index nor surrogate SNPs were present for nine SNPs in the genotyping array. Of the remaining 35, associations were replicated at seven genes namely PTPN22 (rs1217407, p?=?3×10?3); IL2–21 (rs13119723, p?=?0.008); HLA-DRB1 (rs660895, p?=?2.56×10?5; rs6457617, p?=?1.6×10?09; rs13192471, p?=?6.7×10?16); TNFA1P3 (rs9321637, p?=?0.03); CCL21 (rs13293020, p?=?0.01); IL2RA (rs2104286, p?=?1.9×10?4) and ZEB1 (rs2793108, p?=?0.006). Of the three Asian specific loci tested, rs2977227 in PADI4 showed modest association (p<0.02). Further, of the 140 SNPs (in LE with index/surrogate variant) tested, association was observed at 11 additional genes: PTPRC, AFF3, CD28, CTLA4, PXK, ANKRD55, TAGAP, CCR6, BLK, CD40 and IL2RB. This study indicates limited replication of European and Asian index SNPs and apparent allelic heterogeneity in RA etiology among north Indians warranting independent GWAS in this population. However, replicated associations of HLA-DRB1, PTPN22 (which confer ?50% of the heritable risk to RA) and IL2RA suggest that cross-ethnicity fine mapping of such loci is apposite for identification of causal variants.

Prasad, Pushplata; Kumar, Ashok; Gupta, Rajiva; Juyal, Ramesh C.; B. K., Thelma

2012-01-01

291

Maize ARGOS1 (ZAR1) transgenic alleles increase hybrid maize yield  

PubMed Central

Crop improvement for yield and drought tolerance is challenging due to the complex genetic nature of these traits and environmental dependencies. This study reports that transgenic over-expression of Zea mays ARGOS1 (ZAR1) enhanced maize organ growth, grain yield, and drought-stress tolerance. The ZAR1 transgene exhibited environmental interactions, with yield increase under Temperate Dry and yield reduction under Temperate Humid or High Latitude environments. Native ZAR1 allele variation associated with drought-stress tolerance. Two founder alleles identified in the mid-maturity germplasm of North America now predominate in Pioneer’s modern breeding programme, and have distinct proteins, promoters and expression patterns. These two major alleles show heterotic group partitioning, with one predominant in Pioneer’s female and the other in the male heterotic groups, respectively. These two alleles also associate with favourable crop performance when heterozygous. Allele-specific transgene testing showed that, of the two alleles discussed here, each allele differed in their impact on yield and environmental interactions. Moreover, when transgenically stacked together the allelic pair showed yield and environmental performance advantages over either single allele, resembling heterosis effects. This work demonstrates differences in transgenic efficacy of native alleles and the differences reflect their association with hybrid breeding performance.

Guo, Mei

2014-01-01

292

Maize ARGOS1 (ZAR1) transgenic alleles increase hybrid maize yield.  

PubMed

Crop improvement for yield and drought tolerance is challenging due to the complex genetic nature of these traits and environmental dependencies. This study reports that transgenic over-expression of Zea mays AR GOS1 (ZAR1) enhanced maize organ growth, grain yield, and drought-stress tolerance. The ZAR1 transgene exhibited environmental interactions, with yield increase under Temperate Dry and yield reduction under Temperate Humid or High Latitude environments. Native ZAR1 allele variation associated with drought-stress tolerance. Two founder alleles identified in the mid-maturity germplasm of North America now predominate in Pioneer's modern breeding programme, and have distinct proteins, promoters and expression patterns. These two major alleles show heterotic group partitioning, with one predominant in Pioneer's female and the other in the male heterotic groups, respectively. These two alleles also associate with favourable crop performance when heterozygous. Allele-specific transgene testing showed that, of the two alleles discussed here, each allele differed in their impact on yield and environmental interactions. Moreover, when transgenically stacked together the allelic pair showed yield and environmental performance advantages over either single allele, resembling heterosis effects. This work demonstrates differences in transgenic efficacy of native alleles and the differences reflect their association with hybrid breeding performance. PMID:24218327

Guo, Mei; Rupe, Mary A; Wei, Jun; Winkler, Chris; Goncalves-Butruille, Marymar; Weers, Ben P; Cerwick, Sharon F; Dieter, Jo Ann; Duncan, Keith E; Howard, Richard J; Hou, Zhenglin; Löffler, Carlos M; Cooper, Mark; Simmons, Carl R

2014-01-01

293

Inheritance of resistance to Fusarium head blight in three European winter wheat populations.  

PubMed

Fusarium head blight (FHB) resistance is of particular importance in wheat breeding programmes due to the detrimental effects of this fungal disease on human and animal health, yield and grain quality. Segregation for FHB resistance in three European winter wheat populations enabled the identification of resistance loci in well-adapted germplasm. Populations obtained from crosses of resistant cultivars Apache, History and Romanus with susceptible semi-dwarfs Biscay, Rubens and Pirat, respectively, were mapped and analysed to identify quantitative trait loci (QTL) for FHB severity, ear emergence time and plant height. The results of the present study together with previous studies in UK winter wheat indicated that the semi-dwarfing allele Rht-D1b seems to be the major source for FHB susceptibility in European winter wheat. The high resistance level of the cultivars Romanus and History was conditioned by several minor resistance QTL interacting with the environment and the absence of Rht-D1b. In contrast, the semi-dwarf parents contributed resistance alleles of major effects apparently compensating the negative effects of Rht-D1b on FHB reaction. The moderately resistant cultivar Apache contributed a major QTL on chromosome 6A in a genome region previously shown to carry resistance loci to FHB. A total of 18 genomic regions were repeatedly associated with FHB resistance. The results indicate that common resistance-associated genes or genomic regions are present in European winter wheats. PMID:18670751

Holzapfel, Josef; Voss, Hans-Henning; Miedaner, Thomas; Korzun, Viktor; Häberle, Jennifer; Schweizer, Günther; Mohler, Volker; Zimmermann, Gerhard; Hartl, Lorenz

2008-11-01

294

Whither Europeanization? Concept Stretching and Substantive Change  

Microsoft Academic Search

This paper discusses the concept of Europeanization in the light of recent research on the impact of the European Union politics and policy. Conceptual analysis is preliminary to empirical analysis. Accordingly, I examine the risk of 'concept stretching', discuss extension and intension of Europeanization, and propose a taxonomy to 'unpack' the concept and organize empirical research. The explanation of Europeanization

Claudio M. Radaelli

2002-01-01

295

Towards a European forum for the neurosciences  

Microsoft Academic Search

In 1994, TINS published a brief analysis of the problems faced by the European neuroscience community in its attempt to meet the challenges associated with the proclamation of the European `Decade of the Brain'. Since then numerous initiatives have been taken by national and European neuroscience societies with the common goals of improving communication among European neuroscientists, increasing the visibility

Wolf Singer

1997-01-01

296

European football and the European union: Governance, participation and social cohesion — towards a policy research agenda  

Microsoft Academic Search

This article considers the changing relationship of European football to the European Union (EU). Given technological, commercial, financial and organizational changes in the political economy of elite European football, and given the application of European law to sports bodies epitomised by the Bosman ruling, this article begins to outline a policy research agenda. Debates within the European Commission have centred

Adam Brown

2000-01-01

297

Building a Strong, Unified European Astronomy  

Microsoft Academic Search

\\u000a European astronomy owes its present positions of leadership to the development of pan-European cooperation. For many years,\\u000a this happened mainly through a few international organisations, chiefly the European Southern Observatory (ESO) and the European Space Agency (ESA). Their success highlights the potential of the much greater resources invested in European astronomy through national\\u000a programmes, especially when including university institutes and

Johannes Andersen

298

Balancer-Cre transgenic mouse germ cells direct the incomplete resolution of a tri-loxP-targeted Cyp1a1 allele, producing a conditional knockout allele.  

PubMed

To generate conditional alleles, genes are commonly engineered to contain recognition sites for bacteriophage recombinases, such as Cre recombinase. When such motifs (lox sites) flank essential gene sequences, and provided that Cre recombinase is expressed, Cre recombinase will excise the flanked sequence-creating a conditional knockout allele. Targeted conditional alleles contain a minimum of three lox sites. It would be desirable to have Cre recombinase perform partial resolution (i.e., recombination some of the time between only the two lox sites flanking the marker gene). Here we report use of the commercially available Balancer2-Cre transgenic mouse line to carry out this function from a tri-loxP-site-containing cytochrome p450 1A1 (Cyp1a1) targeted allele. Such incomplete resolution of this complex locus occurred progressively with age in germ cells of male mice; the conditional Cyp1a1 gene was recovered in offspring from mice containing the targeted Cyp1a1 allele and the Cre recombinase transgene. Removal of the marker gene resulted in a conditional Cyp1a1 allele whose expression was indistinguishable from that of the wild-type allele. PMID:14637164

Uno, Shigeyuki; Wang, Bin; Shertzer, Howard G; Nebert, Daniel W; Dalton, Timothy P

2003-12-12

299

Burden of risk alleles for Hypertension Increases Risk of Intracerebral Hemorrhage  

PubMed Central

SUMMARY Background and Purpose Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (SNPs) associated with blood pressure (BP) levels have been identified. We sought to determine whether the cumulative burden of BP-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods Prospective multicenter case-control study in 2272 subjects of European descent (1025 cases and 1247 controls). Thirty-nine SNPs reported to be associated with BP levels were identified from the National Human Genome Research Institute GWAS catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results No single SNP was associated with either ICH or pre-ICH HTN. The BP-based unweighted genetic risk score was associated with risk of ICH (odds ratio [OR] = 1.11, 95% confidence interval [CI] 1.02–1.21, p=0.01) and the subset of ICH in deep regions (OR=1.18, 95%CI 1.07–1.30, p=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among controls (OR=1.17, 95%CI 1.04–1.31, p=0.009) and ICH cases (OR=1.15, 95%CI 1.01–1.31, p=0.04). Similar results were obtained when using a weighted score. Conclusion Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.

Falcone, Guido J.; Biffi, Alessandro; Devan, William; Jagiella, Jeremiasz M.; Schmidt, Helena; Kissela, Brett; Hansen, Bjorn M.; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Elosua, Roberto; Cuadrado-Godia, Elisa; Soriano, Carolina; Ayres, Alison M.; Schwab, Kristin; Pera, Joanna; Urbanik, Andrzej; Rost, Natalia S.; Goldstein, Joshua N.; Viswanathan, Anand; Pichler, Alexander; Enzinger, Christian; Norrving, Bo; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F.; Kidwell, Chelsea S.; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Broderick, Joseph P.; Greenberg, Steven M.; Roquer, Jaume; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Flaherty, Matthew L.; Kleindorfer, Dawn O.; Langefeld, Carl D.; Woo, Daniel; Rosand, Jonathan

2012-01-01

300

Allelic diversity at the DLA-88 locus in Golden Retriever and Boxer breeds is limited  

PubMed Central

In the dog, previous analyses of major histocompatibility complex (MHC) class I genes suggest a single polymorphic locus, Dog Leukocyte Antigen (DLA)-88. While 51 alleles have been reported, estimates of prevalence have not been made. We hypothesized that, within a breed, DLA-88 diversity would be restricted, and one or more dominant alleles could be identified. Accordingly, we determined allele usage in 47 Golden Retrievers and 39 Boxers. In each population, 10 alleles were found; 4 were shared. Seven novel alleles were identified. DLA-88*05101 and *50801 predominated in Golden Retrievers, while most Boxers carried *03401. In these breeds DLA-88 polymorphisms are limited and largely non-overlapping. The finding of highly prevalent alleles fulfills an important prerequisite for studying canine CD8+ T-cell responses.

Ross, Peter; Buntzman, Adam S.; Vincent, Benjamin G.; Grover, Elise N.; Gojanovich, Gregory S.; Collins, Edward J.; Frelinger, Jeffrey A.; Hess, Paul R.

2012-01-01

301

[Allelic variation at high-molecular-weight glutenin subunit loci in Aegilops biuncialis Vis].  

PubMed

Alleles at the high-molecular-weight glutenin subunit loci Glu-U1 and Glu-M(b)1 were analyzed in the tetraploid species Aegilops biuncialis (UUM(b)M(b)). The material for the investigation included the collection of 39 accessions of Ae. biuncialis from Ukraine (the Crimea), one Hellenic accession, one accession of unknown origin, F2 seeds from different crosses, as well as samples from natural populations from the Crimea. Ae. umbellulata and Ae. comosa accessions were used to allocate components of the HMW glutenin subunit patterns of Ae. biuncialis to U or M(b) genomes. Eight alleles were identified at the Glu-U1 locus and ten alleles were revealed at the Glu-M(b) 1 locus. Among alleles at the Glu-M(b) 1 locus ofAe. biuncialis there were two alleles controlling the y-type subunit only and one allele encoding the x-subunit only. PMID:22117406

Kozub, N A; Sozinov, I A; Ksinias, I N; Sozinov, A A

2011-09-01

302

Two classes of deleterious recessive alleles in a natural population of zebrafish, Danio rerio.  

PubMed Central

Natural populations carry deleterious recessive alleles which cause inbreeding depression. We compared mortality and growth of inbred and outbred zebrafish, Danio rerio, between 6 and 48 days of age. Grandparents of the studied fish were caught in the wild. Inbred fish were generated by brother-sister mating. Mortality was 9% in outbred fish, and 42% in inbred fish, which implies at least 3.6 lethal equivalents of deleterious recessive alleles per zygote. There was no significant inbreeding depression in the growth, perhaps because the surviving inbred fish lived under less crowded conditions. In contrast to alleles that cause embryonic and early larval mortality in the same population, alleles responsible for late larval and early juvenile mortality did not result in any gross morphological abnormalities. Thus, deleterious recessive alleles that segregate in a wild zebrafish population belong to two sharply distinct classes: early-acting, morphologically overt, unconditional lethals; and later-acting, morphologically cryptic, and presumably milder alleles.

McCune, Amy R.; Houle, David; McMillan, Kyle; Annable, Rebecca; Kondrashov, Alexey S.

2004-01-01

303

PCR-based genotyping of MNSs blood group: subtyping of M allele to MG and MT.  

PubMed

PCR-based genotyping of MNSs blood group system was investigated in combination with restriction fragment length polymorphism (RFLP), single-stand conformation polymorphism (SSCP) and allele-specific PCR amplification (ASPA) techniques. M and N alleles are based on three nucleotide substitutions in exon 2 and one base change (G or T) in an intron of glycophorin A locus. The latter single base change was also found among M alleles analyzed in this study, so that M allele appeared to be subdivided into MG and MT. All three alleles, MG, MT and N were identified clearly by RFLP or SSCP analysis following a single amplification. S and s alleles are based on one nucleotide substitution in exon 3 of glycophorin B gene. Genotyping of Ss blood group system was also explored by PCR-SSCP or ASPA analysis, and problems in the methods were discussed. PMID:9560948

Akane, A; Kobayashi, T; Li, Z X; Yoshimura, S; Okii, Y; Yoshida, M; Tokiyasu, T; Watabiki, T

1997-12-01

304

DEMETER DNA Glycosylase Establishes MEDEA Polycomb Gene Self-Imprinting by Allele-Specific Demethylation  

PubMed Central

SUMMARY MEDEA (MEA) is an Arabidopsis Polycomb group gene that is imprinted in the endosperm. The maternal allele is expressed and the paternal allele is silent. MEA is controlled by DEMETER (DME), a DNA glycosylase required to activate MEA expression, and METHYLTRANSFERASE I (MET1), which maintains CG methylation at the MEA locus. Here we show that DME is responsible for endosperm maternal-allele-specific hypomethylation at the MEA gene. DME can excise 5-methylcytosine in vitro and when expressed in E. coli. Abasic sites opposite 5-methylcytosine inhibit DME activity and might prevent DME from generating double-stranded DNA breaks. Unexpectedly, paternal-allele silencing is not controlled by DNA methylation. Rather, Polycomb group proteins that are expressed from the maternal genome, including MEA, control paternal MEA silencing. Thus, DME establishes MEA imprinting by removing 5-methylcytosine to activate the maternal allele. MEA imprinting is subsequently maintained in the endosperm by maternal MEA silencing the paternal allele.

Gehring, Mary; Huh, Jin Hoe; Hsieh, Tzung-Fu; Penterman, Jon; Choi, Yeonhee; Harada, John J.; Goldberg, Robert B.; Fischer, Robert L.

2014-01-01

305

Haplotype variation of Glu-D1 locus and the origin of Glu-D1d allele conferring superior end-use qualities in common wheat.  

PubMed

In higher plants, seed storage proteins (SSPs) are frequently expressed from complex gene families, and allelic variation of SSP genes often affects the quality traits of crops. In common wheat, the Glu-D1 locus, encoding 1Dx and 1Dy SSPs, has multiple alleles. The Glu-D1d allele frequently confers superior end-use qualities to commercial wheat varieties. Here, we studied the haplotype structure of Glu-D1 genomic region and the origin of Glu-D1d. Using seven diagnostic DNA markers, 12 Glu-D1 haplotypes were detected among common wheat, European spelt wheat (T. spelta, a primitive hexaploid relative of common wheat), and Aegilops tauschii (the D genome donor of hexaploid wheat). By comparatively analyzing Glu-D1 haplotypes and their associated 1Dx and 1Dy genes, we deduce that the haplotype carrying Glu-D1d was likely differentiated in the ancestral hexaploid wheat around 10,000 years ago, and was subsequently transmitted to domesticated common wheat and T. spelta. A group of relatively ancient Glu-D1 haplotypes was discovered in Ae. tauschii, which may serve for the evolution of other haplotypes. Moreover, a number of new Glu-D1d variants were found in T. spelta. The main steps in Glu-D1d differentiation are proposed. The implications of our work for enhancing the utility of Glu-D1d in wheat quality improvement and studying the SSP alleles in other crop species are discussed. PMID:24098671

Dong, Zhenying; Yang, Yushuang; Li, Yiwen; Zhang, Kunpu; Lou, Haijuan; An, Xueli; Dong, Lingli; Gu, Yong Qiang; Anderson, Olin D; Liu, Xin; Qin, Huanju; Wang, Daowen

2013-01-01

306

Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease  

SciTech Connect

Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

Lucotte, G.; David, F.; Berriche, S. [Regional Center of Neurogenetics, Reims (France)] [and others

1994-09-15

307

Model to estimate the increase of genetic variability due to electrophoretically cryptic alleles  

SciTech Connect

To consider the problem of the increase of genetic variability due to electrophoretically cryptic alleles, the equally degenerate electromorph model is proposed. Mutation, random sampling drift and selection can be incorporated in this model. Simple formulas are obtained to show how genetic variability increases when cryptic alleles are distinguished. This model is extended to a two-population system to see the effect of cryptic allele variation on genetic differentiation.

Iizuka, M.

1988-02-01

308

Variation for glutenin and waxy alleles in the US hard winter wheat germplasm  

Microsoft Academic Search

We conducted a survey of high- and low-molecular-weight glutenin subunits (HMW-GS and LMW-GS, respectively) and waxy (Wx) allele composition in 111 winter wheat cultivars and advanced lines developed in the US Hard Winter Wheat Region since 1991. At the HMW-GS Glu-A1 locus, 76.1% of entries had allele b (encoding subunit 2*), 21.2% carried allele a (subunit 1), and 2.7% had

Xueyan Shan; Sally R. Clayshulte; Scott D. Haley; Patrick F. Byrne

2007-01-01

309

High-Throughput SNP Allele-Frequency Determination in Pooled DNA Samples by Kinetic PCR  

Microsoft Academic Search

We have developed an accurate, yet inexpensive and high-throughput, method for determining the allele frequency of biallelic polymorphisms in pools of DNA samples. The assay combines kinetic (real-time quantitative) PCR with allele-specific amplification and requires no post-PCR processing. The relative amounts of each allele in a sample are quantified. This is performed by dividing equal aliquots of the pooled DNA

Søren Germer; Michael J. Holland; Russell Higuchi

2000-01-01

310

Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population  

PubMed Central

Mutations in the aldolase B gene (ALDOB) impairing enzyme activity toward fructose-1-phosphate cleavage cause hereditary fructose intolerance (HFI). Diagnosis of the disease is possible by identifying known mutant ALDOB alleles in suspected patients; however, the frequencies of mutant alleles can differ by population. Here, 153 American HFI patients with 268 independent alleles were analyzed to identify the prevalence of seven known HFI-causing alleles (A149P, A174D, N334K, ?4E4, R59Op, A337V, and L256P) in this population. Allele-specific oligonucleotide hybridization analysis was performed on polymerase chain reaction (PCR)-amplified genomic DNA from these patients. In the American population, the missense mutations A149P and A174D are the two most common alleles, with frequencies of 44% and 9%, respectively. In addition, the nonsense mutations ?4E4 and R59Op are the next most common alleles, with each having a frequency of 4%. Together, the frequencies of all seven alleles make up 65% of HFI-causing alleles in this population. Worldwide, these same alleles make up 82% of HFI-causing mutations. This difference indicates that screening for common HFI alleles is more difficult in the American population. Nevertheless, a genetic screen for diagnosing HFI in America can be improved by including all seven alleles studied here. Lastly, identification of HFI patients presenting with classic symptoms and who have homozygous null genotypes indicates that aldolase B is not required for proper development or metabolic maintenance.

Coffee, Erin M.; Yerkes, Laura; Ewen, Elizabeth P.; Zee, Tiffany

2010-01-01

311

Cis-regulation and sporogenic reversion frequency of a new mutable Anl allele in Petunia hybrida  

Microsoft Academic Search

A new mutable Anl allele is described: anls\\/p7. The genetic analysis of this allele supports the model of the Anl locus as consisting of a structural gene and a cis-acting regulating region. The anls\\/p7 allele shows a constant number of sporogenic revertants towards an anl+\\/p7 state in subsequent generations. There is a systemic difference in number of sporogenic revertants between

A G M Gerats; S P C Groot; F Bianchi

1985-01-01

312

Non-imprinted allele-specific DNA methylation on human autosomes  

Microsoft Academic Search

ABSTRACT: BACKGROUND: Differential DNA methylation between alleles is well established in imprinted genes and the X chromosomes in females but has rarely been reported at non-imprinted loci on autosomes. RESULTS: We studied DNA methylation of cytosine-guanine dinucleotide (CpG) islands on chromosome 21 in leukocytes from several healthy individuals and observed novel cases of pronounced differential methylation of alleles. Allele-specific methylation

Yingying Zhang; Christian Rohde; Richard Reinhardt; Claudia Voelcker-Rehage; Albert Jeltsch

2009-01-01

313

Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease  

Microsoft Academic Search

Several studies have reported an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (LOAD). Here we report on the relationship between APOE*4 and early-onset Alzheimer's disease (EOAD) in a Dutch population-based study. The frequency of the APOE*4 allele was 2.3 times higher among EOAD cases compared to controls. Among patients, the allele

Duijn van C. M; Peter de Knijff; Marc Cruts; Anita Wehnert; Louis M. Havekes; Broeckhoven van C; A. Hofman

1994-01-01

314

Cystic fibrosis-related diabetes is associated with HLA DQB1 alleles encoding Asp57 ? molecules  

Microsoft Academic Search

The incidence of insulin-dependent diabetes in individuals with cystic fibrosis is nearly 100 times greater than in the general population. In the latter group, strong associations with specific HLADQ\\/A1 andDQB1 alleles have been observed. To determine if a similar distribution of alleles occurs in cystic fibrosis patients with diabetes, a cohort of these individuals was typed forDQA1 andDQB1 alleles. HLADQB1*0201

Mary Carrington; Leslie J. Krueger; Douglas S. Holsclaw; Michael C. Iannuzzi; Michael Dean; Dean Mann

1994-01-01

315

Allelic Combinations of Promoter and Exon 2 in DQB1 in Dogs and Wolves  

Microsoft Academic Search

Polymorphism of PBRs of the major histocompatibility complex (MHC) genes is well recognized, but the polymorphism also extends\\u000a to proximal promoter regions. Examining DQB1 variability in dogs and wolves, we identified 7 promoter variants and 13 exon 2 alleles among 89 dogs, including a previously\\u000a unknown DQB1 exon 2 allele, and 8 promoter variants and 9 exon 2 alleles among

Karin T. Berggren; Jennifer M. Seddon

2008-01-01

316

HLA-B typing by allele separation followed by direct sequencing.  

PubMed

Due to the enormous allelic diversity of the HLA-B locus, it has been difficult to design an unambiguous molecular typing method for the alleles at this locus. Here we describe a technique for the direct sequencing of HLA-B alleles. Initially, HLA-B alleles were PCR-amplified after locus-specific reverse transcription of RNA. Alleles were then separated using denaturing gradient gel electrophoresis (DGGE), which separates DNA fragments based on their sequence composition. Amplification products were excised from the gel and eluted DNA was reamplified and directly sequenced. The derived sequences were aligned to a database of published HLA-B sequences, and an initial allele assignment was made. This approach was theoretically sufficient to type 92 of the 118 known HLA-B alleles. The majority of the remaining 26 alleles contain differences at the beginning of exon 2, a region outside the DGGE-separated PCR products. Therefore, we used heterozygous sequencing of this region to identify 19 of these 26 alleles, raising the resolution power to 111 alleles. Using this technique, we analyzed immortalized cell lines and blood samples from several different sources. Nine immortalized cell lines were obtained from the 10th International Histocompatibility Workshop (IHWS) and nine were derived from aboriginal peoples. Additionally, 25 blood samples were acquired from a panel of donors previously shown to be difficult to type using serological techniques. Altogether, using this new method of allele separation by DGGE followed by direct sequencing, we typed 52 different alleles from 57 individuals, covering 40 serological specificities. PMID:9151388

Eberle, M; Knapp, L A; Iwanaga, K K; Domanico, M J; Aiyer, K; Watkins, D I

1997-04-01

317

Undetected Genotyping Errors Cause Apparent Overtransmission of Common Alleles in the Transmission/Disequilibrium Test  

PubMed Central

The transmission/disequilibrium test (TDT), a family-based test of linkage and association, is a popular and intuitive statistical test for studies of complex inheritance, as it is nonparametric and robust to population stratification. We carried out a literature search and located 79 significant TDT-derived associations between a microsatellite marker allele and a disease. Among these, there were 31 (39%) in which the most common allele was found to exhibit distorted transmission to affected offspring, implying that the allele may be associated with either susceptibility to or protection from a disease. In 27 of these 31 studies (87%), the most common allele appeared to be overtransmitted to affected offspring (a risk factor), and, in the remaining 4 studies, the most common allele appeared to be undertransmitted (a protective factor). In a second literature search, we identified 92 case-control studies in which a microsatellite marker allele was found to have significantly different frequencies in case and control groups. Of these, there were 37 instances (40%) in which the most common allele was involved. In 12 of these 37 studies (32%), the most common allele was enriched in cases relative to controls (a risk factor), and, in the remaining 25 studies, the most common allele was enriched in controls (a protective factor). Thus, the most common allele appears to be a risk factor when identified through the TDT, and it appears to be protective when identified through case-control analysis. To understand this phenomenon, we incorporated an error model into the calculation of the TDT statistic. We show that undetected genotyping error can cause apparent transmission distortion at markers with alleles of unequal frequency. We demonstrate that this distortion is in the direction of overtransmission for common alleles. Therefore, we conclude that undetected genotyping errors may be contributing to an inflated false-positive rate among reported TDT-derived associations and that genotyping fidelity must be increased.

Mitchell, Adele A.; Cutler, David J.; Chakravarti, Aravinda

2003-01-01

318

Identification of alleles of carotenoid pathway genes important for zeaxanthin accumulation in potato tubers  

PubMed Central

We have investigated the genetics and molecular biology of orange flesh colour in potato (Solanum tuberosum L.). To this end the natural diversity in three genes of the carotenoid pathway was assessed by SNP analyses. Association analysis was performed between SNP haplotypes and flesh colour phenotypes in diploid and tetraploid potato genotypes. We observed that among eleven beta-carotene hydroxylase 2 (Chy2) alleles only one dominant allele has a major effect, changing white into yellow flesh colour. In contrast, none of the lycopene epsilon cyclase (Lcye) alleles seemed to have a large effect on flesh colour. Analysis of zeaxanthin epoxidase (Zep) alleles showed that all (diploid) genotypes with orange tuber flesh were homozygous for one specific Zep allele. This Zep allele showed a reduced level of expression. The complete genomic sequence of the recessive Zep allele, including the promoter, was determined, and compared with the sequence of other Zep alleles. The most striking difference was the presence of a non-LTR retrotransposon sequence in intron 1 of the recessive Zep allele, which was absent in all other Zep alleles investigated. We hypothesise that the presence of this large sequence in intron 1 caused the lower expression level, resulting in reduced Zep activity and accumulation of zeaxanthin. Only genotypes combining presence of the dominant Chy2 allele with homozygosity for the recessive Zep allele produced orange-fleshed tubers that accumulated large amounts of zeaxanthin. Electronic supplementary material The online version of this article (doi:10.1007/s11103-010-9647-y) contains supplementary material, which is available to authorized users.

Uitdewilligen, Jan G. A. M. L.; Kloosterman, Bjorn A.; Hutten, Ronald C. B.; Visser, Richard G. F.; van Eck, Herman J.

2010-01-01

319

Association between clozapine response and allelic variation in 5HT 2A receptor gene  

Microsoft Academic Search

We report allelic association between a polymorphism (T102C) within the coding region of the 5-HT2A gene (HTR2A, 13q14-21) and response to clozapine in schizophrenic patients. Homozygosity for the C102 allele was more frequent (30\\/57, 53%) among patients who did not respond to clozapine than in those who responded (23\\/92, 25%). This finding is evidence that allelic variation of genes which

M. J. Arranz; D. A. Collier; M. Sodhi; D. Ball; G. W. Roberts; P. Sham; R. Kerwin; J. Price

1995-01-01

320

A Model to Estimate the Increase of Genetic Variability Due to Electrophoretically Cryptic Alleles  

PubMed Central

To consider the problem of the increase of genetic variability due to electrophoretically cryptic alleles, the equally degenerate electromorph model is proposed. Mutation, random sampling drift and selection can be incorporated in this model. Simple formulas are obtained to show how genetic variability increases when cryptic alleles are distinguished. This model is extended to a two-population system to see the effect of cryptic allele variation on genetic differentiation.

Iizuka, M.

1988-01-01

321

Non-Equilibrium Allele Frequency Spectra Via Spectral Methods  

PubMed Central

A major challenge in the analysis of population genomics data consists of isolating signatures of natural selection from background noise caused by random drift and gene flow. Analyses of massive amounts of data from many related populations require high-performance algorithms to determine the likelihood of different demographic scenarios that could have shaped the observed neutral single nucleotide polymorphism (SNP) allele frequency spectrum. In many areas of applied mathematics, Fourier Transforms and Spectral Methods are firmly established tools to analyze spectra of signals and model their dynamics as solutions of certain Partial Differential Equations (PDEs). When spectral methods are applicable, they have excellent error properties and are the fastest possible in high dimension; see [15]. In this paper we present an explicit numerical solution, using spectral methods, to the forward Kolmogorov equations for a Wright-Fisher process with migration of K populations, influx of mutations, and multiple population splitting events.

Hey, Jody; Chen, Kevin

2011-01-01

322

Fine-mapping natural alleles: quantitative complementation to the rescue.  

PubMed

Mapping the genes responsible for natural variation and divergence is a challenging task. Many studies have mapped genes to genomic regions or generated lists of candidates, but few studies have implicated specific genes with a high standard of evidence. I propose that combining recent advances in genomic engineering with a modified version of the quantitative complementation test will help turn candidate genes into causal genes. By creating loss-of-function mutations in natural strains, and using these mutations to quantitatively fail-to-complement natural alleles, fine mapping should be greatly facilitated. As an example, I propose that the CRISPR/Cas9 system could be combined with the FLP/FRT system to fine-map genes in the numerous systems where inversions have frustrated these efforts. PMID:24628660

Turner, Thomas L

2014-05-01

323

Fine-mapping natural alleles: quantitative complementation to the rescue  

PubMed Central

Mapping the genes responsible for natural variation and divergence is a challenging task. Many studies have mapped genes to genomic regions, or generated lists of candidates, but few studies have implicated specific genes with a high standard of evidence. I propose that combining recent advances in genomic engineering with a modified version of the quantitative complementation test will help turn candidate genes into causal genes. By creating loss-of-function mutations in natural strains, and using these mutations to quantitatively fail-to-complement natural alleles, fine mapping should be greatly facilitated. As an example, I propose that the CRISPR/Cas9 system could be combined with the FLP/FRT system to fine-map genes in the numerous systems where inversions have frustrated these efforts.

Turner, Thomas L.

2014-01-01

324

Phage display antibodies to allelic determinants of canine blood cells.  

PubMed

Techniques were developed to select useful allele-specific antibodies directed to canine red blood cell alloantigens from a phage display library in which antibody single chain variable fragments (scFv) were expressed on filamentous bacteriophage. First, techniques were developed to detect specific antigens displayed on red blood cells using flow cytometry. Next, techniques permitting the efficient selection of red blood cell binders from a large phage library were developed. Finally, the amplified library was depleted using the red blood cells of one animal and the remainder enriched using cells from a genetically different animal. A high frequency of clones derived from this population bound antigen(s) of the second animal but not the first. Sequence analysis of these clones revealed that at least 11 clonally distinct isolates were present within the selected population. The procedure used to obtain these reagents is simple and inexpensive and the techniques developed should find applications in canine transfusion medicine and parentage assignment. PMID:16529769

Chang, Hsuen-Wen; Nguyen, Duy D; Washington, Elizabeth; Walker, Ian D; Holloway, Steven A

2006-04-20

325

Associations of HLA alleles with specific language impairment  

PubMed Central

Background Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals affected by language impairment. Methods We perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types. Results Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD). Conclusion These preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders.

2014-01-01

326

Key considerations for measuring allelic expression on a genomic scale using high-throughput sequencing  

PubMed Central

Differences in gene expression are thought to be an important source of phenotypic diversity, so dissecting the genetic components of natural variation in gene expression is important for understanding the evolutionary mechanisms that lead to adaptation. Gene expression is a complex trait that, in diploid organisms, results from transcription of both maternal and paternal alleles. Directly measuring allelic expression rather than total gene expression offers greater insight into regulatory variation. The recent emergence of high-throughput sequencing offers an unprecedented opportunity to study allelic transcription at a genomic scale for virtually any species. By sequencing transcript pools derived from heterozygous individuals, estimates of allelic expression can be directly obtained. The statistical power of this approach is influenced by the number of transcripts sequenced and the ability to unambiguously assign individual sequence fragments to specific alleles on the basis of transcribed nucleotide polymorphisms. Here, using mathematical modelling and computer simulations, we determine the minimum sequencing depth required to accurately measure relative allelic expression and detect allelic imbalance via high-throughput sequencing under a variety of conditions. We conclude that, within a species, a minimum of 500–1000 sequencing reads per gene are needed to test for allelic imbalance, and consequently, at least five to 10 millions reads are required for studying a genome expressing 10 000 genes. Finally, using 454 sequencing, we illustrate an application of allelic expression by testing for cis-regulatory divergence between closely related Drosophila species.

FONTANILLAS, PIERRE; LANDRY, CHRISTIAN R.; WITTKOPP, PATRICIA J.; RUSS, CARSTEN; GRUBER, JONATHAN D.; NUSBAUM, CHAD; HARTL, DANIEL L.

2011-01-01

327

Lethal Effects of Low and "Null" Activity Alleles of 6-Phosphogluconate Dehydrogenase in DROSOPHILA MELANOGASTER  

PubMed Central

EMS-induced "null" and low activity alleles for 6-phosphogluconate dehydrogenase were characterized with respect to enzymatic activity, relative viability, fertility, and the effective lethal phase. It was determined that flies hemizygous and homozygous for the low activity allele, Pgd-, possessed a depressed developmental rate, diminished viability, and loss of female fertility. Heterozygotes for Pgd- and a deficiency for Pgd+ were lethal. The "null" activity allele demonstrated a lethal phenotype in both the hemizygous and homozygous condition. The effective lethal phase for the "null" allele occurs during late embryonic development (20–22 hr).

Bewley, Glenn C.; Lucchesi, John C.

1975-01-01

328

Effect of Osteopontin Alleles on ?-Glucan-Induced Granuloma Formation in the Mouse Liver  

PubMed Central

The granuloma formation is a host defense response against persistent irritants. Osteopontin is centrally involved in the formation of granulomas. Three osteopontin alleles, designated a, b, and c, have been found in mice. Here we used a murine model of zymosan (?-glucan)-induced granuloma formation in the liver to determine possible functional differences between the osteopontin alleles in cell-mediated immunity. In contrast to mice with alleles a or c, mice with the allele b was defective in granuloma formation. As detected by mRNA expression, cytokines and chemokines known to be critically involved in granuloma formation were elicited in liver tissue, regardless of the osteopontin allele expressed. Alignment of the deduced amino acid sequences showed that unlike osteopontin c, b differs from a in 11 amino acids. All three osteopontin alleles had normal cell-binding properties. However, only the b allelic form was defective in the induction of cell migration as tested with dendritic cells. In conclusion, generation of a granulomatous response in mice depends critically on the presence of a functional osteopontin allele. Defective granuloma formation in mice with allele b is likely to be because of an impaired chemotactic function of the osteopontin b protein on immunocompetent cells.

Tanaka, Kumiko; Morimoto, Junko; Kon, Shigeyuki; Kimura, Chiemi; Inobe, Manabu; Diao, Hongyan; Hirschfeld, Gregor; Weiss, Johannes M.; Uede, Toshimitsu

2004-01-01

329

Gene-Environment Interaction of Body Mass Index and Apolipoprotein E ?4 Allele on Cognitive Decline.  

PubMed

Genetic variation alone may not account for common chronic disease susceptibility. Rather, an interaction between genetic and environmental factors may clarify the underlying disease mechanism. Hence, we tested whether body mass index (BMI) modified the genetic association of the apolipoprotein E ?4 allele with cognitive decline. The data came from a longitudinal population-based sample of 4055 participants interviewed at 3-year intervals from 1993 to 2012. Cognitive function was assessed using a standardized global cognitive score and BMI was assessed at baseline and classified as normal, overweight, and obese. There were 1374 (34%) participants with the ?4 allele. In normal BMI participants, cognitive decline was 0.048 units/y without the ?4 allele, and increased by an additional 0.031 units/y with the ?4 allele. In overweight participants, cognitive decline was 0.038 units/y without the ?4 allele, and increased by an additional 0.026 units/y with the ?4 allele. Finally, in obese participants, cognitive decline was 0.038 units/y without the ?4 allele, and increased by an additional 0.014 units/y with the ?4 allele. The association of ?4 allele with cognitive decline was significantly lower in obese participants compared with normal BMI participants (P=0.003), thereby suggesting significant gene-environment interaction on cognitive decline. PMID:24145695

Rajan, Kumar B; Skarupski, Kimberly A; Rasmussen, Heather E; Evans, Denis A

2014-01-01

330

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2  

PubMed Central

Allelic exclusion requires that the two alleles at antigen-receptor loci attempt to recombine variable (V), diversity (D), and joining (J) gene segments [V(D)J recombination] asynchronously in nuclei of developing lymphocytes. It previously was shown that T-cell receptor ? (Tcrb) alleles frequently and stochastically associate with the nuclear lamina and pericentromeric heterochromatin in CD4?CD8? thymocytes. Moreover, rearranged alleles were underrepresented at these locations. Here we used 3D immunofluorescence in situ hybridization to identify recently rearranged Tcrb alleles based on the accumulation of the DNA-repair protein 53BP1. We found that Tcrb alleles recombine asynchronously in double-negative thymocytes and that V(D)J recombination is suppressed on peripheral as compared with central Tcrb alleles. Moreover, the recombination events that did take place at the nuclear periphery preferentially occurred on Tcrb alleles that were partially dissociated from the nuclear lamina. To understand better the mechanism by which V(D)J recombination is suppressed at the nuclear periphery, we evaluated the subnuclear distribution of recombination-activating gene 2 (RAG2) protein. We found that RAG2 abundance was reduced at the nuclear periphery. Moreover, RAG2 was distributed differently from RNA polymerase II and histone H3K4 trimethylation. Our data suggest that the nuclear periphery suppresses V(D)J recombination, at least in part, by segregating Tcrb alleles from RAG proteins.

Chan, Elizabeth A. W.; Teng, Grace; Corbett, Elizabeth; Choudhury, Kingshuk Roy; Bassing, Craig H.; Schatz, David G.; Krangel, Michael S.

2013-01-01

331

Validation study of the TrueAllele automated data review system.  

PubMed

The New York State Convicted Offender DNA Databank is the first U.S. lab to complete an internal validation of the TrueAllele expert data review system. TrueAllele is designed to assess short tandem repeat (STR) DNA data based on several key features such as peak height, shape, area, and position relative to a standard ladder and use this information to make accurate allele calls. The software then prioritizes the allele calls based on several user-defined rules. As a result, the user need only review low-quality data. The validation of this system consisted of an extensive optimization phase and a large concordance phase. During optimization, the rule settings were tailored to minimize the amount of high-quality data viewed by the user. In the concordance phase, a large dataset was typed in parallel with the ABI software Gene Scan and Genotyper (manual review) and TrueAllele (automated review) for comparison of allele calls and sample state assignment. Only one significant difference was discovered out of 2048 samples in the concordance study. In this case, TrueAllele revealed a spike in the profile that was interpreted as a DNA peak by the analyst in Genotyper. TrueAllele was designed to focus the review on poor data and to eliminate the need for complete reanalysis technical review. This validation project proved TrueAllele to be dependable for use at the NYS Convicted Offender DNA Databank. PMID:15317179

Kadash, Kristy; Kozlowski, Brian E; Biega, Lisa A; Duceman, Barry W

2004-07-01

332

Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D).  

PubMed

We describe the generation of two genetically related human immunodeficiency virus type 1 (HIV-1) isolates highly (>20,000-fold) resistant to the small molecule CCR5 inhibitor, SCH-417690 (formerly SCH-D). Both viruses were cross-resistant to other small molecules targeting entry via CCR5, but they were inhibited by some MAbs against the same coreceptor on primary CD4+ T-cells. The resistant isolates remained sensitive to inhibitors of other stages of virus entry, and to replication inhibitors acting post-entry. Neither escape mutant could replicate detectably in peripheral blood mononuclear cells (PBMC) from two donors homozygous for the CCR5-Delta32 allele and both were insensitive to the CXCR4-specific inhibitor, AMD3100. Hence, the SCH-D escape mutants retained the R5 phenotype. One of the resistant isolates was, however, capable of replication in U87.CD4.CXCR4 cells and, after expansion in those cells, was sensitive to AMD3100 in primary CD4+ T-cells. Hence, some X4 variants may be present in this escape mutant swarm. A notable observation was that the SCH-D escape mutants were also cross-resistant to PSC-RANTES and AOP-RANTES, chemokine derivatives that are reported to down-regulate cell surface CCR5 almost completely. However, the extent to which CCR5 is down-regulated was dependent upon the detection MAb. Hence, the escape mutants may be using a CCR5 configuration that is only detected by some anti-CCR5 MAbs. Finally, two SCH-D-resistant clonal viruses revealed no amino acid changes in the gp120 V3 region relative to the parental viruses, in marked contrast to clones resistant to the AD101 small molecule CCR5 inhibitor that possess 4 such sequence changes. Several sequence changes elsewhere in gp120 (V2, C3 and V4) were present in the SCH-D-resistant clones. Their influence on the resistant phenotype remains to be determined. PMID:15935415

Marozsan, Andre J; Kuhmann, Shawn E; Morgan, Thomas; Herrera, Carolina; Rivera-Troche, Enid; Xu, Serena; Baroudy, Bahige M; Strizki, Julie; Moore, John P

2005-07-20

333

Guide to European Legal Databases  

NSDL National Science Digital Library

The New York University (NYU) Law School Reference Librarian For International and Foreign Law, Mirela Roznovschi, has prepared this excellent Guide to European Legal Databases. The Guide offers recommendations for search engines and search tips/strategies for researching foreign law topics. Visitors will find the annotated list of European Websites useful for finding constitutional, copyright, and environmental laws (many laws listed by country). Also referenced in the Guide are sites covering the laws of Austria, Belgium, Denmark, England, France, Germany, Italy, Norway, Russia, Spain, Sweden, Switzerland, the Council of Europe, and the European Union. A section entitled Indices, Guides, Journals, Dictionaries, Library Catalogs covers consolidated resource guides and notable collections, to facilitate further research efforts.

334

Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin.  

PubMed

A genetic polymorphism in the metabolism of the anticonvulsant drug S-mephenytoin has been attributed to defective CYP2C19 alleles. This genetic polymorphism displays large interracial differences with the poor metabolizer (PM) phenotype representing 2-5% of Caucasian and 13-23% of Oriental populations. In the present study, we identified two new mutations in CYP2C19 in a single Swiss Caucasian PM outlier (JOB 1) whose apparent genotype (CYP2C19*1/CYP2C19*2) did not agree with his PM phenotype. These mutations consisted of a single base pair mutation (G395A) in exon 3 resulting in an Arg132-->Gln coding change and a (G276C) mutation in exon 2 resulting in a coding change Glu92-->Asp. However, the G276C mutation and the G395A mutation resided on separate alleles. Genotyping tests of a family study of JOB1 showed that the exon 2 change occurred on the CYP2C19*2 allele, which also contained the known splice mutation in exon 5 (this variant is termed CYP2C19*2B to distinguish it from the original splice variant now termed CYP2C19*2A). The exon 3 mutation resided on a separate allele (termed CYP2C19*6). In all other respects this allele was identical to one of two wild-type alleles, CYP2C19*1B. The incidence of CYP2C19*6 in a European Caucasian population phenotyped for mephenytoin metabolism was 0/344 (99% confidence limits of 0 to 0.9%). Seven of 46 Caucasian CYP2C19*2 alleles were CYP2C19*2B(15%) and 85% were CYP2C19*2A. The Arg132Gln mutation was produced by site-directed mutatgenesis and the recombinant protein expressed in a bacterial cDNA expression system. Recombinant CYP2C19 6 had negligible catalytic activity toward S-mephenytoin compared with CYP2C19 1B, which is consistent with the conclusion that CYP2C19*6 represents a PM allele. Thus, the new CYP2C19*6 allele contributes to the PM phenotype in Caucasians. PMID:9732415

Ibeanu, G C; Goldstein, J A; Meyer, U; Benhamou, S; Bouchardy, C; Dayer, P; Ghanayem, B I; Blaisdell, J

1998-09-01

335

Genome-wide Ancestry Association Testing Identifies a Common European Variant on 6q14.1 as a Risk Factor for Asthma in African Americans  

PubMed Central

Background Genetic variants that contribute to asthma susceptibility may be present at varying frequencies in different populations, which is an important consideration and advantage for performing genetic association studies in admixed populations. Objective To identify asthma-associated loci in African Americans. Methods We compared local African and European ancestry estimated from dense single nucleotide polymorphism (SNP) genotype data in African American adults with asthma and non-asthmatic controls. Allelic tests of association were performed within the candidate regions identified, correcting for local European admixture. Results We identified a significant ancestry association peak on chromosomes 6q. Allelic tests for association within this region identified a SNP (rs1361549) on 6q14.1 that was associated with asthma exclusively in African Americans with local European admixture (OR=2.2). The risk allele is common in Europe (42% in the HapMap CEU) but absent in West Africa (0% in the HapMap YRI), suggesting the allele is present in African Americans due to recent European admixture. We replicated our findings in Puerto Ricans and similarly found that the signal of association is largely specific to individuals who are heterozygous for African and non-African ancestry at 6q14.1. However, we found no evidence for association in European Americans or in Puerto Ricans in the absence of local African ancestry, suggesting that the association with asthma at rs1361549 is due to an environmental or genetic interaction. Conclusion We identified a novel asthma-associated locus that is relevant to admixed populations with African ancestry, and highlight the importance of considering local ancestry in genetic association studies of admixed populations.

Torgerson, Dara G.; Capurso, Daniel; Ampleford, Elizabeth J.; Li, Xingnan; Moore, Wendy C.; Gignoux, Christopher R.; Hu, Donglei; Eng, Celeste; Mathias, Rasika A.; Busse, William W.; Castro, Mario; Erzurum, Serpil C.; Fitzpatrick, Anne M.; Gaston, Benjamin; Israel, Elliot; Jarjour, Nizar N.; Teague, W. Gerald; Wenzel, Sally E.; Rodriguez-Santana, Jose R.; Rodriguez-Cintron, William; Avila, Pedro C.; Ford, Jean G.; Barnes, Kathleen C.; Burchard, Esteban G.; Howard, Timothy D.; Bleecker, Eugene R.; Meyers, Deborah A.; Cox, Nancy J.; Ober, Carole; Nicolae, Dan L.

2012-01-01

336

Diversity of immune genes and associated gill microbes of European plaice Pleuronectes platessa  

NASA Astrophysics Data System (ADS)

Genetic variability of marine fish species is much higher than in most other vertebrates. Nevertheless, some species with large population sizes including flatfish such as European plaice Pleuronectes platessa show signs of population collapse and inbreeding. Taking plaice as a flagship example for fisheries-induced genetic changes also affecting the Wadden Sea, we determined the amount of genetic variability at antigen-presenting genes of the Major Histocompatibility Complex (MHC) and its potential interaction with the microbiota associated to gill tissue using a next-generation parallel tag sequencing approach. Genetic variation at MHC class IIB genes was extremely large, with 97 alleles found in 40 fish from different age cohorts. Although a strong signal of positive selection was present (dN/dS = 4.01) and we found significantly higher allelic diversity in 0+ fish than in older age classes, the amount of genetic variation maintained within the population may not have exceeded neutral expectations derived from mitochondrial markers. Associated microbes revealed significant spatiotemporal structure with 0+ fish displaying the highest microbial diversity as well as the highest diversity of potentially pathogenic genera. Overall the correlation between MHC genotypes and bacterial abundance was weak, and only few alleles significantly correlated with certain bacterial genera. These associations all conferred susceptibility (i.e. presence of an allele correlated to higher number of bacteria), either suggesting age-dependent selection on common alleles or weak selection on resistance against these bacterial genera. Taken together, our data suggest that selection coefficients of balancing selection maintaining immunogenetic diversity may be relatively small in large marine populations. However, if population sizes are further reduced by overharvesting, the response to increasing balancing selection coefficients will be largely unpredictable and may also negatively influence the adaptive potential of populations.

Wegner, K. Mathias; Shama, Lisa N. S.; Kellnreitner, Florian; Pockberger, Moritz

2012-08-01

337

Western European Specialists Section (WESS)  

NSDL National Science Digital Library

This site, hosted by the University of Virginia Library, is devoted to research into Western European history, literature, culture, and politics. The site provides links to well-maintained, quality sites in the aforementioned fields, including regional and historical resources, Websites on contemporary Europe, e-texts and e-text collections, guides to Library Resources, and book review sites. In addition, WESS offers an online newsletter which features articles of particular relevance to Western European subject specialists. WESS is part of the Association of College and Research Libraries, a division of the American Library Association.

338

Security Economics and European Policy  

NASA Astrophysics Data System (ADS)

In September 2007, we were awarded a contract by the European Network and Information Security Agency (ENISA) to investigate failures in the market for secure electronic communications within the European Union, and come up with policy recommendations. In the process, we spoke to a large number of stakeholders, and held a consultative meeting in December 2007 in Brussels to present draft proposals, which established most had wide stakeholder support. The formal outcome of our work was a detailed report, “Security Economics and the Internal Market”, published by ENISA in March 2008. This paper presents a much abridged version: in it, we present the recommendations we made, along with a summary of our reasoning.

Anderson, Ross; Böhme, Rainer; Clayton, Richard; Moor, Tyler

339

Interactions between European Citizenship and Language Learning among Adolescent Europeans  

ERIC Educational Resources Information Center

Recent enlargement of the European Union (EU) has created debate as to the suitability of current structures and policies for effectively engaging citizens and developing social cohesion. Education and specifically modern foreign language (MFL) teaching are argued by the literature to play a key role in equipping young people to interact and…

Hennebry, Mairin

2011-01-01

340

Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis.  

PubMed

Pyridoxine dependent seizure (PDS) is a disorder of neonates or infants with autosomal recessive inheritance characterized by seizures, which responds to pharmacological dose of pyridoxine. Recently, mutations have been identified in the ALDH7A1 gene in Caucasian families with PDS. To elucidate further the genetic background of PDS, we screened for ALDH7A1 mutations in five PDS families (patients 1-5) that included four Orientals. Diagnosis as having PDS was confirmed by pyridoxine-withdrawal test. Exon sequencing analysis of patients 1-4 revealed eight ALDH7A1 mutations in compound heterozygous forms: five missense mutations, one nonsense mutation, one point mutation at the splicing donor site in intron 1, and a 1937-bp genomic deletion. The deletion included the entire exon 17, which was flanked by two Alu elements in introns 16 and 17. None of the mutations was found in 100 control chromosomes. In patient 5, no mutation was found by the exon sequencing analysis. Furthermore, expression level or nucleotide sequences of ALDH7A1 mRNA in lymphoblasts were normal. Plasma pipecolic acid concentration was not elevated in patient 5. These observations suggest that ALDH7A1 mutation is unlikely to be responsible for patient 5. Abnormal metabolism of GABA/glutamate in brain has long been suggested as the underlying pathophysiology of PDS. CSF glutamate concentration was elevated during the off-pyridoxine period in patient 3, but not in patient 2 or 5. These results suggest allelic and non-allelic heterogeneities of PDS, and that the CSF glutamate elevation does not directly correlate with the presence of ALDH7A1 mutations. PMID:17433748

Kanno, Junko; Kure, Shigeo; Narisawa, Ayumi; Kamada, Fumiaki; Takayanagi, Masaru; Yamamoto, Katsuya; Hoshino, Hisao; Goto, Tomohide; Takahashi, Takao; Haginoya, Kazuhiro; Tsuchiya, Shigeru; Baumeister, Fritz A M; Hasegawa, Yuki; Aoki, Yoko; Yamaguchi, Seiji; Matsubara, Yoichi

2007-08-01

341

A "successful allele" at Campylobacter jejuni contingency locus Cj0170 regulates motility; "successful alleles" at locus Cj0045 are strongly associated with mouse colonization  

PubMed Central

Campylobacter jejuniis an important foodborne pathogen of humans and its primary reservoir is the gastrointestinal (GI) tract of chickens. Our previous studies demonstrated that phase variation to specific “successful alleles” at C. jejuni contingency loci Cj0045 (successful alleles carry 9G or 10G homopolymeric tracts) and Cj0170 (successful allele carries a 10G homopolymeric tract) in C. jejuni populations is strongly associated with colonization and enteritis in C57BL/6 IL-10 deficient mice. In the current study, we strengthened the association between locus Cj0170, Cj0045, and mouse colonization. We generated 8 independent strains derived from C. jejuni 11168 strain KanR4 that carried a Cj0170 gene disruption and these were all non motile. Two randomly chosen strains with the Cj0170 gene disruption (DM0170-2 and DM0170-6) were gavaged into mice. DM0170-2 and DM0170-6 failed to colonize mice while the control strain that carried a “successful” Cj0170 10G allele was motile and did colonize mice. In parallel studies, when we inoculated C. jejuni strain 33292 into mice, the “unsuccessful” Cj0045 11G allele experienced phase variation to “successful” 9G and 10G alleles in 2 independent experiments prior to d4 post inoculation in mice while the “successful” 9G allele in the control strain remained stable through d21 post inoculation or shifted to other successful alleles. These data confirm that locus Cj0170 regulates motility in C. jejuni strain KanR4 and is a virulence factor in the mouse model. The data also support a possible role of locus Cj0045 as a virulence factor in strain 33292 in infection of mice.

Artymovich, Katherine; Kim, Joo-Sung; Linz, John E.; Hall, David F.; Kelley, Lauren E.; Kalbach, Harrison L.; Kathariou, Sophia; Gaymer, Jean; Paschke, Brenda

2013-01-01

342

Differential expression of HLA-DQ alleles in peripheral blood mononuclear cells: alleles associated with susceptibility to and protection from autoimmune type 1 diabetes.  

PubMed

Differential expression of human leucocyte antigen (HLA) class II genes has been postulated to influence the risk of developing autoimmune disease. In this study, we investigated the relationship between the level of mRNA expression of DQA1 and DQB1 alleles in peripheral blood mononuclear cells and the influence of the alleles on susceptibility to type 1 diabetes (T1D). Transcripts from pairs of DQA1 and DQB1 alleles were quantified in 59 DQ-heterozygous individuals (29 patients with T1D and 30 healthy control subjects). Luciferase reporter gene assays were used to investigate the relative promoter activities of the alleles associated with high and low risk of disease. DQA1*0301 and the DQB1*06 group of alleles (*0601, *0602, *0603 and *0604) were generally overexpressed in comparison to other alleles. In contrast, mRNA for DQB1*0201/*0202 was generally less abundant than other DQB1 transcripts. These data correlated well with the relative promoter activities observed for the diabetes-associated alleles; the strongest promoters were those derived from DQA1*0301 and DQB1*0602, while a 700-bp fragment derived from the DQB1*0201 promoter showed the lowest activity of the DQB1 constructs. There was no simple correlation between the level of expression of specific DQ alleles and their influence on the risk of diabetes. The functional relevance of our findings and their implications for the pathogenesis of autoimmunity remain to be determined. PMID:19207936

Britten, A C; Mijovic, C H; Barnett, A H; Kelly, M A

2009-02-01

343

Burden of Blood Pressure-Related Alleles is Associated with Larger Hematoma Volume and Worse Outcome in Intracerebral Hemorrhage  

PubMed Central

Background and purpose Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease appears to influence not only risk of ICH, but also the size of the hematoma. As the burden of high blood pressure(BP)-related alleles is associated with both hypertension-related end-organ damage and risk of ICH, we sought to determine if this burden influences ICH baseline hematoma volume (BHV). Methods Prospective study in subjects of European descent with supratentorial ICH who underwent genome-wide genotyping. Forty-two single nucleotide polymorphisms (SNPs) associated with high BP were identified from a publicly available database. A genetic risk score was constructed based on these SNPs. The score was utilized as the independent variable in univariate and multivariate regression models for admission ICH volume and poor clinical outcome (modified Rankin Scale 3–6). Results A total of 323 ICH cases were enrolled in the study (135 deep and 188 lobar intracranial hematomas). The BP-based genetic risk score was associated with both BHV and poor clinical outcome specifically in deep ICH. In multivariate regression analyses, each additional standard deviation of the score increased mean deep ICH volume by 28% (or 2.7-mL increase, beta=0.28, standard error=0.11, p=0.009) and risk of poor clinical outcome by 71% (odds ratio=1.71, 95% confidence interval 1.05–2.80, p=0.03). Conclusion Increasing numbers of high BP-related alleles are associated with mean BHV and poor clinical outcome after an ICH. These findings suggest that the small vessel vasculopathy responsible for the occurrence of the hemorrhage could also influence its volume.

Falcone, Guido J.; Biffi, Alessandro; Devan, William J.; Brouwers, H. Bart; Anderson, Christopher D.; Valant, Valerie; Ayres, Alison M.; Schwab, Kristin; Rost, Natalia S.; Goldstein, Joshua N.; Viswanathan, Anand; Greenberg, Steven M.; Selim, Magdy; Meschia, James F.; Brown, Devin L.; Worrall, Bradford B.; Silliman, Scott L.; Tirschwell, David L.; Rosand, Jonathan

2013-01-01

344

Apolipoprotein E alleles in Alzheimer`s and Parkinson`s patients  

SciTech Connect

A number of investigators have found an association between the apolipoprotein E4 allele and Alzheimer`s disease. The E4 allele appears at a higher frequency in late onset familial Alzheimer`s patients. In our studies we obtained blood samples from early and late onset familial and sporadic Alzheimer`s patients and spouses, as well as from Parkinson`s patients. The patients were diagnosed as probable Alzheimer`s patients after a neurological examination, extensive blood work, and a CAT scan. The diagnosis was made according to the NINCDS-ADRDA criteria. The apolipoprotein E4 polymorphism was detected after PCR amplification of genomic DNA, restriction enzyme digestion with Hhal, and polyacrylamide gel electrophoresis. Ethidium bromide-stained bands at 91 bp were designated as allele 3, at 83 bp as allele 2, and at 72 bp as allele 4. Of the 84 probable Alzheimer`s patients (all of whom were Caucasian), 47 were heterozygous and 13 were homozygous for the E4 allele. There were 26 early onset patients; 13 were heterozygous and 7 homozygous for the E4 allele. The frequencies for the E4 allele for late onset familial patients was 0.45 and for sporadic patients was 0.37. We analyzed 77 spouses with an average age of 71.9 {plus_minus} 7.4 years as controls, and 15 were heterozygous for the E4 allele for an E4 frequency of 0.097. Of the 53 Parkinson`s patients, 11 had the E4 allele for a frequency of 0.113. Thus our findings support the association of the ApoE4 allele with Alzheimer`s disease.

Poduslo, S.E. [Texas Tech Univ., Lubbock, TX (United States); Schwankhaus, J.D. [Department of Veterans Affairs, Lubbock, TX (United States)

1994-09-01

345

Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase  

PubMed Central

Duarte galactosemia is a mild to asymptomatic condition that results from partial impairment of galactose-1-phosphate uridylyltransferase (GALT). Patients with Duarte galactosemia demonstrate reduced GALT activity and carry one profoundly impaired GALT allele (G) along with a second, partially impaired GALT allele (Duarte-2, D2). Molecular studies reveal at least five sequence changes on D2 alleles: a p.N314D missense substitution, three intronic base changes and a 4 bp deletion in the 5? proximal sequence. The four non-coding sequence changes are unique to D2. The p.N314D substitution, however, is not; it is found together with a silent polymorphism, p.L218(TTA), on functionally normal Duarte-1 alleles (D1, also called Los Angeles or LA alleles). The HapMap database reveals that p.N314D is a common human variant, and cross-species comparisons implicate D314 as the ancestral allele. The p.N314D substitution is also functionally neutral in mammalian cell and yeast expression studies. In contrast, the 4 bp 5? deletion characteristic of D2 alleles appears to be functionally impaired in reporter gene transfection studies. Here we present allele-specific qRT–PCR evidence that D2 alleles express less mRNA in vivo than their wild-type counterparts; the difference is small but statistically significant. Furthermore, we characterize the prevalence of the 4 bp deletion in GG, NN and DG populations; the deletion appears exclusive to D2 alleles. Combined, these data strongly implicate the 4 bp 5? deletion as a causal mutation in Duarte galactosemia and suggest that direct tests for this deletion, as proposed here, could enhance or supplant current tests, which define D2 alleles on the basis of the presence and absence of linked coding sequence polymorphisms.

Carney, Amanda E.; Sanders, Rebecca D.; Garza, Kerry R.; McGaha, Lee Anne; Bean, Lora J. H.; Coffee, Bradford W.; Thomas, James W.; Cutler, David J.; Kurtkaya, Natalie L.; Fridovich-Keil, Judith L.

2009-01-01

346

Allelic variation at the VRN-1 promoter region in polyploid wheat.  

PubMed

Vernalization, the requirement of a long exposure to low temperatures to induce flowering, is an essential adaptation of plants to cold winters. We have shown recently that the vernalization gene VRN-1 from diploid wheat Triticum monococcum is the meristem identity gene APETALA1, and that deletions in its promoter were associated with spring growth habit. In this study, we characterized the allelic variation at the VRN-1 promoter region in polyploid wheat. The Vrn-A1a allele has a duplication including the promoter region. Each copy has similar foldback elements inserted at the same location and is flanked by identical host direct duplications (HDD). This allele was found in more than half of the hexaploid varieties but not among the tetraploid lines analyzed here. The Vrn-A1b allele has two mutations in the HDD region and a 20-bp deletion in the 5' UTR compared with the winter allele. The Vrn-A1b allele was found in both tetraploid and hexaploid accessions but at a relatively low frequency. Among the tetraploid wheat accessions, we found two additional alleles with 32 bp and 54 bp deletions that included the HDD region. We found no size polymorphisms in the promoter region among the winter wheat varieties. The dominant Vrn-A1 allele from two spring varieties from Afghanistan and Egypt ( Vrn-A1c allele) and all the dominant Vrn-B1 and Vrn-D1 alleles included in this study showed no differences from their respective recessive alleles in promoter sequences. Based on these results, we concluded that the VRN-1 genes should have additional regulatory sites outside the promoter region studied here. PMID:15480533

Yan, L; Helguera, M; Kato, K; Fukuyama, S; Sherman, J; Dubcovsky, J

2004-11-01

347

NKX2-3 and IRGM variants are associated with disease susceptibility to IBD in Eastern European patients  

PubMed Central

AIM: To investigate variants of immunity-related GTPase family M (IRGM) and NKX2-3 genes and genotype-phenotype in Eastern European patients with inflammatory bowel disease (IBD). METHODS: We analyzed 1707 Hungarian and Czech subjects with Crohn’s disease (CD) (n = 810, age: 37.1 ± 12.6 years, duration: 10.7 ± 8.4 years) and ulcerative colitis (UC) (n = 428, age: 43.7 ± 15.0 years, duration: 12.6 ± 9.9 years), as well as 469 healthy controls. IRGM rs13361189, NKX2-3 rs10883365 and ECM1 rs13294 polymorphisms were tested by LightCycler allele discrimination. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: NKX2-3 rs10883365 variant allele was associated with increased risk for CD (P = 0.009, OR = 1.24, 95% CI = 1.06-1.48) and UC (P = 0.001, OR = 1.36, 95% CI = 1.13-1.63), whereas variant IRGM allele increased risk for CD (P = 0.029, OR = 1.36, 95% CI = 1.03-1.79). In contrast, ECM1 rs13294 was not associated with either CD or UC. In CD, the variant IRGM allele was associated with a colon-only location (P = 0.02, OR = 1.62, 95% CI = 1.07-2.44), whereas in UC, the ECM1 variant was associated with cutaneous manifestations (P = 0.002, OR = 3.36, 95% CI = 1.48-7.63). Variant alleles did not predict resistance to steroids or azathioprine, efficacy of infliximab, or need for surgery. CONCLUSION: NKX2-3 and IRGM are susceptibility loci for IBD in Eastern European patients. Further studies are needed to confirm the reported phenotype-genotype associations.

Meggyesi, Nora; Kiss, Lajos S; Koszarska, Magdalena; Bortlik, Martin; Duricova, Dana; Lakatos, Laszlo; Molnar, Tamas; Lenicek, Martin; Vitek, Libor; Altorjay, Istvan; Papp, Maria; Tulassay, Zsolt; Miheller, Pal; Papp, Janos; Tordai, Attila; Andrikovics, Hajnalka; Lukas, Milan; Lakatos, Peter Laszlo

2010-01-01

348

Identification and DNA sequence analysis of 15 new {alpha}{sub 1}-antitrypsin variants, including two PI*QO alleles and one deficient PI*M allele  

SciTech Connect

The authors have investigated the molecular basis of 15 new {alpha}{sub 1}-antitrypsin ({alpha}1AT) variants. Phenotyping by isoelectric focusing (IEF) was used as a screening method to detect {alpha}1AT variants at the protein level. Genotyping was then performed by sequence analysis of all coding exons, exon-intron junctions, and the hepatocyte-specific promotor region including exon Ic. Three of these rare variants are alleles of clinical relevance, associated with undetectable or very low serum levels of {alpha}1AT: the PI*Q0saarbruecken allele generated by a 1-bp C-nucleotide insertion within a stretch of seven cytosines spanning residues 360-362, resulting in a 3{prime} frameshift and the acquisition of a stop codon at residue 376; a point mutation in the PI*Q0lisbon allele, resulting in a single amino acid substitution Thr{sup 68}(ACC){yields}Ile(ATC); and an in-frame trinucleotide deletion {Delta}Phe{sup 51} (TTC) in the highly deficient PI*Mpalermo allele. The remaining 12 alleles are associated with normal {alpha}1AT serum levels and are characterized by point mutations causing single amino acid substitutions in all but one case. This exception is a silent mutation, which does not affect the amino acid sequence. The limitation of IEF compared with DNA sequence analysis, for identification of new variants, their generation by mutagenesis, and the clinical relevance of the three deficiency alleles are discussed.

Faber, J.P.; Kirchgesser, M.; Schwaab, R.; Bidlingmaier, F. [Universitaet Bonn (Germany); Poller, W. [Universitaet Wuerzburg (Germany); Weidinger, S. [Medizinische Immunologische Laboratorien, Munich (Germany); Olek, K. [Universitaet Bonn (Germany)]|[Institut fuer Molekularbiologische Diagnostik, Bornheim-Hersel (Germany)

1994-12-01

349

ELDONET – European Light Dosimeter Network  

Microsoft Academic Search

The European Light Dosimeter Network (ELDONET) project has been designed with the purpose of establishing an efficient system to monitor solar radiation in Europe, in as many as possible locations. This paper describes the structure of the server that collects and processes the data acquired by the different stations belonging to the network, and makes them freely available on the

Roberto Marangoni; Domenico Gioffré; Giuliano Colombetti; Michael Lebert; Donat-P. Häder

2000-01-01

350

European perspectives in thoracic surgery.  

PubMed

Europe, the old Continent, has been the cradle of thoracic surgery from the beginning of the last century. The structure and the activities of the European Society of Thoracic Surgeons (ESTS) activities are directed to enlighten the path, provide the tools and set the standards for a quality inspired practice in thoracic surgery. PMID:24868436

Venuta, Federico

2014-05-01

351

Changes in the European business.  

National Technical Information Service (NTIS)

The paper gives a view on some of the changes that the European gas business is currently undergoing and the possible effects of these changes. There are two major items that stand out in this respect covering the continued deregulation of the UK gas mark...

S. J. Stoehle

1997-01-01

352

Freight Transportation: The European Market.  

National Technical Information Service (NTIS)

The purpose of the international scan was to investigate the issues, constraints, opportunities, and challenges faced by the European Union (EU) in developing a policy of open boundaries and what strategies it uses to implement the policy. The panel met w...

H. Caldwell R. K. Halvorson C. Casgar G. Cleckley O. de Buen

2002-01-01

353

European urology: quality, impact, online.  

PubMed

European Urology provides contemporary, cutting-edge urologic research, guidance, and discussion. The journal continues to invite collaborative reviews, to invest in rapid but fair peer review, to seek the best research, and to serve the needs of readers and patients. PMID:23928576

Catto, James W F; Montorsi, Francesco; Schulman, Claude

2013-10-01

354

The Americanization of European football  

Microsoft Academic Search

Will European football keep leagues open, or adopt the American system of closed leagues? Would this reform be to the benefit of consumers? This paper develops a framework to analyse the consequences of the structure of competition - whether teams play in both national and international competitions or not - and the effects on performance of revenue sharing among teams

Thomas Hoehn; Stefan Szymanski

1999-01-01

355

Publication output of European physics  

Microsoft Academic Search

More recently, samples have been drawn from Physics Abstrscts to reveal publication output in the Netherlands, Belgium, Denmark, Sweden and Canada \\/6,7\\/, Spain \\/8\\/ and Czechoslovakia \\/3\\/. Seversl ~inds of trends and proportions have been computed for the journals participating in the Euro- physics scheme \\/5\\/ and for citation analyses of world and European physics journals \\/9\\/. Physics Abstracts also

Jan Vlachý

1979-01-01

356

European perspectives in thoracic surgery  

PubMed Central

Europe, the old Continent, has been the cradle of thoracic surgery from the beginning of the last century. The structure and the activities of the European Society of Thoracic Surgeons (ESTS) activities are directed to enlighten the path, provide the tools and set the standards for a quality inspired practice in thoracic surgery.

2014-01-01

357

Reconstructing Indo-European Syllabification  

ERIC Educational Resources Information Center

The chief concern of this dissertation is to investigate a fundamental, yet unsolved problem within the phonology of Proto-Indo-European (PIE): the process of syllabification. I show that by analyzing the much more easily reconstructable word-edge clusters we may predict which types of consonant clusters can occur word-medially, provided that we…

Byrd, Andrew Miles

2010-01-01

358

Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants  

PubMed Central

Objective Our aims were to evaluate the effects of polymorphisms in the hepatic drug uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and efflux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSEP, ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacokinetics in healthy European- and African-American participants. Methods The pharmacokinetics of a single oral 40mg dose of pravastatin was determined in 107 participants (69 European-Americans and 38 African-Americans). Participants were genotyped for known OATP1B1, MRP2, BSEP, and BCRP polymorphisms. Baseline serum total and unconjugated plasma bilirubin concentrations were also determined. Results OATP1B1 genotypes were ethnicity-dependent with a 521C allele frequency of ~15% in European-Americans and ~1% in African-Americans. SLCO1B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC(0–5)] (P =0.01) and Cmax values (P< 0.05). When analyzed by diplotype, SLCO1B1*1a/*15 (N =8) participants exhibited 45 and 80% higher AUC values than SLCO1B1*1a/*1a (N=29) (P=0.013) and SLCO1B1*1b/*1b (N=34) (P=0.001) carriers, respectively. SLCO1B1*15/*15 (N=2) participants exhibited 92 and 149% higher AUC values than SLCO1B1*1a/*1a (P=0.017) and SLCO1B1*1b/*1b (P= 0.011) carriers, respectively. European-Americans had significantly higher plasma pravastatin AUC(0–5) (P =0.01) and Cmax values (P=0.009) than African-Americans. Neither ABCC2, ABCB11, nor ABCG2 genotypes were associated with differences in pravastatin pharmacokinetics. We did not observe an effect of SLCO1B1 genotype on baseline total or unconjugated bilirubin levels. Conclusion SLCO1B1 genotype, in particular the 521C allele, had a significant effect on the pharmacokinetics of pravastatin. Even when adjusted for the presence of the SLCO1B1 521C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and Cmax values than African-Americans.

Ho, Richard H.; Choi, Leena; Lee, Wooin; Mayo, Gail; Schwarz, Ute I.; Tirona, Rommel G.; Bailey, David G.; Stein, C. Michael; Kim, Richard B.

2014-01-01

359

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

PubMed Central

DNA haplotype data from the phenylalanine hydroxylase (PAH) locus are available from a number of European populations as a result of RFLP testing for genetic counseling in families with phenylketonuria (PKU). We have analyzed data from Hungary and Czechoslovakia together with published data from five additional countries–Denmark, Switzerland, Scotland, Germany, and France–representing a broad geographic and ethnographic range. The data include 686 complete chromosomal haplotypes for eight RFLP sites assayed in 202 unrelated Caucasian families with PKU. Forty-six distinct RFLP haplotypes have been observed to date, 10 unique to PKU-bearing chromosomes, 12 unique to non-PKU chromosomes, and the remainder found in association with both types. Despite the large number of haplotypes observed (still much less than the theoretical maximum of 384), five haplotypes alone account for more than 76% of normal European chromosomes and four haplotypes alone account for more than 80% of PKU-bearing chromosomes. We evaluated the distribution of haplotypes and alleles within these populations and calculated pairwise disequilibrium values between RFLP sites and between these sites and a hypothetical PKU “locus.” There are statistically significant differences between European populations in the frequencies of non-PKU chromosomal haplotypes (P = .025) and PKU chromosomal haplotypes (P < < .001). Haplotype frequencies of the PKU and non-PKU chromosomes also differ significantly (P < < .001. Disequilibrium values are consistent with the PAH physical map and support the molecular evidence for multiple, independent PKU mutations in Caucasians. However, the data do not support a single geographic origin for these mutations. Within these European populations a parent carrying a PKU mutation has an average probability of greater than 86% of being heterozygous–and hence informative for linkage–at one or more PAH RFLP sites. Thus these RFLP alleles and haplotypes provide an effective tool for linkage diagnosis of disease and carrier status in PKU families.

Daiger, Stephen P.; Chakraborty, Ranajit; Reed, Lori; Fekete, Gyorgy; Schuler, Dezso; Berenssi, Gyorgy; Nasz, Istvan; Brdicka, Radim; Kamaryt, Jaromir; Pijackova, Anna; Moore, Sharon; Sullivan, Susan; Woo, Savio L. C.

1989-01-01

360

Two point mutations identified in emmer wheat generate null Wx - A1 alleles  

Microsoft Academic Search

In this report, the Wx- A1 mutations carried by a Triticum dicoccoides line from Israel and a Triticum dicoccum line from Yugoslavia are characterized. A single nucleotide insertion in the T. dicoccoides null allele and a single nucleotide deletion in the T. dicoccum null allele each cause frameshift mutations that induce premature termination codons more than 55 nucleotides upstream of

M. Saito; T. Nakamura

2005-01-01

361

Sequence analysis of the novel HLA-B35 (B*3576) allele in an African individual.  

PubMed

A novel human leucocyte antigen (HLA)-B35 (HLA-B*3576) allele has been described in an African individual by polymerase chain reaction sequence-based typing. This new allele contains six nucleotide substitutions and is homologous to B*3501 with the exception of residues 66-74 resulting in five amino acid mutations. PMID:17919267

Aubert, V; Mayerat, C; Lopez, N; Pantaleo, G

2007-11-01

362

Chemokine Receptor 5 ?32 Allele in Patients with Severe Pandemic (H1N1) 2009  

PubMed Central

Because chemokine receptor 5 (CCR5) may have a role in pulmonary immune response, we explored whether patients with severe pandemic (H1N1) 2009 were more likely to carry the CCR5?32 allele than were members of the general population. We found a large proportion of heterozygosity for the CCR5?32 allele among white patients with severe disease.

Juno, Jennifer; Meyers, Adrienne; Ball, T. Blake; Kumar, Anand; Rubinstein, Ethan; Fowke, Keith R.

2010-01-01

363

Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function  

Microsoft Academic Search

Coat colors in the chestnut horse, the yellow Labrador retriever, the red fox, and one type of yellow mouse are due to recessive alleles at the extension locus. Similarly, dominant alleles at this locus are often responsible for dark coat colors in mammals, such as the melanic form of the leopard, Panthera pardus. We show here that the murine extension

L S Robbins; J H Nadeau; K R Johnson; M A Kelly; Rehfuss L Roselli; E Baack; K G Mountjoy; R D Cone

1993-01-01

364

Sexual selection on alleles that determine body size in the swordtail Xiphophorus nigrensis  

Microsoft Academic Search

In a natural population, we document changes in the frequencies of alleles influencing body size and size-correlated alternative male reproductive tactics, and we examine the possible role of sexual selection in producing these changes. Male swordtails (Xiphophorus nigrensis, Rio Choy) exhibit three body size classes (small, intermediate, and large) that primarily derive from allelic variation (s, I, L) at the

Michael J. Ryan; Diana K. Hews; William E. Wagner Jr

1990-01-01

365

Temporal variation of allele frequencies in a natural population of wild Vigna unguiculata  

Microsoft Academic Search

Temporal variation in allele frequencies in a natural population of wild Vigna unguiculata was studied by making monthly collections of seeds over a two-year period. Using starch gel electrophoresis, four out of seven loci analysed were shown to be polymorphic (Enp, Fdh, Fle3 and Pgd2). These four loci showed significant variation in allele frequencies over time. Changes in population structure

E. B. Kouam; R. S. Pasquet; G. M. Muluvi

2012-01-01

366

Molecular and physiological characterization of Arabidopsis GAI alleles obtained in targeted Ds -tagging experiments  

Microsoft Academic Search

Bioactive gibberellin (GA) is an essential regulator of vascular plant development. The GAI gene of Arabidopsis thaliana (L.) Heynh. encodes a product (GAI) that is involved in GA signalling. The dominant mutant gai allele encodes an altered product (gai) that confers reduced GA responses, dwarfism, and elevated endogenous GA levels. Recessive, presumed loss-of-function alleles of GAI confer normal height and

Jinrong Peng; Donald E. Richards; Thomas Moritz; Hiroshi Ezura; Pierre Carol; Nicholas P. Harberd

2002-01-01

367

Models of frequency-dependent selection with mutation from parental alleles.  

PubMed

Frequency-dependent selection (FDS) remains a common heuristic explanation for the maintenance of genetic variation in natural populations. The pairwise-interaction model (PIM) is a well-studied general model of frequency-dependent selection, which assumes that a genotype's fitness is a function of within-population intergenotypic interactions. Previous theoretical work indicated that this type of model is able to sustain large numbers of alleles at a single locus when it incorporates recurrent mutation. These studies, however, have ignored the impact of the distribution of fitness effects of new mutations on the dynamics and end results of polymorphism construction. We suggest that a natural way to model mutation would be to assume mutant fitness is related to the fitness of the parental allele, i.e., the existing allele from which the mutant arose. Here we examine the numbers and distributions of fitnesses and alleles produced by construction under the PIM with mutation from parental alleles and the impacts on such measures due to different methods of generating mutant fitnesses. We find that, in comparison with previous results, generating mutants from existing alleles lowers the average number of alleles likely to be observed in a system subject to FDS, but produces polymorphisms that are highly stable and have realistic allele-frequency distributions. PMID:23852384

Trotter, Meredith V; Spencer, Hamish G

2013-09-01

368

Allelic Frequencies of FBN1 Gene Polymorphisms and Genetic Analysis of Italian Families with Marfan Syndrome  

Microsoft Academic Search

The fibrillin gene (FBN1) is the disease locus for Marfan syndrome. This disorder shows a high degree of clinical and allelic heterogeneity. Direct mutation screening has proven difficult and inefficient and at present cannot be utilized for routine analysis. In familial cases linkage analysis represents a useful tool for molecular diagnosis. We have determined the allelic frequencies of 5 polymorphic

Monica Mottes; Stefania Mirandola; Federica Rigatelli; Francesca Zolezzi; Veronica Lisi; Derek Gordon; Pier Franco Pignatti

2000-01-01

369

Modified allelic replication in lymphocytes of patients with neurofibromatosis type 1  

Microsoft Academic Search

Transcription activity of genes is related to their replication timing, accordingly gene activation is coupled with a shift from late replication to early replication and vice versa. The relationship between replication timing and gene expression is best manifested by monoallelically expressed genes which show an asynchronous pattern of allelic replication, with the active allele replicating earlier than the inactive counterpart.

Orit Reish; Ana Orlovski; Maya Mashevitz; Carron Sher; Vitalia Libman; Malka Rosenblat; Lydia Avivi

2003-01-01

370

Surrogate genetics and metabolic profiling for characterization of human disease alleles.  

PubMed

Cystathionine-?-synthase (CBS) deficiency is a human genetic disease causing homocystinuria, thrombosis, mental retardation, and a suite of other devastating manifestations. Early detection coupled with dietary modification greatly reduces pathology, but the response to treatment differs with the allele of CBS. A better understanding of the relationship between allelic variants and protein function will improve both diagnosis and treatment. To this end, we tested the function of 84 CBS alleles previously sequenced from patients with homocystinuria by ortholog replacement in Saccharomyces cerevisiae. Within this clinically associated set, 15% of variant alleles were indistinguishable from the predominant CBS allele in function, suggesting enzymatic activity was retained. An additional 37% of the alleles were partially functional or could be rescued by cofactor supplementation in the growth medium. This large class included alleles rescued by elevated levels of the cofactor vitamin B6, but also alleles rescued by elevated heme, a second CBS cofactor. Measurement of the metabolite levels in CBS-substituted yeast grown with different B6 levels using LC-MS revealed changes in metabolism that propagated beyond the substrate and product of CBS. Production of the critical antioxidant glutathione through the CBS pathway was greatly decreased when CBS function was restricted through genetic, cofactor, or substrate restriction, a metabolic consequence with implications for treatment. PMID:22267502

Mayfield, Jacob A; Davies, Meara W; Dimster-Denk, Dago; Pleskac, Nick; McCarthy, Sean; Boydston, Elizabeth A; Fink, Logan; Lin, Xin Xin; Narain, Ankur S; Meighan, Michael; Rine, Jasper

2012-04-01

371

Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project  

Microsoft Academic Search

BACKGROUND: There is a lack of knowledge regarding the frequency of disease associated polymorphisms in populations and population attributable risk for many populations remains unknown. Factors that could affect the association of the allele with disease, either positively or negatively, such as race, ethnicity, and gender, may not be possible to determine without population based allele frequencies. Here we used

Deanna S Cross; Lynn C Ivacic; Elisha L Stefanski; Catherine A McCarty

2010-01-01

372

Fluorescent-labeled microsatellite panels useful for detecting allelic diversity in cultivated rice ( Oryza sativa L.)  

Microsoft Academic Search

Four multiplex panels of fluorescent-labeled rice microsatellite markers were designed to survey allelic diversity at a total of 27 simple sequence repeat loci. Automated fragment detection, size calling and binning were used to identify the microsatellite alleles. The panels were tested on 72 accessions representing the diversity of ecotypes and isozyme groups in cultivated rice (Oryza sativa L.). Genetic diversity

Matthew W. Blair; Veena Hedetale; Susan R. McCouch

2002-01-01

373

Problems meeting basic needs moderate the association between the APOE ?4 allele and cognitive decline  

Microsoft Academic Search

Objectives: The ApolipoproteinE ?4 (APOE ?4) allele influences cognitive decline (CD) in some but not in all individuals. The purpose of this study was to investigate whether problems meeting basic needs (BN) (e.g., having enough money to meet needs, having enough money for emergencies, having adequate housing, and having enough heat) influences the relationship between the APOE ?4 allele and

Natalie Sachs-Ericsson; Elizabeth Corsentino; Nicole Collins; Kathryn Sawyer; Dan G. Blazer

2010-01-01

374

Assessment of Plasma DNA Levels, Allelic Imbalance, and CA 125 as Diagnostic Tests for Cancer  

Microsoft Academic Search

Background: Allelic imbalance (AI), the loss or gain of chro- mosomal regions, is found in many cancers. AI can be de- tected in genomic tumor DNA released into the blood after necrosis or apoptosis. We evaluated plasma DNA concentra- tion, allelic status in plasma DNA, and serum CA 125 level as screening tests for ovarian and other cancers. Methods: Plasma

Hsueh-Wei Chang; Shing M. Lee; Steven N. Goodman; Gad Singer; Sarah K. R. Cho; Lori J. Sokoll; Fredrick J. Montz; Richard Roden; Zhen Zhang; Daniel W. Chan; Robert J. Kurman; Ie-Ming Shih

2002-01-01

375

Estimating minimum allele frequencies for DNA profile frequency estimates for PCR-based loci  

Microsoft Academic Search

In order that there can be confidence that DNA profile frequency estimates will not place undue bias against a defendant, 2 methods are described for estimating minimum allele frequency bounds for PCR-based loci. One approach estimates minimum allele frequencies for VNTR and STR loci using sample size and the observed heterozygosity at a locus, while the second approach, appropriate for

B. Budowle; K. L. Monson; R. Chakraborty

1996-01-01

376

Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues.  

PubMed

Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants. PMID:24786518

Kukurba, Kimberly R; Zhang, Rui; Li, Xin; Smith, Kevin S; Knowles, David A; How Tan, Meng; Piskol, Robert; Lek, Monkol; Snyder, Michael; Macarthur, Daniel G; Li, Jin Billy; Montgomery, Stephen B

2014-05-01

377

HLA-A*01 allele: a risk factor for dengue haemorrhagic fever in Brazil's population.  

PubMed

Severe forms of dengue, such as dengue haemorrhagic fever (DHF) and dengue shock syndrome, are examples of a complex pathogenic mechanism in which the virus, environment and host immune response interact. The influence of the host's genetic predisposition to susceptibility or resistance to infectious diseases has been evidenced in several studies. The association of the human leukocyte antigen gene (HLA) class I alleles with DHF susceptibility or resistance has been reported in ethnically and geographically distinct populations. Due to these ethnic and viral strain differences, associations occur in each population, independently with a specific allele, which most likely explains the associations of several alleles with DHF. As the potential role of HLA alleles in the progression of DHF in Brazilian patients remains unknown, we then identified HLA-A alleles in 67 patients with dengue fever and 42 with DHF from Rio de Janeiro, Brazil, selected from 2002-2008 by the sequence-based typing technique. Statistical analysis revealed an association between the HLA-A*01 allele and DHF [odds ratio (OR) = 2.7, p = 0.01], while analysis of the HLA-A*31 allele (OR = 0.5, p = 0.11) suggested a potential protective role in DHF that should be further investigated. This study provides evidence that HLA class I alleles might be important risk factors for DHF in Brazilian patients. PMID:22415262

Monteiro, Sérgio Pereira; Brasil, Pedro Emmanuel Alvarenga Americano do; Cabello, Giselda Maria Kalil; Souza, Rogério Valls de; Brasil, Patrícia; Georg, Ingebourg; Cabello, Pedro Hernan; De Castro, Liane

2012-03-01

378

Profiling of HLA-B Alleles for Association Studies with Ankylosing Spondylitis in the Chinese Population  

PubMed Central

Human leucocyte antigen (HLA) B*27 is a susceptibility allele to ankylosing spondylitis (AS). However, major AS-associated subtypes of HLA-B*27 and other HLA-B alleles vary in different ethnic populations. Herein, we examined HLA-B alleles in a total of 360 AS patients and 350 controls of Chinese Han ancestry. The HLA-B genotyping was performed with sequence-based typing (SBT) method. Six HLA-B*27 subtypes B*27:04, B*27:05, B*27:07, B*27:08, B*27:10 and B*27:15 were observed in the cohorts. HLA-B*27:04:01 and -B*27:05:02 appeared significantly increased in AS patients, which indicated as two major susceptibility alleles to AS. Homozygous B*27 was observed only in AS patients. There are 30 HLA-B alleles identified in the studies. HLA-B*15, especially B*15:01:01:01, appeared as the major allele type in the Chinese controls. Some common HLA-B alleles such as HLA-B*15, B*13, B*46 and B*51 were significantly reduced in Chinese AS patients. In conclusion, the studies profiled the HLA-B alleles, and identified major susceptibility subtypes of B27 to AS in Han Chinese population

Yi, Lin; Wang, Jiucun; Guo, Xinjian; Espitia, Maribel G.; Chen, Enuo; Assassi, Shervin; Jin, Li; Zou, Hejian; Reveille, John D.; Zhou, Xiaodong

2013-01-01

379

Allelic effects of mouse Pas1 candidate genes in human lung cancer cell lines.  

PubMed

Four of the six genes constituting the mouse Pulmonary adenoma susceptibility 1 (Pas1) locus haplotype carry amino acid variants: Lrmp, Casc1, Ghiso, and Lmna-rs1. In vitro colony formation assay of human lung cancer cell lines A549 and NCI-H520 transfected with the allelic variants of the four genes revealed allele-specific modulations of colony numbers by Lmna-rs1 and Casc1, but not by Lrmp or Ghiso. In A549 and NCI-H520 cells, the A/J allele of Lmna-rs1 produced approximately 4- and approximately 2-fold, respectively, more transfectants than did the C57BL/6J allele, whereas the A/J allele of Casc1 produced approximately 6- and approximately 5-fold fewer transfectants, respectively, as compared to the C57BL/6J allele. Inhibition of clonogenicity by allelic forms of Pas1 candidate genes was not mediated by induction of apoptosis. These findings provide evidence that allelic variants of mouse Pas1 candidate genes differentially modulate growth of human cancer cells. PMID:16458428

Galbiati, Federica; Pettinicchio, Angela; Dragani, Tommaso A; Manenti, Giacomo

2006-12-01

380

Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas  

Microsoft Academic Search

Introduction: Allelic loss of the short arm of chromosome 1 predicts radiographic response to chemotherapy and long overall survival times in patients with anaplastic oligodendrogliomas. Using a database of patients with oligodendrogliomas in whom chromosome 1p status was known, we explored whether allelic loss of 1p also predicted longer duration of tumor control when radiotherapy was part of the initial

G. S Bauman; Y Ino; K Ueki; M. C Zlatescu; B. J Fisher; D. R Macdonald; L Stitt; D. N Louis; J. G Cairncross

2000-01-01

381

Genetic Variability and Distribution of Mating Type Alleles in Field Populations of Leptosphaeria maculans from France  

Microsoft Academic Search

scales (leaf, 2-m2 field plot, and field) enabling the evaluation of spatial distribution of the mating type alleles and of genetic variability within and among field populations. Within each field population, no gametic disequilibrium between the minisatellite loci was detected and the mating type alleles were present at equal frequencies. Both sexual and asexual reproduction occur in the field, but

Lilian Gout; Maria Eckert; Thierry Rouxel; Marie-Helene Balesdent

2006-01-01

382

High frequency of HLA-A*0103 allele in a Somali population.  

PubMed

We report the existence of class I HLA allele A*0103 in an ethnic group (Somali) where this allele has not been reported. This allele was discovered in a study to examine the relationship between HLA alleles and humoral antibody response to measles vaccine among recent immigrants from Somalia to Olmsted County, Minnesota. We initially used polymerase chain reaction-sequence-specific primers (PCR-SSP) to carry out HLA class I typing. Based on PCR-SSP, 55 subjects were assigned the allele HLA-A*0101. Following direct DNA sequencing of the PCR products, 37 of the 55 subjects (67.3%) that were initially assigned the A*0101 allele were found to actually be A*0103. Our data are significant because it demonstrates that many of the previously typed A*0101 individuals are actually A*0103 as the SSP or sequence-specific oligonucleotide probes method cannot distinguish between the two alleles. Lastly, this is the first identification of this allele in the homozygous state. PMID:11182232

Poland, G A; Sohni, Y; Domanico, M; Kroning, C M; DeGoey, S R; Jimale, M; Jacobson, R M; Moore, S B

2001-02-01

383

Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues  

PubMed Central

Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants.

Kukurba, Kimberly R.; Zhang, Rui; Li, Xin; Smith, Kevin S.; Knowles, David A.; How Tan, Meng; Piskol, Robert; Lek, Monkol; Snyder, Michael; MacArthur, Daniel G.; Li, Jin Billy; Montgomery, Stephen B.

2014-01-01

384

Africanization in the United States: replacement of feral European honeybees (Apis mellifera L.) by an African hybrid swarm.  

PubMed

The expansion of Africanized honeybees from South America to the southwestern United States in <50 years is considered one of the most spectacular biological invasions yet documented. In the American tropics, it has been shown that during their expansion Africanized honeybees have low levels of introgressed alleles from resident European populations. In the United States, it has been speculated, but not shown, that Africanized honeybees would hybridize extensively with European honeybees. Here we report a continuous 11-year study investigating temporal changes in the genetic structure of a feral population from the southern United States undergoing Africanization. Our microsatellite data showed that (1) the process of Africanization involved both maternal and paternal bidirectional gene flow between European and Africanized honeybees and (2) the panmitic European population was replaced by panmitic mixtures of A. m. scutellata and European genes within 5 years after Africanization. The post-Africanization gene pool (1998-2001) was composed of a diverse array of recombinant classes with a substantial European genetic contribution (mean 25-37%). Therefore, the resulting feral honeybee population of south Texas was best viewed as a hybrid swarm. PMID:15937139

Pinto, M Alice; Rubink, William L; Patton, John C; Coulson, Robert N; Johnston, J Spencer

2005-08-01

385

Student Mobility within the European Union.  

ERIC Educational Resources Information Center

Discusses European laws enabling people to receive training in other Member States of the European Union, conditions for student mobility, programs encouraging it, and recognition of diplomas across states. (SK)

de la Porte, Heleen Andre

1997-01-01

386

On the exact distribution of the numbers of alleles in DNA mixtures.  

PubMed

When more than one individual contributes biological material to a forensic stain, the resulting DNA type is termed a DNA mixture. DNA mixtures occur frequently in forensic genetic casework, and in recent years, much research has been devoted to this subject. This paper presents a derivation of the exact distribution of the number of alleles for any number of profiles and investigated loci. The per locus number of observed alleles is of interest as it indicates the plausible range on the number of contributors. Hence, by specifying a prior distribution on the number of contributors, the locus distribution may be used to assess the number of contributors. Furthermore, the total number of alleles across all loci is used by some forensic geneticists to estimate the probability that an allele has failed to be detected (allelic drop-out). PMID:24337321

Tvedebrink, Torben

2014-05-01

387

Global distribution of allele frequencies at the human dopamine D4 receptor locus  

SciTech Connect

The dopamine D4 receptor (DRD4) is a candidate gene for schizophrenia because the dopaminergic system has been implicated in this neuropsychiatric disorder. Several research groups have reported an association between allelic variants at DRD4 and schizophrenia, while others have been unable to replicate that finding. Knowledge of the appropriate gene frequencies in the underlying populations may resolve these inconsistencies. We have determined the frequencies of 8 different alleles of the 48 bp imperfect tandem repeat of exon 3 at the DRD4 locus in samples from 33 populations around the world. The frequencies vary considerably in the different populations with the most common allele ranging from 16% to 95%. Frequencies and Fst values will be presented for the 3 most common alleles (4-, 7-, and 2- repeat) by continental groupings, but the individual populations vary significantly around the averages. The populations averaged 4.3 alleles (range 2 to 7).

Chang, F.M.; Kidd, J.R. [Yale Univ. School of Medicine, New Haven, CT (United States); Livak, K.J. [DuPont-Merch Pharmaceutical Company, Wilmington, DE (United States)] [and others

1994-09-01

388

Allelic imbalance in selected chromosomal regions in ovarian cancer.  

PubMed

Ovarian cancer (OC) is often asymptomatic at the initial stage. When diagnosed, up to 75% of the patients present grade III or IV tumors with metastasis in nearby organs of the abdomen. Genetic imbalance is abundant in OC, and allelic loss (AL) of specific chromosomal regions is considered an early event. To establish association between genetic markers for early diagnosis/prognosis of OC, our target was to define narrow specific regions of AL. We analyzed 65 ovarian carcinomas by using 19 microsatellite markers located in three different chromosomes. First, a 7.6-Mb region containing the estrogen receptor (ESR1) and the tumor suppressor gene LATS1 was analyzed. Several chromosomal breakpoints flanking ESR1 affecting the region harboring LATS1 were found. Second, we found chromosomal breakpoints on 13q13.1 approximately q13.3 that defined two narrow regions flanking the BRCA2 locus. Third, our ovarian tumors exhibited a very high frequency of AL on 16q and chromosomal breakpoints defining two narrow regions within 16q22.2 approximately q24.3. In this article, we report three new polymorphic microsatellite markers and strong evidence of AL of narrow well-defined regions in hot spots on 6q, 13q, and 16q in ovarian tumors. PMID:12547149

Hansen, Lise Lotte; Jensen, Lise Lind; Dimitrakakis, Constantine; Michalas, Stylianos; Gilbert, Fred; Barber, Hugh R K; Overgaard, Jens; Arzimanoglou, Iordanis I

2002-11-01

389

FINDbase: a worldwide database for genetic variation allele frequencies updated  

PubMed Central

Frequency of INherited Disorders database (FIND base; http://www.findbase.org) records frequencies of causative genetic variations worldwide. Database records include the population and ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related external resources and the genetic variation together with its frequency in that population. In addition to the regular data content updates, we report the following significant advances: (i) the systematic collection and thorough documentation of population/ethnic group-specific pharmacogenomic markers allele frequencies for 144 markers in 14 genes of pharmacogenomic interest from different classes of drug-metabolizing enzymes and transporters, representing 150 populations and ethnic groups worldwide; (ii) the development of new data querying and visualization tools in the expanded FINDbase data collection, built around Microsoft’s PivotViewer software (http://www.getpivot.com), based on Microsoft Silverlight technology (http://www.silverlight.net) that facilitates querying of large data sets and visualizing the results; and (iii) the establishment of the first database journal, by affiliating FINDbase with Human Genomics and Proteomics, a new open-access scientific journal, which would serve as a prime example of a non-profit model for sustainable database funding.

Georgitsi, Marianthi; Viennas, Emmanouil; Antoniou, Dimitris I.; Gkantouna, Vassiliki; van Baal, Sjozef; Petricoin, Emanuel F.; Poulas, Konstantinos; Tzimas, Giannis; Patrinos, George P.

2011-01-01

390

Allelic Prevalence of ABO Blood Group Genes in Iranian Azari Population  

PubMed Central

Introduction ABO blood group system is the most important blood group in transfusion and has been widely used in population studies. Several molecular techniques for ABO allele’s detection are widely used for distinguishing various alleles of glycosyl transferase locus on chromosome 9. Methods 744 randomly selected samples from Azari donors of East Azerbaijan province (Iran) were examined using well-adjusted multiplex allele- specific PCR ABO genotyping technique. Results The results were consistent for all individuals. The ABO blood group genotype of 744 healthy Azari blood donors was: 25.8% AA/AO (2), 7.6% AO (1), 1.6% BB, 11.3% B0 (1), 10% AB, 9.3% 0(1)0(1) and 15.3%0(1)0(2). The highest genotype frequency belonged to O01/O02 genotype (15.3%) and the lowest frequency belonged to A101/A102 genotype (0.4%). Conclusions: The frequencies of ABO alleles didn’t show significant differences between East Azerbaijan province population and that of other areas of the country. Meanwhile, statistical analysis of frequencies of A and B alleles between East Azerbaijan province population and neighbor countries showed significant differences whereas the frequency of allele O between them did not show significant difference (P>0.05). Conclusions The frequencies of ABO alleles didn’t show significant differences between East Azerbaijan province population and that of other areas of the country. Meanwhile, statistical analysis of frequencies of A and B alleles between East Azerbaijan province population and neighbor countries showed significant differences whereas the frequency of allele O between them did not show significant difference (P>0.05).

Nojavan, Mohammad; Shamsasenjan, Karrim; Movassaghpour, Ali Akbar; Akbarzadehlaleh, Parvin; Torabi, Seyd Esmail; Ghojazadeh, Morteza

2012-01-01

391

The frequency and distribution of thiopurine S-methyltransferase alleles in south Iranian population.  

PubMed

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathiopurine. Variability in TPMT activity is mainly due to genetic polymorphism. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G) were determined in an Iranian population from south of Iran (n = 500), using polymerase chain reaction (PCR)-RFLP and allele-specific PCR-based assays. Four hundred seventy four persons (94.8%) were homozygous for the wild type allele (TPMT*1/*1) and twenty five people were TPMT*1/*3C (5%). One patient was found to be heterozygous in terms TPMT*1 and *2 alleles with genotype of TPMT*1/*2 (0.2%). None of the participants had both defective alleles. The TPMT*3C and *2 were the only variant alleles observed in this population. The total frequency of variant alleles was 2.6% and the wild type allele frequency was 97.4%. The TPMT*3B and *3A alleles were not detected. Distributions of TPMT genotype and allele frequency in Iranian populations are different from the genetic profile found among Caucasian or Asian populations. Our findings also revealed inter-ethnic differences in TPMT frequencies between different parts of Iran. This view may help clinicians to choose an appropriate strategy for thiopurine drugs and reduce adverse drug reactions such as bone marrow suppression. PMID:21938428

Moini, Maryam; Ghaderi, Fatemeh; Sagheb, Mohamad Mehdi; Tavasolli, Ali Reza; Azarpira, Negar; Darai, Masumeh; Geramizadeh, Bita

2012-04-01

392

Dombrock genotyping in Brazilian blood donors reveals different regional frequencies of the HY allele  

PubMed Central

Background Dombrock blood group system genotyping has revealed various rearrangements of the Dombrock gene and identified new variant alleles in Brazil (i.e., DO*A-SH, DO*A-WL and DO*B-WL). Because of the high heterogeneity of the Brazilian population, interregional differences are expected during the investigation of Dombrock genotypes. Objective The present study aims to determine the frequencies of Dombrock genotypes in blood donors from Minas Gerais and compare the frequencies of the HY and JO alleles to those of another population in Brazil. Methods The frequencies of the DO alleles in Minas Gerais, a southeastern state of Brazil, were determined from the genotyping of 270 blood donors. Genotyping involved polymerase chain reaction and restriction fragment length polymorphism analysis to identify the 323G>T, 350C>T, 793A>G, and 898C>G mutations, which are related to the HY, JO, DO*A/DO*B, and DO*A-WL/DO*B-WL alleles, respectively. Moreover, the frequencies of rare HY and JO alleles were statistically compared using the chi-square test with data from another Brazilian region. Results The HY allele frequency in Minas Gerais (2.4%) was almost twice that of the JO allele (1.5%). The frequency of the HY allele was significantly higher (p-value = 0.001) than that in another Brazilian population and includes a rare homozygous donor with the Hy- phenotype. In addition, the DO*A-WL and DO*B-WL alleles, which were first identified in Brazil, were found in the state of Minas Gerais. Conclusions The data confirm that the frequencies of DO alleles differ between regions in Brazil. The population of Minas Gerais could be targeted in a screening strategy to identify the Hy- phenotype in order to develop a rare blood bank.

Piassi, Fabiana Chagas Camargos; Santos, Silvana Maria Eloi; de Castilho, Lilian Maria; Baleotti Junior, Wilson; Suzuki, Rodrigo Buzinaro; da Cunha, Debora Moura

2013-01-01

393

Identification of New Alleles and the Determination of Alleles and Genotypes Frequencies at the CYP2D6 Gene in Emiratis  

PubMed Central

CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20–25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls.

Qumsieh, Rula Y.; Ali, Bassam R.; Abdulrazzaq, Yousef M.; Osman, Ossama; Akawi, Nadia A.; Bastaki, Salim M. A.

2011-01-01

394

The European market for lighting fixtures  

Microsoft Academic Search

CSIL report The European market for lighting fixtures offers a comprehensive picture of the lighting fixtures market in 16 Western European countries, providing trends in lighting fixtures production and consumption, imports and exports, prices, sales and market shares, marketing policies and distribution for both indoor and outdoor lighting. Total European lighting fixtures production, consumption and international trade are broken down

Aurelio Volpe

2011-01-01

395

European Initiatives in Postgraduate Education in Gerontology  

ERIC Educational Resources Information Center

This paper describes three innovative European initiatives in postgraduate education in gerontology. The first is the European Masters Program in Gerontology (EuMaG), developed as an interdisciplinary joint program, supported and delivered by 22 European universities. Second, the Nordplus initiative to increase mobility of students and staff in…

van Rijsselt, Rene J. T.; Parkatti, Terttu; Troisi, Joseph

2007-01-01

396

A Geographer's Contribution to European Studies  

ERIC Educational Resources Information Center

Describes traditional ways of teaching geography in European studies, suggests changes emphasizing human geography and environment, and specifies learning outcomes for students. An appendix lists 1i books providing geographical resource material on European studies. Available from: Centre for Contemporary European Studies, University of Sussex,…

Price, Brian

1977-01-01

397

Competitiveness in the European dairy industries  

Microsoft Academic Search

International competitiveness has gained high importance for national food sectors in European countries, particularly initiated by the completion of the European Common Market, the rapid expansion of international business activities of private companies, and the accelerated concentration of food industries. Due to increasing interest in the competitive situation of these industries, the paper investigates the international competitiveness of European dairy

Klaus Drescher; Oswin Maurer

1999-01-01

398

The European traffic observatory measurement infrastructure (ETOMIC)  

Microsoft Academic Search

The European traffic observatory is a European Union VI framework program sponsored effort, within the integrated project EVERGROW, that aims at providing an panEuropean traffic measurement infrastructure with high-precision, GPS-synchronized monitoring nodes. This paper describes the system and node architectures, together with the management system.

E. Magafia; D. Morato; M. Izal; J. Aracil; F. Naranjo; F. Astiz; U. Alonso; I. Csabai; P. Haga; G. Simon; J. Steger; G. Vattay

2004-01-01

399

Constitutional political economy in the European Union  

Microsoft Academic Search

This article surveys recent research in constitutional political economy in Europe. Although not all of the works discussed necessarily focus only on European constitutional issues or are written by Europeans, European constitutional issues figure importantly in each area surveyed. The article examines the literatures linking constitutional institutions to economic growth, government size, government deficits and corruption, bicameralism, direct democracy and

Dennis C. Mueller

2005-01-01

400

European Imperatives and the Welfare State  

Microsoft Academic Search

The study of social policy within the context of the European Uni