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Sample records for european ccr5-delta32 allele

  1. Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?

    PubMed

    Faure, Eric; Royer-Carenzi, Manuela

    2008-12-01

    We studied the possible effects of the expansion of ancient Mediterranean civilizations during the five centuries before and after Christ on the European distribution of the mutant allele for the chemokine receptor gene CCR5 which has a 32-bp deletion (CCR5-Delta32). There is a strong evidence for the unitary origin of the CCR5-Delta32 mutation, this it is found principally in Europe and Western Asia, with generally a north-south downhill cline frequency. Homozygous carriers of this mutation show a resistance to HIV-1 infection and a slower progression towards AIDS. However, HIV has clearly emerged too recently to have been the selective force on CCR5. Our analyses showed strong negative correlations in Europe between the allele frequency and two historical parameters, i.e. the first colonization dates by the great ancient Mediterranean civilizations, and the distances from the Northern frontiers of the Roman Empire in its greatest expansion. Moreover, other studies have shown that the deletion frequencies in both German Bronze Age and Swedish Neolithic populations were similar to those found in the corresponding modern populations, and this deletion has been found in ancient DNA of around 7000 years ago, suggesting that in the past, the deletion frequency could have been relatively high in European populations. In addition, in West Nile virus pathogenesis, CCR5 plays an antimicrobial role showing that host genetic factors are highly pathogen-specific. Our results added to all these previous data suggest that the actual European allele frequency distribution might not be due to genes spreading, but to a negative selection resulting in the spread of pathogens principally during Roman expansion. Indeed, as gene flows from colonizers to European native populations were extremely low, the mutational changes might be associated with vulnerability to imported infections. To date, the nature of the parasites remains unknown; however, zoonoses could be incriminated. PMID:18790087

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

    PubMed Central

    Faure, Eric

    2008-01-01

    Background In Europe, the north-south downhill cline frequency of the chemokine receptor CCR5 allele with a 32-bp deletion (CCR5-Δ32) 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-Δ32 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-Δ32 distribution. PMID:18925940

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

    PubMed

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

    2005-11-01

    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

  4. Distribution of the CCR5delta32 allele (gene variant CCR5) in Rondnia, Western Amazonian region, Brazil.

    PubMed

    de Farias, Josileide Duarte; Santos, Marlene Guimares; de Frana, Andonai Krauze; Delani, Daniel; Tada, Mauro Shugiro; Casseb, Almeida Andrade; Simes, Aguinaldo Luiz; Engracia, Vera

    2012-01-01

    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 Candelria/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. PMID:22481870

  5. Distribution of the CCR5delta32 allele (gene variant CCR5) in Rondnia, Western Amazonian region, Brazil

    PubMed Central

    de Farias, Josileide Duarte; Santos, Marlene Guimares; de Frana, Andonai Krauze; Delani, Daniel; Tada, Mauro Shugiro; Casseb, Almeida Andrade; Simes, Aguinaldo Luiz; Engracia, Vera

    2012-01-01

    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 Candelria/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. PMID:22481870

  6. Low-cost simultaneous detection of CCR5-delta32 and HLA-B*5701 alleles in human immunodeficiency virus type 1 infected patients by selective multiplex endpoint PCR.

    PubMed

    Rosi, Andrea; Meini, Genny; Materazzi, Angelo; Vicenti, Ilaria; Saladini, Francesco; Zazzi, Maurizio

    2015-11-01

    Host genetic traits impact susceptibility to human immunodeficiency virus type 1 (HIV-1) infection, disease progression as well as antiretroviral drug pharmacokinetics and toxicity. Remarkable examples include a 32-bp deletion in the CCR5 coreceptor molecule (CCR5-delta32) impairing attachment of monocytotropic HIV-1 to the host cell membrane and the HLA-B*5701 allele, strongly associated with a potentially fatal hypersensitivity reaction triggered by abacavir, a nucleoside inhibitor of HIV reverse transcriptase. We developed a simple selective multiplex endpoint PCR method for simultaneous analysis of both genetic traits. Two primers were designed for amplification of a region surrounding the CCR5 32-bp deletion site. One common forward primer and two reverse primers with different 3' termini targeting the HLA-B*570101 and HLA-B*570102 alleles were designed for HLA-B*5701 analysis. A panel of 110 reference DNA samples typed in the HLA-B locus was used for development and blind validation of the assay. All the 45 HLA-B*5701 positive and the 55 HLA-B*5701 negative samples were correctly identified. The CCR5-delta32 allele was readily detected in 7 samples and did not interfere with detection of HLA-B*5701 while providing an internal amplification control. Multiplex PCR products were easily identified in agarose gels with no background noise. This simple and low-cost end-point selective multiplex PCR can conveniently screen HIV patients for the protective CCR5-delta32 allele and the risk of developing abacavir hypersensitivity reaction. PMID:26341061

  7. Frequency of the CCR5-delta32 mutation in the Atlantic island populations of Madeira, the Azores, Cabo Verde, and So Tom e Prncipe.

    PubMed

    Freitas, Tamira; Brehm, Antnio; Fernandes, Ana Teresa

    2006-12-01

    There is evidence that the CCR5-delta32 mutation confers protection against HIV-1 infection to homozygous individuals. It is believed that this mutation spread through Europe with the Vikings and that it has been subjected to positive selection, leading to a high frequency in Europe (approximately 10%). We carried out the present study to determine the 32-bp deletion allele and genotype frequencies of the CCR5 gene (CCR5-delta32) in the Atlantic island populations of Madeira, the Azores, Cabo Verde, and So Tom e Principe. These Atlantic archipelagos were all colonized by the Portuguese in the 15th and 16th centuries, but the latter two received most of their settlers from the West African coast. The frequency of the CCR5-delta32 mutation varies between 0% in So Tom e Prncipe and 16.5% in the Azores. The Azores Islands have one of the highest frequencies of homozygotes found in Europe (4.8%). There are significant differences (P < 0.05) between some of these populations, for example, between So Tom e Prncipe and Cabo Verde, and even within populations (e.g., Portugal, Madeira, and the Azores). PMID:17564248

  8. Distribution of CCR5 genotypes and HLA Class I B alleles in HIV-1 infected and uninfected injecting drug users from Rio de Janeiro, Brazil.

    PubMed

    Teixeira, Sylvia Lopes Maia; Bastos, Francisco Incio; Hacker, Mariana A; Morgado, Mariza Gonalves

    2009-07-01

    Host genetic factors play an important role in the HIV epidemic dynamics, and have been considered in studies assessing susceptibility/resistance to HIV-1 infection as well as clinical evolution. Class I and Class II HLA alleles have been associated with the heterogeneity of HIV-1 infection susceptibility, as protective or risk factors for HIV-1 transmission. Moreover, a 32-base pair deletion in the HIV-1 CCR5 gene-coding region confers resistance to HIV-1 infection in homozygous individuals for the deleted allele. In this study, DNA samples from HIV-1 infected and uninfected injecting drug users (IDUs) from Rio de Janeiro were PCR amplified to determine CCR5 genotypes based on the presence of the CCR5Delta32 mutation and typed for the HLA-B locus, in an attempt to assess possible associations between these genetic factors and susceptibility/resistance to HIV-1 infection. The distribution of CCR5 genotypes between the two IDU groups did not differ. The homozygous mutant genotype Delta32/Delta32 was not found in this study. Except for HLA-B*45 (4.0% vs. 3.0%; p=0.04) and for B*51 (12.1% vs. 4.4%; p=0.002), no statistically significant differences were made evident when analyzing the frequencies of each HLA-B allele between Caucasian and non-Caucasian IDUs. The most frequent HLA-B alleles were B*15; B*35; B*44 and B*51. Although some differences in the allele frequencies could be observed between the two IDU groups, none of these was statistically significant. Therefore, no putative association between these genetic markers and susceptibility/resistance to HIV-1 infection could be made evident in the present study. So far, the assessment of genetic markers among the IDU population has been restricted to North American, European, and Asian studies and this report represents a pioneer descriptive study of the distribution of CCR5 genotypes and HLA-B alleles in Rio de Janeiro, Brazil. PMID:19460331

  9. Rare alleles of the ABO blood group system in two European populations.

    PubMed

    Nishimukai, Hiroaki; Fukumori, Yasuo; Tsujimura, Ryusuke; Okiura, Tatsuyuki; Tanabe, Ryosuke; Orimoto, Chitoshi; Ueda, Norifumi

    2009-04-01

    We performed genotyping of the ABO system in Italian and Israeli population samples. The nucleotides at 11 positions, nts 261, 297, 467, 526, 646, 681, 703, 796, 802, 803 and 1060, were analyzed by PCR-RFLP, PCR-SSP and PCR direct sequencing methods. We found three rare ABO alleles besides the common alleles (*)A1(Pro) (=(*)A101), (*)A2(Leu) (=(*)A201), (*)B (=(*)B101), (*)O(T) (=(*)O01), (*)O(A) (=(*)O02) and (*)O2 (=(*)O03), but did not detect ( *)A1(Leu) (=( *)A102) which is a common allele in Asians. The rare alleles were tentatively named (*)Ov1, (*)Ov2, and (*)Bv. As ( *)Bv has been found in two Japanese individuals and (*)O2 is not a rare ABO allele in Europeans, not only (*)O2 but also the (*)Ov1 and (*)Ov2 alleles may be characteristic of European populations. PMID:19254866

  10. A comparison of type 2 diabetes risk allele load between African Americans and European Americans.

    PubMed

    Keaton, Jacob M; Cooke Bailey, Jessica N; Palmer, Nicholette D; Freedman, Barry I; Langefeld, Carl D; Ng, Maggie C Y; Bowden, Donald W

    2014-12-01

    The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38-67 (53.7 4.0, mean SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38-65 (50.9 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 10(-89)) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility. PMID:25273842

  11. European ACP1*C Allele Has Recessive Deleterious Effects on Early Life Viability

    PubMed Central

    WILDER, JASON A.; HAMMER, MICHAEL F.

    2005-01-01

    The acid phosphatase locus (ACP1) is a classical polymorphism that has been surveyed in hundreds of human populations worldwide. Among individuals of European ancestry, the ACP1*C allele occurs with an average frequency of approximately 0.05, whereas it is nearly absent in all other human populations. It has been hypothesized that this allele is maintained by over dominant selection among European populations. Here, we analyze ACP1 protein polymorphism data from more than 50,000 individuals previously surveyed in 67 populations across Europe as well as inheritance data from more than 6,000 European parentoffspring pairs to assess the signature of natural selection currently acting on this allele. Although we see a significant excess of ACP1*C heterozygotes relative to HardyWeinberg expectations, we find no evidence that natural selection favors ACP1*C heterozygotes. Instead, ACP1*C appears to have a strongly deleterious and recessive fitness effect. We observed only 48.9% of expected homozygous offspring from heterozygous parents and significantly fewer homozygotes than expected within populations. Because parentoffspring pairs indicate a significant deficiency of ACP1*C homozygotes, we infer that viability selection is acting on ACP1*C homozygotes very early in life, perhaps before birth. We estimate that approximately 1.2% of all couples of European ancestry are composed of individuals who both carry the APC1*C allele. As such, selection against ACP1*C homozygotes may represent a nonnegligible contribution to the overall number of spontaneous abortions among women of European ancestry and may cause substantial fertility reductions among some combinations of parental genotypes. PMID:15974295

  12. Genotypic and Allelic Variability in CYP19A1 among Populations of African and European Ancestry

    PubMed Central

    Starlard-Davenport, Athena; Orloff, Mohammed S.; Dhakal, Ishwori; Penney, Rosalind B.; Kadlubar, Susan A.

    2015-01-01

    CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten candidate intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary, we demonstrate that differences in the allele frequencies of CYP19A1 intron SNPs are not consistent between populations of African and European ancestry. Thus, investigations into whether CYP19A1 intron SNPs contribute to variations in cancer incidence, outcomes and pharmacological response seen in populations of different ancestry may prove beneficial. PMID:25647083

  13. Absence of the lactase-persistence-associated allele in early Neolithic Europeans

    PubMed Central

    Burger, J.; Kirchner, M.; Bramanti, B.; Haak, W.; Thomas, M. G.

    2007-01-01

    Lactase persistence (LP), the dominant Mendelian trait conferring the ability to digest the milk sugar lactose in adults, has risen to high frequency in central and northern Europeans in the last 20,000 years. This trait is likely to have conferred a selective advantage in individuals who consume appreciable amounts of unfermented milk. Some have argued for the culture-historical hypothesis, whereby LP alleles were rare until the advent of dairying early in the Neolithic but then rose rapidly in frequency under natural selection. Others favor the reverse cause hypothesis, whereby dairying was adopted in populations with preadaptive high LP allele frequencies. Analysis based on the conservation of lactase gene haplotypes indicates a recent origin and high selection coefficients for LP, although it has not been possible to say whether early Neolithic European populations were lactase persistent at appreciable frequencies. We developed a stepwise strategy for obtaining reliable nuclear ancient DNA from ancient skeletons, based on (i) the selection of skeletons from archaeological sites that showed excellent biomolecular preservation, (ii) obtaining highly reproducible human mitochondrial DNA sequences, and (iii) reliable short tandem repeat (STR) genotypes from the same specimens. By applying this experimental strategy, we have obtained high-confidence LP-associated genotypes from eight Neolithic and one Mesolithic human remains, using a range of strict criteria for ancient DNA work. We did not observe the allele most commonly associated with LP in Europeans, thus providing evidence for the culture-historical hypothesis, and indicating that LP was rare in early European farmers. PMID:17360422

  14. Derived Immune and Ancestral Pigmentation Alleles in a 7,000-Year-old Mesolithic European

    PubMed Central

    Olalde, Iñigo; Allentoft, Morten E.; Sánchez-Quinto, Federico; Santpere, Gabriel; Chiang, Charleston W. K.; DeGiorgio, Michael; Prado-Martínez, 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

    2014-01-01

    Ancient genomic sequences have started revealing the origin and the demographic impact of Neolithic farmers spreading into Europe1–3. The adoption of farming, stock breeding and sedentary societies during the Neolithic may have resulted in adaptive changes in genes associated with immunity and diet4. However, the limited data available from earlier hunter-gatherers precludes an understanding of the selective processes associated with this crucial transition to agriculture in recent human evolution. By sequencing a ~7,000-year-old Mesolithic skeleton discovered at the La Braña-Arintero site in León (Spain), we retrieved the first 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. Hence, these genomic variants cannot represent novel mutations that occurred during the adaptation to the farming lifestyle. PMID:24463515

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

    PubMed

    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

    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

  16. Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts

    PubMed Central

    Mitchell, Anna L.; Macarthur, Katie D. R.; Gan, Earn H.; Baggott, Lucy E.; Wolff, Anette S. B.; Skinningsrud, Beate; Platt, Hazel; Short, Andrea; Lobell, Anna; Kmpe, Olle; Bensing, Sophie; Betterle, Corrado; Kasperlik-Zaluska, Anna; Zurawek, Magdalena; Fichna, Marta; Kockum, Ingrid; Nordling Eriksson, Gabriel; Ekwall, Olov; Wahlberg, Jeanette; Dahlqvist, Per; Hulting, Anna-Lena; Penna-Martinez, Marissa; Meyer, Gesine; Kahles, Heinrich; Badenhoop, Klaus; Hahner, Stephanie; Quinkler, Marcus; Falorni, Alberto; Phipps-Green, Amanda; Merriman, Tony R.; Ollier, William; Cordell, Heather J.; Undlien, Dag; Czarnocka, Barbara; Husebye, Eystein; Pearce, Simon H. S.

    2014-01-01

    Background Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P?=?0.00016; rs10931481: P?=?0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-?B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis. PMID:24614117

  17. Y-chromosome specific alleles and haplotypes in European and Asian populations: linkage disequilibrium and geographic diversity.

    PubMed

    Mitchell, R J; Earl, L; Fricke, B

    1997-10-01

    Variation on the Y chromosome may permit our understanding the evolution of the human paternal lineage and male gene flow. This study reports upon the distribution and non random association of alleles at four Y-chromosome specific loci in four populations, three Caucasoid (Italian, Greek and Slav) and one Asian. The markers include insertion/deletion (p12f), point mutation (92R7 and pY alpha I), and repeat sequence (p21A1) polymorphisms. Our data confirm that the p12f/TaqI 8 kb allele is a Caucasoid marker and that Asians are monomorphic at three of the loci (p12f, 92R7, and pY alpha I). The alleles at 92R7 and pY alpha I were found to be in complete disequilibrium in Europeans. Y-haplotype diversity was highly significant between Asians and all three European groups (P < 0.001), but the Greeks and Italians were also significantly different with respect to some alleles and haplotypes (P < 0.02). We find strong evidence that the p12f/TaqI 8 kb allele may have arisen only once, as a deletion event, and, additionally, that the present-day frequency distribution of Y chromosomes carrying the p12f/8 kb allele suggests that it may have been spread by colonising sea-faring peoples from the Near East, possibly the Phoenicians, rather than by expansion of Neolithic farmers into continental Europe. The p12f deletion is the key marker of a unique Y chromosome, found only in Caucasians to date, labelled 'Mediterranean' and this further increases the level of Y-chromosome diversity seen among Caucasoids when compared to the other major population groups. PMID:9386824

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

    PubMed

    Deng, Zhihui; Gao, Xiaojiang; Kirk, Gregory D; Wolinsky, Steven; Carrington, Mary

    2012-07-01

    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. PMID:22548719

  19. The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent

    PubMed Central

    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

    2013-01-01

    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

  20. Rare allelic variants determine folate status in an unsupplemented European population.

    PubMed

    Pavlkov, Markta; Sokolov, Jitka; Janoskov, Bohumila; Melenovsk, Petra; Krupkov, Lucie; Zvrov, Jana; Kozich, Viktor

    2012-08-01

    The role of folates as coenzymes in 1-carbon metabolism and the clinical consequences of disturbed folate metabolism are widely known. Folate status is a complex trait determined by both exogenous and endogenous factors. This study analyzed the association between 12 genetic variants and folate status in a Czech population with no folate fortification program. These 12 genetic variants were selected from 56 variant alleles found by resequencing the coding sequences and adjacent intronic regions of 6 candidate genes involved in folate metabolism or transport (FOLR1, FOLR2, FOLR3, MTHFR, PCFT, and RFC) from 29 individuals with low plasma and erythrocyte folate concentrations. Regression analyses of a cohort of 511 Czech controls not taking folate supplements revealed that only 2 variants in the MTHFR gene were associated with altered folate concentrations in plasma and/or erythrocytes. In our previous study, we observed that the common variant MTHFR c.665C > T (known as c.677C > T; p.A222V) was associated with decreased plasma folate concentrations. In the present study, we show in addition that the rare variant MTHFR c.1958C > T (p.T653M) is associated with significantly increased erythrocyte folate concentrations (P = 0.02). Multivariate regression analysis revealed that this uncommon variant, which is present in 2% of Czech control chromosomes, explains 0.9% of the total variability of erythrocyte folate concentrations; the magnitude of this effect size was comparable with that of the common MTHFR c.665C > T variant. This result indicates that the rare genetic variants may determine folate status to a similar extent as the common allelic variant. PMID:22695967

  1. Shared and independent colorectal cancer risk alleles in TGF?-related genes in African and European Americans

    PubMed Central

    Kupfer, Sonia S.; Skol, Andrew D.; Hong, Ellie; Ludvik, Anton; Kittles, Rick A.; Keku, Temitope O.; Sandler, Robert S.; Ellis, Nathan A.

    2014-01-01

    Genome-wide association studies (GWAS) in colorectal cancer (CRC) identified five regions near transforming growth factor ?-related genes BMP4, GREM1, CDH1, SMAD7 and RPHN2. The true risk alleles remain to be identified in these regions, and their role in CRC risk in non-European populations has been understudied. Our previous work noted significant genetic heterogeneity between African Americans (AAs) and European Americans (EAs) for single nucleotide polymorphisms (SNPs) identified in GWAS. We hypothesized that associations may not have been replicated in AAs due to differential or independent genetic structures. In order to test this hypothesis, we genotyped 195 tagging SNPs across these five gene regions in 1194 CRC cases (795 AAs and 399 EAs) and 1352 controls (985 AAs and 367 EAs). Imputation was performed, and association testing of genotyped and imputed SNPs included ancestry, age and sex as covariates. In two of the five genes originally associated with CRC, we found evidence for association in AAs including rs1862748 in CDH1 (ORAdd = 0.82, P = 0.02) and in GREM1 the SNPs rs10318 (ORRec = 60.1, P = 0.01), rs11632715 (ORRec = 2.36; P = 0.004) and rs12902616 (ORRec = 1.28, P = 0.005), the latter which is in linkage disequilibrium with the previously identified SNP rs4779584. Testing more broadly for associations in these gene regions in AAs, we noted three statistically significant association peaks in GREM1 and RHPN2 that were not identified in EAs. We conclude that some CRC risk alleles are shared between EAs and AAs and others are population specific. PMID:24753543

  2. [Allelic variants of the gene bamyl barley in Eastern European and central Asian areas].

    PubMed

    Stratula, O R; Kalendar, R N; Sivolap, Yu M

    2015-01-01

    The collections of varieties of spring barley cultivars from the Eastern European and Central Asian areas were analyzed by exonpecific PCR (EPIC) for beta-amylase genes. The endosperm beta-amylase gene (bamyl) was differentiated by the presence of 126 bp MITE insertion into intron 3 that is associated with low activity beta-amylase. The findings suggest that a low level of genetic variation for bamylgene within climatic zones is associated with individual breeding program for each climatic zone. PMID:26030968

  3. Common filaggrin null alleles are not associated with hymenoptera venom allergy in Europeans.

    PubMed

    Aslam, A; Lloyd-Lavery, A; Warrell, D A; Misbah, S; Ogg, G S

    2011-01-01

    The association of filaggrin mutations with atopic eczema (atopic dermatitis, AD) is well established and it is thought that filaggrin dysfunction impairs the skin's barrier function allowing allergen penetration and subsequent cutaneous sensitisation and inflammation. However, as most forms of barrier dysfunction are not associated with allergic sensitisation to common allergens, the possibility that filaggrin itself is involved in Th1/Th2 polarisation remains. We tested the hypothesis that allergen delivered to the skin independently of the stratum corneum is not associated with filaggrin mutations. Wasp stings bypass the stratum corneum and deliver antigen to the dermis. We found that European individuals with AD (n = 32) have an increased frequency of the 2 commonest filaggrin null mutations (R501X and 2282del4) compared to those with vespid allergy (n = 56) and healthy controls (n = 30). Thus, filaggrin does not appear to have a downstream effect on the development of allergic disease, and it is indeed filaggrin's role in the epithelial function that is likely to determine the link between filaggrin mutations and allergic sensitisation. PMID:20975288

  4. Regional European differences in allele and genotype frequencies of low density lipoprotein receptor-related protein 1 polymorphism in Alzheimer's disease.

    PubMed

    Panza, Francesco; D'Introno, Alessia; Colacicco, Anna M; Capurso, Cristiano; Basile, Anna M; Capurso, Sabrina; Capurso, Antonio; Solfrizzi, Vincenzo

    2004-04-01

    The low density lipoprotein receptor-related protein 1 (LRP1 gene) is a candidate gene for Alzheimer's disease (AD), because it is a ligand for proteins involved in AD pathogenesis, such as apolipoprotein E (APOE), alpha2-macroglobulin (A2M), amyloid precursor protein (APP), and is located on chromosome 12, within a region linked with AD. An association between a silent polymorphism (C/T) in exon 3 and late onset AD has been reported, with an increased frequency of the C allele, although with conflicting results. We examined this polymorphism in a cohort of 166 sporadic AD patients and 225 sex- and age-matched nondemented controls from Southern Italy. No statistically significant differences were found in LRP1 genotype and allele frequencies between the whole AD sample and controls, nor in early- and late-onset subsets of AD patients. No statistically significant differences in frequencies between LRP1 alleles and AD among APOE allele, age, or gender strata were found. Finally, comparing our results with the findings from other European populations, the LRP1 C allele frequency showed a statistically significant decreasing trend from Northern to Southern regions of Europe, with a concomitant increase in LRP1 T allele frequency, but in AD patients only. Finally, in the AD sample, a decreasing geographical trend from North to South of Europe was found for LRP1 CC genotype, and an inverse trend for LRP1 CT genotype frequency. We suggest that these regional variations in LRP1 genotype and allele frequencies in AD could be related to the different patterns of association between this polymorphism and the disease in various European studies. PMID:15048651

  5. 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

    Li, M; Luo, X-j; Rietschel, M; Lewis, CM; Mattheisen, M; Müller-Myhsok, B; Jamain, S; Leboyer, M; Landén, M; Thompson, PM; Cichon, S; Nöthen, 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

    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

  6. 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

    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

    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

  7. The Contribution of Common UGT2B10 and CYP2A6 Alleles to Variation in Nicotine Glucuronidation among European Americans

    PubMed Central

    Bloom, A. Joseph; von Weymarn, Linda B.; Martinez, Maribel; Bierut, Laura J.; Goate, Alison; Murphy, Sharon E.

    2014-01-01

    UDP-glucuronosytransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. To develop a predictive genetic model of nicotine metabolism, the conversion of deuterated (D2)-nicotine to D2-nicotine-glucuronide, D2-cotinine, D2-cotinine-glucuronide, and D2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotine-glucuronide (D2-nicotine-glucuronide/ (D2-nicotine +D2-nicotine-glucuronide +D2-cotinine +D2-cotinine-glucuronide +D2-trans-3'-hydroxycotinine)) was the primary phenotype. The variant, rs61750900T (D67Y) (minor allele frequency (MAF) = 10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (MAF = 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with un-deuterated (D0) nicotine glucuronidation in subjects smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. PMID:24192532

  8. Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-specific Silencing in Huntington Disease Patients of European Ancestry.

    PubMed

    Kay, Chris; Collins, Jennifer A; Skotte, Niels H; Southwell, Amber L; Warby, Simon C; Caron, Nicholas S; Doty, Crystal N; Nguyen, Betty; Griguoli, Annamaria; Ross, Colin J; Squitieri, Ferdinando; Hayden, Michael R

    2015-11-01

    Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene (HTT). Heterozygous polymorphisms in cis with the mutation allow for allele-specific suppression of the pathogenic HTT transcript as a therapeutic strategy. To prioritize target selection, precise heterozygosity estimates are needed across diverse HD patient populations. Here we present the first comprehensive investigation of all common target alleles across the HTT gene, using 738 reference haplotypes from the 1000 Genomes Project and 2364 haplotypes from HD patients and relatives in Canada, Sweden, France, and Italy. The most common HD haplotypes (A1, A2, and A3a) define mutually exclusive sets of polymorphisms for allele-specific therapy in the greatest number of patients. Across all four populations, a maximum of 80% are treatable using these three target haplotypes. We identify a novel deletion found exclusively on the A1 haplotype, enabling potent and selective silencing of mutant HTT in approximately 40% of the patients. Antisense oligonucleotides complementary to the deletion reduce mutant A1 HTT mRNA by 78% in patient cells while sparing wild-type HTT expression. By suppressing specific haplotypes on which expanded CAG occurs, we demonstrate a rational approach to the development of allele-specific therapy for a monogenic disorder. PMID:26201449

  9. Helicobacter pylori Genotyping from American Indigenous Groups Shows Novel Amerindian vacA and cagA Alleles and Asian, African and European Admixture

    PubMed Central

    Camorlinga-Ponce, Margarita; Perez-Perez, Guillermo; Gonzalez-Valencia, Gerardo; Mendoza, Irma; Peñaloza-Espinosa, Rosenda; Ramos, Irma; Kersulyte, Dangeruta; Reyes-Leon, Adriana; Romo, Carolina; Granados, Julio; Muñoz, Leopoldo; Berg, Douglas E.; Torres, Javier

    2011-01-01

    It is valuable to extend genotyping studies of Helicobacter pylori to strains from indigenous communities across the world to better define adaption, evolution, and associated diseases. We aimed to genetically characterize both human individuals and their infecting H. pylori from indigenous communities of Mexico, and to compare them with those from other human groups. We studied individuals from three indigenous groups, Tarahumaras from the North, Huichols from the West and Nahuas from the center of Mexico. Volunteers were sampled at their community site, DNA was isolated from white blood cells and mtDNA, Y-chromosome, and STR alleles were studied. H. pylori was cultured from gastric juice, and DNA extracted for genotyping of virulence and housekeeping genes. We found Amerindian mtDNA haplogroups (A, B, C, and D), Y-chromosome DYS19T, and Amerindian STRs alleles frequent in the three groups, confirming Amerindian ancestry in these Mexican groups. Concerning H.pylori cagA phylogenetic analyses, although most isolates were of the Western type, a new Amerindian cluster neither Western nor Asian, was formed by some indigenous Mexican, Colombian, Peruvian and Venezuelan isolates. Similarly, vacA phylogenetic analyses showed the existence of a novel Amerindian type in isolates from Alaska, Mexico and Colombia. With hspA strains from Mexico and other American groups clustered within the three major groups, Asian, African or European. Genotyping of housekeeping genes confirmed that Mexican strains formed a novel Asian-related Amerindian group together with strains from remote Amazon Aborigines. This study shows that Mexican indigenous people with Amerindian markers are colonized with H. pylori showing admixture of Asian, European and African strains in genes known to interact with the gastric mucosa. We present evidence of novel Amerindian cagA and vacA alleles in indigenous groups of North and South America. PMID:22073291

  10. The Interplay between Natural Selection and Susceptibility to Melanoma on Allele 374F of SLC45A2 Gene in a South European Population

    PubMed Central

    Lpez, Saioa; Garca, scar; Yurrebaso, Iaki; Flores, Carlos; Acosta-Herrera, Marialbert; Chen, Hua; Gardeazabal, Jess; Careaga, Jess Mara; Boyano, Mara Dolores; Snchez, Ana; Ratn-Nieto, Juan Antonio; Sevilla, Arrate; Smith-Zubiaga, Isabel; de Galdeano, Alicia Garca; Martinez-Cadenas, Conrado; Izagirre, Neskuts; de la Ra, Concepcin; Alonso, Santos

    2014-01-01

    We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans. PMID:25093503

  11. The interplay between natural selection and susceptibility to melanoma on allele 374F of SLC45A2 gene in a South European population.

    PubMed

    Lpez, Saioa; Garca, Oscar; Yurrebaso, Iaki; Flores, Carlos; Acosta-Herrera, Marialbert; Chen, Hua; Gardeazabal, Jess; Careaga, Jess Mara; Boyano, Mara Dolores; Snchez, Ana; Ratn-Nieto, Juan Antonio; Sevilla, Arrate; Smith-Zubiaga, Isabel; de Galdeano, Alicia Garca; Martinez-Cadenas, Conrado; Izagirre, Neskuts; de la Ra, Concepcin; Alonso, Santos

    2014-01-01

    We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans. PMID:25093503

  12. Ancient DNA Analysis Reveals High Frequency of European Lactase Persistence Allele (T-13910) in Medieval Central Europe

    PubMed Central

    Akgül, Gülfirde; Della Casa, Philippe; Rühli, Frank; Warinner, Christina

    2014-01-01

    Ruminant milk and dairy products are important food resources in many European, African, and Middle Eastern societies. These regions are also associated with derived genetic variants for lactase persistence. In mammals, lactase, the enzyme that hydrolyzes the milk sugar lactose, is normally down-regulated after weaning, but at least five human populations around the world have independently evolved mutations regulating the expression of the lactase-phlorizin-hydrolase gene. These mutations result in a dominant lactase persistence phenotype and continued lactase tolerance in adulthood. A single nucleotide polymorphism (SNP) at C/T-13910 is responsible for most lactase persistence in European populations, but when and where the T-13910 polymorphism originated and the evolutionary processes by which it rose to high frequency in Europe have been the subject of strong debate. A history of dairying is presumed to be a prerequisite, but archaeological evidence is lacking. In this study, DNA was extracted from the dentine of 36 individuals excavated at a medieval cemetery in Dalheim, Germany. Eighteen individuals were successfully genotyped for the C/T-13910 SNP by molecular cloning and sequencing, of which 13 (72%) exhibited a European lactase persistence genotype: 44% CT, 28% TT. Previous ancient DNA-based studies found that lactase persistence genotypes fall below detection levels in most regions of Neolithic Europe. Our research shows that by AD 1200, lactase persistence frequency had risen to over 70% in this community in western Central Europe. Given that lactase persistence genotype frequency in present-day Germany and Austria is estimated at 71–80%, our results suggest that genetic lactase persistence likely reached modern levels before the historic population declines associated with the Black Death, thus excluding plague-associated evolutionary forces in the rise of lactase persistence in this region. This new evidence sheds light on the dynamic evolutionary history of the European lactase persistence trait and its global cultural implications. PMID:24465990

  13. Ancient DNA analysis reveals high frequency of European lactase persistence allele (T-13910) in medieval central europe.

    PubMed

    Krttli, Annina; Bouwman, Abigail; Akgl, Glfirde; Della Casa, Philippe; Rhli, Frank; Warinner, Christina

    2014-01-01

    Ruminant milk and dairy products are important food resources in many European, African, and Middle Eastern societies. These regions are also associated with derived genetic variants for lactase persistence. In mammals, lactase, the enzyme that hydrolyzes the milk sugar lactose, is normally down-regulated after weaning, but at least five human populations around the world have independently evolved mutations regulating the expression of the lactase-phlorizin-hydrolase gene. These mutations result in a dominant lactase persistence phenotype and continued lactase tolerance in adulthood. A single nucleotide polymorphism (SNP) at C/T-13910 is responsible for most lactase persistence in European populations, but when and where the T-13910 polymorphism originated and the evolutionary processes by which it rose to high frequency in Europe have been the subject of strong debate. A history of dairying is presumed to be a prerequisite, but archaeological evidence is lacking. In this study, DNA was extracted from the dentine of 36 individuals excavated at a medieval cemetery in Dalheim, Germany. Eighteen individuals were successfully genotyped for the C/T-13910 SNP by molecular cloning and sequencing, of which 13 (72%) exhibited a European lactase persistence genotype: 44% CT, 28% TT. Previous ancient DNA-based studies found that lactase persistence genotypes fall below detection levels in most regions of Neolithic Europe. Our research shows that by AD 1200, lactase persistence frequency had risen to over 70% in this community in western Central Europe. Given that lactase persistence genotype frequency in present-day Germany and Austria is estimated at 71-80%, our results suggest that genetic lactase persistence likely reached modern levels before the historic population declines associated with the Black Death, thus excluding plague-associated evolutionary forces in the rise of lactase persistence in this region. This new evidence sheds light on the dynamic evolutionary history of the European lactase persistence trait and its global cultural implications. PMID:24465990

  14. Functional Significance of Single Nucleotide Polymorphisms in the Lactase Gene in Diverse United States Subjects and Evidence for a Novel Lactase Persistence Allele at -13909 in Those of European Ancestry

    PubMed Central

    Baffour-Awuah, Nana Yaa; Fleet, Sarah; Baker, Susan S.; Butler, Johannah L.; Campbell, Catarina; Tischfield, Samuel; Mitchell, Paul D.; Moon, Jennifer E.; Allende-Richter, Sophie; Fishman, Laurie; Bousvaros, Athos; Fox, Victor; Kuokkanen, Mikko; Montgomery, Robert K.; Grand, Richard J.; Hirschhorn, Joel N.

    2014-01-01

    Objectives Recent data from mainly homogeneous European and African populations implicate a 140 bp region 5? to the transcriptional start site of LCT (the lactase gene) as a regulatory site for lactase persistence and non-persistence. As there are no studies of United States non-homogeneous populations, we performed genotype/phenotype analysis of the -13910 and -22018 LCT SNPs in New England children, mostly of European ancestry. Methods Duodenal biopsies were processed for disaccharidase activities, RNA quantification by RT-PCR, allelic expression ratios by PCR, and genotyping and SNP analysis. Results were compared to clinical information. Results Lactase activity and mRNA levels, as well as sucrase-to-lactase ratios of enzyme activity and mRNA, showed robust correlations with genotype. None of the other LCT SNPs showed as strong a correlation with enzyme or mRNA activities as did -13910. Data were consistent with the -13910 being the causal sequence variant rather than -22018. Four individuals heterozygous for -13910T/C had allelic expression patterns similar to individuals with -13910C/C genotypes; of these, 2 showed equal LCT expression from the 2 alleles and a novel variant (-13909C>A) associated with lactase persistence. Conclusion The identification of -13910C/C genotype is very likely to predict lactase non-persistence, consistent with prior published studies. A -13910T/T genotype will frequently, but not perfectly, predict lactase persistence in this mixed European-ancestry population; a -13910T/C genotype will not predict the phenotype. A long, rare haplotype in 2 individuals with -13910T/C genotype but equal allele-specific expression contains a novel lactase persistence allele present at -13909. PMID:25625576

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

    SciTech Connect

    Rafi, M.A.; Luzi, P.; Hershberger, M.

    1994-09-01

    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.

  16. Allelic Exchange.

    PubMed

    Lehman, McKenzie K; Bose, Jeffrey L; Bayles, Kenneth W

    2016-01-01

    Methods used to understand the function of a gene/protein are one of the hallmarks of modern molecular genetics. The ability to genetically manipulate bacteria has become a fundamental tool in studying these organisms and while basic cloning has become a routine task in molecular biology laboratories, generating directed mutations can be a daunting task. This chapter describes the method of allelic exchange in Staphylococcus aureus using temperature-sensitive plasmids that have successfully produced a variety of chromosomal mutations, including in-frame deletions, insertion of antibiotic-resistance cassettes, and even single-nucleotide point mutations. PMID:25646609

  17. Frequency of alleles conferring resistance to Bt maize in French and US corn belt populations of the European corn borer, Ostrinia nubilalis.

    PubMed

    Bourguet, D; Chaufaux, J; Séguin, M; Buisson, C; Hinton, J L; Stodola, T J; Porter, P; Cronholm, G; Buschman, L L; Andow, D A

    2003-05-01

    Farmers, industry, governments and environmental groups agree that it would be useful to manage transgenic crops producing insecticidal proteins to delay the evolution of resistance in target pests. The main strategy proposed for delaying resistance to Bacillus thuringiensis ( Bt) toxins in transgenic crops is the high-dose/refuge strategy. This strategy is based on the unverified assumption that resistance alleles are initially rare (<10(-3)). We used an F(2) screen on >1,200 isofemale lines of Ostrinia nubilalis Hübner (Lepidoptera: Crambidae) collected in France and the US corn belt during 1999-2001. In none of the isofemale lines did we detect alleles conferring resistance to Bt maize producing the Cry1Ab toxin. A Bayesian analysis of the data indicates that the frequency of resistance alleles in France was <9.20 x 10(-4) with 95% probability, and a detection probability of >80%. In the northern US corn belt, the frequency of resistance to Bt maize was <4.23 x 10(-4) with 95% probability, and a detection probability of >90%. Only 95 lines have been screened from the southern US corn belt, so these data are still inconclusive. These results suggest that resistance is probably rare enough in France and the northern US corn belt for the high-dose plus refuge strategy to delay resistance to Bt maize. PMID:12748773

  18. RHD allele distribution in Africans of Mali

    PubMed Central

    Wagner, Franz F; Moulds, Joann M; Tounkara, Anatole; Kouriba, Bourema; Flegel, Willy A

    2003-01-01

    Background Aberrant and non-functional RHD alleles are much more frequent in Africans than in Europeans. The DAU cluster of RHD alleles exemplifies that the alleles frequent in Africans have evaded recognition until recently. A comprehensive survey of RHD alleles in any African population was lacking. Results We surveyed the molecular structure and frequency of RHD alleles in Mali (West Africa) by evaluating 116 haplotypes. Only 69% could be attributed to standard RHD (55%) or the RHD deletion (14%). The aberrant RHD allele DAU-0 was predicted for 19%, RHD? for 7% and Ccdes for 4% of all haplotypes. DAU-3 and the new RHD allele RHD(L207F), dubbed DMA, were found in one haplotype each. A PCR-RFLP for the detection of the hybrid Rhesus box diagnostic for the RHD deletion in Europeans was false positive in 9 individuals, including all carriers of RHD? . Including two silent mutations and the RHD deletion, a total of 9 alleles could be differentiated. Conclusion Besides standard RHD and the RHD deletion, DAU-0, RHD? and Ccdes are major alleles in Mali. Our survey proved that the most frequent alleles of West Africans have been recognized allowing to devise reliable genotyping and phenotyping strategies. PMID:14505497

  19. Dominance relationships among S-alleles in Corylus avellana L.

    PubMed

    Mehlenbacher, S A; Thompson, M M

    1988-11-01

    Pollen-stigma compatibility relationship were studied in 50 cultivars and more than 800 seedlings of the European hazelnut (Corylus avellana L.). A total of 22 unique S-alleles have been identified. Dominance relationships in 75 of the possible 231 pairs of alleles have been determined in both pistil and pollen. In the pistil, all alleles exhibited independent action, whereas in the pollen, alleles exhibited either dominance or codominance. The dominance relationship was linear with 7 levels of dominance. PMID:24232343

  20. Resolution of HLA-B*44:02:01G, -DRB1*14:01:01G and -DQB1*03:01:01G reveals a high allelic variability among 12 European populations.

    PubMed

    Vidan-Jeras, B; Buhler, S; Dubois, V; Grubic, Z; Ivanova, M; Jaatinen, T; Ligeiro, D; Lokki, M-L; Papasteriades, C; Poli, F; Spyropoulou-Vlachou, M; Tordai, A; Viken, M K; Wenda, S; Nunes, J M; Sanchez-Mazas, A; Tiercy, J-M

    2014-11-01

    Within the framework of the EU-funded HLA-NET action, an analysis of three G-group alleles, HLA-B*44:02:01G, DRB1*14:01:01G and DQB1*03:01:01G, was undertaken in 12 European populations. Ambiguities were resolved by polymerase chain reaction-sequence-specific amplification (PCR-SSP) or PCR-sequence-based typing (PCR-SBT) in a total of 5095 individuals. The results of the DRB1*14:01/14:54 ambiguity showed high relative ratios (24-53%) of DRB1*14:01 in Bulgarians, Croatians, Greeks, Italians and Slovenians, contrasting with low ratios (6-13%) in Austrians, Finnish, French, Hungarians, Norwegians and Swiss. Resolution of the B*44:02/44:27 ambiguity showed that B*44:27 had a high relative ratio in Slovenians (25.5%) and Bulgarians (37%) and low in French and Swiss (0.02-1%), and was not observed in Greeks and Italians. The highest relative ratio of DQB1*03:19 was found in Portuguese (11%), by contrast with low ratios (0-3%) in the other five populations. Analysis of the A, B, DRB1 phenotypes and family-derived haplotypes in 1719 and 403 individuals positive for either HLA-B*44:02G or DRB1*14:01G ambiguities, respectively, showed some preferential associations, such as A*26∼DRB1*14:01, B*35∼DRB1*14:01, B*38∼DRB1*14:01 and B*44:27∼DRB1*16. Because these ambiguities are located outside the peptide-binding site, they may not be recognized by alloreactive T-cells. However, because of strong linkage disequilibrium (LD), the DRB1*14:01 vs DRB1*14:54 and the B*44:02 vs B*44:27 mismatches are associated to DRB3-, and C-mismatches, respectively. These results are informative for algorithms searching unrelated hematopoietic stem cell donors. For B*44:27-positive patients, searches are expected to be more successful when requesting donors from Southeastern-European ancestry. Furthermore, the introduction of human leukocyte antigen (HLA)-typing strategies that allow resolving exon 4 (for class I) and exon 3 (for class II) polymorphisms can be expected to contribute significantly to population genetics studies. PMID:25209151

  1. What Is a Recessive Allele?

    ERIC Educational Resources Information Center

    American Biology Teacher, 1991

    1991-01-01

    Presents four misconceptions students have concerning the concepts of recessive and dominant alleles. Discusses the spectrum of dominant-recessive relationships, different levels of analysis between phenotype and genotype, possible causes of dominance, and an example involving wrinkled peas. (MDH)

  2. Allelic association between marker loci.

    PubMed

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

    1999-02-16

    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 x 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. PMID:9990074

  3. Delimiting Allelic Imbalance of TYMS by Allele-Specific Analysis

    PubMed Central

    Balboa-Beltrn, Emilia; Cruz, Raquel; Carracedo, Angel; Barros, Francisco

    2015-01-01

    Abstract Allelic imbalance of thymidylate synthase (TYMS) is attributed to polymorphisms in the 5?- and 3?-untranslated region (UTR). These polymorphisms have been related to the risk of suffering different cancers, for example leukemia, breast or gastric cancer, and response to different drugs, among which are methotrexate glutamates, stavudine, and specifically 5-fluorouracil (5-FU), as TYMS is its direct target. A vast literature has been published in relation to 5-FU, even suggesting the sole use of these polymorphisms to effectively manage 5-FU dosage. Estimates of the extent to which these polymorphisms influence in TYMS expression have in the past been based on functional analysis by luciferase assays and quantification of TYMS mRNA, but both these studies, as the association studies with cancer risk or with toxicity or response to 5-FU, are very contradictory. Regarding functional assays, the artificial genetic environment created in luciferase assay and the problems derived from quantitative polymerase chain reactions (qPCRs), for example the use of a reference gene, may have distorted the results. To avoid these sources of interference, we have analyzed the allelic imbalance of TYMS by allelic-specific analysis in peripheral blood mononuclear cells (PBMCs) from patients. Allelic imbalance in PBMCs, taken from 40 patients with suspected myeloproliferative haematological diseases, was determined by fluorescent fragment analysis (for the 3?-UTR polymorphism), Sanger sequencing and allelic-specific qPCR in multiplex (for the 5?-UTR polymorphisms). For neither the 3?- nor the 5?-UTR polymorphisms did the observed allelic imbalance exceed 1.5 fold. None of the TYMS polymorphisms is statistically associated with allelic imbalance. The results acquired allow us to deny the previously established assertion of an influence of 2 to 4 fold of the rs45445694 and rs2853542 polymorphisms in the expression of TYMS and narrow its allelic imbalance to 1.5 fold, in our population. These data circumscribe the influence of these polymorphisms in the clinical outcome of 5-FU and question their use for establishing 5-FU dosage, above all when additional genetic factors are not considered. PMID:26166093

  4. Rapid detection of the CYP2A6*12 hybrid allele by Pyrosequencing technology

    PubMed Central

    Koontz, Deborah A; Huckins, Jacqueline J; Spencer, Antonina; Gallagher, Margaret L

    2009-01-01

    Background Identification of CYP2A6 alleles associated with reduced enzyme activity is important in the study of inter-individual differences in drug metabolism. CYP2A6*12 is a hybrid allele that results from unequal crossover between CYP2A6 and CYP2A7 genes. The 5' regulatory region and exons 12 are derived from CYP2A7, and exons 39 are derived from CYP2A6. Conventional methods for detection of CYP2A6*12 consist of two-step PCR protocols that are laborious and unsuitable for high-throughput genotyping. We developed a rapid and accurate method to detect the CYP2A6*12 allele by Pyrosequencing technology. Methods A single set of PCR primers was designed to specifically amplify both the CYP2A6*1 wild-type allele and the CYP2A6*12 hybrid allele. An internal Pyrosequencing primer was used to generate allele-specific sequence information, which detected homozygous wild-type, heterozygous hybrid, and homozygous hybrid alleles. We first validated the assay on 104 DNA samples that were also genotyped by conventional two-step PCR and by cycle sequencing. CYP2A6*12 allele frequencies were then determined using the Pyrosequencing assay on 181 multi-ethnic DNA samples from subjects of African American, European Caucasian, Pacific Rim, and Hispanic descent. Finally, we streamlined the Pyrosequencing assay by integrating liquid handling robotics into the workflow. Results Pyrosequencing results demonstrated 100% concordance with conventional two-step PCR and cycle sequencing methods. Allele frequency data showed slightly higher prevalence of the CYP2A6*12 allele in European Caucasians and Hispanics. Conclusion This Pyrosequencing assay proved to be a simple, rapid, and accurate alternative to conventional methods, which can be easily adapted to the needs of higher-throughput studies. PMID:19703308

  5. Invasive Allele Spread under Preemptive Competition

    NASA Astrophysics Data System (ADS)

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

    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.

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

    PubMed

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

    2007-01-01

    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

  7. Biased Allele Expression and Aggression in Hybrid Honeybees may be Influenced by Inappropriate Nuclear-Cytoplasmic Signaling

    PubMed Central

    Gibson, Joshua D.; Arechavaleta-Velasco, Miguel E.; Tsuruda, Jennifer M.; Hunt, Greg J.

    2015-01-01

    Hybrid effects are often exhibited asymmetrically between reciprocal families. One way this could happen is if silencing of one parent’s allele occurs in one lineage but not the other, which could affect the phenotypes of the hybrids asymmetrically by silencing that allele in only one of the hybrid families. We have previously tested for allele-specific expression biases in hybrids of European and Africanized honeybees and we found that there was an asymmetric overabundance of genes showing a maternal bias in the family with a European mother. Here, we further analyze allelic bias in these hybrids to ascertain whether they may underlie previously described asymmetries in metabolism and aggression in similar hybrid families and we speculate on what mechanisms may produce this biased allele usage. We find that there are over 500 genes that have some form of biased allele usage and over 200 of these are biased toward the maternal allele but only in the family with European maternity, mirroring the pattern observed for aggression and metabolic rate. This asymmetrically biased set is enriched for genes in loci associated with aggressive behavior and also for mitochondrial-localizing proteins. It contains many genes that play important roles in metabolic regulation. Moreover we find genes relating to the piwi-interacting RNA (piRNA) pathway, which is involved in chromatin modifications and epigenetic regulation and may help explain the mechanism underlying this asymmetric allele use. Based on these findings and previous work investigating aggression and metabolism in bees, we propose a novel hypothesis; that the asymmetric pattern of biased allele usage in these hybrids is a result of inappropriate use of piRNA-mediated nuclear-cytoplasmic signaling that is normally used to modulate aggression in honeybees. This is the first report of widespread asymmetric effects on allelic expression in hybrids and may represent a novel mechanism for gene regulation. PMID:26648977

  8. Biased Allele Expression and Aggression in Hybrid Honeybees may be Influenced by Inappropriate Nuclear-Cytoplasmic Signaling.

    PubMed

    Gibson, Joshua D; Arechavaleta-Velasco, Miguel E; Tsuruda, Jennifer M; Hunt, Greg J

    2015-01-01

    Hybrid effects are often exhibited asymmetrically between reciprocal families. One way this could happen is if silencing of one parent's allele occurs in one lineage but not the other, which could affect the phenotypes of the hybrids asymmetrically by silencing that allele in only one of the hybrid families. We have previously tested for allele-specific expression biases in hybrids of European and Africanized honeybees and we found that there was an asymmetric overabundance of genes showing a maternal bias in the family with a European mother. Here, we further analyze allelic bias in these hybrids to ascertain whether they may underlie previously described asymmetries in metabolism and aggression in similar hybrid families and we speculate on what mechanisms may produce this biased allele usage. We find that there are over 500 genes that have some form of biased allele usage and over 200 of these are biased toward the maternal allele but only in the family with European maternity, mirroring the pattern observed for aggression and metabolic rate. This asymmetrically biased set is enriched for genes in loci associated with aggressive behavior and also for mitochondrial-localizing proteins. It contains many genes that play important roles in metabolic regulation. Moreover we find genes relating to the piwi-interacting RNA (piRNA) pathway, which is involved in chromatin modifications and epigenetic regulation and may help explain the mechanism underlying this asymmetric allele use. Based on these findings and previous work investigating aggression and metabolism in bees, we propose a novel hypothesis; that the asymmetric pattern of biased allele usage in these hybrids is a result of inappropriate use of piRNA-mediated nuclear-cytoplasmic signaling that is normally used to modulate aggression in honeybees. This is the first report of widespread asymmetric effects on allelic expression in hybrids and may represent a novel mechanism for gene regulation. PMID:26648977

  9. Functional analysis of human ornithine decarboxylase alleles.

    PubMed

    Guo, Y; Harris, R B; Rosson, D; Boorman, D; O'Brien, T G

    2000-11-15

    It has been known for > 10 years that there are two alleles of the human ornithine decarboxylase (ODC) gene, defined by a polymorphic PstI RFLP in intron 1. We have sequenced a large portion of each of the two alleles, including some of the 5' promoter region, exon 1, intron 1, and exon 2, and determined that a single nucleotide polymorphism at base +317 (relative to transcription start site) is responsible for the presence or absence of the PstI restriction site. We have developed two genotyping assays, a PCR-RFLP assay and a high-throughput TaqMan-based method, and determined the ODC genotype distribution in >900 North American DNA samples. On the basis of its location between two closely spaced Myc/Max binding sites (E-boxes), we speculated that the single nucleotide polymorphism at base +317 could have functional significance. Results of transfection assays with allele-specific reporter constructs support this hypothesis. The promoter/regulatory region derived from the minor ODC allele (A allele) was more effective in driving luciferase expression in these assays than the identical region from the major allele (G allele). Our results suggest that individuals homozygous for the A allele may be capable of greater ODC expression after environmental exposures, especially those that up-regulate c-MYC expression. PMID:11103791

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

    PubMed Central

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

    2011-01-01

    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. PMID:20848568

  11. Characterization of the treefrog null allele, 1991

    SciTech Connect

    Guttman, S.I. . Dept. of Zoology)

    1992-04-01

    Spring peeper (Hyla crucifer) tadpoles collected from the waste storage area during the Biological and Ecological Site Characterization of the Feed Materials Production Center (FEMP) in 1986 and 1987 appeared to be unique. A null (inactive) allele was found at the glucose phosphate isomerase enzyme locus in significant frequencies (approximately 20%) each year; this allele did not appear to occur in the offsite sample collected approximately 15km from the FEMP. Null alleles at this locus have not been reported in other amphibian populations; when they have been found in other organisms they have invariably been lethal in the homozygous condition.

  12. Characterization of the treefrog null allele

    SciTech Connect

    Guttman, S.I. . Dept. of Zoology)

    1990-12-01

    As part of the authors intensive year-long baseline ecological study, they characterized the degree of genetic polymorphism and heterozygosity in selected Feed Materials Production Center (FMPC) populations using electrophoretic techniques. These data are being used as an indicator of stress by comparing populations on and off the FMPC site. The current study was initiated to determine whether this GPI null allele is lethal, when homozygous, in spring peepers. Also, a sampling protocol was implemented to determine whether a linear effect occurs relative to the frequency of the null allele offsite and to determine the origination site of the null allele. 18 refs., 2 figs., 4 tabs.

  13. Nucleotide variation and identification of novel blast resistance alleles of Pib by allele mining strategy.

    PubMed

    Ramkumar, G; Madhav, M S; Devi, S J S Rama; Prasad, M S; Babu, V Ravindra

    2015-04-01

    Pib is one of significant rice blast resistant genes, which provides resistance to wide range of isolates of rice blast pathogen, Magnaporthe oryzae. Identification and isolation of novel and beneficial alleles help in crop enhancement. Allele mining is one of the best strategies for dissecting the allelic variations at candidate gene and identification of novel alleles. Hence, in the present study, Pib was analyzed by allele mining strategy, and coding and non-coding (upstream and intron) regions were examined to identify novel Pib alleles. Allelic sequences comparison revealed that nucleotide polymorphisms at coding regions affected the amino acid sequences, while the polymorphism at upstream (non-coding) region affected the motifs arrangements. Pib alleles from resistant landraces, Sercher and Krengosa showed better resistance than Pib donor variety, might be due to acquired mutations, especially at LRR region. The evolutionary distance, Ka/Ks and phylogenetic analyzes also supported these results. Transcription factor binding motif analysis revealed that Pib (Sr) had a unique motif (DPBFCOREDCDC3), while five different motifs differentiated the resistance and susceptible Pib alleles. As the Pib is an inducible gene, the identified differential motifs helps to understand the Pib expression mechanism. The identified novel Pib resistant alleles, which showed high resistance to the rice blast, can be used directly in blast resistance breeding program as alternative Pib resistant sources. PMID:25964723

  14. Nucleation and Spread of an Invasive Allele

    NASA Astrophysics Data System (ADS)

    Korniss, Gyorgy; Caraco, Thomas

    2005-03-01

    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.

  15. Pyrosequencing for accurate imprinted allele expression analysis.

    PubMed

    Yang, Bing; Damaschke, Nathan; Yao, Tianyu; McCormick, Johnathon; Wagner, Jennifer; Jarrard, David

    2015-07-01

    Genomic imprinting is an epigenetic mechanism that restricts gene expression to one inherited allele. Improper maintenance of imprinting has been implicated in a number of human diseases and developmental syndromes. Assays are needed that can quantify the contribution of each paternal allele to a gene expression profile. We have developed a rapid, sensitive quantitative assay for the measurement of individual allelic ratios termed Pyrosequencing for Imprinted Expression (PIE). Advantages of PIE over other approaches include shorter experimental time, decreased labor, avoiding the need for restriction endonuclease enzymes at polymorphic sites, and prevent heteroduplex formation which is problematic in quantitative PCR-based methods. We demonstrate the improved sensitivity of PIE including the ability to detect differences in allelic expression down to 1%. The assay is capable of measuring genomic heterozygosity as well as imprinting in a single run. PIE is applied to determine the status of Insulin-like Growth Factor-2 (IGF2) imprinting in human and mouse tissues. PMID:25581900

  16. Bovine Polledness – An Autosomal Dominant Trait with Allelic Heterogeneity

    PubMed Central

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

    2012-01-01

    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. PMID:22737241

  17. Allele Workbench: Transcriptome Pipeline and Interactive Graphics for Allele-Specific Expression

    PubMed Central

    Soderlund, Carol A.; Nelson, William M.; Goff, Stephen A.

    2014-01-01

    Sequencing the transcriptome can answer various questions such as determining the transcripts expressed in a given species for a specific tissue or condition, evaluating differential expression, discovering variants, and evaluating allele-specific expression. Differential expression evaluates the expression differences between different strains, tissues, and conditions. Allele-specific expression evaluates expression differences between parental alleles. Both differential expression and allele-specific expression have been studied for heterosis (hybrid vigor), where the hybrid has improved performance over the parents for one or more traits. The Allele Workbench software was developed for a heterosis study that evaluated allele-specific expression for a mouse F1 hybrid using libraries from multiple tissues with biological replicates. This software has been made into a distributable package, which includes a pipeline, a Java interface to build the database, and a Java interface for query and display of the results. The required input is a reference genome, annotation file, and one or more RNA-Seq libraries with optional replicates. It evaluates allelic imbalance at the SNP and transcript level and flags transcripts with significant opposite directional allele-specific expression. The Java interface allows the user to view data from libraries, replicates, genes, transcripts, exons, and variants, including queries on allele imbalance for selected libraries. To determine the impact of allele-specific SNPs on protein folding, variants are annotated with their effect (e.g., missense), and the parental protein sequences may be exported for protein folding analysis. The Allele Workbench processing results in transcript files and read counts that can be used as input to the previously published Transcriptome Computational Workbench, which has a new algorithm for determining a trimmed set of gene ontology terms. The software with demo files is available from https://code.google.com/p/allele-workbench. Additionally, all software is ready for immediate use from an Atmosphere Virtual Machine Image available from the iPlant Collaborative (www.iplantcollaborative.org). PMID:25541944

  18. Functional analysis of 11 novel GBA alleles.

    PubMed

    Malini, Erika; Grossi, Serena; Deganuto, Marta; Rosano, Camillo; Parini, Rossella; Dominisini, Silvia; Cariati, Roberta; Zampieri, Stefania; Bembi, Bruno; Filocamo, Mirella; Dardis, Andrea

    2014-04-01

    Gaucher disease is the most frequent lysosomal storage disorder due to the deficiency of the acid β-glucosidase, encoded by the GBA gene. In this study, we report the structural and functional characterization of 11 novel GBA alleles. Seven single missense alleles, P159S, N188I, E235K, P245T, W312S, S366R and W381C, and two alleles carrying in cis mutations, (N188S; G265R) and (E326K; D380N), were studied for enzyme activity in transiently transfected cells. All mutants were inactive except the P159S, which retained 15% of wild-type activity. To further characterize the alleles carrying two in cis mutations, we expressed constructs bearing singly each mutation. The presence of G265R or D380N mutations completely abolished enzyme activity, while N188S and E326K mutants retained 25 and 54% of wild-type activity, respectively. Two mutations, affecting the acceptor splice site of introns 5 (c.589-1G>A) and 9 (c.1389-1G>A), led to the synthesis of aberrant mRNA. Unpredictably, family studies showed that two alleles resulted from germline or 'de novo' mutations. These results strengthen the importance of performing a complete and accurate molecular analysis of the GBA gene in order to avoid misleading conclusions and provide a comprehensive functional analysis of new GBA mutations. PMID:24022302

  19. Forensic Loci Allele Database (FLAD): Automatically generated, permanent identifiers for sequenced forensic alleles.

    PubMed

    Van Neste, Christophe; Van Criekinge, Wim; Deforce, Dieter; Van Nieuwerburgh, Filip

    2016-01-01

    It is difficult to predict if and when massively parallel sequencing of forensic STR loci will replace capillary electrophoresis as the new standard technology in forensic genetics. The main benefits of sequencing are increased multiplexing scales and SNP detection. There is not yet a consensus on how sequenced profiles should be reported. We present the Forensic Loci Allele Database (FLAD) service, made freely available on http://forensic.ugent.be/FLAD/. It offers permanent identifiers for sequenced forensic alleles (STR or SNP) and their microvariants for use in forensic allele nomenclature. Analogous to Genbank, its aim is to provide permanent identifiers for forensically relevant allele sequences. Researchers that are developing forensic sequencing kits or are performing population studies, can register on http://forensic.ugent.be/FLAD/ and add loci and allele sequences with a short and simple application interface (API). PMID:26456067

  20. Description of a novel HLA-B35 (B*3514) allele found in a Mexican family of Nahua Aztec descent.

    PubMed

    Vargas-Alarcon, G; Martinez-Laso, J; Granados, J; Diaz-Campos, N; Alvarez, M; Gomez-Casado, E; Alcocer-Varela, J; Arnaiz-Villena, A

    1996-02-01

    A new allele, HLA-B*3514, has been found in a Mexican family from Nahua descent. Its exon 2 is identical to that of B*3501 allele, but exon 3 bears a 3-base difference at codons 152 and 156, which results in Val-->Glu and Leu-->Trp changes, respectively, in the corresponding HLA molecule at the peptide-binding site. These substitutions may have originated from a DNA stretch donation from an allele belonging to the B15 group, enabling HLA-B*3514 to cope with the presentation of a new set of antigenic peptides. The high frequency of serologic B35 in Amerindians, together with the variety of B35 alleles detected by DNA sequencing in these populations, suggest that a frequent B35 subtype was present in the founder population and that several B35 subtypes may have been recently generated, probably due to the abrupt arrival of new pathogens following European invasions. PMID:8882414

  1. European Mistletoe

    MedlinePLUS

    ... common names, what the science says, potential side effects and cautions, and resources for more information. European mistletoe is a semiparasitic plant that grows on several types of trees in ...

  2. European Community.

    PubMed

    1987-05-01

    The European Community was established in 1951 to reconcile France and Germany after World War II and to make possible the eventual federation of Europe. By 1986, there were 12 member countries: France, Italy, Belgium, the Federal Republic of Germany, Luxembourg, the Netherlands, Denmark, Ireland, the United Kingdom, Greece, Spain, and Portugal. Principal areas of concern are internal and external trade, agriculture, monetary coordination, fisheries, common industrial and commercial policies, assistance, science and research, and common social and regional policies. The European Community has a budget of US$34.035 billion/year, funded by customs duties and 1.4% of each member's value-added tax. The treaties establishing the European Community call for members to form a common market, a common customs tariff, and common agricultural, transport, economic, and nuclear policies. Major European Community institutions include the Commission, Council of Ministers, European Parliament, Court of Justice, and Economic and Social Committee. The Community is the world's largest trading unit, accounting for 15% of world trade. The 2 main goals of the Community's industrial policy are to create an open internal market and to promote technological innovation in order to improve international competitiveness. The European Community aims to contribute to the economic and social development of Third World countries as well. PMID:12177941

  3. Demographic history and rare allele sharing among human populations.

    PubMed

    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

    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

  4. Overcoming allelic specificity by immunization with five allelic forms of Plasmodium falciparum apical membrane antigen 1.

    PubMed

    Miura, Kazutoyo; 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

    2013-05-01

    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. PMID:23429537

  5. Evolutionary Dynamics of Sporophytic Self-Incompatibility Alleles in Plants

    PubMed Central

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

    1997-01-01

    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. PMID:9335618

  6. Crohn's Disease Risk Alleles on the NOD2 Locus Have Been Maintained by Natural Selection on Standing Variation

    PubMed Central

    Nakagome, Shigeki; Mano, Shuhei; Kozlowski, Lukasz; Bujnicki, Janusz M.; Shibata, Hiroki; Fukumaki, Yasuaki; Kidd, Judith R.; Kidd, Kenneth K.; Kawamura, Shoji; Oota, Hiroki

    2012-01-01

    Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions. PMID:22319155

  7. Spatial proximity of homologous alleles and long noncoding RNAs regulate a switch in allelic gene expression

    PubMed Central

    Stratigi, Kalliopi; Kapsetaki, Manouela; Aivaliotis, Michalis; Town, Terrence; Flavell, Richard A.; Spilianakis, Charalampos G.

    2015-01-01

    Physiological processes rely on the regulation of total mRNA levels in a cell. In diploid organisms, the transcriptional activation of one or both alleles of a gene may involve trans-allelic interactions that provide a tight spatial and temporal level of gene expression regulation. The mechanisms underlying such interactions still remain poorly understood. Here, we demonstrate that lipopolysaccharide stimulation of murine macrophages rapidly resulted in the actin-mediated and transient homologous spatial proximity of Tnfα alleles, which was necessary for the mono- to biallelic switch in gene expression. We identified two new complementary long noncoding RNAs transcribed from the TNFα locus and showed that their knockdown had opposite effects in Tnfα spatial proximity and allelic expression. Moreover, the observed spatial proximity of Tnfα alleles depended on pyruvate kinase muscle isoform 2 (PKM2) and T-helper-inducing POZ-Krüppel-like factor (ThPOK). This study suggests a role for lncRNAs in the regulation of somatic homologous spatial proximity and allelic expression control necessary for fine-tuning mammalian immune responses. PMID:25770217

  8. Initial invasion of gametophytic self-incompatibility alleles in the absence of tight linkage between pollen and pistil S alleles.

    PubMed

    Sakai, Satoki; Wakoh, Haluka

    2014-08-01

    In homomorphic self-incompatibility (SI) systems of plants, the loci controlling the pollen and pistil types are tightly linked, and this prevents the generation of compatible combinations of alleles expressing pollen and pistil types, which would result in self-fertilization. We modeled the initial invasion of the first pollen and pistil alleles in gametophytic SI to determine whether these alleles can stably coexist in a population without tight linkage. We assume pollen and pistil loci each carry an incompatibility allele S and an allele without an incompatibility function N. We assume that pollen with an S allele are incompatible with pistils carrying S alleles, whereas other crosses are compatible. Ovules in pistils carrying an S allele suffer viability costs because recognition consumes resources. We found that the cost of carrying a pistil S allele allows pollen and pistil S alleles to coexist in a stable equilibrium if linkage is partial. This occurs because parents that carry pistil S alleles but are homozygous for pollen N alleles cannot avoid self-fertilization; however, they suffer viability costs. Hence, pollen N alleles are selected again. When pollen and pistil S alleles can coexist in a polymorphic equilibrium, selection will favor tighter linkage. PMID:25058284

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

    PubMed

    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

    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

  10. Allelic variation contributes to bacterial host specificity

    PubMed Central

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; Zhao, Shaohua; McDermott, Patrick F.; Weill, François-Xavier; Mainil, Jacques G.; Arze, Cesar; Fricke, W. Florian; Edwards, Robert A.; Brisson, Dustin; Zhang, Nancy R.; Rankin, Shelley C.; Schifferli, Dieter M.

    2015-01-01

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. PMID:26515720

  11. Allelic variation contributes to bacterial host specificity.

    PubMed

    Yue, Min; Han, Xiangan; De Masi, Leon; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S; Fraser, George P; Zhao, Shaohua; McDermott, Patrick F; Weill, François-Xavier; Mainil, Jacques G; Arze, Cesar; Fricke, W Florian; Edwards, Robert A; Brisson, Dustin; Zhang, Nancy R; Rankin, Shelley C; Schifferli, Dieter M

    2015-01-01

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. PMID:26515720

  12. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, O.E.; Pan, D.

    1994-07-19

    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.

  13. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, Oliver E.; Pan, David

    1994-01-01

    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.

  14. Directional positive selection on an allele of arbitrary dominance.

    PubMed

    Teshima, Kosuke M; Przeworski, Molly

    2006-01-01

    Most models of positive directional selection assume codominance of the beneficial allele. We examine the importance of this assumption by implementing a coalescent model of positive directional selection with arbitrary dominance. We find that, for a given mean fixation time, a beneficial allele has a much weaker effect on diversity at linked neutral sites when the allele is recessive. PMID:16219788

  15. Increasing long term response by selecting for favorable minor alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term response of genomic selection can be improved by considering allele frequencies of selected markers or quantitative trait loci (QTLs). A previous formula to weight allele frequency of favorable minor alleles was tested, and 2 new formulas were developed. The previous formula used nonlinear...

  16. Distribution of HLA alleles in Portugal and Cabo Verde. Relationships with the slave trade route.

    PubMed

    Spnola, H; Brehm, A; Williams, F; Jesus, J; Middleton, D

    2002-07-01

    HLA-A, -B, and -DR frequencies were analysed in populations from Portugal and the Madeira and Cabo Verde Archipelagos, aiming to characterize their genetic composition. Portuguese settlers colonized both Archipelagos in the 15th and 16th centuries. Madeira received many sub-Saharan slaves to work in the sugar plantations, and Cabo Verde served as a pivotal market in the Atlantic slave trade and was populated by individuals coming from the Senegambia region of the West African coast. The population of Madeira shows the highest genetic diversity and the presence of alleles and haplotypes usually linked to sub-Saharan populations, the haplotypes accounting for 3.5% of the total. Cabo Verde presents typical markers acknowledged to be of European or Ibero-Mediterranean origin, thus revealing the admixture of European settlers with Sub-Saharan slaves. Altogether the number of European haplotypes reaches 15% of the total. The Portuguese population shows a perceivable and significant heterogeneity both in allele and haplotype frequencies, unveiling a differential input of peoples from different origins. A PCA of the populations studied, plus other relevant ones, clearly shows gene heterogeneity in mainland Portugal as well as the differences and relationships between these populations and Madeira and Cabo Verde. PMID:12418969

  17. Biased gene conversion skews allele frequencies in human populations, increasing the disease burden of recessive alleles.

    PubMed

    Lachance, Joseph; Tishkoff, Sarah A

    2014-10-01

    Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications. PMID:25279983

  18. Characterizing allelic association in the genome era

    PubMed Central

    WEIR, B. S.; LAURIE, C. C.

    2015-01-01

    Summary Whole genome data are allowing the estimation of population genetic parameters with an accuracy not imagined 50 years ago. Variation in these parameters along the genome is being found empirically where once only approximate theoretical values were available. Along with increased information, however, has come the issue of multiple testing and the realization that high values of the coefficients of variation of quantities such as relatedness measures may make it difficult to draw inferences. This review concentrates on measures of allelic association within and between individuals and within and between populations. PMID:21429275

  19. Allelic genealogies in sporophytic self-incompatibility systems in plants.

    PubMed Central

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

    1998-01-01

    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. PMID:9799270

  20. The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles

    PubMed Central

    Powers, Natalie R; Eicher, John D; Miller, Laura L; Kong, Yong; Smith, Shelley D; Pennington, Bruce F; Willcutt, Erik G; Olson, Richard K; Ring, Susan M; Gruen, Jeffrey R

    2016-01-01

    Background Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6. Objective To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319. Methods We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap. Results and conclusions READ1 and KIAHap show interdependence—READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction. PMID:26660103

  1. Genotype and allele frequency of CYP2C19*17 in a healthy Iranian population

    PubMed Central

    Payan, Maryam; Tajik, Nader; Rouini, Mohammad Reza; Ghahremani, Mohammad Hossein

    2015-01-01

    Background: Cytochrome P450 2C19 (CYP2C19) is important in metabolism of wide range of drugs. CYP2C19*17 is a novel variant allele which increases gene transcription and therefore results in ultra-rapid metabolizer phenotype (URM). Distribution of this variant allele has not been well studied worldwide. The aim of present study was to investigate allele and genotype frequencies of CYP2C19*17 in a healthy Iranian population and compare them with other ethnic groups. Methods: One hundred eighty healthy unrelated Iranian volunteer took part in this study and were genotyped for CYP2C19 *2, *3, *17 (-3402) by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and CYP2C19*17 (-806) by a nested-PCR assays. The distribution of CYP2C19*17 polymorphism in Iranian population was then compared with other ethnic groups. Results: The CYP2C19*17 allele frequency was 21.6% in Iranian population. Among studied subjects 5.5% were homozygous for CYP2C19*17 and phenotyped as ultra-rapid metabolizers; 28.8% were genotyped as CYP2C19*1*17 (extensive metabolizers) and 3.3% as CYP2C19*2*17 (intermediate metabolizers). Conclusion: The CYP2C19*17 genetic distribution in Iranian population is similar to Middle East or European countries. The high frequency of CYP2C19*17 in Iranian population highlights the importance of this new variant allele in metabolism of CYP2C19 substrates. Thus, future association studies are required to reveal clinical consequence of this genetic polymorphism in carrier individuals.

  2. Distribution of CYP2D6 Alleles and Phenotypes in the Brazilian Population

    PubMed Central

    Sortica, Vinicius A.; Suarez-Kurtz, Guilherme; de Moraes, Maria Elizabete; Pena, Sergio D. J.; dos Santos, Ândrea K. Ribeiro; Romano-Silva, Marco A.; Hutz, Mara H.

    2014-01-01

    Abstract The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The CYP2D6 gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of CYP2D6 alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and CYP2D6 duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen CYP2D6 alleles were identified in the Brazilian population. The CYP2D6*1 and CYP2D6*2 alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of CYPD6 alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil) to 10.2% (Northern Brazil). The analysis of molecular variance showed that CYP2D6 is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%). Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique CYP2D6 testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions. PMID:25329392

  3. Exquisite allele discrimination by toehold hairpin primers

    PubMed Central

    Byrom, Michelle; Bhadra, Sanchita; Jiang, Yu Sherry; Ellington, Andrew D.

    2014-01-01

    The ability to detect and monitor single nucleotide polymorphisms (SNPs) in biological samples is an enabling research and clinical tool. We have developed a surprising, inexpensive primer design method that provides exquisite discrimination between SNPs. The field of DNA computation is largely reliant on using so-called toeholds to initiate strand displacement reactions, leading to the execution of kinetically trapped circuits. We have now similarly found that the short toehold sequence to a target of interest can initiate both strand displacement within the hairpin and extension of the primer by a polymerase, both of which will further stabilize the primer:template complex. However, if the short toehold does not bind, neither of these events can readily occur and thus amplification should not occur. Toehold hairpin primers were used to detect drug resistance alleles in two genes, rpoB and katG, in the Mycobacterium tuberculosis genome, and ten alleles in the Escherichia coli genome. During real-time PCR, the primers discriminate between mismatched templates with Cq delays that are frequently so large that the presence or absence of mismatches is essentially a ‘yes/no’ answer. PMID:24990378

  4. Deleterious Alleles in the Human Genome Are on Average Younger Than Neutral Alleles of the Same Frequency

    PubMed Central

    Kiezun, Adam; Pulit, Sara L.; Francioli, Laurent C.; van Dijk, Freerk; Swertz, Morris; Boomsma, Dorret I.; van Duijn, Cornelia M.; Slagboom, P. Eline; van Ommen, G. J. B.; Wijmenga, Cisca; de Bakker, Paul I. W.; Sunyaev, Shamil R.

    2013-01-01

    Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669–673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans. PMID:23468643

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

    PubMed

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

    2012-04-01

    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 human leukocyte antigen (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 observed the largest differences between the groups 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 disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain the increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes. PMID:22326585

  6. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain

    PubMed Central

    Richards, Alexander L; Jones, Lesley; Moskvina, Valentina; Kirov, George; Gejman, Pablo V; Levinson, Douglas F; Sanders, Alan R; Purcell, Shaun; Visscher, Peter M; Craddock, Nick; Owen, Michael J; Holmans, Peter; ODonovan, Michael C

    2016-01-01

    It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. Since only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among SNPs selected for marginal evidence for association (p<0.5) from genome wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs which are also eQTLs should carry more true association signals compared with SNPs which are not. To test this, we identified marginally associated (p<0.5) SNPs from two of the largest available schizophrenia GWAS datasets. We assigned eQTL status to those SNPs based upon an eQTL dataset derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can in principle allow relevant susceptibility eQTLs to be identified. PMID:21339752

  7. Four novel PEPD alleles causing prolidase deficiency.

    PubMed Central

    Ledoux, P.; Scriver, C.; Hechtman, P.

    1994-01-01

    Mutations at the PEPD locus cause prolidase 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. We used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragment spanning all or part of exons 13-15 in three of the probands. Direct sequencing of the mutant cDNAs showed a G-->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-->C substitution at position -1 of intron 4 and an A-->G substitution at position -2 of intron 6. Our results indicate that the severe form of prolidase deficiency is caused by multiple PEPD alleles. In this report we attempt to begin the process of describing these alleles and cataloging their phenotypic expression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:8198124

  8. Wheat alleles introgress into selfing wild relatives: empirical estimates from approximate Bayesian computation in Aegilops triuncialis.

    PubMed

    Pajkovic, Mila; Lappe, Sylvain; Barman, Rachel; Parisod, Christian; Neuenschwander, Samuel; Goudet, Jerome; Alvarez, Nadir; Guadagnuolo, Roberto; Felber, Franois; Arrigo, Nils

    2014-10-01

    Extensive gene flow between wheat (Triticum sp.) and several wild relatives of the genus Aegilops has recently been detected despite notoriously high levels of selfing in these species. Here, we assess and model the spread of wheat alleles into natural populations of the barbed goatgrass (Aegilops triuncialis), a wild wheat relative prevailing in the Mediterranean flora. Our sampling, based on an extensive survey of 31 Ae. triuncialis populations collected along a 60 km 20 km area in southern Spain (Grazalema Mountain chain, Andalousia, totalling 458 specimens), is completed with 33 wheat cultivars representative of the European domesticated pool. All specimens were genotyped with amplified fragment length polymorphism with the aim of estimating wheat admixture levels in Ae. triuncialis populations. This survey first confirmed extensive hybridization and backcrossing of wheat into the wild species. We then used explicit modelling of populations and approximate Bayesian computation to estimate the selfing rate of Ae. triuncialis along with the magnitude, the tempo and the geographical distance over which wheat alleles introgress into Ae. triuncialis populations. These simulations confirmed that extensive introgression of wheat alleles (2.7 10(-4) wheat immigrants for each Ae. triuncialis resident, at each generation) into Ae. triuncialis occurs despite a high selfing rate (Fis ? 1 and selfing rate = 97%). These results are discussed in the light of risks associated with the release of genetically modified wheat cultivars in Mediterranean agrosystems. PMID:25223217

  9. Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression.

    PubMed

    Burkhardt, Jana; Blume, Mechthild; Petit-Teixeira, Elisabeth; Hugo Teixeira, Vitor; Steiner, Anke; Quente, Elfi; Wolfram, Grit; Scholz, Markus; Pierlot, Cline; Migliorini, Paola; Bombardieri, Stefano; Balsa, Alejandro; Westhovens, Ren; Barrera, Pilar; Radstake, Timothy R D J; Alves, Helena; Bardin, Thomas; Prum, Bernard; Emmrich, Frank; Cornelis, Franois; Ahnert, Peter; Kirsten, Holger

    2014-01-01

    In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies?=?407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal?=?0.003). This allele was also expressed preferentially (p<10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1?=?0.004; p2?=?0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA. PMID:25147926

  10. Linkage Disequilibrium and Allele-Frequency Distributions for 114 Single-Nucleotide Polymorphisms in Five Populations

    PubMed Central

    Goddard, Katrina A. B.; Hopkins, Penelope J.; Hall, Jeff M.; Witte, John S.

    2000-01-01

    Summary Single-nucleotide polymorphisms (SNPs) may be extremely important for deciphering the impact of genetic variation on complex human diseases. The ultimate value of SNPs for linkage and association mapping studies depends in part on the distribution of SNP allele frequencies and intermarker linkage disequilibrium (LD) across populations. Limited information is available about these distributions on a genomewide scale, particularly for LD. Using 114 SNPs from 33 genes, we compared these distributions in five American populations (727 individuals) of African, European, Chinese, Hispanic, and Japanese descent. The allele frequencies were highly correlated across populations but differed by >20% for at least one pair of populations in 35% of SNPs. The correlation in LD was high for some pairs of populations but not for others (e.g., Chinese American or Japanese American vs. any other population). Regardless of population, average minor-allele frequencies were significantly higher for SNPs in noncoding regions (20%25%) than for SNPs in coding regions (12%16%). Interestingly, we found that intermarker LD may be strongest with pairs of SNPs in which both markers are nonconservative substitutions, compared to pairs of SNPs where at least one marker is a conservative substitution. These results suggest that population differences and marker location within the gene may be important factors in the selection of SNPs for use in the study of complex disease with linkage or association mapping methods. PMID:10631153

  11. First report on HLA-DPA1 gene allelic distribution in the general Lebanese population

    PubMed Central

    Haddad, Joseph; Shammaa, Dina; Abbas, Fatmeh; Mahfouz, Rami A.R.

    2016-01-01

    Aims HLA-DPA1 is an important marker in bone marrow and organ transplantation and a highly emerging screening parameter in histocompatibility laboratories. Being highly polymorphic, it has another significant value in detecting population origins and migrations. This is the first study to assess DPA1 allele frequencies in an Arab population. Methods The HLA DPA1 alleles were identified using the One-Lambda assays on a Luminex reverse SSO DNA typing system. Our study included 101 individuals coming from different Lebanese geographical areas representing the different communities and religious sects of the country. Results We compared the results of this study to 16 different populations and found very interesting similarities and differences between Lebanese people and individuals of European ancestry. Conclusion This study is the first to describe the different allelic frequencies of HLA-DPA1 in the Lebanese population and will serve as a template that can be later used for disease association studies both at the level of the country and internationally. PMID:27014585

  12. Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression

    PubMed Central

    Petit-Teixeira, Elisabeth; Hugo Teixeira, Vitor; Steiner, Anke; Quente, Elfi; Wolfram, Grit; Scholz, Markus; Pierlot, Cline; Migliorini, Paola; Bombardieri, Stefano; Balsa, Alejandro; Westhovens, Ren; Barrera, Pilar; Radstake, Timothy R. D. J.; Alves, Helena; Bardin, Thomas; Prum, Bernard; Emmrich, Frank; Cornelis, Franois

    2014-01-01

    In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies?=?407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal?=?0.003). This allele was also expressed preferentially (p<10?6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1?=?0.004; p2?=?0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA. PMID:25147926

  13. Novel thymidylate synthase enhancer region alleles in African populations.

    PubMed

    Marsh, S; Ameyaw, M M; Githang'a, J; Indalo, A; Ofori-Adjei, D; McLeod, H L

    2000-12-01

    Thymidylate synthase (TS) regulates the production of DNA synthesis precursors and is an important target of cancer chemotherapy. A polymorphic tandem repeat sequence in the enhancer region of the TS promoter was previously described, where the triple repeat gives higher in vitro gene expression than a double repeat. We recently identified ethnic differences in allele frequencies between Caucasian and Asian populations. We now describe assessment of genotype and allele frequencies of the TS polymorphism in 640 African (African American, Ghanaian and Kenyan) and Caucasian (UK, USA) subjects. The double and triple repeat were the predominant alleles in all populations studied. The frequency of the triple repeat allele was similar between Kenyan (49%), Ghanaian (56%), African American (52%), American Caucasian (54%) and British Caucasian (54%) subjects. However, two novel alleles contained 4 and 9 copies of the tandem repeat. These novel alleles were found at a higher allele frequency in African populations (Kenyan 7%, Ghanaian 3%, African American 2%) than Caucasians (UK 1%, USA 0%). The novel alleles identified in this study decrease in frequency with Western migration, while the common alleles are relatively stable. This is a unique example suggesting the influence of multiple selection pressures within individual populations. Hum Mutat 16:528, 2000. PMID:11102983

  14. Analyses of Allele-Specific Gene Expression in Highly Divergent Mouse Crosses Identifies Pervasive Allelic Imbalance

    PubMed Central

    Crowley, James J; Zhabotynsky, Vasyl; Sun, Wei; Huang, Shunping; Pakatci, Isa Kemal; Kim, Yunjung; Wang, Jeremy R; Morgan, Andrew P; Calaway, John D; Aylor, David L; Yun, Zaining; Bell, Timothy A; Buus, Ryan J; Calaway, Mark E; Didion, John P; Gooch, Terry J; Hansen, Stephanie D; Robinson, Nashiya N; Shaw, Ginger D; Spence, Jason S; Quackenbush, Corey R; Barrick, Cordelia J; Nonneman, Randal J.; Kim, Kyungsu; Xenakis, James; Xie, Yuying; Valdar, William; Lenarcic, Alan B; Wang, Wei; Welsh, Catherine E; Fu, Chen-Ping; Zhang, Zhaojun; Holt, James; Guo, Zhishan; Threadgill, David W; Tarantino, Lisa M; Miller, Darla R; Zou, Fei; McMillan, Leonard; Sullivan, Patrick F; de Villena, Fernando Pardo-Manuel

    2015-01-01

    Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Since regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in this process. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. These effects influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a novel, global allelic imbalance in favor of the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals. PMID:25730764

  15. Identification of the third/extra allele for forensic application in cases with TPOX tri-allelic pattern.

    PubMed

    Picano, Juliane Bentes; Raimann, Paulo Eduardo; da Motta, Carlos Henrique Ares Silveira; Rodenbusch, Rodrigo; Gusmo, Leonor; Alho, Clarice Sampaio

    2015-05-01

    Genotyping of polymorphic short tandem repeats (STRs) loci is widely used in forensic DNA analysis. STR loci eventually present tri-allelic pattern as a genotyping irregularity and, in that situation, the doubt about the tri-allele locus frequency calculation can reduce the analysis strength. In the TPOX human STR locus, tri-allelic genotypes have been reported with a widely varied frequency among human populations. We investigate whether there is a single extra allele (the third allele) in the TPOX tri-allelic pattern, what it is, and where it is, aiming to understand its genomic anatomy and to propose the knowledge of this TPOX extra allele from genetic profile, thus preserving the two standard TPOX alleles in forensic analyses. We looked for TPOX tri-allelic subjects in 75,113 Brazilian families. Considering only the parental generation (mother+father) we had 150,226 unrelated subjects evaluated. From this total, we found 88 unrelated subjects with tri-allelic pattern in the TPOX locus (0.06%; 88/150,226). Seventy three of these 88 subjects (73/88; 83%) had the Clayton's original Type 2 tri-allelic pattern (three peaks of even intensity). The remaining 17% (15/88) show a new Type 2 derived category with heterozygote peak imbalance (one double dose peak plus one regular sized peak). In this paper we present detailed data from 66 trios (mother+father+child) with true biological relationships. In 39 of these families (39/66; 59%) the extra TPOX allele was transmitted either from the mother or from the father to the child. Evidences indicated the allele 10 as the extra TPOX allele, and it is on the X chromosome. The present data, which support the previous Lane hypothesis, improve the knowledge about tri-allelic pattern of TPOX CODIS' locus allowing the use of TPOX profile in forensic analyses even when with tri-allelic pattern. This evaluation is now available for different forensic applications. PMID:25549886

  16. Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations.

    PubMed

    Kim-Howard, Xana; Sun, Celi; Molineros, Julio E; Maiti, Amit K; Chandru, Hema; Adler, Adam; Wiley, Graham B; Kaufman, Kenneth M; Kottyan, Leah; Guthridge, Joel M; Rasmussen, Astrid; Kelly, Jennifer; Snchez, Elena; Raj, Prithvi; Li, Quan-Zhen; Bang, So-Young; Lee, Hye-Soon; Kim, Tae-Hwan; Kang, Young Mo; Suh, Chang-Hee; Chung, Won Tae; Park, Yong-Beom; Choe, Jung-Yoon; Shim, Seung Cheol; Lee, Shin-Seok; Han, Bok-Ghee; Olsen, Nancy J; Karp, David R; Moser, Kathy; Pons-Estel, Bernardo A; Wakeland, Edward K; James, Judith A; Harley, John B; Bae, Sang-Cheol; Gaffney, Patrick M; Alarcn-Riquelme, Marta; Looger, Loren L; Nath, Swapan K

    2014-03-15

    Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (P(EA) = 1.01 10(-54), PHS = 3.68 10(-10), P(AA) = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 10(-9)), and rs13306575 in HS and KR (P(HS) = 7.04 10(-7), P(KR) = 3.30 10(-3)). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 10(-7)), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE. PMID:24163247

  17. Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations

    PubMed Central

    Kim-Howard, Xana; Sun, Celi; Molineros, Julio E.; Maiti, Amit K.; Chandru, Hema; Adler, Adam; Wiley, Graham B.; Kaufman, Kenneth M.; Kottyan, Leah; Guthridge, Joel M.; Rasmussen, Astrid; Kelly, Jennifer; Snchez, Elena; Raj, Prithvi; Li, Quan-Zhen; Bang, So-Young; Lee, Hye-Soon; Kim, Tae-Hwan; Kang, Young Mo; Suh, Chang-Hee; Chung, Won Tae; Park, Yong-Beom; Choe, Jung-Yoon; Shim, Seung Cheol; Lee, Shin-Seok; Han, Bok-Ghee; Olsen, Nancy J.; Karp, David R.; Moser, Kathy; Pons-Estel, Bernardo A.; Wakeland, Edward K.; James, Judith A.; Harley, John B.; Bae, Sang-Cheol; Gaffney, Patrick M.; Alarcn-Riquelme, Marta; Looger, Loren L.; Nath, Swapan K.; Acevedo, Eduardo; Acevedo, Eduardo; La Torre, Ignacio Garca-De; Maradiaga-Cecea, Marco A.; Cardiel, Mario H.; Esquivel-Valerio, Jorge A.; Rodriguez-Amado, Jacqueline; Moctezuma, Jos Francisco; Miranda, Pedro; Perandones, Carlos; Aires, Buenos; Castel, Cecilia; Laborde, Hugo A.; Alba, Paula; Musuruana, Jorge; Goecke, Annelise; Foster, Carola; Orozco, Lorena; Baca, Vicente

    2014-01-01

    Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (PEA = 1.01 10?54, PHS = 3.68 10?10, PAA = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 10?9), and rs13306575 in HS and KR (PHS = 7.04 10?7, PKR = 3.30 10?3). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 10?7), implying that SLE predisposing variants were tagged. Significant SNPSNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance (missing heritability) of complex diseases like SLE. PMID:24163247

  18. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots

    PubMed Central

    Baker, Christopher L.; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M.; Paigen, Kenneth

    2015-01-01

    Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape. PMID:26368021

  19. Distributions of HLA class I alleles and haplotypes in Bulgarians--contribution to understanding the origin of the population.

    PubMed

    Ivanova, M; Spassova, P; Michailova, A; Naumova, E

    2001-03-01

    In this study we present for the first time HLA class I allele and haplotype frequencies at DNA level in the Bulgarian population. HLA class I profile of Bulgarians has been compared to other European and Mediterranean populations of common historical background in order to clarify more precisely the origin of our population. Genetic distances, phylogenetic trees and correspondence analyses show that the Bulgarian population is more closely related to the Italian, the Mediterranean, the Armenian and the Romanian population than to the other East and West European population. This is further supported by the analysis of HLA class I haplotypes in Bulgarians. Most of them are also common in Europe. However their frequency pattern in Bulgarians is similar to the South European populations. The presence of some rare alleles and haplotypes indicated Asian genetic inflow. On the basis of HLA class I profile and supported by historical and anthropological data, we suggest that the Bulgarian population is characterized by the features of the Southern European anthropological type with some influence of other groups such as Asians, Turks, Armenians. Migrations and assimilation of many different ethnic groups are the major factor determining the genetic diversity of our population. PMID:11285128

  20. Molecular inversion probe assay for allelic quantitation

    PubMed Central

    Ji, Hanlee; Welch, Katrina

    2010-01-01

    Molecular inversion probe (MIP) technology has been demonstrated to be a robust platform for large-scale dual genotyping and copy number analysis. Applications in human genomic and genetic studies include the possibility of running dual germline genotyping and combined copy number variation ascertainment. MIPs analyze large numbers of specific genetic target sequences in parallel, relying on interrogation of a barcode tag, rather than direct hybridization of genomic DNA to an array. The MIP approach does not replace, but is complementary to many of the copy number technologies being performed today. Some specific advantages of MIP technology include: Less DNA required (37 ng vs. 250 ng), DNA quality less important, more dynamic range (amplifications detected up to copy number 60), allele specific information cleaner (less SNP crosstalk/contamination), and quality of markers better (fewer individual MIPs versus SNPs needed to identify copy number changes). MIPs can be considered a candidate gene (targeted whole genome) approach and can find specific areas of interest that otherwise may be missed with other methods. PMID:19488872

  1. Biased Allelic Expression in Human Primary Fibroblast Single Cells

    PubMed Central

    Borel, Christelle; Ferreira, Pedro G.; Santoni, Federico; Delaneau, Olivier; Fort, Alexandre; Popadin, Konstantin Y.; Garieri, Marco; Falconnet, Emilie; Ribaux, Pascale; Guipponi, Michel; Padioleau, Ismael; Carninci, Piero; Dermitzakis, Emmanouil T.; Antonarakis, Stylianos E.

    2015-01-01

    The study of gene expression in mammalian single cells via genomic technologies now provides the possibility to investigate the patterns of allelic gene expression. We used single-cell RNA sequencing to detect the allele-specific mRNA level in 203 single human primary fibroblasts over 133,633 unique heterozygous single-nucleotide variants (hetSNVs). We observed that at the snapshot of analyses, each cell contained mostly transcripts from one allele from the majority of genes; indeed, 76.4% of the hetSNVs displayed stochastic monoallelic expression in single cells. Remarkably, adjacent hetSNVs exhibited a haplotype-consistent allelic ratio; in contrast, distant sites located in two different genes were independent of the haplotype structure. Moreover, the allele-specific expression in single cells correlated with the abundance of the cellular transcript. We observed that genes expressing both alleles in the majority of the single cells at a given time point were rare and enriched with highly expressed genes. The relative abundance of each allele in a cell was controlled by some regulatory mechanisms given that we observed related single-cell allelic profiles according to genes. Overall, these results have direct implications in cellular phenotypic variability. PMID:25557783

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

    PubMed Central

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

    1980-01-01

    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. PMID:17249018

  3. The frequency of HLA alleles in the Romanian population.

    PubMed

    Constantinescu, Ileana; Bo?caiu, Voicu; Cianga, Petru; Dinu, Andrei-Antoniu; Gai, Elena; Melinte, Mihaela; Moise, Ana

    2016-03-01

    Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania. PMID:26711124

  4. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences. PMID:26416087

  5. CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles

    PubMed Central

    Pretto, Dalyir I.; Mendoza-Morales, Guadalupe; Lo, Joyce; Cao, Ru; Hadd, Andrew; Latham, Gary J.; Durbin-Johnson, Blythe; Hagerman, Randi; Tassone, Flora

    2014-01-01

    Background Greater than 200 CGG repeats in the 5′UTR of the FMR1 gene leads to epigenetic silencing and lack of the FMR1 protein, causing Fragile X Syndrome. Individuals carriers of a premutation (PM) allele with 55–200 CGG repeats are typically unmethylated and can present with clinical features defined as FMR1 associated conditions. Methods Blood samples from 17 male PM carriers were assessed clinically and molecularly by Southern Blot, Western Blot, PCR and QRT-PCR. Blood and brain tissue from additional 18 PM males were also similarly examined. Continuous outcomes were modeled using linear regression and binary outcomes were modeled using logistic regression. Results Methylated alleles were detected in different fractions of blood cells in all PM cases (n= 17). CGG repeat numbers correlated with percent of methylation and mRNA levels and, especially in the upper PM range, with greater number of clinical involvements. Inter/intra- tissue somatic instability and differences in percent methylation were observed between blood and fibroblasts (n=4) and also observed between blood and different brain regions in three of the 18 premutation cases examined. CGG repeat lengths in lymphocytes remained unchanged over a period of time ranging from 2–6 years, three cases for whom multiple samples were available. Conclusion In addition to CGG size instability, individuals with a PM expanded alleles can exhibit methylation and display more clinical features likely due to RNA toxicity and/or FMR1 silencing. The observed association between CGG repeat length and percent of methylation with the severity of the clinical phenotypes underscores the potential value of methylation in affected PM to further understand penetrance, inform diagnosis and to expand treatment options. PMID:24591415

  6. 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

    Golovchenko, Maryna; Hnig, Vclav; Malltov, Nadja; Krbkov, Lenka; Mikulek, Peter; Fedorova, Natalia; Belfiore, Natalia M.; Grubhoffer, Libor; Lane, Robert S.; Oliver, James H.

    2013-01-01

    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

  7. 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

    Rudenko, Nataliia; Golovchenko, Maryna; Hnig, Vclav; Malltov, Nadja; Krbkov, Lenka; Mikulsek, Peter; Fedorova, Natalia; Belfiore, Natalia M; Grubhoffer, Libor; Lane, Robert S; Oliver, James H

    2013-03-01

    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

  8. Allele frequencies at microsatellite loci: The stepwise mutation model revisited

    SciTech Connect

    Valdes, A.M.; Slatkin, M. ); Freimer, N.B. )

    1993-03-01

    The authors summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. They show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. It is also shown that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size. 39 refs., 6 figs., 4 tabs.

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

    PubMed Central

    2014-01-01

    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 133.3kb from the core) and to a lesser extent in Europeans (3.5, at 37.7kb) and Asians (2.8, at ?29.7kb). 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 10,000years which coincides with the development of systematic agricultural practices. PMID:24690327

  10. MHC class II genes in European wolves: a comparison with dogs.

    PubMed

    Seddon, Jennifer M; Ellegren, Hans

    2002-10-01

    The genome of the grey wolf, one of the most widely distributed land mammal species, has been subjected to both stochastic factors, including biogeographical subdivision and population fragmentation, and strong selection during the domestication of the dog. To explore the effects of drift and selection on the partitioning of MHC variation in the diversification of species, we present nine DQA, 10 DQB, and 17 DRB1 sequences of the second exon for European wolves and compare them with sequences of North American wolves and dogs. The relatively large number of class II alleles present in both European and North American wolves attests to their large historical population sizes, yet there are few alleles shared between these regions at DQB and DRB1. Similarly, the dog has an extensive array of class II MHC alleles, a consequence of a genetically diverse origin, but allelic overlap with wolves only at DQA. Although we might expect a progression from shared alleles to shared allelic lineages during differentiation, the partitioning of diversity between wolves and dogs at DQB and DRB1 differs from that at DQA. Furthermore, an extensive region of nucleotide sequence shared between DRB1 and DQB alleles and a shared motif suggests intergenic recombination may have contributed to MHC diversity in the Canidae. PMID:12389097

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

    PubMed Central

    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.; Vil, Luis M.; Alarcn, 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

    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?=?6.510?10, odds ratio (OR) (95%CI)?=?1.27 (1.171.36)]. 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?=?7.510?11, OR?=?1.24 [1.181.34]). 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?=?2.010?19, OR?=?1.25 [1.201.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148. PMID:23468661

  12. Multiple sclerosis susceptibility alleles in African Americans

    PubMed Central

    Johnson, Britt A.; Wang, Joanne; Taylor, Elise M.; Caillier, Stacy J.; Herbert, Joseph; Khan, Omar A.; Cross, Anne H.; De Jager, Philip L.; Gourraud, Pierre-Antoine F.; Cree, Bruce C.A.; Hauser, Stephen L.; Oksenberg, Jorge R.

    2009-01-01

    Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American dataset. EVI5 showed the strongest association outside the MHC (rs10735781, OR = 1.233, 95% CI = 1.061.43, P value = 0.006). In addition, RGS1 appears to affect age of onset whereas TNFRSF1A appears to be associated with disease progression. None of the tested variants showed results that were statistically in-consistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry. PMID:19865102

  13. Analysis and interpretation of short tandem repeat microvariants and three-banded allele patterns using multiple allele detection systems.

    PubMed

    Crouse, C A; Rogers, S; Amiott, E; Gibson, S; Masibay, A

    1999-01-01

    The Palm Beach County Sheriffs Office (PBSO) Crime Laboratory and the Alabama Department of Forensic Sciences (ADFS) have validated and implemented analysis of short tandem repeat (STR) sequences on casework using silver staining kit and SYBR Green I detection systems and are presently validating fluorescently tagged STR alleles using the Hitachi FMBIO 100 instrument. Concurrently, the Broward County Sheriff's Office (BSO) Crime Laboratory is validating the ABI Prism310 Genetic Analyzer capillary electrophoresis STR detection system (ABI CE310) from Perkin Elmer Applied BioSystems. During the course of analyzing over 10,000 individuals for the STR loci CSF1PO, TPOX and THO1 (CTT) using silver staining for allele detection, 42 samples demonstrated alleles that were "off ladder," contained three-banded patterns at a single locus, or exhibited an apparent THO1 "9.3,10" allele pattern. PBSO, ADFS and BSO Crime Laboratories have collaborated on the verification of the allele patterns observed in these 42 samples using the following allele detection systems: (1) manual silver staining, (2) SYBR Green I staining, and/or (3) fluorescently tagged amplified products separated by polyacrylamide gel electrophoresis or capillary electrophoresis followed by laser detection. Regardless of the CTT allele detection system utilized, concordant results were obtained for 41 of the 42 samples. The only exception was a sample in which a wide band within the THO1 locus was identified as a THO1 "9.3, 10" genotype by silver staining kit and SYBR Green I staining but was verified to be a THO1 "9.3" homozygote by all other allele detection systems. Manual allele detection could readily identify microvariants, as a visual assessment of stained gels clearly shows that alleles do not migrate coincident with well-characterized allele size standards. As would be predicted, however, the manual detection systems did not provide adequate resolution to approximate the basepair size for off-ladder variants. All fluorescent software program systems were consistent in designating alleles "not in range" or "off ladder," thereby indicating true microvariants. All single-locus three-banded patterns were detected using all of the STR multiplex systems. In addition, individual locus-specific primers verified multiplexed amplified products were specific for the locus in question. PMID:9987875

  14. Estimating the time since the fixation of a beneficial allele.

    PubMed Central

    Przeworski, Molly

    2003-01-01

    The fixation of a beneficial allele in a population leaves a well-characterized signature in patterns of nucleotide variation at linked sites. This signature can be used to estimate the time since fixation from patterns of polymorphism in extant individuals. I introduce a method to assess the support in polymorphism data for a recent episode of directional positive selection and to estimate the time since fixation. I summarize the polymorphism data by three statistics that carry information about levels of diversity, the allele frequency spectrum, and the extent of allelic associations. Simulations are then used to obtain a sample from the posterior distribution of the time since fixation, conditional on the observed summaries. I test the performance of the approach on simulated data and apply it to the gene tb1 in maize. The data support the recent fixation of a favored allele, consistent with what is known about the importance of tb1 in the domestication process of maize. PMID:12930770

  15. A New Electrophoresis Technique to Seperate Microsatellite Alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Traditional agarose and polyacrylamide gel electrophoresis have been used commonly for microsatellite (simple sequence repeats, SSRs) analysis, but they are labor- intensive and not always able to provide accurate sizes for different alleles. Capillary sequencers provide automated analysis and accur...

  16. Identification of incompatibility alleles in the tetraploid species sour cherry.

    PubMed

    Tobutt, K R; Boskovi?, R; Cerovi?, R; Sonneveld, T; Ruzi?, D

    2004-03-01

    The incompatibility genetics of sour cherry ( Prunus cerasus), an allotetraploid species thought to be derived from sweet cherry (diploid) and ground cherry (tetraploid), were investigated by test crossing and by analysis of stylar ribonucleases which are known to be the products of incompatibility alleles in sweet cherry. Stylar extracts of 36 accessions of sour cherry were separated electrophoretically and stained for ribonuclease activity. The zymograms of most accessions showed three bands, some two or four. Of the ten bands seen, six co-migrated with bands that in sweet cherry are attributed to the incompatibility alleles S(1), S(3), S(4), S(6, ) S(9) and S(13). 'Cacanski Rubin', 'Erdi Botermo B', 'Koros' and 'Ujfehertoi Furtos', which showed bands apparently corresponding to S(1) and S(4), were test pollinated with the sweet cherry 'Merton Late' ( S(1) S(4)). Monitoring pollen tube growth, and, in one case, fruit set, showed that these crosses were incompatible and that the four sour cherries indeed have the alleles S(1) and S(4). Likewise, test pollination of 'Marasca Piemonte', 'Marasca Savena' and 'Morello, Dutch' with 'Noble' ( S(6) S(13)) showed that these three sour cherries have the alleles S(6) and S(13). S(13) was very frequent in sour cherry cultivars, but is rare in sweet cherry cultivars, whereas with S(3) the situation is reversed. It was suggested that the other four bands are derived from ground cherry and one of these, provisionally attributed to S(B), occurred frequently in a small set of ground cherry accessions surveyed. Analysing some progenies from sour by sweet crosses by S allele-specific PCR and monitoring the success of some sweet by sour crosses were informative. They indicated mostly disomic inheritance, with sweet cherry S alleles belonging to one locus and, presumably, the ground cherry alleles to the other, and helped clarify the genomic arrangement of the alleles and the interactions in heteroallelic pollen. PMID:14689184

  17. Robust Identification of Local Adaptation from Allele Frequencies

    PubMed Central

    Gnther, Torsten; Coop, Graham

    2013-01-01

    Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of standardized allele frequencies that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to FST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population poolsa cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org. PMID:23821598

  18. DRD4 dopamine receptor allelic diversity in various primate species

    SciTech Connect

    Adamson, M.; Higley, D.; O`Brien, S.

    1994-09-01

    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.

  19. Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.

    PubMed

    Lalani, Seema R; Liu, Pengfei; Rosenfeld, Jill A; Watkin, Levi B; Chiang, Theodore; Leduc, Magalie S; Zhu, Wenmiao; Ding, Yan; Pan, Shujuan; Vetrini, Francesco; Miyake, Christina Y; Shinawi, Marwan; Gambin, Tomasz; Eldomery, Mohammad K; Akdemir, Zeynep Hande Coban; Emrick, Lisa; Wilnai, Yael; Schelley, Susan; Koenig, Mary Kay; Memon, Nada; Farach, Laura S; Coe, Bradley P; Azamian, Mahshid; Hernandez, Patricia; Zapata, Gladys; Jhangiani, Shalini N; Muzny, Donna M; Lotze, Timothy; Clark, Gary; Wilfong, Angus; Northrup, Hope; Adesina, Adekunle; Bacino, Carlos A; Scaglia, Fernando; Bonnen, Penelope E; Crosson, Jane; Duis, Jessica; Maegawa, Gustavo H B; Coman, David; Inwood, Anita; McGill, Jim; Boerwinkle, Eric; Graham, Brett; Beaudet, Art; Eng, Christine M; Hanchard, Neil A; Xia, Fan; Orange, Jordan S; Gibbs, Richard A; Lupski, James R; Yang, Yaping

    2016-02-01

    The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ?34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations. PMID:26805781

  20. SSR allelic variation in almond (Prunus dulcis Mill.).

    PubMed

    Xie, Hua; Sui, Yi; Chang, Feng-Qi; Xu, Yong; Ma, Rong-Cai

    2006-01-01

    Sixteen SSR markers including eight EST-SSR and eight genomic SSRs were used for genetic diversity analysis of 23 Chinese and 15 international almond cultivars. EST- and genomic SSR markers previously reported in species of Prunus, mainly peach, proved to be useful for almond genetic analysis. DNA sequences of 117 alleles of six of the 16 SSR loci were analysed to reveal sequence variation among the 38 almond accessions. For the four SSR loci with AG/CT repeats, no insertions or deletions were observed in the flanking regions of the 98 alleles sequenced. Allelic size variation of these loci resulted exclusively from differences in the structures of repeat motifs, which involved interruptions or occurrences of new motif repeats in addition to varying number of AG/CT repeats. Some alleles had a high number of uninterrupted repeat motifs, indicating that SSR mutational patterns differ among alleles at a given SSR locus within the almond species. Allelic homoplasy was observed in the SSR loci because of base substitutions, interruptions or compound repeat motifs. Substitutions in the repeat regions were found at two SSR loci, suggesting that point mutations operate on SSRs and hinder the further SSR expansion by introducing repeat interruptions to stabilize SSR loci. Furthermore, it was shown that some potential point mutations in the flanking regions are linked with new SSR repeat motif variation in almond and peach. PMID:16307227

  1. Overdominant alleles in a population of variable size.

    PubMed Central

    Slatkin, M; Muirhead, C A

    1999-01-01

    An approximate method is developed to predict the number of strongly overdominant alleles in a population of which the size varies with time. The approximation relies on the strong-selection weak-mutation (SSWM) method introduced by J. H. Gillespie and leads to a Markov chain model that describes the number of common alleles in the population. The parameters of the transition matrix of the Markov chain depend in a simple way on the population size. For a population of constant size, the Markov chain leads to results that are nearly the same as those of N. Takahata. The Markov chain allows the prediction of the numbers of common alleles during and after a population bottleneck and the numbers of alleles surviving from before a bottleneck. This method is also adapted to modeling the case in which there are two classes of alleles, with one class causing a reduction in fitness relative to the other class. Very slight selection against one class can strongly affect the relative frequencies of the two classes and the relative ages of alleles in each class. PMID:10353917

  2. Allele-specific MMP-3 transcription under in vivo conditions

    SciTech Connect

    Zhu Chaoyong; Odeberg, Jacob; Hamsten, Anders; Eriksson, Per . E-mail: Per.Eriksson@ki.se

    2006-09-29

    A common matrix metalloproteinases-3 (MMP-3) -1612 5A/6A promoter polymorphism is associated with risk for cardiovascular disease, rheumatoid arthritis, and other diseases. Here we used the haplotype chromatin immunoprecipitation method to study allele-specific MMP-3 expression under in vivo conditions in heterozygous THP-1 cells. Pyrosequencing was used to analyse the ratio of 5A-allele to 6A-allele after chromatin immunoprecipitation using an antibody against phosphorylated active RNA polymerase II. There was no allele-specific difference in transcriptional activity during basal conditions, i.e., in unstimulated monocytic THP-1 cells. However, after stimulation of MMP-3 expression by monocyte differentiation or incubation with IL-1{beta}, the haplotype containing the 5A-allele was associated with higher transcriptional activity compared with the 6A-containing haplotype. Electromobility shift assay demonstrated increased binding of nuclear proteins to the 5A-allele after monocyte differentiation. In conclusion, the common MMP-3 5A/6A promoter polymorphism appears to be functional only during specific environmental conditions involving inflammation.

  3. Mucopolysaccharidosis type I. Identification of 93% of mutant alleles in a group of 70 patients

    SciTech Connect

    Bunge, S.; Steglich, C.; Kleijer, W.J.

    1994-09-01

    Mucopolysaccharidosis type I (MPS I) is caused by alpha-L-iduronidase (IDUA) deficiency. Clinical severity ranges from mild (Scheie) and intermediate (Hurler/Scheie) to severe (Hurler) forms. We investigated 70 patients with various MPS I phenotypes for mutations of the IDUA gene. 28 different mutations on 93% of mutant alleles, defining 90% of the genotypes were characterized. The two common missense mutations Q70X and W402X were found on, respectively, 31% and 28% of mutant alleles. However, Q70X is much more frequent in Scandinavia (64%) than in other European countries (16%). L218P (4.3%) and A327P (6.4%) were also identified in several patients, while all other mutations were found on only one or two alleles each. Of the 11 novel mutations identified in this study, G51D, L218P, D315Y, A327P, R489P, E404X, and R621X were associated with severe phenotypes. Eleven different small deletions and insertions were detected (134del12, 964delC, 1132del6, 1782del11, 1995del11, {Delta}D444/445, 252insC, 396insAC, 682insAC, 974ins12, and 1277ins9), most of them causing severe MPS I. Two novel Hurler/Scheie (M504T and W626R) and two novel Scheie point mutations (R89W and R383H) were also identified. Characterization of the primary genetic defect and establishing genotype/phenotype correlation is important for prognostic predictions, evaluation of therapeutic success, and prenatal diagnosis.

  4. Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population.

    PubMed

    Alex, Livy; Chahil, Jagdish Kaur; Lye, Say Hean; Bagali, Pramod; Ler, Lian Wee

    2012-06-01

    Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n=141) and healthy control subjects (n=111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups. By comparing to publicly available data, out of the 137 mono-allelic markers, 23 markers showed significant differences in allele frequency among Malaysians, European Whites, Han Chinese, Yoruba and Gujarati Indians. Our data can serve as reference for others in related fields of study during the planning of their experiments. PMID:22534770

  5. Testing for Ancient Selection Using Cross-population Allele Frequency Differentiation.

    PubMed

    Racimo, Fernando

    2016-02-01

    A powerful way to detect selection in a population is by modeling local allele frequency changes in a particular region of the genome under scenarios of selection and neutrality and finding which model is most compatible with the data. A previous method based on a cross-population composite likelihood ratio (XP-CLR) uses an outgroup population to detect departures from neutrality that could be compatible with hard or soft sweeps, at linked sites near a beneficial allele. However, this method is most sensitive to recent selection and may miss selective events that happened a long time ago. To overcome this, we developed an extension of XP-CLR that jointly models the behavior of a selected allele in a three-population tree. Our method - called "3-population composite likelihood ratio" (3P-CLR) - outperforms XP-CLR when testing for selection that occurred before two populations split from each other and can distinguish between those events and events that occurred specifically in each of the populations after the split. We applied our new test to population genomic data from the 1000 Genomes Project, to search for selective sweeps that occurred before the split of Yoruba and Eurasians, but after their split from Neanderthals, and that could have led to the spread of modern-human-specific phenotypes. We also searched for sweep events that occurred in East Asians, Europeans, and the ancestors of both populations, after their split from Yoruba. In both cases, we are able to confirm a number of regions identified by previous methods and find several new candidates for selection in recent and ancient times. For some of these, we also find suggestive functional mutations that may have driven the selective events. PMID:26596347

  6. An ancestral allele of grapevine transcription factor MYB14 promotes plant defence.

    PubMed

    Duan, Dong; Fischer, Sabine; Merz, Patrick; Bogs, Jochen; Riemann, Michael; Nick, Peter

    2016-04-01

    Stilbene synthase is a key enzyme for the production of the phytoalexin resveratrol. Some clones of Vitis sylvestris, a wild European grapevine species which is almost extinct, have been shown to accumulate more resveratrol in response to different forms of stress. In the current study, we asked whether the induction of stilbene synthase transcripts in Hoe29, one of the V. sylvestris clones with elevated stilbene inducibility, might result from the elevated induction of the transcription factor MYB14. The MYB14 promoter of Hoe29 and of Ke83 (a second stilbene-inducible genotype) harboured distinct regions and were applied to a promoter-reporter system. We show that stilbene synthase inducibility correlates with differences in the induction of MYB14 transcripts for these two genotypes. Both alleles were induced by UV in a promoter-reporter assay, but only the MYB14 promoter from Hoe29 was induced by flg22, consistent with the stilbene synthase expression of the donor genotypes, where both respond to UV but only Hoe29 is responsive to Plasmopara viticola during defence. We mapped upstream signals and found that a RboH-dependent oxidative burst, calcium influx, a MAPK cascade, and jasmonate activated the MYB14 promoter, whereas salicylic acid was ineffective. Our data suggest that the Hoe29 allele of the MYB14 promoter has potential as a candidate target for resistance breeding. PMID:26842984

  7. APOE ε4, an Alzheimer’s disease susceptibility allele, and smoking cessation

    PubMed Central

    Ashare, Rebecca L.; Karlawish, Jason H.; Wileyto, E. Paul; Pinto, Angela; Lerman, Caryn

    2012-01-01

    Possessing an APOE ε4 allele, advanced age, and smoking are risk factors for Alzheimer’s disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ε4 allele (n=252) have more difficulty quitting smoking compared to noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (p=0.04) and time to 7-day failure (p=0.03). Among smokers over age 60, ε4 carriers were less likely to quit (OR=0.27, p=0.018) and relapsed more quickly (HR=3.38, p=0.001) compared to noncarriers. The genotype association with relapse was non-significant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline. PMID:23247396

  8. APOE ɛ4, an Alzheimer's disease susceptibility allele, and smoking cessation.

    PubMed

    Ashare, R L; Karlawish, J H; Wileyto, E P; Pinto, A; Lerman, C

    2013-12-01

    Possessing an apolipoprotein E (APOE) ɛ4 allele, advanced age and smoking are risk factors for Alzheimer's disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ɛ4 allele (n=252) have more difficulty quitting smoking compared with noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (P=0.04) and time to 7-day failure (P=0.03). Among smokers over age 60, ɛ4 carriers were less likely to quit (odds ratio=0.27, P=0.018) and relapsed more quickly (hazard ratio=3.38, P=0.001) compared with noncarriers. The genotype association with relapse was nonsignificant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline. PMID:23247396

  9. An ancestral allele of grapevine transcription factor MYB14 promotes plant defence

    PubMed Central

    Duan, Dong; Fischer, Sabine; Merz, Patrick; Bogs, Jochen; Riemann, Michael; Nick, Peter

    2016-01-01

    Stilbene synthase is a key enzyme for the production of the phytoalexin resveratrol. Some clones of Vitis sylvestris, a wild European grapevine species which is almost extinct, have been shown to accumulate more resveratrol in response to different forms of stress. In the current study, we asked whether the induction of stilbene synthase transcripts in Hoe29, one of the V. sylvestris clones with elevated stilbene inducibility, might result from the elevated induction of the transcription factor MYB14. The MYB14 promoter of Hoe29 and of Ke83 (a second stilbene-inducible genotype) harboured distinct regions and were applied to a promoter–reporter system. We show that stilbene synthase inducibility correlates with differences in the induction of MYB14 transcripts for these two genotypes. Both alleles were induced by UV in a promoter–reporter assay, but only the MYB14 promoter from Hoe29 was induced by flg22, consistent with the stilbene synthase expression of the donor genotypes, where both respond to UV but only Hoe29 is responsive to Plasmopara viticola during defence. We mapped upstream signals and found that a RboH-dependent oxidative burst, calcium influx, a MAPK cascade, and jasmonate activated the MYB14 promoter, whereas salicylic acid was ineffective. Our data suggest that the Hoe29 allele of the MYB14 promoter has potential as a candidate target for resistance breeding. PMID:26842984

  10. Interleukin 6-174 G/C promoter gene polymorphism and sporadic Alzheimer's disease: geographic allele and genotype variations in Europe.

    PubMed

    Capurso, Cristiano; Solfrizzi, Vincenzo; D'Introno, Alessia; Colacicco, Anna M; Capurso, Sabrina A; Capurso, Antonio; Panza, Francesco

    2004-10-01

    The interleukin 6 (IL-6) gene in humans is located in the short arm of chromosome 7 and has a-174 G/C polymorphism in its promoter region. The C allele at position-174 in the promoter of the interleukin 6 (IL-6) gene has been associated with reduced gene expression and reduced plasma levels of IL-6. Given the supposed role of several inflammatory mediators in neurodegeneration and Alzheimer's disease (AD), the IL-6-174 G/C promoter polymorphism has been associated with AD with contrasting findings. First aim of the present study was to investigate whether there was evidence in Southern Italy of an association between the IL-6-174 G/C promoter polymorphism and AD. Secondly, we also tested a possible effect of geographic genetic variations on existing reported associations comparing our results with the findings from published studies on other European populations. We examined apolipoprotein E (APOE) and IL-6-174 G/C promoter polymorphisms in a cohort of 168 sporadic AD patients and 220 sex- and age-matched nondemented controls from Southern Italy. No differences have been found in the IL-6-174 G/C promoter allele and genotype frequencies between AD patients and controls nor in early- and late-onset subsets of AD patients. No statistically significant differences in frequencies between IL-6-174 G/C promoter alleles and AD among APOE allele strata were found. Finally, comparing our results with the findings from other European populations, the IL-6*G/*G genotype frequency showed a statistically significant increasing trend from Northern to Southern regions of Europe in AD patients and controls, with a concomitant increase in IL-6*C/*G genotype frequency. Furthermore, an increasing geographical trend from North to South was found for the IL-6*G allele, with a concomitant inverse trend for IL-6*C allele. We suggest that regional European differences in genotype and allele frequencies of the IL-6-174 G/C promoter polymorphism may explain in part controversial findings on this polymorphism in AD in various European studies. PMID:15501028

  11. European Elder (Elderberry)

    MedlinePLUS

    ... T U V W X Y Z European Elder Share: On This Page Introduction What the Science ... For More Information Key References Common Names: European elder, black elder, elder, elderberry, elder flower, sambucus Latin ...

  12. Impriniting of human H19: Allele-specific CpG methylation, loss of the active allele in Wilms tumor, and potential for somatic allele switching

    SciTech Connect

    Zhang, Y.; Shields, T.; Crenshaw, T.; Hao, Y.; Moulton, T.; Tycko, B. )

    1993-07-01

    Genomic imprinting and monoallelic gene expression appear to play a role in human genetic disease and tumorigenesis. The human H19 gene, at chromosome 11p15, has previously been shown to be monoallelically expressed. Since CpG methylation has been implicated in imprinting, the authors analyzed methylation of H19 DNA. In fetal and adult organs the transcriptionally silent H19 allele was extensively hypermethylated through the entire gene and its promoter, and, consistent with a functional role for DNA methylation, expression of an H19 promoter-reporter construct was inhibited by in vitro methylation. Gynogenetic ovarian teratomas were found to contain only hypomethylated H19 DNA, suggesting that the expressed H19 allele might be maternal. This was confirmed by analysis of 11p15 polymorphisms in a patient with Wilms tumor. The tumor had lost the maternal 11p15, and H19 expression in the normal kidney was exclusively from this allele. Imprinting of human H19 appears to be susceptible to tissue-specific modulation in somatic development; in one individual, cerebellar cells were found to express only the otherwise silent allele. Implications of these findings for the role of DNA methylation in imprinting and for H19 as a candidate imprinted tumor-suppressor gene are discussed. 57 refs., 7 figs.

  13. Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping

    PubMed Central

    Prahalad, Sampath; Walters, Thomas; Guthery, Stephen L.; Dubinsky, Marla; Baldassano, Robert; Crandall, Wallace V.; Rosh, Joel; Markowitz, James; Stephens, Michael; Kellermayer, Richard; Pfefferkorn, Marian; Heyman, Melvin B.; LeLeiko, Neal; Mack, David; Moulton, Dedrick; Kappelman, Michael D.; Kumar, Archana; Prince, Jarod; Bose, Promita; Mondal, Kajari; Ramachandran, Dhanya; Bohnsack, John F.; Griffiths, Anne M.; Haberman, Yael; Essers, Jonah; Thompson, Susan D.; Aronow, Bruce; Keljo, David J.; Hyams, Jeffrey S.; Denson, Lee A.; Kugathasan, Subra

    2015-01-01

    Background The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent. Methods We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohns disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohns disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases. Conclusions The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD. PMID:26098103

  14. Globalization: The European Experience.

    ERIC Educational Resources Information Center

    Goldsmith, Peter

    1996-01-01

    The experience of the United Kingdom and other European countries in designing legal education which responds to the changing needs of the European Union is described. The three-stage British system of legal education is outlined, and the impact of European Union formation discussed briefly. Changes in undergraduate study, professional training,…

  15. Globalization: The European Experience.

    ERIC Educational Resources Information Center

    Goldsmith, Peter

    1996-01-01

    The experience of the United Kingdom and other European countries in designing legal education which responds to the changing needs of the European Union is described. The three-stage British system of legal education is outlined, and the impact of European Union formation discussed briefly. Changes in undergraduate study, professional training,

  16. European biofuel plan snagged

    SciTech Connect

    Chynoweth, E.

    1992-12-16

    European Commission proposals for a directive aimed at boosting production of biofuels have been set back by the European Parliament and will not be implemented on the January 1, 1993 deadline. Furthermore, the commission has agreed to carry out an environmental impact study on biofuels. European industrial ethanol, fatty acid, and glycerin producers oppose the directive proposals fearing distortions in their markets.

  17. How the Number of Alleles Influences Gene Expression

    NASA Astrophysics Data System (ADS)

    Hat, Beata; Paszek, Pawel; Kimmel, Marek; Piechor, Kazimierz; Lipniacki, Tomasz

    2007-07-01

    The higher organisms, eukaryotes, are diploid and most of their genes have two homological copies (alleles). However, the number of alleles in a cell is not constant. In the S phase of the cell cycle all the genome is duplicated and then in the G2 phase and mitosis, which together last for several hours, most of the genes have four copies instead of two. Cancer development is, in many cases, associated with a change in allele number. Several genetic diseases are caused by haploinsufficiency: Lack of one of the alleles or its improper functioning. In the paper we consider the stochastic expression of a gene having a variable number of copies. We applied our previously developed method in which the reaction channels are split into slow (connected with change of gene state) and fast (connected with mRNA/protein synthesis/decay), the later being approximated by deterministic reaction rate equations. As a result we represent gene expression as a piecewise deterministic time-continuous Markov process, which is further related with a system of partial differential hyperbolic equations for probability density functions (pdfs) of protein distribution. The stationary pdfs are calculated analytically for haploidal gene or numerically for diploidal and tetraploidal ones. We distinguished nine classes of simultaneous activation of haploid, diploid and tetraploid genes. This allows for analysis of potential consequences of gene duplication or allele loss. We show that when gene activity is autoregulated by a positive feedback, the change in number of gene alleles may have dramatic consequences for its regulation and may not be compensated by the change of efficiency of mRNA synthesis per allele.

  18. HLA-A, HLA-B and HLA-DRB1 allele and haplotype diversity among volunteer bone marrow donors from Croatia.

    PubMed

    Grubic, Z; Burek Kamenaric, M; Mikulic, M; Stingl Jankovic, K; Maskalan, M; Zunec, R

    2014-06-01

    The determination of human leucocyte antigen (HLA)-A, HLA-B and HLA-DRB1 alleles in the routine procedure of a volunteer hematopoietic stem cell (HSC) donor's registration in the Croatian Bone Marrow Donor Registry (CBMDR) is performed to enhance the odds of finding a suitable HLA compatible donor for patients in need of a HSC transplantation worldwide. However, besides its original purpose, it also provides valuable information about the HLA polymorphism among Croats. The aim of the present study was to analyse the HLA allele and haplotype frequencies in a sample of 4000 donors from CBMDR. The distribution of HLA-A, HLA-B and HLA-DRB1 alleles did not demonstrate significant differences from the data reported for other European populations. The higher frequency of B*40:02 allele in comparison with B*40:01 and DRB1*11:04 in comparison with DRB1*11:01 is interesting because it represents a difference in comparison with the Western and Northern European populations which are a main source of donors for Croatian patients. The haplotype frequencies show a greater variation and difference in comparison with data from other registries and populations; however, due to a lack of high-resolution haplotype data, comparison was possible only with a very limited number of other populations. PMID:24762167

  19. Construction of a library of cloned short tandem repeat (STR) alleles as universal templates for allelic ladder preparation.

    PubMed

    Wang, Le; Zhao, Xing-Chun; Ye, Jian; Liu, Jin-Jie; Chen, Ting; Bai, Xue; Zhang, Jian; Ou, Yuan; Hu, Lan; Jiang, Bo-Wei; Wang, Feng

    2014-09-01

    Short tandem repeat (STR) genotyping methods are widely used for human identity testing applications, including forensic DNA analysis. Samples of DNA containing the length-variant STR alleles are typically separated and genotyped by comparison to an allelic ladder. Here, we describe a newly devised library of cloned STR alleles. The library covers alleles X and Y for the sex-determining locus Amelogenin and 259 other alleles for 22 autosomal STR loci (TPOX, D3S1358, FGA, D5S818, CSF1PO, D7S820, D8S1179, TH01, vWA, D13S317, D16S539, D18S51, D21S11, D2S1338, D6S1043, D12S391, Penta E, D19S433, D11S4463, D17S974, D3S4529 and D12ATA63). New primers were designed for all these loci to construct recombinant plasmids so that the library retains core repeat elements of STR as well as 5'- and 3'-flanking sequences of ∼500 base pairs. Since amplicons of commercial STR genotyping kits and systems developed in laboratories are usually distributed from 50 to <500 base pairs, this library could provide universal templates for allelic ladder preparation. We prepared three different sets of allelic ladders for this locus TH01 and an updated version of an allelic ladder for the DNATyper(®)19 multiplex system using these plasmids to confirm the suitability of the library as a good source for allelic ladder preparation. Importantly, the authenticity of each construct was confirmed by bidirectional nucleotide sequencing and we report the repeat structures of the 259 STR alleles. The sequencing results showed all repeat structures we obtained for TPOX, CSF1PO, D7S820, TH01, D16S539, D18S51 and Penta E were the same as reported. However, we identified 102 unreported repeat structures from the other 15 STR loci, supplementing our current knowledge of repeat structures and leading to further understanding of these widely used loci. PMID:24997318

  20. STR allele sequence variation: Current knowledge and future issues.

    PubMed

    Gettings, Katherine Butler; Aponte, Rachel A; Vallone, Peter M; Butler, John M

    2015-09-01

    This article reviews what is currently known about short tandem repeat (STR) allelic sequence variation in and around the twenty-four loci most commonly used throughout the world to perform forensic DNA investigations. These STR loci include D1S1656, TPOX, D2S441, D2S1338, D3S1358, FGA, CSF1PO, D5S818, SE33, D6S1043, D7S820, D8S1179, D10S1248, TH01, vWA, D12S391, D13S317, Penta E, D16S539, D18S51, D19S433, D21S11, Penta D, and D22S1045. All known reported variant alleles are compiled along with genomic information available from GenBank, dbSNP, and the 1000 Genomes Project. Supplementary files are included which provide annotated reference sequences for each STR locus, characterize genomic variation around the STR repeat region, and compare alleles present in currently available STR kit allelic ladders. Looking to the future, STR allele nomenclature options are discussed as they relate to next generation sequencing efforts underway. PMID:26197946

  1. Allele-specific silencing of dominant disease genes.

    PubMed

    Miller, Victor M; Xia, Haibin; Marrs, Ginger L; Gouvion, Cynthia M; Lee, Gloria; Davidson, Beverly L; Paulson, Henry L

    2003-06-10

    Small interfering RNA (siRNA) holds therapeutic promise for silencing dominantly acting disease genes, particularly if mutant alleles can be targeted selectively. In mammalian cell models we demonstrate that allele-specific silencing of disease genes with siRNA can be achieved by targeting either a linked single-nucleotide polymorphism (SNP) or the disease mutation directly. For a polyglutamine neurodegenerative disorder in which we first determined that selective targeting of the disease-causing CAG repeat is not possible, we took advantage of an associated SNP to generate siRNA that exclusively silenced the mutant Machado-Joseph disease/spinocerebellar ataxia type 3 allele while sparing expression of the WT allele. Allele-specific suppression was accomplished with all three approaches currently used to deliver siRNA: in vitro-synthesized duplexes as well as plasmid and viral expression of short hairpin RNA. We further optimized siRNA to specifically target a missense Tau mutation, V337M, that causes frontotemporal dementia. These studies establish that siRNA can be engineered to silence disease genes differing by a single nucleotide and highlight a key role for SNPs in extending the utility of siRNA in dominantly inherited disorders. PMID:12782788

  2. Apolipoprotein E Allele and Hearing Thresholds in Older Adults

    PubMed Central

    Mener, David J.; Betz, Joshua; Yaffe, Kristine; Harris, Tamara B.; Helzner, Elizabeth P.; Satterfield, Suzanne; Houston, Denise K.; Strotmeyer, Elsa S.; Pratt, Sheila R.; Simonsick, Eleanor M.; Lin, Frank R.

    2014-01-01

    Background Whether ApolipoproteinE (APOE) E4 allele status which is associated with an increased risk of cognitive decline is also associated with hearing impairment is unknown. Methods We studied 1833 men and women enrolled in the Health, Aging and Body Composition study. Regression models adjusted for demographic and cardiovascular risk factors were used to assess the cross-sectional association of APOE-E4 status with individual pure tone hearing thresholds and the 4-frequency pure tone average (0.5 kHz4kHz) in the better hearing ear. Results Compared to participants with no APOE-E4 alleles, participants with one allele had better thresholds at 4.0kHz (?= ?2.72dB, p = 0.013) and 8.0 kHz (?= ?3.05kHz, p = 0.006), and participants with two alleles had better hearing thresholds at 1.0kHz (?= ?8.56dB, p=0.021). Conclusion Our results suggest that APOE-E4 allele status may be marginally associated with better hearing thresholds in older adults. PMID:24906966

  3. Assessing allelic dropout and genotype reliability using maximum likelihood.

    PubMed Central

    Miller, Craig R; Joyce, Paul; Waits, Lisette P

    2002-01-01

    A growing number of population genetic studies utilize nuclear DNA microsatellite data from museum specimens and noninvasive sources. Genotyping errors are elevated in these low quantity DNA sources, potentially compromising the power and accuracy of the data. The most conservative method for addressing this problem is effective, but requires extensive replication of individual genotypes. In search of a more efficient method, we developed a maximum-likelihood approach that minimizes errors by estimating genotype reliability and strategically directing replication at loci most likely to harbor errors. The model assumes that false and contaminant alleles can be removed from the dataset and that the allelic dropout rate is even across loci. Simulations demonstrate that the proposed method marks a vast improvement in efficiency while maintaining accuracy. When allelic dropout rates are low (0-30%), the reduction in the number of PCR replicates is typically 40-50%. The model is robust to moderate violations of the even dropout rate assumption. For datasets that contain false and contaminant alleles, a replication strategy is proposed. Our current model addresses only allelic dropout, the most prevalent source of genotyping error. However, the developed likelihood framework can incorporate additional error-generating processes as they become more clearly understood. PMID:11805071

  4. Puroindoline allelic diversity in Indian wheat germplasm and identification of new allelic variants

    PubMed Central

    Kumar, Rohit; Arora, Shaweta; Singh, Kashmir; Garg, Monika

    2015-01-01

    Grain hardness is an important quality trait that influences product development in wheat. This trait is governed by variation in puroindoline proteins (PINA and PINB). Our study evaluated 551 Indian wheat germplasm lines for diversity in Pina and Pinb genes. Eighty-two lines were shortlisted for full length sequencing and grain hardness studies. Sequencing studies identified six unknown alleles: two for the Pina gene and four for the Pinb gene. Five of them were novel with non-synonymous changes in the corresponding amino acid sequences. Identified mutations in the deduced mature proteins and their pre- and pro-peptides influenced the hardness characteristics of the grain. We classified these 82 varieties into different hardness categories with reference to international and Indian systems of classification. The majority of Indian wheat varieties were categorized as hard. This study revealed that unexplored Indian wheat germplasm can be a good source of genetic variability for both Pina and Pinb genes, helping in marker-assisted breeding and in obtaining wheat with different textural properties. PMID:26366114

  5. Failure to confirm allelic and haplotypic association between markers at the chromosome 6p22.3 dystrobrevin-binding protein 1 (DTNBP1) locus and schizophrenia

    PubMed Central

    Datta, Susmita R; McQuillin, Andrew; Puri, Vinay; Choudhury, Khalid; Thirumalai, Srinivasa; Lawrence, Jacob; Pimm, Jonathan; Bass, Nicholas; Lamb, Graham; Moorey, Helen; Morgan, Jenny; Punukollu, Bhaskar; Kandasami, Gomathinayagam; Kirwin, Simon; Sule, Akeem; Quested, Digby; Curtis, David; Gurling, Hugh MD

    2007-01-01

    Background Previous linkage and association studies may have implicated the Dystrobrevin-binding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia. Methods We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies. Results We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample. Conclusion The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family. PMID:17888175

  6. Long allele designations at D2S1338 and D19S433 loci as influenced by various multiplex STR kits.

    PubMed

    Dell'Ariccia-Carmon, Aviva; Raziel, Aliza; Oz, Carla; Berdugo, Reouven; Zamir, Ashira

    2014-05-01

    European forensic laboratories are replacing the STR multiplex kits with the new generation 16/17 STR kits. This study examines the influence of the new generation kits and the new Applied Biosystems 3500xL Genetic Analyzer on the designation of long D2S1338 and D19S433 off-ladder alleles. Different allele calls were obtained using the new NGM™ (Applied Biosystems) and PowerPlex(®) ESI™ (Promega) kits compared with AmpFℓSTR(®) SGM Plus™ kit (Applied Biosystems). Sequence analysis was used to determine accurate allele designation. The new multiplex kits and the 3500xL Genetic Analyzer improved accuracy of long allele designations. DNA databases worldwide include countless profiles obtained by previous kits. Discrepancies between the new and former technologies may cause failure to detect hits. Discordance is expected due to primer sequence differences between various kits. An additional discordance, occurring in long alleles, independent of primer sequence is reported in this study. PMID:24261684

  7. Single nucleotide polymorphism detection: allelic discrimination using TaqMan.

    PubMed

    McGuigan, Fiona E A; Ralston, Stuart H

    2002-09-01

    Candidate gene studies are one of the most widely used approaches in the dissection of the genetic basis of disease. High-throughput methods for genotyping single nucleotide polymorphisms (SNPs) are necessary to perform large-scale association studies. We describe the use of the TaqMan or 5' nuclease allelic discrimination assay for genotyping polymorphisms of the collagen I alpha 1 (COLIA1) and vitamin D receptor (VDR) genes. The basis for the assay is an allele specific oligonucleotide probe, labelled with a fluorescent reporter dye and a quencher dye, which is cleaved during the amplification process generating an increase in the intensity of fluorescence related to the accumulation of PCR product which is measured directly in the reaction well. Suitable for the discrimination of alleles differing by a single base change, this technique is robust, accurate, cost effective, and sufficiently high-throughput for a medium sized laboratory performing association analyses. PMID:12218656

  8. Allele frequency distribution of CYP2C19*2 allelic variants associated with clopidogrel resistance in cardiac patients

    PubMed Central

    REHMAN, KASHIF UR; AKHTAR, TANVEER; SABAR, MUHAMMAD FAROOQ; TARIQ, MUHAMMAD AKRAM

    2015-01-01

    Drug resistance is a phenomenon that has become a critical issue in medical practice. Such is the case in the response to clopidogrel treatment, which is variable inter-individually and inter-ethnically due to genetic polymorphisms in the cytochrome P40 (CYP) gene. Clopidogrel is an anti-platelet agent administered to cardiac patients in the form of a prodrug, which is further metabolized into an active form by CYP enzymes. There are many allelic variants of the CYP gene that are involved in clopidogrel resistance, of which CYP2C19*2 has been demonstrated to be one of the most significant loss-of-function alleles. In the present study, 100 cardiac patients with percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS) who were undergoing treatment with clopidogrel were selected and the patients were analyzed for CYP2C19*2 allelic variants using an allele-specific primer extension polymerase chain reaction method. The variant amplicons were visualized on gel and validated by Sanger sequencing. The observed allelic frequency distribution of CYP2C19*2 variants was 18% heterozygous for CYP2C19*2 A/C/G variants, 35% heterozygous for A/G variants, 13% heterozygous for C/G variants, 6% heterozygous for A/C variants, 7% homozygous for A variant, 5% homozygous for C variant and 16% homozygous for G wild-type. Furthermore, tri-allelic single nucleotide polymorphisms (SNPs) were identified in the CYP2C19*2 allele in cardiac patients for the first time, to the best of our knowledge; these were CYP2C19*2 A/C/G SNPs (18%). The overall frequency observed for new allelic variant C of CYP2C19*2 was 42%. These results suggested that there are significant inter-ethnic variations in the allelic frequencies of CYP2C19*2, which may be responsible for the variable clopidogrel response in cardiac patients. PMID:26170954

  9. Four alleles of AtCESA3 form an allelic series with respect to root phenotype in Arabidopsis thaliana.

    PubMed

    Pysh, Leonard; Alexander, Nathan; Swatzyna, Laura; Harbert, Robert

    2012-04-01

    Plant cell shape is determined by the orientation of cellulose microfibrils in the primary cell wall. Consequently, mutations that affect genes encoding the enzymes responsible for the synthesis of cellulose, namely, the cellulose synthase catalytic subunits, can alter cell shape substantially, particularly in the roots of affected plants. The multiple response expansion1 (mre1) mutant of Arabidopsis thaliana results from a point mutation in the AtCESA3 gene, which encodes one of the three isoforms of the cellulose synthase catalytic subunit required for synthesis of cellulose in the primary cell wall. Phenotypic comparison of the mre1 mutant with three other alleles (ectopic lignification1-1, ectopic lignification1-2 and constitutive expression of vsp1) showed that these four alleles form an allelic series with respect to their root phenotypes, with mre1 being the weakest allele identified to date. These analyses demonstrated that sucrose affects a significant alteration of cell shape in the roots of these mutants and likely suppresses root cell division in them as well, and that the chemical aminoisobutyric acid can suppress these effects of sucrose. Interestingly, the cell walls in the roots of these four AtCESA3 alleles contain different percentages of cellulose, and these percentages correlate with the lengths of the roots and cortex cells in these roots when grown on media containing high levels of sucrose. PMID:22514801

  10. MHC class II DR allelic diversity in bighorn sheep.

    PubMed

    Subramaniam, Renuka; White, Stephen N; Herrmann-Hoesing, Lynn M; Srikumaran, Subramaniam

    2012-09-10

    We hypothesized that decreased diversity and/or unique polymorphisms in MHC class II alleles of bighorn sheep (BHS, Ovis canadensis) are responsible for lower titer of antibodies against Mannheimia haemolytica leukotoxin, in comparison to domestic sheep (DS, Ovis aries). To test this hypothesis, DRA and DRB transcripts from 24 captive BHS (Ovca-DRA and Ovca-DRB) were sequenced. Based on exon 2 (β1 domain) sequences, eight different Ovca-DRB cDNA sequences were identified in BHS. Six of them were 100% identical to previously reported Ovca-DRB genomic DNA sequences. The new alleles DRB*23 and DRB*24, were closely related to two other Ovca-DRB exon 2 genomic DNA sequences. Nineteen out of 24 BHS (79%) Ovca-DRB exon 3 (β2 domain) sequences were 100% identical to exon 3 sequence of DRB1 of DS (Ovar-DRB1). Ovca-DRA full length cDNA sequences exhibited >99% identity. Based upon exon 2 sequences, this BHS herd yielded higher Ovca-DRB allelic diversity than that reported in the previous study. Positively selected amino acid positions were identified in the peptide-binding groove of BHS and DS, but BHS showed more such sites. This highlights differing population histories, and may suggest differing needs for DR peptide-binding specificities. Presence of glutamine at position 52 (52Q) in some of the desert and captive BHS is predicted to alter the efficiency of DR dimerization, which may influence antigen presentation and T(h) cell activation. Functional assays with unique alleles should reveal whether the presentation of M. haemolytica leukotoxin peptides to T(h) cells by Ovca-DRB alleles is equivalent to that of Ovar-DRB1 alleles. PMID:22750296

  11. Distribution of a pseudodeficiency allele among Tay-Sachs carriers

    SciTech Connect

    Tomczak, J.; Grebner, E.E. ); Boogen, C. )

    1993-08-01

    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.

  12. A common allele on chromosome 9 associated with coronary heartdisease

    SciTech Connect

    McPherson, Ruth; Pertsemlidis, Alexander; Kavaslar, Nihan; Stewart, Alexandre; Roberts, Robert; Cox, David R.; Hinds, David; Pennachio, Len; Tybjaerg-Hansen, Anne; Folsom, Aaron R.; Boerwinkle,Eric; Hobbs, Helen H.; Cohen, Jonathan C.

    2007-03-01

    Coronary heart disease (CHD) is a major cause of death in Western countries. Here we used genome-wide association scanning to identify a 58 kb interval on chromosome 9 that was consistently associated with CHD in six independent samples. The interval contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension or diabetes. Homozygotes for the risk allele comprise 20-25% of Caucasians and have a {approx}30-40% increased risk of CHD. These data indicate that the susceptibility allele acts through a novel mechanism to increase CHD risk in a large fraction of the population.

  13. Simultaneous inference of haplotypes and alleles at a causal gene

    PubMed Central

    Larribe, Fabrice; Dupont, Mathieu J.; Boucher, Gabrielle

    2015-01-01

    We present a methodology which jointly infers haplotypes and the causal alleles at a gene influencing a given trait. Often in human genetic studies, the available data consists of genotypes (series of genetic markers along the chromosomes) and a phenotype. However, for many genetic analyses, one needs haplotypes instead of genotypes. Our methodology is not only able to estimate haplotypes conditionally on the disease status, but is also able to infer the alleles at the unknown disease locus. Some applications of our methodology are in genetic mapping and in genetic counseling. PMID:26500677

  14. Power Laws for Heavy-Tailed Distributions: Modeling Allele and Haplotype Diversity for the National Marrow Donor Program

    PubMed Central

    Gragert, Loren; Maiers, Martin; Chatterjee, Ansu; Albrecht, Mark

    2015-01-01

    Measures of allele and haplotype diversity, which are fundamental properties in population genetics, often follow heavy tailed distributions. These measures are of particular interest in the field of hematopoietic stem cell transplant (HSCT). Donor/Recipient suitability for HSCT is determined by Human Leukocyte Antigen (HLA) similarity. Match predictions rely upon a precise description of HLA diversity, yet classical estimates are inaccurate given the heavy-tailed nature of the distribution. This directly affects HSCT matching and diversity measures in broader fields such as species richness. We, therefore, have developed a power-law based estimator to measure allele and haplotype diversity that accommodates heavy tails using the concepts of regular variation and occupancy distributions. Application of our estimator to 6.59 million donors in the Be The Match Registry revealed that haplotypes follow a heavy tail distribution across all ethnicities: for example, 44.65% of the European American haplotypes are represented by only 1 individual. Indeed, our discovery rate of all U.S. European American haplotypes is estimated at 23.45% based upon sampling 3.97% of the population, leaving a large number of unobserved haplotypes. Population coverage, however, is much higher at 99.4% given that 90% of European Americans carry one of the 4.5% most frequent haplotypes. Alleles were found to be less diverse suggesting the current registry represents most alleles in the population. Thus, for HSCT registries, haplotype discovery will remain high with continued recruitment to a very deep level of sampling, but population coverage will not. Finally, we compared the convergence of our power-law versus classical diversity estimators such as Capture recapture, Chao, ACE and Jackknife methods. When fit to the haplotype data, our estimator displayed favorable properties in terms of convergence (with respect to sampling depth) and accuracy (with respect to diversity estimates). This suggests that power-law based estimators offer a valid alternative to classical diversity estimators and may have broad applicability in the field of population genetics. PMID:25901749

  15. Distribution of the FYBES and RHCE*ce(733C>G) alleles in an Argentinean population: Implications for transfusion medicine

    PubMed Central

    Cotorruelo, Carlos M; Fiori, Silvana V; Borrs, Silvia E Garca; Racca, Liliana L; Biondi, Claudia S; Racca, Amelia L

    2008-01-01

    Background The understanding of the molecular bases of blood groups makes possible the identification of red cell antigens and antibodies using molecular approaches, especially when haemagglutination is of limited value. The practical application of DNA typing requires the analysis of the polymorphism and allele distribution of the blood group genes under study since genetic variability was observed among different ethnic groups. Urban populations of Argentina are assumed to have a white Caucasian European genetic component. However, historical and biological data account for the influence of other ethnic groups. In this work we analyse FY and RH blood group alleles attributed to Africans and that could have clinical implications in the immune destruction of erythrocytes. Methods We studied 103 white trios (father, mother and child, 309 samples) from the city of Rosario by allele specific PCRs and serological methods. The data obtained were analysed with the appropriate statistical test considering only fathers and mothers (n = 206). Results We found the presence of the FY*BES and RHCE*ce(733C>G) alleles and an elevated frequency (0.0583) for the Dce haplotype. The number of individuals with a concomitant occurrence of both alleles was significantly higher than that expected by chance. We found that 4.68% of the present gene pool is composed by alleles primarily associated with African ancestry and about 10% of the individuals carried at least one RH or FY allele that is predominantly observed among African populations. Thirteen percent of Fy(b-) subjects were FY*A/FY*BES. Conclusion Taken together, the results suggest that admixture events between African slaves and European immigrants at the beginning of the 20th century made the physical characteristics of black Africans to be invisible nowadays. Considering that it was a recent historical event, the FY*BES and RHCE*ce(733C>G) alleles did not have time to become widespread but remain concentrated within families. These findings have considerable impact for typing and transfusion strategy in our population, increasing the pool of compatible units for Fy(b-) individuals requiring chronic transfusion. Possible difficulties in transfusion therapy and in genotyping could be anticipated and appropriately improved strategies devised, allowing a better management of the alloimmunization in the blood bank. PMID:18460195

  16. Short mucin 6 alleles are associated with H pylori infection

    PubMed Central

    Nguyen, Thai V; Janssen, Marcel JR; Gritters, Paulien; te Morsche, Ren HM; Drenth, Joost PH; van Asten, Henri; Laheij, Robert JF; Jansen, Jan BMJ

    2006-01-01

    AIM: To investigate the relationship between mucin 6 (MUC6) VNTR length and H pylori infection. METHODS: Blood samples were collected from patients visiting the Can Tho General Hospital for upper gastrointestinal endoscopy. DNA was isolated from whole blood, the repeated section was cut out using a restriction enzyme (PvuII) and the length of the allele fragments was determined by Southern blotting. H pylori infection was diagnosed by 14C urea breath test. For analysis, MUC6 allele fragment length was dichotomized as being either long (> 13.5 kbp) or short (? 13.5 kbp) and patients were classified according to genotype [long-long (LL), long-short (LS), short-short (SS)]. RESULTS: 160 patients were studied (mean age 43 years, 36% were males, 58% H pylori positive). MUC6 PvuII-restricted allele fragment lengths ranged from 7 to 19 kbp. Of the patients with the LL, LS, SS MUC6 genotype, 43% (24/56), 57% (25/58) and 76% (11/46) were infected with H pylori, respectively (P = 0.003). CONCLUSION: Short MUC6 alleles are associated with H pylori infection. PMID:17009402

  17. Functional Allelic Variation at Key Photoperiod Response QTL in Maize

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tropical maize represents a valuable genetic resource containing unique alleles not present in elite temperate maize. The strong delay in flowering in response to long daylength photoperiods exhibited by most tropical maize hinders its incorporation into temperate maize breeding programs. We tested ...

  18. Extensive allele-specific translational regulation inhybrid mice

    PubMed Central

    Hou, Jingyi; Wang, Xi; McShane, Erik; Zauber, Henrik; Sun, Wei; Selbach, Matthias; Chen, Wei

    2015-01-01

    Translational regulation is mediated through the interaction between diffusible trans-factors and cis-elements residing within mRNA transcripts. In contrast to extensively studied transcriptional regulation, cis-regulation on translation remains underexplored. Using deep sequencing-based transcriptome and polysome profiling, we globally profiled allele-specific translational efficiency for the first time in an F1 hybrid mouse. Out of 7,156 genes with reliable quantification of both alleles, we found 1,008 (14.1%) exhibiting significant allelic divergence in translational efficiency. Systematic analysis of sequence features of the genes with biased allelic translation revealed that local RNA secondary structure surrounding the start codon and proximal out-of-frame upstream AUGs could affect translational efficiency. Finally, we observed that the cis-effect was quantitatively comparable between transcriptional and translational regulation. Such effects in the two regulatory processes were more frequently compensatory, suggesting that the regulation at the two levels could be coordinated in maintaining robustness of protein expression. PMID:26253569

  19. Experimental evolution of a novel sexually antagonistic allele.

    PubMed

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

    2012-01-01

    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

  20. Registration of two allelic erect leaf mutants of sorghum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two allelic sorghum [Sorghum bicolor (L.) Moench] erect leaf (erl) mutants were isolated from an Annotated Individually-pedigreed Mutagenized Sorghum (AIMS) mutant library developed at the Plant Stress and Germplasm Development Unit, at Lubbock, Texas. The two mutants, erl1-1 and erl1-2, were isol...

  1. Haplotype allelic classes for detecting ongoing positive selection

    PubMed Central

    2010-01-01

    Background Natural selection eliminates detrimental and favors advantageous phenotypes. This process leaves characteristic signatures in underlying genomic segments that can be recognized through deviations in allelic or haplotypic frequency spectra. To provide an identifiable signature of recent positive selection that can be detected by comparison with the background distribution, we introduced a new way of looking at genomic polymorphisms: haplotype allelic classes. Results The model combines segregating sites and haplotypic information in order to reveal useful data characteristics. We developed a summary statistic, Svd, to compare the distribution of the haplotypes carrying the selected allele with the distribution of the remaining ones. Coalescence simulations are used to study the distributions under standard population models assuming neutrality, demographic scenarios and selection models. To test, in practice, haplotype allelic class performance and the derived statistic in capturing deviation from neutrality due to positive selection, we analyzed haplotypic variation in detail in the locus of lactase persistence in the three HapMap Phase II populations. Conclusions We showed that the Svd statistic is less sensitive than other tests to confounding factors such as demography or recombination. Our approach succeeds in identifying candidate loci, such as the lactase-persistence locus, as targets of strong positive selection and provides a new tool complementary to other tests to study natural selection in genomic data. PMID:20109229

  2. Disease-Causing Allele-Specific Silencing by RNA Interference

    PubMed Central

    Hohjoh, Hirohiko

    2013-01-01

    Small double-stranded RNAs (dsRNAs) of approximately 21-nucleotides in size, referred to as small interfering RNA (siRNA) duplexes, can induce sequence-specific posttranscriptional gene silencing, or RNA interference (RNAi). Since chemically synthesized siRNA duplexes were found to induce RNAi in mammalian cells, RNAi has become a powerful reverse genetic tool for suppressing the expression of a gene of interest in mammals, including human, and its application has been expanding to various fields. Recent studies further suggest that synthetic siRNA duplexes have the potential for specifically inhibiting the expression of an allele of interest without suppressing the expression of other alleles, i.e., siRNA duplexes likely confer allele-specific silencing. Such gene silencing by RNAi is an advanced technique with very promising applications. In this review, I would like to discuss the potential utility of allele-specific silencing by RNAi as a therapeutic method for dominantly inherited diseases, and describe possible improvements in siRNA duplexes for enhancing their efficacy. PMID:24276122

  3. Multifragment alleles in DNA fingerprints of the parrot, Amazona ventralis

    USGS Publications Warehouse

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

    1991-01-01

    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.

  4. RECOVERY OF EXOTIC ALLELES IN ENHANCED TROPICAL YELLOW GERMPLASM

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Enhancement of overall diversity levels and the incorporation of new favorable traits are major benefits of using exotic germplasm in elite breeding programs. Agronomic deficiencies and poor adaptation often limits use of exotic germplasm in plant breeding programs. To introgress exotic alleles into...

  5. Estimating the age of alleles by use of intraallelic variability

    SciTech Connect

    Slatkin, M.; Rannala, B.

    1997-02-01

    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.

  6. Efficient nonmeiotic allele introgression in livestock using custom endonucleases

    PubMed Central

    Tan, Wenfang; Carlson, Daniel F.; Lancto, Cheryl A.; Garbe, John R.; Webster, Dennis A.; Hackett, Perry B.; Fahrenkrug, Scott C.

    2013-01-01

    We have expanded the livestock gene editing toolbox to include transcription activator-like (TAL) effector nuclease (TALEN)- and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-stimulated homology-directed repair (HDR) using plasmid, rAAV, and oligonucleotide templates. Toward the genetic dehorning of dairy cattle, we introgressed a bovine POLLED allele into horned bull fibroblasts. Single nucleotide alterations or small indels were introduced into 14 additional genes in pig, goat, and cattle fibroblasts using TALEN mRNA and oligonucleotide transfection with efficiencies of 10–50% in populations. Several of the chosen edits mimic naturally occurring performance-enhancing or disease- resistance alleles, including alteration of single base pairs. Up to 70% of the fibroblast colonies propagated without selection harbored the intended edits, of which more than one-half were homozygous. Edited fibroblasts were used to generate pigs with knockout alleles in the DAZL and APC genes to model infertility and colon cancer. Our methods enable unprecedented meiosis-free intraspecific and interspecific introgression of select alleles in livestock for agricultural and biomedical applications. PMID:24014591

  7. A genotype probability index for multiple alleles and haplotypes.

    PubMed

    Percy, A; Kinghorn, B P

    2005-12-01

    We use linear algebra to calculate an index of information content in genotype probabilities which has previously been calculated using trigonometry. The new method can be generalized allowing the index to be calculated for loci with more than two alleles. Applications of this index include its use in genotyping strategies, strategies to manage genetic disorders and in estimation of genotype effects. PMID:16274422

  8. Efficient nonmeiotic allele introgression in livestock using custom endonucleases.

    PubMed

    Tan, Wenfang; Carlson, Daniel F; Lancto, Cheryl A; Garbe, John R; Webster, Dennis A; Hackett, Perry B; Fahrenkrug, Scott C

    2013-10-01

    We have expanded the livestock gene editing toolbox to include transcription activator-like (TAL) effector nuclease (TALEN)- and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-stimulated homology-directed repair (HDR) using plasmid, rAAV, and oligonucleotide templates. Toward the genetic dehorning of dairy cattle, we introgressed a bovine POLLED allele into horned bull fibroblasts. Single nucleotide alterations or small indels were introduced into 14 additional genes in pig, goat, and cattle fibroblasts using TALEN mRNA and oligonucleotide transfection with efficiencies of 10-50% in populations. Several of the chosen edits mimic naturally occurring performance-enhancing or disease- resistance alleles, including alteration of single base pairs. Up to 70% of the fibroblast colonies propagated without selection harbored the intended edits, of which more than one-half were homozygous. Edited fibroblasts were used to generate pigs with knockout alleles in the DAZL and APC genes to model infertility and colon cancer. Our methods enable unprecedented meiosis-free intraspecific and interspecific introgression of select alleles in livestock for agricultural and biomedical applications. PMID:24014591

  9. MHC class II DR allelic diversity in bighorn sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We hypothesized that decreased diversity and/or unique polymorphisms in MHC class II alleles of bighorn sheep (BHS, Ovis canadensis) are responsible for lower titer of antibodies against Mannheimia haemolytica leukotoxin, in comparison to domestic sheep (DS, Ovis aries). To test this hypothesis, DRA...

  10. Allelism and Molecular Mapping of Soybean Necrotic Root Mutants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutability of the w4 flower color locus in soybean [Glycine max (L.) Merr.] is conditioned by an allele designated w4-m. Germinal revertants recovered among self-pollinated progeny of mutable plants have been associated with the generation of necrotic root mutations, chlorophyll-deficiency mutation...

  11. Bipolar disorder risk alleles in children with ADHD.

    PubMed

    Schimmelmann, B G; Hinney, A; Scherag, A; Ptter, C; Pechlivanis, S; Cichon, S; Jckel, K-H; Schreiber, S; Wichmann, H E; Albayrak, ; Dauvermann, M; Konrad, K; Wilhelm, C; Herpertz-Dahlmann, B; Lehmkuhl, G; Sinzig, J; Renner, T J; Romanos, M; Warnke, A; Lesch, K P; Reif, A; Hebebrand, J

    2013-11-01

    Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of ? = 5 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies. PMID:23712748

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

    PubMed Central

    Hall, H. G.

    1990-01-01

    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. PMID:1974226

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

    PubMed Central

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

    1992-01-01

    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. PMID:1732162

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

    PubMed

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

    2014-02-10

    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

  15. The Number of Alleles at a Microsatellite Defines the Allele Frequency Spectrum and Facilitates Fast Accurate Estimation of ?

    PubMed Central

    Haasl, Ryan J.; Payseur, Bret A.

    2010-01-01

    Theoretical work focused on microsatellite variation has produced a number of important results, including the expected distribution of repeat sizes and the expected squared difference in repeat size between two randomly selected samples. However, closed-form expressions for the sampling distribution and frequency spectrum of microsatellite variation have not been identified. Here, we use coalescent simulations of the stepwise mutation model to develop gamma and exponential approximations of the microsatellite allele frequency spectrum, a distribution central to the description of microsatellite variation across the genome. For both approximations, the parameter of biological relevance is the number of alleles at a locus, which we express as a function of ?, the population-scaled mutation rate, based on simulated data. Discovered relationships between ?, the number of alleles, and the frequency spectrum support the development of three new estimators of microsatellite ?. The three estimators exhibit roughly similar mean squared errors (MSEs) and all are biased. However, across a broad range of sample sizes and ? values, the MSEs of these estimators are frequently lower than all other estimators tested. The new estimators are also reasonably robust to mutation that includes step sizes greater than one. Finally, our approximation to the microsatellite allele frequency spectrum provides a null distribution of microsatellite variation. In this context, a preliminary analysis of the effects of demographic change on the frequency spectrum is performed. We suggest that simulations of the microsatellite frequency spectrum under evolutionary scenarios of interest may guide investigators to the use of relevant and sometimes novel summary statistics. PMID:20605970

  16. Allelic divergence and cultivar-specific SSR alleles revealed by capillary electrophoresis using fluorescence-labeled SSR markers in sugarcane

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Though sugarcane cultivars (Saccharum spp. hybrids) are complex aneu-polyploid hybrids, genetic evaluation and tracking of clone- or cultivar-specific alleles become possible due to capillary electrophoregrams (CE) using fluorescence-labeled SSR primer pairs. Twenty-four sugarcane cultivars, 12 each...

  17. The number of alleles at a microsatellite defines the allele frequency spectrum and facilitates fast accurate estimation of theta.

    PubMed

    Haasl, Ryan J; Payseur, Bret A

    2010-12-01

    Theoretical work focused on microsatellite variation has produced a number of important results, including the expected distribution of repeat sizes and the expected squared difference in repeat size between two randomly selected samples. However, closed-form expressions for the sampling distribution and frequency spectrum of microsatellite variation have not been identified. Here, we use coalescent simulations of the stepwise mutation model to develop gamma and exponential approximations of the microsatellite allele frequency spectrum, a distribution central to the description of microsatellite variation across the genome. For both approximations, the parameter of biological relevance is the number of alleles at a locus, which we express as a function of ?, the population-scaled mutation rate, based on simulated data. Discovered relationships between ?, the number of alleles, and the frequency spectrum support the development of three new estimators of microsatellite ?. The three estimators exhibit roughly similar mean squared errors (MSEs) and all are biased. However, across a broad range of sample sizes and ? values, the MSEs of these estimators are frequently lower than all other estimators tested. The new estimators are also reasonably robust to mutation that includes step sizes greater than one. Finally, our approximation to the microsatellite allele frequency spectrum provides a null distribution of microsatellite variation. In this context, a preliminary analysis of the effects of demographic change on the frequency spectrum is performed. We suggest that simulations of the microsatellite frequency spectrum under evolutionary scenarios of interest may guide investigators to the use of relevant and sometimes novel summary statistics. PMID:20605970

  18. Hemochromatosis: Niche Construction and the Genetic Domino Effect in the European Neolithic.

    PubMed

    McCullough, John M; Heath, Kathleen M; Smith, Alexis M

    2015-01-01

    Hereditary hemochromatosis is caused by a potentially lethal recessive gene (HFE, C282Y allele) that increases iron absorption and reaches polymorphic levels in northern European populations. Because persons carrying the allele absorb iron more readily than do noncarriers, it has often been suggested that HFE is an adaptation to anemia. We hypothesize positive selection for HFE began during or after the European Neolithic with the adoption of an iron-deficient high-grain and dairying diet and consequent anemia, a finding confirmed in Neolithic and later European skeletons. HFE frequency compared with rate of lactase persistence in Eurasia yields a positive linear correlation coefficient of 0.86. We suggest this is just one of many mutations that became common after the adoption of agriculture. PMID:26416321

  19. European auxiliary propulsion, 1972

    NASA Technical Reports Server (NTRS)

    Holcomb, L. B.

    1972-01-01

    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.

  20. Chemokine receptor CCR5 genotype influences the kinetics of human immunodeficiency virus type 1 infection in human PBL-SCID mice.

    PubMed Central

    Picchio, G R; Gulizia, R J; Mosier, D E

    1997-01-01

    Individuals homozygous for a 32-bp deletion (delta 32) in the CCR5 gene encoding the coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1) are resistant to virus infection, and heterozygous individuals show some slowing of disease progression. The impact of the CCR5 genotype on HIV-1 infection was assessed in vitro and in the human PBL-SCID (hu-PBL-SCID) model. Cells and hu-PBL-SCID mice from CCR5 delta 32/delta 32 donors were resistant to infection with macrophage-tropic HIV-1 and showed slower replication of dual-tropic HIV-1. hu-PBL-SCID mice derived from CCR5 delta 32/+ heterozygotes showed delayed replication of macrophage-tropic HIV-1 despite a small and variable effect of heterozygosity on viral replication in vitro. The level of CCR5 expression appears to limit replication of macrophage-tropic and dual-tropic HIV-1 strains in vivo. PMID:9261448

  1. Future of European urology.

    PubMed

    Debruyne, F M

    2000-10-01

    To provide the highest medical service and to maintain the most advanced research work across national boundaries, we have developed many organizations, including the European Association of Urology (EAU), the European Board of Urology (EBU), and the European Organization for Research and Treatment of Cancer (EORTC). They also have functioned to provide equal health service for all European people. In the future, superspecialization and the multidisciplinary approach are inevitable. Major changes will occur, such as prevention of stone diseases, reconstructive urology, and immune and gene therapy in oncology. Specialists will assume major roles in the urologic clinic. In those circumstances, Europe will continue to play an important role because urologists are very much involved in future strategic developments on national and Pan-European levels. PMID:11071465

  2. ATM allelic variants associated to hereditary breast cancer in 94 Chilean women: susceptibility or ethnic influences?

    PubMed

    Tapia, Teresa; Sanchez, Alejandro; Vallejos, Maricarmen; Alvarez, Carolina; Moraga, Mauricio; Smalley, Susan; Camus, Mauricio; Alvarez, Manuel; Carvallo, Pilar

    2008-01-01

    Besides BRCA1 and BRCA2, two genes accounting for a small proportion of breast cancer cases, ATM has been widely proposed as a low-penetrance susceptibility gene. Several nucleotide changes have been proposed to be associated with breast cancer, still remaining a high controversy in this sense. We screened the ATM gene in 94 breast cancer patients selected from 78 high-risk families, not presenting a mutation in BRCA1 or BRCA2. We found three novel allelic variants: IVS64 + 51delT and p.L752L, not showing association with hereditary breast cancer, and p.L694L found in one family in two breast cancer patients. Two amino acid substitutions p.S707P and p.F858L, previously reported to be associated with breast cancer, were present in our study in cases and controls, lacking of association with breast cancer. A positive association of c.5557G>A (p.D1853N) was found (OR 2.52, P = 0.008), when analyzed alone and in combination with an intronic variant IVS24-9delT (OR 3.97; P = 0.0003). We postulate that our discrepancies with other reports related to the associated ATM alleles to hereditary breast cancer, as well as discrepancies in the literature between other groups, could be explained by the diversity in the ethnic origins of families gathered in a sole study, and the selection of the control group. In relation to this issue, and based on genetic markers, we found that the Chilean group of breast cancer families in this study has a stronger European genetic component than our control sample selected randomly from the Chilean population. PMID:17351744

  3. Human Leukocyte Antigen Alleles and Cytomegalovirus Infection After Renal Transplantation

    PubMed Central

    Futohi, Farzaneh; Saber, Azadeh; Nemati, Eglim; Einollahi, Behzad; Rostami, Zohre

    2015-01-01

    Background: Several studies have been conducted on the relationship between a number of human leukocyte antigen (HLA) alleles and cytomegalovirus infection (CMV), in kidney transplant recipients, after transplantation. However, only a limited number of HLAs have been investigated, so far, and the results have been contradictory. Objectives: This study aimed to investigate the relationship between 59 HLA alleles and the CMV infection, in transplant recipients, after kidney transplantation. Patients and Methods: This retrospective cohort study was conducted on 200 patients, receiving a kidney transplant, in Baqiyatallah Hospital, in Tehran, during 2013. Throughout a one-year follow-up of kidney transplant recipients, in case of detecting the CMV antigen in patients’ blood, at any time, they were placed in the group of patients with CMV infection, whereas, if no CMV-specific antigen was developed, over a year, patients were placed in the group of patients without CMV infection, after transplantation. This study investigated the relationship between CMV infection in kidney transplant recipients and 59 HLA alleles, including 14 HLA-A, 28 HLA-B, and 17 HLA-DRB1 cases. Results: Of all participants, 104 patients (52%) were diagnosed with CMV infection. There was no significant difference between the two groups, with and without CMV infection, in terms of patient’s characteristics. The CMV infection, in patients receiving a transplanted organ from deceased donor, was significantly more prevalent than in those receiving kidney transplant from living donor (63% vs. 39%, respectively, P = 0.001). Recipients with HLA-B44 were more infected with CMV compared with patients without this allele (80% vs. 50%, respectively, P = 0.024); on the contrary, kidney recipients with HLA-DRB1-1 were less infected with CMV than patients without this allele (31% vs. 55%, respectively, P = 0.020). There was no significant relationship between CMV infection and other HLA alleles. Results of multivariate logistic regression analysis showed that deceased donor renal transplantation (OR = 3.018, 95%CI: 1.662 - 5.480, P < 0.001), presence of HLA-B44 (OR = 4.764, 95%CI: 1.259 - 18.032, P = 0.022) and lack of HLA-B8 (OR = 3.246, 95%CI: 1.030 - 10.230, P = 0.044) were the independent risk factors for developing CMV infection, after kidney transplantation. Conclusions: The findings of this study showed that deceased donor renal transplantation and the presence of HLA-B44 can make the kidney recipient susceptible to CMV infection after kidney transplantation; on the other hand, the presence of HLA-B8 can have a protective effect. PMID:26866009

  4. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly.

    PubMed

    Ho, April J; Stein, Jason L; Hua, Xue; Lee, Suh; Hibar, Derrek P; Leow, Alex D; Dinov, Ivo D; Toga, Arthur W; Saykin, Andrew J; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Huentelman, Matthew J; Craig, David W; Gerber, Jill D; Allen, April N; Corneveaux, Jason J; Stephan, Dietrich A; DeCarli, Charles S; DeChairo, Bryan M; Potkin, Steven G; Jack, Clifford R; Weiner, Michael W; Raji, Cyrus A; Lopez, Oscar L; Becker, James T; Carmichael, Owen T; Thompson, Paul M

    2010-05-01

    A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an approximately 1.2 kg higher weight, on average, in adults and an approximately 1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of approximately 8% in the frontal lobes and 12% in the occipital lobes-these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly. PMID:20404173

  5. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly

    PubMed Central

    Stein, Jason L.; Hua, Xue; Lee, Suh; Hibar, Derrek P.; Leow, Alex D.; Dinov, Ivo D.; Toga, Arthur W.; Saykin, Andrew J.; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Huentelman, Matthew J.; Craig, David W.; Gerber, Jill D.; Allen, April N.; Corneveaux, Jason J.; Stephan, Dietrich A.; DeCarli, Charles S.; DeChairo, Bryan M.; Potkin, Steven G.; Jack, Clifford R.; Weiner, Michael W.; Raji, Cyrus A.; Lopez, Oscar L.; Becker, James T.; Carmichael, Owen T.; Thompson, Paul M.; Weiner, Michael; Thal, Leon; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Gamst, Anthony; Potter, William Z.; Montine, Tom; Anders, Dale; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Trojanowki, John; Shaw, Les; Lee, Virginia M.-Y.; Korecka, Magdalena; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Harvey, Danielle; Gamst, Anthony; Kornak, John; Kachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Vorobik, Remi; Quinn, Joseph; Schneider, Lon; Pawluczyk, Sonia; Spann, Bryan; Fleisher, Adam S.; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Badger, Beverly; Grossman, Hillel; Tang, Cheuk; Stern, Jessica; deToledo-Morrell, Leyla; Shah, Raj C.; Bach, Julie; Duara, Ranjan; Isaacson, Richard; Strauman, Silvia; Albert, Marilyn S.; Pedroso, Julia; Toroney, Jaimie; Rusinek, Henry; de Leon, Mony J; De Santi, Susan M; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Aiello, Marilyn; Clark, Christopher M.; Pham, Cassie; Nunez, Jessica; Smith, Charles D.; Given II, Curtis A.; Hardy, Peter; DeKosky, Steven T.; Oakley, MaryAnn; Simpson, Donna M.; Ismail, M. Saleem; Porsteinsson, Anton; McCallum, Colleen; Cramer, Steven C.; Mulnard, Ruth A.; McAdams-Ortiz, Catherine; Diaz-Arrastia, Ramon; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Laubinger, Mary M.; Bartzokis, George; Silverman, Daniel H.S.; Lu, Po H.; Fletcher, Rita; Parfitt, Francine; Johnson, Heather; Farlow, Martin; Herring, Scott; Hake, Ann M.; van Dyck, Christopher H.; MacAvoy, Martha G.; Bifano, Laurel A.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Graham, Simon; Caldwell, Curtis; Feldman, Howard; Assaly, Michele; Hsiung, Ging-Yuek R.; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Gitelman, Darren; Johnson, Nancy; Mesulam, Marsel; Sadowsky, Carl; Villena, Teresa; Mesner, Scott; Aisen, Paul S.; Johnson, Kathleen B.; Behan, Kelly E.; Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.; Rosen, Allyson; Tinklenberg, Jared; Ashford, Wes; Sabbagh, Marwan; Connor, Donald; Obradov, Sanja; Killiany, Ron; Norbash, Alex; Obisesan, Thomas O.; Jayam-Trouth, Annapurni; Wang, Paul; Auchus, Alexander P.; Huang, Juebin; Friedland, Robert P.; DeCarli, Charles; Fletcher, Evan; Carmichael, Owen; Kittur, Smita; Mirje, Seema; Johnson, Sterling C.; Borrie, Michael; Lee, T-Y; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Highum, Diane; Preda, Adrian; Nguyen, Dana; Tariot, Pierre N.; Hendin, Barry A.; Scharre, Douglas W.; Kataki, Maria; Beversdorf, David Q.; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Gandy, Sam; Marenberg, Marjorie E.; Rovner, Barry W.; Pearlson, Godfrey; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Pare, Nadia; Williamson, Jeff D.; Sink, Kaycee M.; Potter, Huntington; Ashok Raj, B.; Giordano, Amy; Ott, Brian R.; Wu, Chuang-Kuo; Cohen, Ronald; Wilks, Kerri L.

    2010-01-01

    A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobesthese regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly. PMID:20404173

  6. Parallel Mapping of Antibiotic Resistance Alleles in Escherichia coli.

    PubMed

    Weiss, Sophie J; Mansell, Thomas J; Mortazavi, Pooneh; Knight, Rob; Gill, Ryan T

    2016-01-01

    Chemical genomics expands our understanding of microbial tolerance to inhibitory chemicals, but its scope is often limited by the throughput of genome-scale library construction and genotype-phenotype mapping. Here we report a method for rapid, parallel, and deep characterization of the response to antibiotics in Escherichia coli using a barcoded genome-scale library, next-generation sequencing, and streamlined bioinformatics software. The method provides quantitative growth data (over 200,000 measurements) and identifies contributing antimicrobial resistance and susceptibility alleles. Using multivariate analysis, we also find that subtle differences in the population responses resonate across multiple levels of functional hierarchy. Finally, we use machine learning to identify a unique allelic and proteomic fingerprint for each antibiotic. The method can be broadly applied to tolerance for any chemical from toxic metabolites to next-generation biofuels and antibiotics. PMID:26771672

  7. Parallel Mapping of Antibiotic Resistance Alleles in Escherichia coli

    PubMed Central

    Mortazavi, Pooneh; Knight, Rob; Gill, Ryan T.

    2016-01-01

    Chemical genomics expands our understanding of microbial tolerance to inhibitory chemicals, but its scope is often limited by the throughput of genome-scale library construction and genotype-phenotype mapping. Here we report a method for rapid, parallel, and deep characterization of the response to antibiotics in Escherichia coli using a barcoded genome-scale library, next-generation sequencing, and streamlined bioinformatics software. The method provides quantitative growth data (over 200,000 measurements) and identifies contributing antimicrobial resistance and susceptibility alleles. Using multivariate analysis, we also find that subtle differences in the population responses resonate across multiple levels of functional hierarchy. Finally, we use machine learning to identify a unique allelic and proteomic fingerprint for each antibiotic. The method can be broadly applied to tolerance for any chemical from toxic metabolites to next-generation biofuels and antibiotics. PMID:26771672

  8. A coalescent model of ancestry for a rare allele.

    PubMed Central

    Graham, J; Thompson, E A

    2000-01-01

    In disequilibrium mapping from data on a rare allele, interest may focus on the ancestry of a random sample of current descendants of a mutation. The mutation is assumed to have been introduced into the population as a single copy a known time ago and to have reached a given copy number within the population. Theory has been developed to describe the ancestral distribution under arbitrary patterns of population expansion. Further results permit convenient realization of the ancestry for a random sample of copies of a rare allele within populations of constant size or within populations growing or shrinking at constant exponential rate. In this article, we present an efficient approximate method for realizing coalescence times under more general patterns of population growth. We also apply diagnostics, checking the age of the mutation. In the course of the derivation, some additional insight is gained into the dynamics of the descendants of the mutation. PMID:10978301

  9. Fast spatial ancestry via flexible allele frequency surfaces

    PubMed Central

    Raola, John Michael; Novembre, John; Lange, Kenneth

    2014-01-01

    Motivation: Unique modeling and computational challenges arise in locating the geographic origin of individuals based on their genetic backgrounds. Single-nucleotide polymorphisms (SNPs) vary widely in informativeness, allele frequencies change non-linearly with geography and reliable localization requires evidence to be integrated across a multitude of SNPs. These problems become even more acute for individuals of mixed ancestry. It is hardly surprising that matching genetic models to computational constraints has limited the development of methods for estimating geographic origins. We attack these related problems by borrowing ideas from image processing and optimization theory. Our proposed model divides the region of interest into pixels and operates SNP by SNP. We estimate allele frequencies across the landscape by maximizing a product of binomial likelihoods penalized by nearest neighbor interactions. Penalization smooths allele frequency estimates and promotes estimation at pixels with no data. Maximization is accomplished by a minorizemaximize (MM) algorithm. Once allele frequency surfaces are available, one can apply Bayes rule to compute the posterior probability that each pixel is the pixel of origin of a given person. Placement of admixed individuals on the landscape is more complicated and requires estimation of the fractional contribution of each pixel to a persons genome. This estimation problem also succumbs to a penalized MM algorithm. Results: We applied the model to the Population Reference Sample (POPRES) data. The model gives better localization for both unmixed and admixed individuals than existing methods despite using just a small fraction of the available SNPs. Computing times are comparable with the best competing software. Availability and implementation: Software will be freely available as the OriGen package in R. Contact: ranolaj@uw.edu or klange@ucla.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25012181

  10. Mammalian interspecies substitution of immune modulatory alleles by genome editing.

    PubMed

    Lillico, Simon G; Proudfoot, Chris; King, Tim J; Tan, Wenfang; Zhang, Lei; Mardjuki, Rachel; Paschon, David E; Rebar, Edward J; Urnov, Fyodor D; Mileham, Alan J; McLaren, David G; Whitelaw, C Bruce A

    2016-01-01

    We describe a fundamentally novel feat of animal genetic engineering: the precise and efficient substitution of an agronomic haplotype into a domesticated species. Zinc finger nuclease in-embryo editing of the RELA locus generated live born domestic pigs with the warthog RELA orthologue, associated with resilience to African Swine Fever. The ability to efficiently achieve interspecies allele introgression in one generation opens unprecedented opportunities for agriculture and basic research. PMID:26898342

  11. Mammalian interspecies substitution of immune modulatory alleles by genome editing

    PubMed Central

    Lillico, Simon G.; Proudfoot, Chris; King, Tim J.; Tan, Wenfang; Zhang, Lei; Mardjuki, Rachel; Paschon, David E.; Rebar, Edward J.; Urnov, Fyodor D.; Mileham, Alan J.; McLaren, David G.; Whitelaw, C. Bruce A.

    2016-01-01

    We describe a fundamentally novel feat of animal genetic engineering: the precise and efficient substitution of an agronomic haplotype into a domesticated species. Zinc finger nuclease in-embryo editing of the RELA locus generated live born domestic pigs with the warthog RELA orthologue, associated with resilience to African Swine Fever. The ability to efficiently achieve interspecies allele introgression in one generation opens unprecedented opportunities for agriculture and basic research. PMID:26898342

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

    PubMed Central

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

    1995-01-01

    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). PMID:7498746

  13. Microsatellite variation in honey bee (Apis mellifera L.) populations: hierarchical genetic structure and test of the infinite allele and stepwise mutation models.

    PubMed

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

    1995-06-01

    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). PMID:7498746

  14. Generation of a conditional null allele for Cftr in mice.

    PubMed

    Hodges, Craig A; Cotton, Calvin U; Palmert, Mark R; Drumm, Mitchell L

    2008-10-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cAMP-regulated chloride channel that is important in controlling the exchange of fluid and electrolytes across epithelial cells. Mutation of CFTR can lead to cystic fibrosis (CF), the most common lethal genetic disease in Caucasians. CF is a systemic illness with multiple organ systems affected including pulmonary, gastrointestinal, pancreatic, immune, endocrine, and reproductive systems. To understand the role of CFTR in the various tissues in which it is expressed, we generated a murine conditional null allele of Cftr (Cftr(fl10)) in which loxP sites were inserted around exon 10 of the Cftr gene. The Cftr(fl10) allele was validated by generating constitutive Cftr null (Cftr(Delta10)) mice using the protamine-cre system. The Cftr(Delta10/Delta10) mice displayed almost identical phenotypes to previously published CF mouse models, including poor growth, decreased survival, intestinal obstruction, and loss of Cftr function as assessed by electrophysiology measurements on gut and nasal epithelium. Mice containing the conditional null Cftr allele will be useful in future studies to understand the role of Cftr in specific tissues and developmental time points and lead to a better understanding of CF disease. PMID:18802965

  15. A survey of FRAXE allele sizes in three populations

    SciTech Connect

    Zhong, N.; Ju, W.; Curley, D.

    1996-08-09

    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.

  16. Tracing pastoralist migrations to southern Africa with lactase persistence alleles.

    PubMed

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

    2014-04-14

    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

  17. Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11

    SciTech Connect

    Falchetti, A.; Brandi, M.L. Yale Univ. School of Medicine, New Haven, CT ); Amorosi, A.; Cicchi, P.; Bandini, S. ); Bordi, C. ); Marx, S.J. )

    1993-01-01

    In occasional cases of secondary hyperparathyroidism, long term stimulation of the parathyroid glands leads from compensatory to autonomous hyperfunction, and thus, hypercalcemia develops. This clinical entity, named tertiary hyperparathyroidism, is possibly due to the formation of an adenoma in one of the hyperplastic glands. Previous studies have shown that parathyroid adenomas may arise with allelic loss on chromosome 11. The authors tested for allelic loss at several loci on chromosome 11 in 12 enlarged parathyroid glands from 6 uremic patients and found loss of heterozygosity in 2 of the glands from 2 different patients with higher serum calcium levels (11.3 [+-] 0.29 vs. 9.8 [+-] 0.28 mg/dL; P < 0.004) and, therefore, ascribable to the so-called tertiary hyperparathyroidism. The 2 glands with allelic loss were significantly greater in mass than those without loss (3.42 [+-] 0.37 vs. 1.60 [+-] 0.54 g; P < 0.001). These data offer new evidence that autonomous parathyroid proliferation in uremic patients can develop through over-growth by a monoclonal tumor, presumably with inactivation of a tumor suppressor gene(s) on chromosome 11. 33 refs., 4 figs., 2 tabs.

  18. FKBP5 risk alleles and the development of intrusive memories.

    PubMed

    Cheung, Jessica; Bryant, Richard A

    2015-11-01

    Intrusive memories are unwanted recollections that maintain distress and are central to numerous psychological disorders, including posttraumatic stress disorder (PTSD). Convergent evidence suggests that glucocorticoid increases enhance the strength of emotional memories. The FKBP5 polymorphism modulates glucocorticoid receptor sensitivity, and has been shown to increase risk for PTSD. Healthy high and low risk FKBP5 allele carriers (N=46) underwent a cold pressor task, and then viewed negative and neutral images. Two days later participants were given a surprise recall test and measure of intrusive memories of the images. Following the cold pressor task, high-risk allele participants had a higher cortisol response than low-risk participants. High-risk carriers also reported more intrusive memories of the negative and neutral images than low-risk carriers. These findings point to the minor alleles of the FKBP5 polymorphism being a risk factor for development of intrusive memories, possibly as a result of impaired glucocorticoid receptor sensitivity. This may explain one mechanism for FKBP5 being a risk factor for PTSD following traumatic events. PMID:26456144

  19. European psychotraumatology alongside the recent European history

    PubMed Central

    Lueger-Schuster, Brigitte

    2013-01-01

    This article outlines a personal reflection of experiences within the field of traumatic stress, especially in relation to specific events, which affected the author's professional life. Conclusions for further challenges for European Society for Traumatic Stress Studies (ESTSS) are delineated. ESTSS's role in the global network of traumatic stress societies is discussed. This is a personal view of Brigitte Lueger-Schuster, president of ESTSS on behalf of the 20th birthday of ESTSS. PMID:23755321

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

    PubMed Central

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

    2014-01-01

    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. PMID:24945156

  1. European PTTI report

    NASA Technical Reports Server (NTRS)

    Cordara, Franco; Grimaldi, Sabrina; Leschiutta, Sigfrido

    1994-01-01

    Time and frequency metrology in Europe presents some peculiar features in its three main components: research on clocks, comparisons and dissemination methods, and dissemination services. Apart from the usual activities of the national metrological laboratories, an increasing number of cooperation between the European countries are promoted inside some European organizations, such as the ECC, EFTA, EUROMET, and WECC. Cooperation between these organizations is covered. The present, evolving situation will be further influenced by the recent political changes in Eastern Europe.

  2. Increasing long-term response by selecting for favorable minor alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term response of genomic selection can be improved by considering allele frequencies of selected markers or quantitative trait loci (QTLs). A previous formula to weight allele frequency of favorable minor alleles was tested, and 2 new formulas were developed. The previous formula used nonlinear...

  3. Genome-wide interaction studies reveal sex-specific asthma risk alleles

    PubMed Central

    Myers, Rachel A.; Scott, Nicole M.; Gauderman, W. James; Qiu, Weiliang; Mathias, Rasika A.; Romieu, Isabelle; Levin, Albert M.; Pino-Yanes, Maria; Graves, Penelope E.; Villarreal, Albino Barraza; Beaty, Terri H.; Carey, Vincent J.; Croteau-Chonka, Damien C.; del Rio Navarro, Blanca; Edlund, Christopher; Hernandez-Cadena, Leticia; Navarro-Olivos, Efrain; Padhukasahasram, Badri; Salam, Muhammad T.; Torgerson, Dara G.; Van den Berg, David J.; Vora, Hita; Bleecker, Eugene R.; Meyers, Deborah A.; Williams, L. Keoki; Martinez, Fernando D.; Burchard, Esteban G.; Barnes, Kathleen C.; Gilliland, Frank D.; Weiss, Scott T.; London, Stephanie J.; Raby, Benjamin A.; Ober, Carole; Nicolae, Dan L.; Santana, Jose Rodriguez; Cintron, William Rodriguez; Chapela, Rocio; Ford, Jean; Thyne, Shannon; Avila, Pedro C.; Monge, Juan Jose Sienra; Boorgula, Meher; Cheadle, Chris; Eng, Celeste S.; Kiley, J.; Banks-Schlegel, S.; Gan, W.

    2014-01-01

    Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 10?6, of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses. PMID:24824216

  4. Genome-wide interaction studies reveal sex-specific asthma risk alleles.

    PubMed

    Myers, Rachel A; Scott, Nicole M; Gauderman, W James; Qiu, Weiliang; Mathias, Rasika A; Romieu, Isabelle; Levin, Albert M; Pino-Yanes, Maria; Graves, Penelope E; Villarreal, Albino Barraza; Beaty, Terri H; Carey, Vincent J; Croteau-Chonka, Damien C; del Rio Navarro, Blanca; Edlund, Christopher; Hernandez-Cadena, Leticia; Navarro-Olivos, Efrain; Padhukasahasram, Badri; Salam, Muhammad T; Torgerson, Dara G; Van den Berg, David J; Vora, Hita; Bleecker, Eugene R; Meyers, Deborah A; Williams, L Keoki; Martinez, Fernando D; Burchard, Esteban G; Barnes, Kathleen C; Gilliland, Frank D; Weiss, Scott T; London, Stephanie J; Raby, Benjamin A; Ober, Carole; Nicolae, Dan L

    2014-10-01

    Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses. PMID:24824216

  5. Allele Name Translation Tool and Update NomenCLature: Software tools for the automated translation of HLA allele names between successive nomenclatures

    PubMed Central

    Mack, Steven J.; Hollenbach, Jill A.

    2010-01-01

    In this brief communication, we describe the Allele Name Translation Tool (ANTT) and Update NomenCLature (UNCL), free programs developed to facilitate the translation of HLA allele names recorded using the December 2002 version of the HLA allele nomenclature (e.g., A*01010101) to those recorded using the colon-delimited version of the HLA allele nomenclature (e.g., A*01:01:01:01) adopted in April of 2010. In addition, the ANTT and UNCL translate specific HLA allele-name changes (e.g., DPB1*0502 is translated to DPB1*104:01), as well as changes to the locus-prefix for HLA-C (i.e., Cw* is translated to C*). The ANTT and UNCL will also translate allele names that have been truncated to two, four or six digits, as well as ambiguous allele-strings. The ANTT is a locally installed and run application, while UNCL is a web-based tool that requires only an internet connection and a modern browser. The ANTT accepts a variety of HLA data-presentation and allele-name formats. In addition, the ANTT can translate using user-defined conversion settings (e.g., the names of alleles that encode identical peptide binding domains can be translated to a common P-code), and can serve as a preliminary data-sanity tool. The ANTT is available for download, and UNCL for use, at www.igdawg.org/software. PMID:20412076

  6. Allele Name Translation Tool and Update NomenCLature: software tools for the automated translation of HLA allele names between successive nomenclatures.

    PubMed

    Mack, S J; Hollenbach, J A

    2010-05-01

    In this brief communication, we describe the Allele Name Translation Tool (antt) and Update NomenCLature (uncl), free programs developed to facilitate the translation of human leukocyte antigen (HLA) allele names recorded using the December 2002 version of the HLA allele nomenclature (e.g. A*01010101) to those recorded using the colon-delimited version of the HLA allele nomenclature (e.g. A*01:01:01:01) that was adopted in April 2010. In addition, the antt and uncl translate specific HLA allele-name changes (e.g. DPB1*0502 is translated to DPB1*104:01), as well as changes to the locus prefix for HLA-C (i.e. Cw* is translated to C*). The antt and uncl will also translate allele names that have been truncated to two, four, or six digits, as well as ambiguous allele strings. The antt is a locally installed and run application, while uncl is a web-based tool that requires only an Internet connection and a modern browser. The antt accepts a variety of HLA data-presentation and allele-name formats. In addition, the antt can translate using user-defined conversion settings (e.g. the names of alleles that encode identical peptide binding domains can be translated to a common 'P-code'), and can serve as a preliminary data-sanity tool. The antt is available for download, and uncl for use, at www.igdawg.org/software. PMID:20412076

  7. Allele frequencies and population data for 17 Y-STR loci (The AmpFlSTR Y-filer) in Casablanca resident population.

    PubMed

    Laouina, Adil; El Houate, Brahim; Yahia, Hakima; Azeddoug, Houssine; Boulouiz, Redouane; Chbel, Faiza

    2011-01-01

    Allele frequencies and population data for 17 Y-STR loci included in the AmpFlSTR Y-filer PCR amplification kit (Applied Biosystems, Foster City, USA), that permit the simultaneous amplification of all the markers included in the actually used European "extended haplotype", DYS19, DYS189I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385I/II, DYS438, DYS439 and also DYS437, DYS448, DYS456, DYS458, DYS635 and Y GATA H4, were obtained from a sample of 166 healthy unrelated males resident in Casablanca (from Morocco). A total of 166 haplotypes were identified, of which 142 were unique. The overall haplotype diversity for the 17 Y-STR loci reached 0.9974, and a discrimination capacity was 0.855. We report some non-standard situations, including duplications and microvariant alleles. PMID:21126935

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

    PubMed Central

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

    2014-01-01

    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 pathwaysHERC2, SLC45A2, and TYRusing 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 210% 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

  9. Allelic Frequencies of 20 Visible Phenotype Variants in the Korean Population

    PubMed Central

    Lim, Ji Eun

    2013-01-01

    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

  10. Detection of new genetic profiles and allelic variants in improperly classified grapevine accessions.

    PubMed

    Gismondi, A; Impei, S; Di Marco, G; Crespan, M; Leonardi, D; Canini, A

    2014-02-01

    Thirty-seven grapevine accessions, collected in Central Italy, were characterized by morphological and genetic analysis, according to guidelines developed by European Union programs of grapevine research and standardization. Traditional denominations of some sampled varieties were revealed to be incorrect; moreover, 10 synonymies and 12 homonymies were recognized. Ampelographic and ampelometric measurements of leaf characters were performed. These data generated a phenotypic similarity matrix and a relative diagram showing morphological differences between specimens. Many samples presented different morphology even in the presence of the same genotype, probably as a result of various environmental pressures. Grapevines were typed by 12 microsatellite loci and then compared with the CRA-VIT genetic resource database. Twenty-five SSR profiles were clearly identified as well-known cultivars, while nine genotypes did not find a direct correspondence: these samples could represent putative new autochthonous Latial Vitis vinifera cultivars or hybrid varieties. The genetic approach also detected three new (169 and 173 in VVMD27 locus; 179 in ISV2 locus) and seven rare allelic variants. Plant sample classification by oral history, morphological observations, and molecular results were compared and discussed. Scions of samples were planted in the Botanic Garden of the University of Rome "Tor Vergata", to preserve grapevine biodiversity and to protect possible new autochthonous varieties. PMID:24702068

  11. A Hypomorphic Vasopressin Allele Prevents Anxiety-Related Behavior

    PubMed Central

    Horvath, Charlotte; Graf, Cornelia; Frank, Elisabeth; Keßler, Melanie S.; Murgatroyd, Chris; Müller-Myhsok, Bertram; Gonik, Mariya; Weber, Peter; Pütz, Benno; Muigg, Patrik; Panhuysen, Markus; Singewald, Nicolas; Bettecken, Thomas; Deussing, Jan M.; Holsboer, Florian; Spengler, Dietmar; Landgraf, Rainer

    2009-01-01

    Background To investigate neurobiological correlates of trait anxiety, CD1 mice were selectively bred for extremes in anxiety-related behavior, with high (HAB) and low (LAB) anxiety-related behavior mice additionally differing in behavioral tests reflecting depression-like behavior. Methodology/ Principal Findings In this study, microarray analysis, in situ hybridization, quantitative real-time PCR and immunohistochemistry revealed decreased expression of the vasopressin gene (Avp) in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei of adult LAB mice compared to HAB, NAB (normal anxiety-related behavior) and HABxLAB F1 intercross controls, without detecting differences in receptor expression or density. By sequencing the regions 2.5 kbp up- and downstream of the Avp gene locus, we could identify several polymorphic loci, differing between the HAB and LAB lines. In the gene promoter, a deletion of twelve bp Δ(−2180–2191) is particularly likely to contribute to the reduced Avp expression detected in LAB animals under basal conditions. Indeed, allele-specific transcription analysis of F1 animals revealed a hypomorphic LAB-specific Avp allele with a reduced transcription rate by 75% compared to the HAB-specific allele, thus explaining line-specific Avp expression profiles and phenotypic features. Accordingly, intra-PVN Avp mRNA levels were found to correlate with anxiety-related and depression-like behaviors. In addition to this correlative evidence, a significant, though moderate, genotype/phenotype association was demonstrated in 258 male mice of a freely-segregating F2 panel, suggesting a causal contribution of the Avp promoter deletion to anxiety-related behavior. Discussion Thus, the identification of polymorphisms in the Avp gene promoter explains gene expression differences in association with the observed phenotype, thus further strengthening the concept of the critical involvement of centrally released AVP in trait anxiety. PMID:19357765

  12. Autoimmune Disease Classification by Inverse Association with SNP Alleles

    PubMed Central

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

    2009-01-01

    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 variation profile for a given disease to capture strength of association with multiple SNPs in an allele-specific fashion. We apply this method to compare genetic variation profiles of six autoimmune diseases: multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), Crohn's disease (CD), and type 1 diabetes (T1D), as well as five non-autoimmune diseases. We quantify pair-wise relationships between these diseases and find two broad clusters of autoimmune disease where SNPs that make an individual susceptible to one class of autoimmune disease also protect from diseases in the other autoimmune class. We find that RA and AS form one such class, and MS and ATD another. We identify specific SNPs and genes with opposite risk profiles for these two classes. We furthermore explore individual SNPs that play an important role in defining similarities and differences between disease pairs. We present a novel, systematic, cross-platform approach to identify allele-specific relationships between disease pairs based on genetic variation as well as the individual SNPs which drive the relationships. While recognizing similarities between diseases might lead to identifying novel treatment options, detecting differences between diseases previously thought to be similar may point to key novel disease-specific genes and pathways. PMID:20041220

  13. Improvements to a Markerless Allelic Exchange System for Bacillus anthracis

    PubMed Central

    Plaut, Roger D.; Stibitz, Scott

    2015-01-01

    A system was previously developed for conducting I-SceI-mediated allelic exchange in Bacillus anthracis. In this system, recombinational loss of a chromosomally-integrated allelic exchange vector is stimulated by creation of a double-stranded break within the vector by the homing endonuclease I-SceI. Although this system is reasonably efficient and represents an improvement in the tools available for allelic exchange in B. anthracis, researchers are nonetheless required to “pick and patch” colonies in order to identify candidate "exchangeants." In the present study, a number of improvements have been made to this system: 1) an improved I-SceI-producing plasmid includes oriT so that both plasmids can now be introduced by conjugation, thus avoiding the need for preparing electro-competent cells of each integration intermediate; 2) antibiotic markers have been changed to allow the use of the system in select agent strains; and 3) both plasmids have been marked with fluorescent proteins, allowing the visualization of plasmid segregation on a plate and obviating the need for “picking and patching.” These modifications have made the process easier, faster, and more efficient, allowing for parallel construction of larger numbers of mutant strains. Using this improved system, the genes encoding the tripartite anthrax toxin were deleted singly and in combination from plasmid pXO1 of Sterne strain 34F2. In the course of this study, we determined that DNA transfer to B. anthracis could be accomplished by conjugation directly from a methylation-competent E. coli strain. PMID:26624016

  14. Allelic melanism in American and British peppered moths.

    PubMed

    Grant, B S

    2004-01-01

    Parallel evolutionary changes in the incidence of melanism are well documented in widely geographically separated subspecies of the peppered moth (Biston betularia). The British melanic phenotype (f. carbonaria) and the American melanic phenotype (f. swettaria) are indistinguishable in appearance, and previous genetic analysis has established that both are inherited as autosomal dominants. This report demonstrates through hybridizations of the subspecies and Mendelian testcrosses of melanic progeny that carbonaria and swettaria are phenotypes produced by alleles (isoalleles) at a single locus. The possibility of close linkage at two loci remains, but the simpler one-locus model cannot be rejected in the absence of contrary evidence. PMID:15073224

  15. Mapping rare and common causal alleles for complex human diseases

    PubMed Central

    Raychaudhuri, Soumya

    2011-01-01

    Advances in genotyping and sequencing technologies have revolutionized the genetics of complex disease by locating rare and common variants that influence an individual’s risk for diseases, such as diabetes, cancers, and psychiatric disorders. However, to capitalize on this data for prevention and therapies requires the identification of causal alleles and a mechanistic understanding for how these variants contribute to the disease. After discussing the strategies currently used to map variants for complex diseases, this Primer explores how variants may be prioritized for follow-up functional studies and the challenges and approaches for assessing the contributions of rare and common variants to disease phenotypes. PMID:21962507

  16. The Timing of Pigmentation Lightening in Europeans

    PubMed Central

    Beleza, Sandra; Santos, Antnio M.; McEvoy, Brian; Alves, Isabel; Martinho, Cludia; Cameron, Emily; Shriver, Mark D.; Parra, Esteban J.; Rocha, Jorge

    2013-01-01

    The inverse correlation between skin pigmentation and latitude observed in human populations is thought to have been shaped by selective pressures favoring lighter skin to facilitate vitamin D synthesis in regions far from the equator. Several candidate genes for skin pigmentation have been shown to exhibit patterns of polymorphism that overlap the geospatial variation in skin color. However, little work has focused on estimating the time frame over which skin pigmentation has changed and on the intensity of selection acting on different pigmentation genes. To provide a temporal framework for the evolution of lighter pigmentation, we used forward Monte Carlo simulations coupled with a rejection sampling algorithm to estimate the time of onset of selective sweeps and selection coefficients at four genes associated with this trait in Europeans: KITLG, TYRP1, SLC24A5, and SLC45A2. Using compound haplotype systems consisting of rapidly evolving microsatellites linked to one single-nucleotide polymorphism in each gene, we estimate that the onset of the sweep shared by Europeans and East Asians at KITLG occurred approximately 30,000 years ago, after the out-of-Africa migration, whereas the selective sweeps for the European-specific alleles at TYRP1, SLC24A5, and SLC45A2 started much later, within the last 11,00019,000 years, well after the first migrations of modern humans into Europe. We suggest that these patterns were influenced by recent increases in size of human populations, which favored the accumulation of advantageous variants at different loci. PMID:22923467

  17. Polymorphisms in Chemokine Receptor 5 and Toll-Like Receptor 3 Genes Are Risk Factors for Clinical Tick-Borne Encephalitis in the Lithuanian Population

    PubMed Central

    Nordgren, Johan; Carlsson, Beatrice; Hagbom, Marie; Svensson, Lennart; Lindquist, Lars

    2014-01-01

    Background Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings The prevalence of CCR5?32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (p<0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p?=?0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p?=?0.022 and 65.2% vs 76.4% p?=?0.009; respectively). Conclusions Independently of age, nonfunctional CCR5?32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms in susceptibility to TBEV infection. PMID:25226020

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

    PubMed Central

    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

    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. PMID:23828614

  19. The P86L common allele of CALHM1 does not influence risk for Alzheimer disease in Japanese cohorts.

    PubMed

    Inoue, Ken; Tanaka, Noriko; Yamashita, Fumio; Sawano, Yoshie; Asada, Takashi; Goto, Yu-ichi

    2010-03-01

    A common P86L variant in CALHM1 was recently identified to increase susceptibility to Alzheimer disease (AD) in individuals of European-descent. To determine whether or not this association is also valid in a different ethnic population, we directly sequenced three nearby SNPs including P86L in more than 2,500 Japanese AD case-control samples. We found no association between CALHM1 P86L polymorphism and AD risk in Japanese individuals. We also found a small number of non-synonymous minor variants in both control and case populations, some of which are predicted to affect protein function, but are unlikely to increase this risk of AD in this population. We also determined that the P86L allele frequency is lower in non-Caucasian populations than in Caucasians. Our findings suggest that the CALHM1 P86L common variant may not influence AD risk in Japanese. PMID:19655363

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

    PubMed Central

    Fernández-Torres, Javier; Flores-Jiménez, Denhi; Arroyo-Pérez, Antonio; Granados, Julio; López-Reyes, Alberto

    2013-01-01

    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. PMID:24364037

  1. Identification and functional characterization of three novel alleles for the serotonin transporter-linked polymorphic region.

    PubMed

    Ehli, E A; Hu, Y; Lengyel-Nelson, T; Hudziak, J J; Davies, G E

    2012-02-01

    A promoter polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to confer relative risk for phenotypes (depression/anxiety) and endophenotypes (amygdala reactivity). In this report, we identify and characterize three rare 5-HTTLPR alleles not previously described in the human literature. The three novel alleles were identified while genotyping 5-HTTLPR in a family-based attention deficit hyperactivity disorder clinical population. Two of the novel alleles are longer than the common 16-repeat long (L) allele (17 and 18 repeats) and the third is significantly smaller than the 14-repeat short (S) allele (11 repeats). The sequence and genetic architecture of each novel allele is described in detail. We report a significant decrease in the expression between the XL?? (17r) allele and the L(A) (16r) allele. The XS?? (11r) allele showed similar expression with the S (14r) allele. A 1.8-fold increase in expression was observed with the L(A)(16r) allele compared with the L(G) (16r) allele, which replicates results from earlier 5-HTTLPR expression experiments. In addition, transcription factor binding site (TFBS) analysis was performed using MatInspector (Genomatix) that showed the presence or absence of different putative TFBSs between the novel alleles and the common L (16r) and S (14r) alleles. The identification of rare variants and elucidation of their functional impact could potentially lead to understanding the contribution that the rare variant may have on the inheritance/susceptibility of multifactorial common diseases. PMID:21200389

  2. European Universe Awareness

    NASA Astrophysics Data System (ADS)

    Russo, P.; Miley, G.; Westra van Holthe, F.; Schrier, W.; Reed, S.

    2011-10-01

    The European Universe Awareness (EU-UNAWE) programme uses the beauty and grandeur of the cosmos to encourage young children, particularly those from underprivileged backgrounds, to develop an interest in science and technology and to foster a sense of global citizenship. EU-UNAWE is already active in 40 countries and comprises a global network of almost 500 astronomers, teachers and other educators. The programme was recently awarded a grant of 1.9 million euros by the European Union so that it can be further developed in five European countries and South Africa. The grant will be used to organise teacher training workshops and to develop educational materials, such as an astronomy news service for children and games. During this presentation we will outline some of the biggest achievements of EU-UNAWE to date and discuss future plans for the programme.

  3. Allele-specific silencing of mutant Huntington's disease gene.

    PubMed

    Zhang, Yu; Engelman, Joshua; Friedlander, Robert M

    2009-01-01

    Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a poly-glutamine expansion in huntingtin, the protein encoded by the HD gene. PolyQ-expanded huntingtin is toxic to neurons, especially the medium spiny neurons of the striatum. At the same time, wild-type huntingtin has important - indeed essential - protective functions. Any effective molecular therapy must preserve the expression of wild-type huntingtin, while silencing the mutant allele. We hypothesized that an appropriate siRNA molecule would display the requisite specificity and efficacy. As RNA interference is incapable of distinguishing among alleles with varying numbers of CAG (glutamine) codons, another strategy is needed. We used HD fibroblasts in which the pathogenic mutation is linked to a polymorphic site: the Delta2642 deletion of one of four tandem GAG triplets. We silenced expression of the harmful Delta2642-marked polyQ-expanded huntingtin without compromising synthesis of its wild-type counterpart. Following this success in HD fibroblasts, we obtained similar results with neuroblastoma cells expressing both wild-type and mutant HD genes. As opposed to the effect of depleting wild-type huntingtin, specifically silencing the mutant species actually lowered caspase-3 activation and protected HD cells under stress conditions. These findings have therapeutic implications not only for HD, but also for other autosomal dominant diseases. This approach has great promise: it may lead to personalized genetic therapy, a holy grail in contemporary medicine. PMID:19094060

  4. An allele of the crm gene blocks cyanobacterial circadian rhythms.

    PubMed

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

    2013-08-20

    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. PMID:23918383

  5. Genomic landscape of human allele-specific DNA methylation

    PubMed Central

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

    2012-01-01

    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

  6. Allelic loss and linkage studies in prostate cancer

    SciTech Connect

    Johnson, D.R.; Bale, A.E.; Lytton, B.

    1994-09-01

    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.

  7. Allelic variation of human serotonin transporter gene expression.

    PubMed

    Heils, A; Teufel, A; Petri, S; Stöber, G; Riederer, P; Bengel, D; Lesch, K P

    1996-06-01

    Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior. PMID:8632190

  8. The clinical spectrum of complete FBN1 allele deletions.

    PubMed

    Hilhorst-Hofstee, Yvonne; Hamel, Ben C J; Verheij, Joke B G M; Rijlaarsdam, Marry E B; Mancini, Grazia M S; Cobben, Jan M; Giroth, Cindy; Ruivenkamp, Claudia A L; Hansson, Kerstin B M; Timmermans, Janneke; Moll, Henriette A; Breuning, Martijn H; Pals, Gerard

    2011-03-01

    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 complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome. PMID:21063442

  9. The clinical spectrum of complete FBN1 allele deletions

    PubMed Central

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

    2011-01-01

    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 complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome. PMID:21063442

  10. Substitution processes in molecular evolution. III. Deleterious alleles.

    PubMed

    Gillespie, J H

    1994-11-01

    The substitution processes for various models of deleterious alleles are examined using computer simulations and mathematical analyses. Most of the work focuses on the house-of-cards model, which is a popular model of deleterious allele evolution. The rate of substitution is shown to be a concave function of the strength of selection as measured by alpha = 2N sigma, where N is the population size and sigma is the standard deviation of fitness. For alpha < 1, the house-of-cards model is essentially a neutral model; for alpha > 4, the model ceases to evolve. The stagnation for large alpha may be understood by appealing to the theory of records. The house-of-cards model evolves to a state where the vast majority of all mutations are deleterious, but precisely one-half of those mutations that fix are deleterious (the other half are advantageous). Thus, the model is not a model of exclusively deleterious evolution as is frequently claimed. It is argued that there are no biologically reasonable models of molecular evolution where the vast majority of all substitutions are deleterious. Other models examined include the exponential and gamma shift models, the Hartl-Dykhuizen-Dean (HDD) model, and the optimum model. Of all those examined, only the optimum and HDD models appear to be reasonable candidates for silent evolution. None of the models are viewed as good candidates for protein evolution, as none are both biologically reasonable and exhibit the variability in substitutions commonly observed in protein sequence data. PMID:7851786

  11. Allelic discrimination using fluorogenic probes and the 5' nuclease assay.

    PubMed

    Livak, K J

    1999-02-01

    Large-scale screening for known polymorphisms will require techniques with few steps and the ability to automate each of these steps. In this regard, the 5' nuclease, or TaqMan, PCR assay is especially attractive. A fluorogenic probe, consisting of an oligonucleotide labeled with both a fluorescent reporter dye and a quencher dye, is included in a typical PCR. Amplification of the probe-specific product causes cleavage of the probe, generating an increase in reporter fluorescence. By using different reporter dyes, cleavage of allele-specific probes can be detected in a single PCR. The 5' nuclease assay has been successfully used to discriminate alleles that differ by a single base substitution. Guidelines have been developed so that an assay for any single nucleotide polymorphism (SNP) can be quickly designed and implemented. All assays are performed using a single reaction buffer and single thermocycling protocol. Furthermore, a standard method of analysis has been developed that enables automated genotype determination. Applications of this assay have included typing a number of polymorphisms in human drug metabolism genes. PMID:10084106

  12. Measuring and Testing Genetic Differentiation with Ordered versus Unordered Alleles

    PubMed Central

    Pons, O.; Petit, R. J.

    1996-01-01

    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. PMID:8913764

  13. Clonal population structure of Legionella pneumophila inferred from allelic profiling.

    PubMed

    Edwards, Martin T; Fry, Norman K; Harrison, Timothy G

    2008-03-01

    The population structure of Legionella pneumophila was investigated by analysing nucleotide sequences from six loci (flaA, pilE, asd, mip, mompS and proA) of 335 globally distributed isolates from clinical and environmental sources over a 29-year period (1977-2006). Data were obtained from unrelated isolates from Europe (n=270), Japan (n=31), Canada (n=7), the USA (n=24) and Australia (n=1). The country of origin of two strains was unknown. Analysis of these isolates indicated significant linkage disequilibrium between the six loci. Application of six sequence-based recombination detection tests did not reveal evidence of recombination, but estimates of rates of recombination and mutation made by a seventh test suggested that recombination could have occurred at a rate similar to, but probably lower than, that of mutation. Genealogies inferred under models with and without recombination were congruent with each other, providing no definitive evidence regarding recombination, and were in agreement with sequence clusters identified by graph methods. Further evidence supporting the distinct nature of two of the three subspecies of L. pneumophila, subsp. fraseri and subsp. pascullei, was also found. The ratios of non-synonymous to synonymous nucleotide polymorphisms for each of the allele sets were examined and revealed that the putative virulence loci mompS and pilE are under diversifying pressure, while the allelic regions of three other loci linked to virulence (flaA, proA and mip) do not appear to be. PMID:18310031

  14. Null allele, allelic dropouts or rare sex detection in clonal organisms: simulations and application to real data sets of pathogenic microbes

    PubMed Central

    2014-01-01

    Background Pathogens and their vectors are organisms whose ecology is often only accessible through population genetics tools based on spatio-temporal variability of molecular markers. However, molecular tools may present technical difficulties due to the masking of some alleles (allelic dropouts and/or null alleles), which tends to bias the estimation of heterozygosity and thus the inferences concerning the breeding system of the organism under study. This is especially critical in clonal organisms in which deviation from panmixia, as measured by Wrights FIS, can, in principle, be used to infer both the extent of clonality and structure in a given population. In particular, null alleles and allelic dropouts are locus specific and likely produce high variance of Wrights FIS across loci, as rare sex is expected to do. In this paper we propose a tool enabling to discriminate between consequences of these technical problems and those of rare sex. Methods We have performed various simulations of clonal and partially clonal populations. We introduce allelic dropouts and null alleles in clonal data sets and compare the results with those that exhibit increasing rates of sexual recombination. We use the narrow relationship that links Wrights FIS to genetic diversity in purely clonal populations as assessment criterion, since this relationship disappears faster with sexual recombination than with amplification problems of certain alleles. Results We show that the relevance of our criterion for detecting poorly amplified alleles depends partly on the population structure, the level of homoplasy and/or mutation rate. However, the interpretation of data becomes difficult when the number of poorly amplified alleles is above 50%. The application of this method to reinterpret published data sets of pathogenic clonal microbes (yeast and trypanosomes) confirms its usefulness and allows refining previous estimates concerning important pathogenic agents. Conclusion Our criterion of superimposing between the FIS expected under clonality and the observed FIS, is effective when amplification difficulties occur in low to moderate frequencies (20-30%). PMID:25027508

  15. HLA class II alleles in the Otomi population of the Mezquital Valley: a genetic approach to the history of interethnic migrations in the Mexican Central Plateau.

    PubMed

    Jurez-Martn, Ana Itzel; Gonzlez-Sobrino, Blanca Zoila; Olvera, ngel Eduardo Camarena; Falfn-Valencia, Ramcs

    2014-01-01

    From a historical and genetic point of view, the Otomi of the Mezquital Valley are a frontier people that have played an important role in the population dynamics of the Mexican Central Plateau. Due to the antiquity of their presence in the area, the Otomi may be bearers of ancient genetic variability, shared mainly today with other groups belonging to the Otomanguean linguistic family and with the Nahua. In this study we analyzed the HLA class II allele frequencies reported in Mexican indigenous populations, in order to provide an intraregional-level historical perspective of the genetic relationships between the Otomi of the Mezquital Valley and indigenous populations from other regions of Mexico. We examined genetic variation in HLA-DRB1 and -DQB1 loci in 66 nonrelated individuals belonging to seven indigenous communities from the Ixmiquilpan municipality in the Mezquital Valley, in the State of Hidalgo, Mexico. The variability of the HLA-DRB1 gene among the Otomi of the Mezquital Valley was mainly concentrated in five alleles: -DRB1*08:02 (31.06%), -DRB1*04:07 (25.77%), -DRB1*14:06 (7.55%), -DRB1*14:02 (6.06%), and -DRB1*16:02 (4.55%); these alleles have been previously described in other indigenous populations. The most frequent alleles at the HLA-DQB1 locus were -DQB1*03:02 (34.09%), -DQB1*04:02 (31.03%), and -DQB1*03:01 (19.7%). Furthermore, the HLA-DQB1*02:02 allele was found in the Otomi group with a frequency of 2.27%; this allele has not been reported in Mexican indigenous populations. In conclusion, the genetic constitution of the Otomi population is intermediate to the northern groups and the genetic variability shared by the peoples of the central regions of Mexico. Furthermore, HLA-DRB1 and -DQB1 allelic variability among the Otomi provides insight into the historical processes implied in the biological admixture with European, Asian, and African populations as well as in the admixture with the population of Mexico City associated with long-standing migratory processes. PMID:25836745

  16. Major histocompatibility complex variation and age-specific endoparasite load in subadult European rabbits.

    PubMed

    Oppelt, Claus; Starkloff, Anett; Rausch, Philipp; Von Holst, Dietrich; Rdel, Heiko G

    2010-10-01

    Genes of the major histocompatibility complex (MHC) play a fundamental role in the vertebrate immune response and are amongst the most polymorphic genes in vertebrate genomes. It is generally agreed that the highly polymorphic nature of the MHC is maintained through host-parasite co-evolution. Two nonexclusive mechanisms of selection are supposed to act on MHC genes: superiority of MHC heterozygous individuals (overdominance) and an advantage for rare MHC alleles. However, the precise mechanisms and their relative importance are still unknown. Here, we examined MHC dependent parasite load in European rabbits (Oryctolagus cuniculus) from a distinct population with low MHC diversity (three alleles, six genotypes). Using a multivariate approach, we tested for associations of individual MHC class II DRB constitution and the rabbits' intestinal burden with nematodes and coccidia. Rabbits having a particular allele showed lower infestations with hepatic coccidia (E.stiedai). However, a comparison of all six genotypes in the population revealed that carriers of this allele only benefit when they are heterozygous, and furthermore, MHC heterozygosity in general did not affect individual parasite load. In conclusion, this study suggests an immunogenetic basis of European rabbit resistance to hepatic coccidiosis, which can strongly limit survival to maturity in this species. Our study gives a complex picture of MHC-parasite correlations, unveiling the limits of the classical hypotheses of how MHC polymorphism is maintained in natural systems. PMID:20723049

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

    NASA Astrophysics Data System (ADS)

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

    2011-02-01

    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.

  18. The S11 and S13 self incompatibility alleles in Solanum chacoense Bitt. are remarkably similar.

    PubMed

    Saba-el-Leil, M K; Rivard, S; Morse, D; Cappadocia, M

    1994-02-01

    A genomic clone of the S11 allele from the self-incompatibility locus (S locus) in Solanum chacoense Bitt. has been isolated by cross-hybridization to the S. chacoense S13 allele and sequenced. The sequence of the S11 allele contains all the features expected for S genes of the Solanaceae, and S11 expression, as assessed by northern blots and RNA-PCR, was similar to that of other S. chacoense S alleles. The S11 protein sequence shares 95% identity with the phenotypically distinct S13 protein of S. chacoense and is the gametophytic S allele with the highest similarity to an existing allele so far discovered. Only 10 amino acid changes differentiate the mature proteins from these two alleles, which sets a new lower limit to the number of changes that can produce an altered S allele specificity. The amino acid substitutions are not clustered, suggesting that an accumulation of random point mutations can generate S allele diversity. The S11 intron is unusual in that it could be translated in frame with the coding sequence, thus suggesting an additional mechanism for the generation of new S alleles. PMID:8155878

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

    PubMed Central

    Guo, Mei

    2014-01-01

    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 Pioneers modern breeding programme, and have distinct proteins, promoters and expression patterns. These two major alleles show heterotic group partitioning, with one predominant in Pioneers 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

  20. An association between the risk of ovarian cancer and rare HRAS1 alleles

    SciTech Connect

    Weitzel, J.N.; Patel, J.; Smith, D.M.

    1994-09-01

    The highly polymorphic HRAS1 minisatellite locus just downstream from the proto-oncogene H-ras-1 on chromosome 11p consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for common types of cancer. Rare-sized HRAS1 alleles have been found more frequently in patients with carcinoma of the breast, colorectum, and urinary bladder and acute leukemia, compared to cancer-free controls. This highly significant association (p<1.001) results in a modest relative risk for patients with one rare allele, but the prevalence of this class of mutant alleles implies an important attributable risk: 1 in 11 cancers of the breast, colorectum, and bladder. Therefore, we performed a case-control study using conventional (Southern blot) and PCR-based methods to score HRAS1 alleles in the leukocyte DNA from 59 patients with ovarian cancer, and 51 cancer-free controls. Our preliminary data suggest an increased incidence of rare and intermediate HRAS1 alleles in caucasian ovarian cancer patients (13%) compared to cancer-free controls (4%). These results parallel the allele distribution seen in the large published series, and lend support for a significant association between rare HRAS1 alleles and ovarian cancer predisposition.

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

    PubMed

    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; Lffler, Carlos M; Cooper, Mark; Simmons, Carl R

    2014-01-01

    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

  2. Distribution of HLA class II alleles and haplotypes in Mexican Mestizo population: comparison with other populations.

    PubMed

    Vargas-Alarcón, Gilberto; Granados, Julio; Rodríguez-Pérez, José Manuel; Parga, Carlos; Pérez-Hernández, Nonanzit; Rey, Diego; Zuñiga, Joaquín; Arnaiz-Villena, Antonio

    2010-01-01

    We describe the analysis of the Major Histocompatibility Complex (MHC) class II polymorphism in Mexican Mestizo population. The study provides the HLA-DRB1, DQA1 and DQB1 allele frequencies in 99 Mexican Mestizos. DNA from these individuals was typed by PCR followed by hybridization using sequence specific oligonucleotides (PCR-SSO). The relationship with other worldwide populations was studied by using HLA data from 69 different populations and calculating neighbor-joining dendrograms and correspondence multidimensional values. The highest frequencies were for DRB1*0802 (allele frequency = 0.151), DRB1*0701 (allele frequency = 0.111) and DRB1*0407 (allele frequency = 0.106). Among the eight DQA1 alleles detected, the most frequent were DQA1*03011 (allele frequency = 0.257), DQA1*0501 (allele frequency = 0.227) and DQA1*0401 (allele frequency = 0.166). Twelve DQB1 alleles were found and four of them, DQB1*0302 (allele frequency = 0.237), DQB1*0301 (allele frequency = 0.176), DQB1*0201 (allele frequency = 0.166) and DQB1*0402 (allele frequency = 0.166) showed the highest frequencies. The haplotype DRB1*0802-DQA1*0401-DQB1*0402 (0.151) predominated clearly, followed by DRB1*0701-DQA1*0201-DQB1*0201 (0.111) and DRB1*0407-DQA1*03011-DQB1*0302 (0.101). Both genetic distances and correspondence analyses showed that Mexicans clustered with Amerindian population. These results suggest that the Mexican Mestizo population be principally characterized by haplotypes presents in Amerindian and Caucasian populations with a low frequency of Black haplotypes. In summary, the HLA class II haplotype frequencies demonstrated the tri-racial component existing in Mexican Mestizos. PMID:20380523

  3. Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

    PubMed Central

    Kelly, Jennifer A.; Brown, Elizabeth E.; Harley, John B.; Bae, Sang-Cheol; Alarc?n-Riquelme, Marta E.; Edberg, Jeffrey C.; Kimberly, Robert P.; Ramsey-Goldman, Rosalind; Petri, Michelle A.; Reveille, John D.; Vil, Luis M.; Alarcn, Graciela S.; Kaufman, Kenneth M.; Vyse, Timothy J.; Jacob, Chaim O.; Gaffney, Patrick M.; Sivils, Kathy Moser; James, Judith A.; Kamen, Diane L.; Gilkeson, Gary S.; Niewold, Timothy B.; Merrill, Joan T.; Scofield, R. Hal; Criswell, Lindsey A.; Stevens, Anne M.; Boackle, Susan A.; Kim, Jae-Hoon; Choi, Jiyoung; Pons-Estel, Bernardo A.; Freedman, Barry I.; Anaya, Juan-Manuel; Martin, Javier; Yu, C. Yung; Chang, Deh-Ming; Song, Yeong Wook; Langefeld, Carl D.; Chen, Weiling; Grossman, Jennifer M.; Cantor, Rita M.; Hahn, Bevra H.; Tsao, Betty P.

    2013-01-01

    Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P?=?2.710?8, OR?=?1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans. PMID:24130510

  4. European Music Year 1985.

    ERIC Educational Resources Information Center

    Alexanderson, Thomas; And Others

    1984-01-01

    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

  5. Multilingualism in European Workplaces

    ERIC Educational Resources Information Center

    Gunnarsson, Britt-Louise

    2014-01-01

    This state-of-the-art article includes a review of past and recent studies on multilingualism at work in European environments. One aim is to provide the reader with a cross-cultural picture of workplace studies on various languages in Europe, another to discuss both positive and problem-based accounts of multilingualism at work. The overview…

  6. European Polistes venom allergy.

    PubMed

    Severino, M G; Campi, P; Macchia, D; Manfredi, M; Turillazzi, S; Spadolini, I; Bilò, M B; Bonifazi, F

    2006-07-01

    The American Polistes species venom mixture--that of P. annularis, P. fuscatus, P. metricus and P. exclamans--was the only commercially available mixture for diagnosis and therapy until 1996. However, these species of Polistes are not present in Europe, where P. dominulus and P. gallicus and to a lesser extent P. nimphus are widespread. The aim of this study was to assess the allergenic differences among the commercial American mix, P. dominulus and P. gallicus venom in European patients and therefore to verify if this mixture is suitable for diagnosis in these patients. We carried out skin tests, radioallergosorbent tests (RAST) and RAST inhibition in Italian patients with adverse reactions to Polistes stings. RAST inhibition results demonstrated that cross-reactivity between the American and European species is only partial and that P. dominulus and P. gallicus venoms have exclusive allergens. Skin tests and direct RAST confirmed these results and also showed that European Polistes venom is more suitable than the American mix in Italian patients. Moreover, we found a high rate of cross-reactivity between P. dominulus and P. gallicus. To conclude, P. dominulus and/or P. gallicus venoms are necessary for diagnosis and therefore in the therapy of European patients. PMID:16792585

  7. Eastern European Cinema.

    ERIC Educational Resources Information Center

    Iordanova, Dina

    1999-01-01

    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…

  8. Eastern European Cinema.

    ERIC Educational Resources Information Center

    Iordanova, Dina

    1999-01-01

    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

  9. Multilingualism in European Workplaces

    ERIC Educational Resources Information Center

    Gunnarsson, Britt-Louise

    2014-01-01

    This state-of-the-art article includes a review of past and recent studies on multilingualism at work in European environments. One aim is to provide the reader with a cross-cultural picture of workplace studies on various languages in Europe, another to discuss both positive and problem-based accounts of multilingualism at work. The overview

  10. Trends in European English.

    ERIC Educational Resources Information Center

    Wilkinson, Robert

    It is proposed that a European variety of English without native speakers is emerging as a language of international communication in Europe. This is a consequence of many factors, including the strength of the American economy, the breadth and depth of American research in science and technology, the pervasive influence of American-style popular

  11. European Civilization. Teacher's Manual.

    ERIC Educational Resources Information Center

    Leppert, Ella C.; Halac, Dennis

    The instructional materials in this teaching guide for Course II, Unit IV, follow and build upon a previous sequential course described in SO 003 169 offering ninth grade students a study on the development of Western European Civilization. Focus is upon four periods of high development: The High Middle Ages (12th Century), The Renaissance (15th

  12. The European Economic Community.

    ERIC Educational Resources Information Center

    Schuchart, Kelvin

    1986-01-01

    Maintains that social studies students need to realize the relationship of the European Economic Community to the United States in order to understand the trade bonds that exist between us. Briefly reviews the history of the Community, outlines its Common Agricultural Policy, and provides situations for classroom role playing. (JDH)

  13. Teaching European Identities

    ERIC Educational Resources Information Center

    Raento, Pauliina

    2008-01-01

    The political, cultural and social make-up of Europe is changing fast. A new European identity is under construction, but old contradictions and diversity challenge its contents, forms and boundaries. Migration, the changing role of the nation-state and Europe's regions, the reshaping of politico-administrative and perceptional boundaries, the

  14. European Green Crab

    USGS Multimedia Gallery

    The European green crab (Carcinus maenas), has invaded fisheries in Northern California and in British Columbia, where it may compete with the much more valuable Dungeness crab. The CD it holds in its claws is a database for the USGS Pacific Coast Estuarine Information System, just one source used t...

  15. Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes

    PubMed Central

    Taylor, Kimberly E.; Chung, Sharon A.; Graham, Robert R.; Ortmann, Ward A.; Lee, Annette T.; Langefeld, Carl D.; Jacob, Chaim O.; Kamboh, M. Ilyas; Alarcón-Riquelme, Marta E.; Tsao, Betty P.; Moser, Kathy L.; Gaffney, Patrick M.; Harley, John B.; Petri, Michelle; Manzi, Susan; Gregersen, Peter K.; Behrens, Timothy W.; Criswell, Lindsey A.

    2011-01-01

    Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10−8) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10−128. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8–5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (ORhigh-low = 2.36, p = 9e−9), the immunologic criterion (ORhigh-low = 2.23, p = 3e−7), and age at diagnosis (ORhigh-low = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14–1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59–0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci. PMID:21379322

  16. Four p67 alleles identified in South African Theileria parva field samples.

    PubMed

    Sibeko, Kgomotso P; Geysen, Dirk; Oosthuizen, Marinda C; Matthee, Conrad A; Troskie, Milana; Potgieter, Frederick T; Coetzer, Jacobus A W; Collins, Nicola E

    2010-02-10

    Previous studies characterizing the Theileria parva p67 gene in East Africa revealed two alleles. Cattle-derived isolates associated with East Coast fever (ECF) have a 129bp deletion in the central region of the p67 gene (allele 1), compared to buffalo-derived isolates with no deletion (allele 2). In South Africa, Corridor disease outbreaks occur if there is contact between infected buffalo and susceptible cattle in the presence of vector ticks. Although ECF was introduced into South Africa in the early 20th century, it has been eradicated and it is thought that there has been no cattle to cattle transmission of T. parva since. The variable region of the p67 gene was amplified and the gene sequences analyzed to characterize South African T. parva parasites that occur in buffalo, in cattle from farms where Corridor disease outbreaks were diagnosed and in experimentally infected cattle. Four p67 alleles were identified, including alleles 1 and 2 previously detected in East African cattle and buffalo, respectively, as well as two novel alleles, one with a different 174bp deletion (allele 3), the other with a similar sequence to allele 3 but with no deletion (allele 4). Sequence variants of allele 1 were obtained from field samples originating from both cattle and buffalo. Allele 1 was also obtained from a bovine that tested T. parva positive from a farm near Ladysmith in the KwaZulu-Natal Province. East Coast fever was not diagnosed on this farm, but the p67 sequence was identical to that of T. parva Muguga, an isolate that causes ECF in Kenya. Variants of allele 2 were obtained from all T. parva samples from both buffalo and cattle, except Lad 10 and Zam 5. Phylogenetic analysis revealed that alleles 3 and 4 are monophyletic and diverged early from the other alleles. These novel alleles were not identified from South African field samples collected from cattle; however allele 3, with a p67 sequence identical to those obtained in South African field samples from buffalo, was obtained from a Zambian field isolate of a naturally infected bovine diagnosed with ECF. The p67 genetic profiles appear to be more complex than previously thought and cannot be used to distinguish between cattle- and buffalo-derived T. parva isolates in South Africa. The significance of the different p67 alleles, particularly the novel variants, in the epidemiology of theileriosis in South Africa still needs to be determined. PMID:19836893

  17. Allelic richness following population founding events--a stochastic modeling framework incorporating gene flow and genetic drift.

    PubMed

    Greenbaum, Gili; Templeton, Alan R; Zarmi, Yair; Bar-David, Shirli

    2014-01-01

    Allelic richness (number of alleles) is a measure of genetic diversity indicative of a population's long-term potential for adaptability and persistence. It is used less commonly than heterozygosity as a genetic diversity measure, partially because it is more mathematically difficult to take into account the stochastic process of genetic drift for allelic richness. This paper presents a stochastic model for the allelic richness of a newly founded population experiencing genetic drift and gene flow. The model follows the dynamics of alleles lost during the founder event and simulates the effect of gene flow on maintenance and recovery of allelic richness. The probability of an allele's presence in the population was identified as the relevant statistical property for a meaningful interpretation of allelic richness. A method is discussed that combines the probability of allele presence with a population's allele frequency spectrum to provide predictions for allele recovery. The model's analysis provides insights into the dynamics of allelic richness following a founder event, taking into account gene flow and the allele frequency spectrum. Furthermore, the model indicates that the "One Migrant per Generation" rule, a commonly used conservation guideline related to heterozygosity, may be inadequate for addressing preservation of diversity at the allelic level. This highlights the importance of distinguishing between heterozygosity and allelic richness as measures of genetic diversity, since focusing merely on the preservation of heterozygosity might not be enough to adequately preserve allelic richness, which is crucial for species persistence and evolution. PMID:25526062

  18. Allelic Richness following Population Founding Events – A Stochastic Modeling Framework Incorporating Gene Flow and Genetic Drift

    PubMed Central

    Greenbaum, Gili; Templeton, Alan R.; Zarmi, Yair; Bar-David, Shirli

    2014-01-01

    Allelic richness (number of alleles) is a measure of genetic diversity indicative of a population's long-term potential for adaptability and persistence. It is used less commonly than heterozygosity as a genetic diversity measure, partially because it is more mathematically difficult to take into account the stochastic process of genetic drift for allelic richness. This paper presents a stochastic model for the allelic richness of a newly founded population experiencing genetic drift and gene flow. The model follows the dynamics of alleles lost during the founder event and simulates the effect of gene flow on maintenance and recovery of allelic richness. The probability of an allele's presence in the population was identified as the relevant statistical property for a meaningful interpretation of allelic richness. A method is discussed that combines the probability of allele presence with a population's allele frequency spectrum to provide predictions for allele recovery. The model's analysis provides insights into the dynamics of allelic richness following a founder event, taking into account gene flow and the allele frequency spectrum. Furthermore, the model indicates that the “One Migrant per Generation” rule, a commonly used conservation guideline related to heterozygosity, may be inadequate for addressing preservation of diversity at the allelic level. This highlights the importance of distinguishing between heterozygosity and allelic richness as measures of genetic diversity, since focusing merely on the preservation of heterozygosity might not be enough to adequately preserve allelic richness, which is crucial for species persistence and evolution. PMID:25526062

  19. An ontology for major histocompatibility complex (MHC) alleles and molecules.

    PubMed

    Beisswanger, Elena; DeLuca, David S; Blasczyk, Rainer; Hahn, Udo

    2007-01-01

    We present a formally coherent and consistent multi-species MHC ontology which includes all human MHC alleles and serological groups. The ontology is part of StemNet, a knowledge management system for hematopoietic stem cell transplantation with an integrated semantic search engine. The Owl-encoded MHC ontology contributes to the system in a threefold manner. First, it supports query formulation and query processing as well as mapping onto external terminological resources, second, it eases the interaction with the search engine when navigating through search results, and finally, it provides a formal language for text annotation, a methodological prerequisite for state-of-the-art natural language text processors which are increasingly based on machine learning methods and hence require annotated text corpora. PMID:18693794

  20. Synergistic effect of Adh alleles in Drosophila melanogaster.

    PubMed

    Li, X M

    1992-01-22

    In laboratory cultures of Drosophila melanogaster derived from an African population, the quantities of six out of seven enzymes (G6PD, IDH, GPDH, ME, MDH, PGM and ADH) were higher in Adh-FF homozygotes than they were in Adh-SS. In crosses between Adh-FF and Adh-SS flies, the differences segregated as co-dominant alleles of a single Mendelian gene closely linked, or identical, to the Adh locus. The generality of these associations was suggested by the study of a French population with a very different history and genetic background. The possibility that the associations were caused by artefacts of the immunodiffusion techniques, or to a linked inversion (In(2L)t), was excluded. Possible ways by which the Adh locus may affect the quantities of other enzymes are discussed. PMID:1348124

  1. A Likelihood Approach to Populations Samples of Microsatellite Alleles

    PubMed Central

    Nielsen, R.

    1997-01-01

    This paper presents a likelihood approach to population samples of microsatellite alleles. A Markov chain recursion method previously published by GRIFFITHS and TAVARE is applied to estimate the likelihood function under different models of microsatellite evolution. The method presented can be applied to estimate a fundamental population genetics parameter ? as well as parameters of the mutational model. The new likelihood estimator provides a better estimator of ? in terms of the mean square error than previous approaches. Furthermore, it is demonstrated how the method may easily be applied to test models of microsatellite evolution. In particular it is shown how to compare a one-step model of microsatellite evolution to a multi-step model by a likelihood ratio test. PMID:9178018

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

    PubMed Central

    Turner, Thomas L.

    2014-01-01

    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

  3. Non-Equilibrium Allele Frequency Spectra Via Spectral Methods

    PubMed Central

    Hey, Jody; Chen, Kevin

    2011-01-01

    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. PMID:21376069

  4. A measure of population subdivision based on microsatellite allele frequencies

    SciTech Connect

    Slatkin, M.

    1995-01-01

    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 microsatellite loci. This paper, like the accompanying paper by Goldstein et al. (1995), discusses how information about the mutation process at microsatellite loci can suggest statistics that are more appropriate for the analysis of microsatellite loci than are existing statistics. In this paper, I will introduce a new statistic analogous to Wright`s (1951) F{sub ST} that can be used to estimate effective migration rates or times since population divergence. This statistic is closely related to the distance measures introduced by Goldstein et al. (1995). 15 refs., 15 figs., 1 tab.

  5. Leukemogenic Ptpn11 Allele Causes Defective Erythropoiesis in Mice

    PubMed Central

    Usenko, Tatiana; Chan, Gordon; Torlakovic, Emina; Klingmller, Ursula; Neel, Benjamin G.

    2014-01-01

    Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2), encoded by PTPN11, regulates signaling networks and cell fate in many tissues. Expression of oncogenic PTPN11 in the hematopoietic compartment causes myeloproliferative neoplasm (MPN) in humans and mice. However, the stage-specific effect(s) of mutant Ptpn11 on erythroid development have remained unknown. We found that expression of an activated, leukemogenic Ptpn11 allele, Ptpn11D61Y, specifically in the erythroid lineage causes dyserythropoiesis in mice. Ptpn11D61Y progenitors produce excess cKIT+CD71+Ter119? cells and aberrant numbers of cKITlCD71+ erythroblasts. Mutant erythroblasts show elevated activation of ERK, AKT and STAT3 in response to EPO stimulation, and MEK inhibitor treatment blocks Ptpn11D61Y-evoked erythroid hyperproliferation in vitro. Thus, the expression of oncogenic Ptpn11 causes dyserythropoiesis in a cell-autonomous manner in vivo. PMID:25289670

  6. Genetic characterisation of Toxoplasma gondii isolates from European beavers (Castor fiber) and European wildcats (Felis silvestris silvestris).

    PubMed

    Herrmann, D C; Wibbelt, G; Gtz, M; Conraths, F J; Schares, G

    2013-01-16

    Six free-ranging European beavers (Castor fiber) from Berlin greater metropolitan area and twelve European wildcats (Felis silvestris silvestris) originating from the German Federal State of Saxony-Anhalt were found dead and their carcasses were submitted for necropsy. Brain and lung samples were analysed for the presence of Toxoplasma gondii DNA. Histo-pathologic analysis of one beaver revealed several cyst-like protozoal structures in parts of the brain. Tissue DNA isolated from all animal samples was analysed by a specific T. gondii-PCR. Two beavers and four wildcats tested T. gondii-positive. DNA of the parasites was further analysed by PCR-RFLP typing using nine markers (nSAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico). Only T. gondii type II alleles were detected, except for the Apico locus, where type I alleles were observed in two isolates from beavers and in three from wild cats. The results of this study indicate that type II T. gondii (including type II variant strain) is the most common genotype infecting wildcats and beavers from Germany. PMID:22989954

  7. Generation of Humoral Immune Responses to Multi-Allele PfAMA1 Vaccines; Effect of Adjuvant and Number of Component Alleles on the Breadth of Response

    PubMed Central

    Kusi, Kwadwo A.; Faber, Bart W.; Riasat, Vanessa; Thomas, Alan W.; Kocken, Clemens H. M.; Remarque, Edmond J.

    2010-01-01

    There is increasing interest in multi-allele vaccines to overcome strain-specificity against polymorphic vaccine targets such as Apical Membrane Antigen 1 (AMA1). These have been shown to induce broad inhibitory antibodies in vitro and formed the basis for the design of three Diversity-Covering (DiCo) proteins with similar immunological effects. The antibodies produced are to epitopes that are shared between vaccine alleles and theoretically, increasing the number of component AMA1 alleles is expected to broaden the antibody response. A plateau effect could however impose a limit on the number of alleles needed to achieve the broadest specificity. Moreover, production cost and the vaccine formulation process would limit the number of component alleles. In this paper, we compare rabbit antibody responses elicited with multi-allele vaccines incorporating seven (three DiCos and four natural AMA1 alleles) and three (DiCo mix) antigens for gains in broadened specificity. We also investigate the effect of three adjuvant platforms on antigen specificity and antibody functionality. Our data confirms a broadened response after immunisation with DiCo mix in all three adjuvants. Higher antibody titres were elicited with either CoVaccine HT or Montanide ISA 51, resulting in similar in vitro inhibition (6582%) of five out of six culture-adapted P. falciparum strains. The antigen binding specificities of elicited antibodies were also similar and independent of the adjuvant used or the number of vaccine component alleles. Thus neither the four extra antigens nor adjuvant had any observable benefits with respect to specificity broadening, although adjuvant choice influenced the absolute antibody levels and thus the extent of parasite inhibition. Our data confirms the feasibility and potential of multi-allele PfAMA1 formulations, and highlights the need for adjuvants with improved antibody potentiation properties for AMA1-based vaccines. PMID:21082025

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

    PubMed

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

    2014-06-01

    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

  9. Biochemical genetic relationships among Tunisian hares (Lepus sp.), South African cape hares (L. capensis), and European brown hares (L. europaeus).

    PubMed

    Ben Slimen, Hichem; Suchentrunk, Franz; Memmi, Abdelmajid; Ben Ammar Elgaaied, Amel

    2005-12-01

    Tunisian hares (n = 45), currently assigned to Lepus capensis, were assayed for allelic variation at 40 allozyme loci, and allele frequencies at 32 loci were directly compared with earlier data of South African cape hares (L. capensis, n = 9) and European brown hares (L. europaeus, n = 244) to reveal genetic relationships among them. European mountain hares (L. timidus, n = 200) were used for outgroup comparison. In the Tunisian hares 27.5% of the loci were polymorphic with 2-4 alleles. Among all alleles at polymorphic loci, 15.1% occurred exclusively in Tunisian hares, 5.7% exclusively in cape hares, and 7.5% exclusively in brown hares at low frequencies. Not a single locus showed alternately fixed alleles between the samples of the L. capensis/L. europaeus complex. Levels of absolute and relative genetic differentiation among the samples of the L. capensis/L. europaeus complex were low, relative to pairwise comparisons involving mountain hares. Diverse cluster analyses and multidimensional scaling of various pairwise genetic distance matrices concordantly grouped Tunisian hares with brown hares, and South African cape hares clustered only slightly farther apart, whereas mountain hares were distinctly separate. These results suggest regionally distinct phylogenetic units within an overall cohesive gene pool in the L. capensis/L. europaeus complex, supporting Petter's view that all North African hares belong to L. capensis except for one local population of savanna hares, and that cape hares and brown hares are conspecific. PMID:16382363

  10. Introgressive hybridization: brown bears as vectors for polar bear alleles.

    PubMed

    Hailer, Frank

    2015-03-01

    The dynamics and consequences of introgression can inform about numerous evolutionary processes. Biologists have therefore long been interested in hybridization. One challenge, however, lies in the identification of nonadmixed genotypes that can serve as a baseline for accurate quantification of admixture. In this issue of Molecular Ecology, Cahill et al. (2015) analyse a genomic data set of 28 polar bears, eight brown bears and one American black bear. Polar bear alleles are found to be introgressed into brown bears not only near a previously identified admixture zone on the Alaskan Admiralty, Baranof and Chichagof (ABC) Islands, but also far into the North American mainland. Elegantly contrasting admixture levels at autosomal and X chromosomal markers, Cahill and colleagues infer that male-biased dispersal has spread these introgressed alleles away from the Late Pleistocene contact zone. Compared to a previous study on the ABC Island population in which an Alaskan brown bear served as a putatively admixture-free reference, Cahill et al. (2015) utilize a newly sequenced Swedish brown bear as admixture baseline. This approach reveals that brown bears have been impacted by introgression from polar bears to a larger extent (up to 8.8% of their genome), than previously known, including the bear that had previously served as admixture baseline. No evidence for introgression of brown bear into polar bear is found, which the authors argue could be a consequence of selection. Besides adding new exciting pieces to the puzzle of polar/brown bear evolutionary history, the study by Cahill and colleagues highlights that wildlife genomics is moving from analysing single genomes towards a landscape genomics approach. PMID:25775930

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

    PubMed Central

    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

    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. PMID:22571293

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

    PubMed Central

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

    2014-01-01

    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. PMID:16469697

  13. Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene.

    PubMed

    Chizhikov, Victor; Steshina, Ekaterina; Roberts, Richard; Ilkin, Yesim; Washburn, Linda; Millen, Kathleen J

    2006-10-01

    Mice homozygous for the dreher (dr) mutation are characterized by pigmentation and skeletal abnormalities and striking behavioral phenotypes, including ataxia, vestibular deficits, and hyperactivity. The ataxia is associated with a cerebellar malformation that is remarkably similar to human Dandy-Walker malformation. Previously, positional cloning identified mutations in LIM homeobox transcription factor 1 alpha gene (Lmx1a) in three dr alleles. Two of these alleles, however, are extinct and unavailable for further analysis. In this article we report a new spontaneous dr allele and describe the Lmx1a mutations in this and six additional dr alleles. Strikingly, deletion null, missense, and frameshift mutations in these alleles all cause similar cerebellar malformations, suggesting that all dr mutations analyzed to date are null alleles. PMID:17019651

  14. HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs

    PubMed Central

    Park, Hye Jung; Kim, Young Joo; Kim, Dong Hyun; Kim, Junho; Park, Kyung Hee; Park, Jung-Won

    2016-01-01

    Purpose Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. Materials and Methods We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. Results HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. Conclusion HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN. PMID:26632391

  15. Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases

    PubMed Central

    Amos, Christopher I.

    2015-01-01

    Genome-wide association studies (GWAS) have generated sufficient data to assess the role of selection in shaping allelic diversity of disease-associated SNPs. Negative selection against disease risk variants is expected to reduce their frequencies making them overrepresented in the group of minor (<50%) alleles. Indeed, we found that the overall proportion of risk alleles was higher among alleles with frequency <50% (minor alleles) compared to that in the group of major alleles. We hypothesized that negative selection may have different effects on environment (or lifestyle)-dependent versus environment (or lifestyle)-independent diseases. We used an environment/lifestyle index (ELI) to assess influence of environmental/lifestyle factors on disease etiology. ELI was defined as the number of publications mentioning “environment” or “lifestyle” AND disease per 1,000 disease-mentioning publications. We found that the frequency distributions of the risk alleles for the diseases with strong environmental/lifestyle components follow the distribution expected under a selectively neutral model, while frequency distributions of the risk alleles for the diseases with weak environmental/lifestyle influences is shifted to the lower values indicating effects of negative selection. We hypothesized that previously selectively neutral variants become risk alleles when environment changes. The hypothesis of ancestrally neutral, currently disadvantageous risk-associated alleles predicts that the distribution of risk alleles for the environment/lifestyle dependent diseases will follow a neutral model since natural selection has not had enough time to influence allele frequencies. The results of our analysis suggest that prediction of SNP functionality based on the level of evolutionary conservation may not be useful for SNPs associated with environment/lifestyle dependent diseases. PMID:26201053

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

    PubMed Central

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

    2003-01-01

    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. PMID:12587097

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

    SciTech Connect

    Lucotte, G.; David, F.; Berriche, S.

    1994-09-15

    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.

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

    PubMed Central

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

    2010-01-01

    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. PMID:20490894

  19. The European Dimension in Education.

    ERIC Educational Resources Information Center

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

    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

  20. The European Mobile System (EMS)

    NASA Technical Reports Server (NTRS)

    Jongejans, A.; Rogard, R.; Mistretta, I.; Ananasso, F.

    1993-01-01

    The European Space Agency is presently procuring an L band payload in order to promote a regional European L band system coping with the specific needs of the European market. The payload, and the two communications systems to be supported, are described below. The potential market for EMS in Europe is discussed.

  1. Allele-specific enzymatic amplification of. beta. -globin genomic DNA for diagnosis of sickle cell anemia

    SciTech Connect

    Wu, D.Y.; Ugozzoli, L.; Pal, B.K.; Wallace, B. )

    1989-04-01

    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 allele and one specific for the normal allele, together with another primer complementary to both alleles were used in the polymerase chain reaction with genomic DNA templates. The allele-specific primers differed from each other in their terminal 3{prime} nucleotide. Under the proper annealing temperature and polymerase chain reaction conditions, these primers only directed amplification on their complementary allele. In a single blind study of DNA samples from 12 individuals, this method correctly and unambiguously allowed for the determination of the genotypes with no false negatives or positives. If ASPCR is able to discriminate all allelic variation (both transition and transversion mutations), this method has the potential to be a powerful approach for genetic disease diagnosis, carrier screening, HLA typing, human gene mapping, forensics, and paternity testing.

  2. How-To-Do-It: Multiple Allelic Frequencies in Populations at Equilibrium: Algorithms and Applications.

    ERIC Educational Resources Information Center

    Nussbaum, Francis, Jr.

    1988-01-01

    Presents an algorithm for solving problems related to multiple allelic frequencies in populations at equilibrium. Considers sample problems and provides their solution using this tabular algorithm. (CW)

  3. Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis.

    PubMed Central

    Weyand, C M; Xie, C; Goronzy, J J

    1992-01-01

    Seropositive rheumatoid arthritis is genetically linked to a group of HLA-DRB1 alleles sharing a sequence motif within the third hypervariable region. Controversy exists over the role of the distinct allelic variants in affecting not only the risk to develop disease, but also in modifying the expression of the disease. We have stratified 81 patients according to their patterns of disease manifestations and identified the HLA-DRB1 alleles by polymerase chain reaction amplification and subsequent oligonucleotide hybridization. To identify precisely the allelic combinations at the HLA-DRB1 locus, homozygosity was confirmed by locus-specific cDNA amplification and subsequent sequencing. Our study demonstrated a high correlation of allelic combinations of disease-associated HLA-DRB1 alleles with the clinical manifestations. Characteristic genotypes were identified for patients who had progressed toward nodular disease and patients who had developed major organ involvement. Rheumatoid nodules were highly associated with a heterozygosity for two disease associated HLA-DRB1 alleles. Homozygosity for the HLA-DRB1*0401 allele was a characteristic finding for RA patients with major organ involvement. Our data suggest a role of the disease-associated sequence motif in determining severity of the disease. The finding of a codominant function of HLA-DRB1 alleles suggests that the biological function of HLA-DR molecules in thymic selection might be important in the pathogenesis of RA. Images PMID:1602009

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

    PubMed Central

    Bewley, Glenn C.; Lucchesi, John C.

    1975-01-01

    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 (2022 hr). PMID:805081

  5. Chestnut, European (Castanea sativa).

    PubMed

    Corredoira, Elena; Valladares, Silvia; Vieitez, Ana M; Ballester, Antonio

    2015-01-01

    Development of a system for direct transfer of antifungal candidate genes into European chestnut (Castanea sativa) would provide an alternative approach to conventional breeding for production of chestnut trees that are tolerant to ink disease caused by Phytophthora spp. Overexpression of genes encoding PR proteins (such as thaumatin-like proteins), which display antifungal activity, may represent an important advance in control of the disease. We have used a chestnut thaumatin-like protein gene (CsTL1) isolated from European chestnut cotyledons and have achieved overexpression of the gene in chestnut somatic embryogenic lines used as target material. We have also acclimatized the transgenic plants and grown them on in the greenhouse. Here, we describe the various steps of the process, from the induction of somatic embryogenesis to the production of transgenic plants. PMID:25416257

  6. Telemedicine and European law.

    PubMed

    Callens, Stefaan

    2003-01-01

    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

  7. The European Spallation Source

    SciTech Connect

    Peggs, S; Eshraqi, M; Hahn, H; Jansson, A; Lindroos, M; Ponton, A; Rathsman, K; Trahern, G; Bousso, S; Calaga, R; Devanz, G; Duperrier, R D; Eguia, J; Gammino, S; Moller, S P; Oyon, C; Ruber, R.J.M.Y.

    2011-03-01

    The European Spallation Source (ESS) is a 5 MW, 2.5 GeV long pulse proton linac, to be built and commissioned in Lund, Sweden. The Accelerator Design Update (ADU) project phase is under way, to be completed at the end of 2012 by the delivery of a Technical Design Report. Improvements to the 2003 ESS design will be summarised, and the latest design activities will be presented.

  8. Identification of Allelic Heterogeneity at Type-2 Diabetes Loci and Impact on Prediction

    PubMed Central

    Klimentidis, Yann C.; Zhou, Jin; Wineinger, Nathan E.

    2014-01-01

    Although over 60 single nucleotide polymorphisms (SNPs) have been identified by meta-analysis of genome-wide association studies for type-2 diabetes (T2D) among individuals of European descent, much of the genetic variation remains unexplained. There are likely many more SNPs that contribute to variation in T2D risk, some of which may lie in the regions surrounding established SNPs - a phenomenon often referred to as allelic heterogeneity. Here, we use the summary statistics from the DIAGRAM consortium meta-analysis of T2D genome-wide association studies along with linkage disequilibrium patterns inferred from a large reference sample to identify novel SNPs associated with T2D surrounding each of the previously established risk loci. We then examine the extent to which the use of these additional SNPs improves prediction of T2D risk in an independent validation dataset. Our results suggest that multiple SNPs at each of 3 loci contribute to T2D susceptibility (TCF7L2, CDKN2A/B, and KCNQ1; p<510?8). Using a less stringent threshold (p<510?4), we identify 34 additional loci with multiple associated SNPs. The addition of these SNPs slightly improves T2D prediction compared to the use of only the respective lead SNPs, when assessed using an independent validation cohort. Our findings suggest that some currently established T2D risk loci likely harbor multiple polymorphisms which contribute independently and collectively to T2D risk. This opens a promising avenue for improving prediction of T2D, and for a better understanding of the genetic architecture of T2D. PMID:25393876

  9. A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation.

    PubMed

    Han, Jiali; Kraft, Peter; Nan, Hongmei; Guo, Qun; Chen, Constance; Qureshi, Abrar; Hankinson, Susan E; Hu, Frank B; Duffy, David L; Zhao, Zhen Zhen; Martin, Nicholas G; Montgomery, Grant W; Hayward, Nicholas K; Thomas, Gilles; Hoover, Robert N; Chanock, Stephen; Hunter, David J

    2008-05-01

    We conducted a multi-stage genome-wide association study of natural hair color in more than 10,000 men and women of European ancestry from the United States and Australia. An initial analysis of 528,173 single nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified IRF4 and SLC24A4 as loci highly associated with hair color, along with three other regions encompassing known pigmentation genes. We confirmed these associations in 7,028 individuals from three additional studies. Across these four studies, SLC24A4 rs12896399 and IRF4 rs12203592 showed strong associations with hair color, with p = 6.0x10(-62) and p = 7.46x10(-127), respectively. The IRF4 SNP was also associated with skin color (p = 6.2x10(-14)), eye color (p = 6.1x10(-13)), and skin tanning response to sunlight (p = 3.9x10(-89)). A multivariable analysis pooling data from the initial GWAS and an additional 1,440 individuals suggested that the association between rs12203592 and hair color was independent of rs1540771, a SNP between the IRF4 and EXOC2 genes previously found to be associated with hair color. After adjustment for rs12203592, the association between rs1540771 and hair color was not significant (p = 0.52). One variant in the MATP gene was associated with hair color. A variant in the HERC2 gene upstream of the OCA2 gene showed the strongest and independent association with hair color compared with other SNPs in this region, including three previously reported SNPs. The signals detected in a region around the MC1R gene were explained by MC1R red hair color alleles. Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation. PMID:18483556

  10. Cuckoo parasitism and productivity in different magpie subpopulations predict frequencies of the 457bp allele: a mosaic of coevolution at a small geographic scale.

    PubMed

    Martn-Glvez, David; Soler, Juan J; Martnez, Juan Gabriel; Krupa, Andrew P; Soler, Manuel; Burke, Terry

    2007-10-01

    The level of defense against great spotted cuckoo (Clamator glandarius) parasitism in different European populations of magpie (Pica pica) depends on selection pressures due to parasitism and gene flow between populations, which suggests the existence of coevolutionary hot spots within a European metapopulation. A mosaic of coevolution is theoretically possible at small geographical scales and with strong gene flow, because, among other reasons, plots may differ in productivity (i.e., reproductive success of hosts in the absence of parasitism) and defensive genotypes theoretically should be more common in plots of high productivity. Here, we tested this prediction by exploring the relationship between parasitism rate, level of defense against parasitism (estimated as both rejection rate and the frequency of the 457bp microsatellite allele associated with foreign egg rejection in magpies), and some variables related to the productivity (average laying date, clutch size, and number of hatchlings per nest) of magpies breeding in different subpopulations. We found that both estimates of defensive ability (egg rejection rate and frequency of the 457bp allele) covaried significantly with between-plot differences in probability of parasitism, laying date, and number of hatchlings per nest. Moreover, the parasitism rate was larger in more productive plots. These results confirm the existence of a mosaic of coevolution at a very local geographical scale, and the association between laying date and number of hatchlings with variables related to defensive ability and the selection pressure arising from parasitism supports the prediction of coevolutionary gradients in relation to host productivity. PMID:17711473

  11. Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations.

    PubMed

    Song, K; Nelson, M R; Aponte, J; Manas, E S; Bacanu, S-A; Yuan, X; Kong, X; Cardon, L; Mooser, V E; Whittaker, J C; Waterworth, D M

    2012-10-01

    Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.863.2 vs 204.641.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor. PMID:21606947

  12. Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations

    PubMed Central

    Song, K; Nelson, M R; Aponte, J; Manas, E S; Bacanu, S-A; Yuan, X; Kong, X; Cardon, L; Mooser, V E; Whittaker, J C; Waterworth, D M

    2012-01-01

    Elevated plasma levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.863.2 vs 204.641.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10?000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor. PMID:21606947

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

    PubMed Central

    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

    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. PMID:23541212

  14. Disagreement in genotyping results of drug resistance alleles of the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) gene by allele-specific PCR (ASPCR) assays and Sanger sequencing.

    PubMed

    Sharma, Divya; Lather, Manila; Dykes, Cherry L; Dang, Amita S; Adak, Tridibes; Singh, Om P

    2016-01-01

    The rapid spread of antimalarial drug resistance in Plasmodium falciparum over the past few decades has necessitated intensive monitoring of such resistance for an effective malaria control strategy. P. falciparum dihydropteroate synthase (Pfdhps) and P. falciparum dihydrofolate reductase (Pfdhfr) genes act as molecular markers for resistance against the antimalarial drugs sulphadoxine and pyrimethamine, respectively. Resistance to pyrimethamine which is used as a partner drug in artemisinin combination therapy (ACT) is associated with several mutations in the Pfdhfr gene, namely A16V, N51I, C59R, S108N/T and I164L. Therefore, routine monitoring of Pfdhfr-drug-resistant alleles in a population may help in effective drug resistance management. Allele-specific PCR (ASPCR) is one of the commonly used methods for molecular genotyping of these alleles. In this study, we genotyped 55 samples of P. falciparum for allele discrimination at four codons of Pfdhfr (N51, C59, S108 and I164) by ASPCR using published methods and by Sanger's DNA sequencing method. We found that the ASPCR identified a significantly higher number of mutant alleles as compared to the DNA sequencing method. Such discrepancies arise due to the non-specificity of some of the allele-specific primer sets and due to the lack of sensitivity of Sanger's DNA sequencing method to detect minor alleles present in multiple clone infections. This study reveals the need of a highly specific and sensitive method for genotyping and detecting minor drug-resistant alleles present in multiple clonal infections. PMID:26407876

  15. Human leukocyte antigen-E alleles and expression in patients with serous ovarian cancer.

    PubMed

    Zheng, Hui; Lu, Renquan; Xie, Suhong; Wen, Xuemei; Wang, Hongling; Gao, Xiang; Guo, Lin

    2015-05-01

    Human leukocyte antigen-E (HLA-E) is one of the most extensively studied non-classical MHC class I molecules that is almost non-polymorphic. Only two alleles (HLA-E*0101 and HLA-E*0103) are found in worldwide populations, and suggested to be functional differences between these variants. The HLA-E molecule can contribute to the escape of cancer cells from host immune surveillance. However, it is still unknown whether HLA-E gene polymorphisms might play a role in cancer immune escape. To explore the association between HLA-E alleles and the susceptibility to serous ovarian cancer (SOC), 85 primary SOC patients and 100 healthy women were enrolled. Here, we indicated that high frequency of HLA-E*0103 allele existed in SOC patients by the allele-specific quantitative real-time PCR method. The levels of HLA-E protein expression in SOC patients with the HLA-E*0103 allele were higher than those with the HLA-E*0101 allele using immunohistochemistry analysis. The cell surface expression and functional differences between the two alleles were verified by K562 cells transfected with HLA-E*0101 or HLA-E*0103 allelic heavy chains. The HLA-E*0103 allele made the transfer of the HLA-E molecule to the cell surface easier, and HLA-E/peptides complex more stable. These differences ultimately influenced the function of natural killer cells, showing that the cells transfected with HLA-E*0103 allele inhibited natural killer cells to lysis. This study reveals a novel mechanism regarding the susceptibility to SOC, which is correlated with the HLA-E*0103 allele. PMID:25711417

  16. Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project

    PubMed Central

    2010-01-01

    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 a panel of 51 polymorphisms previously associated with at least one disease and determined the allele frequencies within the entire Personalized Medicine Research Project population based cohort. We compared these allele frequencies to those in dbSNP and other data sources stratified by race. Differences in allele frequencies between self reported race, region of origin, and sex were determined. Results There were 19544 individuals who self reported a single racial category, 19027 or (97.4%) self reported white Caucasian, and 11205 (57.3%) individuals were female. Of the 11,208 (57%) individuals with an identifiable region of origin 8337 or (74.4%) were German. 41 polymorphisms were significantly different between self reported race at the 0.05 level. Stratification of our Caucasian population by self reported region of origin revealed 19 polymorphisms that were significantly different (p = 0.05) between individuals of different origins. Further stratification of the population by gender revealed few significant differences in allele frequencies between the genders. Conclusions This represents one of the largest population based allele frequency studies to date. Stratification by self reported race and region of origin revealed wide differences in allele frequencies not only by race but also by region of origin within a single racial group. We report allele frequencies for our Asian/Hmong and American Indian populations; these two minority groups are not typically selected for population allele frequency detection. Population wide allele frequencies are important for the design and implementation of studies and for determining the relevance of a disease associated polymorphism for a given population. PMID:20565774

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

    SciTech Connect

    Poduslo, S.E.; Schwankhaus, J.D.

    1994-09-01

    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.

  18. Identification and DNA sequence analysis of 15 new alpha 1-antitrypsin variants, including two PI*Q0 alleles and one deficient PI*M allele.

    PubMed Central

    Faber, J. P.; Poller, W.; Weidinger, S.; Kirchgesser, M.; Schwaab, R.; Bidlingmaier, F.; Olek, K.

    1994-01-01

    We have investigated the molecular basis of 15 new alpha 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 promoter 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' 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 Thr68(ACC)-->Ile(ATC); and an in-frame trinucleotide deletion delta Phe51 (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. Images Figure 1 Figure 2 Figure 3D PMID:7977369

  19. Cognitive and neural correlates of the 5-repeat allele of the dopamine D4 receptor gene in a population lacking the 7-repeat allele.

    PubMed

    Takeuchi, Hikaru; Tomita, Hiroaki; Taki, Yasuyuki; Kikuchi, Yoshie; Ono, Chiaki; Yu, Zhiqian; Sekiguchi, Atsushi; Nouchi, Rui; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos Makoto; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Kunitoki, Keiko; Sassa, Yuko; Kawashima, Ryuta

    2015-04-15

    The 5-repeat allele of a common length polymorphism in the gene that encodes the dopamine D4 receptor (DRD4) is robustly associated with the risk of attention deficit hyperactivity disorder (ADHD) and substantially exists in Asian populations, which have a lower ADHD prevalence. In this study, we investigated the effect of this allele on microstructural properties of the brain and on its functional activity during externally directed attention-demanding tasks and creative performance in the 765 Asian subjects. For this purpose, we employed diffusion tensor imaging, N-back functional magnetic resonance imaging paradigms, and a test to measure creativity by divergent thinking. The 5-repeat allele was significantly associated with increased originality in the creative performance, increased mean diffusivity (the measure of how the tissue includes water molecules instead of neural and vessel components) in the widespread gray and white matter areas of extensive areas, particularly those where DRD4 is expressed, and reduced task-induced deactivation in the areas that are deactivated during the tasks in the course of both the attention-demanding working memory task and simple sensorimotor task. The observed neural characteristics of 5-repeat allele carriers may lead to an increased risk of ADHD and behavioral deficits. Furthermore, the increased originality of creative thinking observed in the 5-repeat allele carriers may support the notion of the side of adaptivity of the widespread risk allele of psychiatric diseases. PMID:25659462

  20. Mitochondrial DNA genetic diversity and LCT-13910 and deltaF508 CFTR alleles typing in the medieval sample from Poland.

    PubMed

    Płoszaj, T; Jerszyńska, B; Jędrychowska-Dańska, K; Lewandowska, M; Kubiak, D; Grzywnowicz, K; Masłowska, A; Witas, H W

    2015-06-01

    We attempted to confirm the resemblance of a local medieval population and to reconstruct their contribution to the formation of the modern Polish population at the DNA level. The HVR I mtDNA sequence and two nuclear alleles, LCT-13910C/T SNP and deltaF508 CFTR, were chosen as markers since the distribution of selected nuclear alleles varies among ethnic groups. A total of 47 specimens were selected from a medieval cemetery in Cedynia (located in the western Polish lowland). Regarding the HVR I profile, the analyzed population differed from the present-day population (P = 0.045, F(st) = 0.0103), in contrast to lactase persistence (LP) based on the LCT-13910T allele, thus indicating the lack of notable frequency changes of this allele during the last millennium (P = 0.141). The sequence of the HVR I mtDNA fragment allowed to identify six major haplogroups including H, U5, T, K, and HV0 within the medieval population of Cedynia which are common in today's central Europe. An analysis of haplogroup frequency and its comparison with modern European populations shows that the studied medieval population is more closely related to Finno-Ugric populations than to the present Polish population. Identification of less common haplogroups, i.e., Z and U2, both atypical of the modern Polish population and of Asian origin, provides evidence for some kind of connections between the studied and foreign populations. Furthermore, a comparison of the available aDNA sequences from medieval Europe suggests that populations differed from one another and a number of data from other locations are required to find out more about the features of the medieval gene pool profile. PMID:25896719

  1. Transcriptomes and shRNA Suppressors in a TP53 Allele-specific Model of Early-onset Colon Cancer in African Americans

    PubMed Central

    Weige, Charles C.; Birtwistle, Marc R.; Mallick, Himel; Yi, Nengjun; Berrong, Zuzana; Cloessner, Emily; Duff, Keely; Tidwell, Josephine; Clendenning, Megan; Wilkerson, Brent; Farrell, Christopher; Bunz, Fred; Ji, Hao; Shtutman, Michael; Creek, Kim E.; Banister, Carolyn E.; Buckhaults, Phillip J.

    2014-01-01

    African Americans are disproportionately affected by early-onset, high-grade malignancies. A fraction of this cancer health disparity can be explained by genetic differences between individuals of African or European descent. Here the wild-type Pro/Pro genotype at the TP53Pro72Arg (P72R) polymorphism (SNP: rs1042522) is more frequent in African Americans with cancer than in African Americans without cancer (51% vs 37%), and is associated with a significant increase in the rates of cancer diagnosis in African Americans. To test the hypothesis that p53 allele-specific gene expression may contribute to African American cancer disparities, p53 hemizygous knockout variants were generated and characterized in the RKO colon carcinoma cell line, which is wild-type for p53 and heterozygous at the TP53Pro72Arg locus. Transcriptome profiling, using RNAseq, in response to the DNA-damaging agent etoposide revealed a large number of p53-regulated transcripts, but also a subset of transcripts that were TP53Pro72Arg allele specific. In addition, a shRNA-library suppressor screen for p53 allele-specific escape from p53-induced arrest was performed. Several novel RNAi suppressors of p53 were identified, one of which, PRDM1? (BLIMP-1), was confirmed to be an Arg-specific transcript. PRDM1? silences target genes by recruiting H3K9 trimethyl (H3K9me3) repressive chromatin marks, and is necessary for stem cell differentiation. These results reveal a novel model for African American cancer disparity, in which the TP53 codon 72 allele influences lifetime cancer risk by driving damaged cells to differentiation through an epigenetic mechanism involving gene silencing. Implications TP53 P72R polymorphism significantly contributes to increased African American cancer disparity. PMID:24743655

  2. Pharmacogenomic diversity in Singaporean populations and Europeans.

    PubMed

    Brunham, L R; Chan, S L; Li, R; Aminkeng, F; Liu, X; Saw, W Y; Ong, R T H; Pillai, E N; Carleton, B C; Toh, D; Tan, S H; Koo, S H; Lee, E J D; Chia, K S; Ross, C J D; Hayden, M R; Sung, C; Teo, Y Y

    2014-12-01

    Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of ? 4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes. PMID:24861855

  3. [LEP gene allelic polymorphism in a subpopulation of Ayrshire cattle].

    PubMed

    Kovaljuk, N V; Satsuk, V F; Volchenko, A E; Machulskaja, E V

    2015-02-01

    Genotyping of the leptin gene locus (LEP) (SNP: R25C, Y7F, and A80V) has been conducted in cows from two cattle droves (n = 106 and n = 34) and in bulls of Ayrshire cattle (n = 9) that are intensively used at present for artificial insemination in cows in Krasnodar krai. The absence of A80V polymorphism (C --> T at position 95691973 bp of leptin gene) has been established in the genotypes of Ayrshire cattle as compared to Holstein cattle; however, the F allele (Y7F site A --> T at position 95689996 bp of LEP gene), which is rare in Holstein cattle, was shown to be frequent in Ayrshire cows and producer bulls (with a frequency of 0.22-0.79). The heterozygosity did not exceed 0.11 in adult animals, which might be evidence of a decreased vitality in animals bearing the FF genotype. Moreover, the CC genotype (R25C site T-C at position 95690050 bp of LEP gene) was revealed to be linked to the YY genotype (Y7F site) in 97% of cases from possible combinations of the CCYY, CCYF, and CCFF genotypes, while the FF genotype (Y7F site) was observed to be linked to the RR genotype (R25C site) in 100% of cases of possible combinations of FFCC, FFRC, and FFRR genotypes. PMID:25966594

  4. Expression of CENH3 alleles in synthesized allopolyploid Oryza species.

    PubMed

    Li, Hui; Lu, Li; Heng, Yanfang; Qin, Rui; Xing, Yongzhong; Jin, Weiwei

    2010-10-01

    Synthesized allopolyploids are valuable materials for comparative analyses of two or more distinct genomes, such as the expression changes (activation, inactivation or differential expression) of orthologous genes following allopolyploidization. CENH3 is a centromere- specific histone H3 variant and has been regarded as a central component in kinetochore formation and centromere function. In this study, interspecific hybrids of Oryza genus (AA CC, AA CCDD) and their backcross progenies were produced, and the genome constitutions were identified as AC, ACC, ACD, AACD, or AA(CD) by Genomic in situ hybridization (GISH). We further cloned and sequenced the CENH3 genes from O. sativa (AA), O. officinalis (CC) and O. latifolia (CCDD). Sequencing of RT-PCR products revealed that CENH3_C2 and CENH3_D, the two CENH3 alleles from O. latifolia, showed polymorphism in several sites, while CENH3_C2 and CENH3_C1 from O. officinalis were different at only two amino acids positions. Moreover, we found that the CENH3 genes from both parents are expressed in interspecific hybrids and their progenies. Specifically, based on our cDNA sequencing data, the ratio of expression level between CENH3_A and CENH3_C1 was approximately 1 in AC and 0.5 in ACC genomes, respectively. As a result, the CENH3 expression patterns shed more light on the inter-coordination between varied centromeric DNA sequences and highly conserved kinetochore protein in synthesized allopolyploids of Oryza genus. PMID:21035096

  5. Allele-selective suppression of mutant genes in polyglutamine diseases.

    PubMed

    Liu, Chia-Rung; Cheng, Tzu-Hao

    2015-01-01

    Polyglutamine (polyQ) diseases are heritable dominant neurological disorders, caused by abnormal CAG tri-nucleotide expansion in the coding sequence of affected genes. Extension of CAG repeats results in the production of aberrant gene products that are deleterious to neurons, such as transcripts with a CAG stem-loop secondary structure, and proteins containing a long stretch of polyQ residues. Thus, determining methods for the prevention or elimination of these mutant gene products from neuronal cells and translating this knowledge to clinical application are currently important goals in the fields of neurology and neurogenetics. Recently, several studies have revealed intriguing findings related to the allele-selective regulation of CAG-expanded genes, and have proposed novel designs to selectively diminish the mutant polyQ proteins. In this review, we focus on the genes, genetically engineered proteins, and oligonucleotides that show potential to modulate the expression of mutant genes. We also discuss their respective molecular functions at the levels of transcription, translation, and post-translation. PMID:26174158

  6. Generation of mice with a conditional Foxp2 null allele

    PubMed Central

    French, Catherine A; Groszer, Matthias; Preece, Christopher; Coupe, Anne-Marie; Rajewsky, Klaus; Fisher, Simon E

    2007-01-01

    Disruptions of the human FOXP2 gene cause problems with articulation of complex speech sounds, accompanied by impairment in many aspects of language ability. The FOXP2/Foxp2 transcription factor is highly similar in humans and mice, and shows a complex conserved expression pattern, with high levels in neuronal subpopulations of the cortex, striatum, thalamus, and cerebellum. In the present study we generated mice in which loxP sites flank exons 12–14 of Foxp2; these exons encode the DNA-binding motif, a key functional domain. We demonstrate that early global Cre-mediated recombination yields a null allele, as shown by loss of the loxP-flanked exons at the RNA level and an absence of Foxp2 protein. Homozygous null mice display severe motor impairment, cerebellar abnormalities and early postnatal lethality, consistent with other Foxp2 mutants. When crossed to transgenic lines expressing Cre protein in a spatially and/or temporally controlled manner, these conditional mice will provide new insights into the contributions of Foxp2 to distinct neural circuits, and allow dissection of roles during development and in the mature brain. genesis 45:440–446, 2007. Published 2007 Wiley-Liss, Inc. PMID:17619227

  7. Allele-specific chemical genetics: concept, strategies, and applications.

    PubMed

    Islam, Kabirul

    2015-02-20

    The relationship between DNA and protein sequences is well understood, yet because the members of a protein family/subfamily often carry out the same biochemical reaction, elucidating their individual role in cellular processes presents a challenge. Forward and reverse genetics have traditionally been employed to understand protein functions with considerable success. A fundamentally different approach that has gained widespread application is the use of small organic molecules, known as chemical genetics. However, the slow time-scale of genetics and inherent lack of specificity of small molecules used in chemical genetics have limited the applicability of these methods in deconvoluting the role of individual proteins involved in fast, dynamic biological events. Combining the advantages of both the techniques, the specificity achieved with genetics along with the reversibility and tunability of chemical genetics, has led to the development of a powerful approach to uncover protein functions in complex biological processes. This technique is known as allele-specific chemical genetics and is rapidly becoming an essential toolkit to shed light on proteins and their mechanism of action. The current review attempts to provide a comprehensive description of this approach by discussing the underlying principles, strategies, and successful case studies. Potential future implications of this technology in expanding the frontiers of modern biology are discussed. PMID:25436868

  8. FINDbase: a worldwide database for genetic variation allele frequencies updated.

    PubMed

    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

    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. PMID:21113021

  9. FINDbase: a worldwide database for genetic variation allele frequencies updated

    PubMed Central

    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

    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 Microsofts 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. PMID:21113021

  10. Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.

    PubMed

    McLarren, Keith W; Severson, Tesa M; du Souich, Christle; Stockton, David W; Kratz, Lisa E; Cunningham, David; Hendson, Glenda; Morin, Ryan D; Wu, Diane; Paul, Jessica E; An, Jianghong; Nelson, Tanya N; Chou, Athena; DeBarber, Andrea E; Merkens, Louise S; Michaud, Jacques L; Waters, Paula J; Yin, Jingyi; McGillivray, Barbara; Demos, Michelle; Rouleau, Guy A; Grzeschik, Karl-Heinz; Smith, Raffaella; Tarpey, Patrick S; Shears, Debbie; Schwartz, Charles E; Gecz, Jozef; Stratton, Michael R; Arbour, Laura; Hurlburt, Jane; Van Allen, Margot I; Herman, Gail E; Zhao, Yongjun; Moore, Richard; Kelley, Richard I; Jones, Steven J M; Steiner, Robert D; Raymond, F Lucy; Marra, Marco A; Boerkoel, Cornelius F

    2010-12-10

    CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. PMID:21129721

  11. Maintenance of an aminopeptidase allele frequency cline by natural selection.

    PubMed Central

    Koehn, R K; Newell, R I; Immermann, F

    1980-01-01

    The product of the Lap locus in the marine bivalve Mytilus edulis is a neutral, membrane-associated aminopeptidase that is primarily localized on intestinal microvilli and in digestive cell lysosomes. Natural populations are genetically differentiated at the Lap locus between areas of differing salinity. A steep (0.55-0.15) allele frequency cline connects differentiated populations between the Atlantic Ocean and Long Island Sound. We demonstrate an annual gene flow/mortality cycle in cline populations whereby gene frequencies after mortality are correlated with salinity and enzyme activity. The cline is spatially and temporally unstable in immigrants, but stable in residents after mortality. Mortality is nonrandom with regard to the Lap locus; genotype-dependent properties of the aminopeptidase enzyme apparently led to a differential rate of the utilizaiton of nutrient reserves because selected genotypes exhibited an increased rate of tissue weight loss. Aminopeptidase genotypes are differentially adapted to different temperatures and salinities, which provides a mechanism for the relationship among biochemical, physiological, and population phenotypes. PMID:6933563

  12. Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.

    PubMed

    Rutten, Julie W; Boon, Elles M J; Liem, Michael K; Dauwerse, Johannes G; Pont, Margot J; Vollebregt, Ellen; Maat-Kievit, Anneke J; Ginjaar, Hendrika B; Lakeman, Phillis; van Duinen, Sjoerd G; Terwindt, Gisela M; Lesnik Oberstein, Saskia A J

    2013-11-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. Whether these mutations lead to the CADASIL phenotype via a neomorphic effect, or rather by a hypomorphic effect, is subject of debate. Here, we report two novel NOTCH3 mutations, both leading to a premature stop codon with predicted loss of NOTCH3 function. The first mutation, c.307C>T, p.Arg103*, was detected in two brothers aged 50 and 55 years, with a brain MRI and skin biopsy incompatible with CADASIL. The other mutation was found in a 40-year-old CADASIL patient compound heterozygous for a pathogenic NOTCH3 mutation (c.2129A>G, p.Tyr710Cys) and an intragenic frameshift deletion. The deletion was inherited from his father, who did not have the skin biopsy abnormalities seen in CADASIL patients. These individuals with rare NOTCH3 mutations indicate that hypomorphic NOTCH3 alleles do not cause CADASIL. PMID:24000151

  13. Association analysis reveals effects of wheat glutenin alleles and rye translocations on dough-mixing properties

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The glutenin loci of wheat (Triticum aestivum L.) are important determinants of bread-making quality, although the effects of alleles at those loci are incompletely understood. We applied an association analysis method to assess the effects of glutenin alleles and 1RS wheatrye (Secale cereale L.) t...

  14. Fixation probability and the crossing time in the Wright-Fisher multiple alleles model

    NASA Astrophysics Data System (ADS)

    Gill, Wonpyong

    2009-08-01

    The fixation probability and crossing time in the Wright-Fisher multiple alleles model, which describes a finite haploid population, were calculated by switching on an asymmetric sharply-peaked landscape with a positive asymmetric parameter, r, such that the reversal allele of the optimal allele has higher fitness than the optimal allele. The fixation probability, which was evaluated as the ratio of the first arrival time at the reversal allele to the origination time, was double the selective advantage of the reversal allele compared with the optimal allele in the strong selection region, where the fitness parameter, k, is much larger than the critical fitness parameter, kc. The crossing time in a finite population for r>0 and kallele in the first generation should be greater than one individual in an asymmetric sharply-peaked landscape. It was also found that the crossing time in a finite population for r>0 and k?kc scaled as a power law in the fitness parameter with a similar scaling exponent as the crossing time in an infinite population for r=0, and that the critical fitness parameter decreased with increasing sequence length with a fixed population size.

  15. Competition at the mouse t complex: rare alleles are inherently favored.

    PubMed

    van Boven, M; Weissing, F J

    2001-12-01

    We investigate the competition between alleles at a segregation distorter locus. The focus is on the invasion prospects of rare mutant distorter alleles in a population in which a wildtype and a resident distorter allele are present. The parameters are chosen to reflect the situation at the t complex of the house mouse, one of the best-studied examples of segregation distortion. By analyzing the invasion chances of rare alleles, we provide an analytical justification of earlier simulation results. We show that a new distorter allele can successfully invade even if it is inferior both at the gamete and at the individual level. In fact, newly arising distorter alleles have an inherent rareness advantage if their negative fitness consequences are restricted to homozygous condition. Likewise, rare mutant wildtype alleles may often invade even if their viability or fertility is reduced. As a consequence, the competition between alleles at a segregation distorter locus should lead to a high degree of polymorphism. We discuss the implications of this conclusion for the t complex of the house mouse and for the evolutionary stability of "honest" Mendelian segregation. PMID:11878834

  16. The effect of wild card designations and rare alleles in forensic DNA database searches.

    PubMed

    Tvedebrink, Torben; Bright, Jo-Anne; Buckleton, John S; Curran, James M; Morling, Niels

    2015-05-01

    Forensic DNA databases are powerful tools used for the identification of persons of interest in criminal investigations. Typically, they consist of two parts: (1) a database containing DNA profiles of known individuals and (2) a database of DNA profiles associated with crime scenes. The risk of adventitious or chance matches between crimes and innocent people increases as the number of profiles within a database grows and more data is shared between various forensic DNA databases, e.g. from different jurisdictions. The DNA profiles obtained from crime scenes are often partial because crime samples may be compromised in quantity or quality. When an individual's profile cannot be resolved from a DNA mixture, ambiguity is introduced. A wild card, F, may be used in place of an allele that has dropped out or when an ambiguous profile is resolved from a DNA mixture. Variant alleles that do not correspond to any marker in the allelic ladder or appear above or below the extent of the allelic ladder range are assigned the allele designation R for rare allele. R alleles are position specific with respect to the observed/unambiguous allele. The F and R designations are made when the exact genotype has not been determined. The F and R designation are treated as wild cards for searching, which results in increased chance of adventitious matches. We investigated the probability of adventitious matches given these two types of wild cards. PMID:25576850

  17. Identification of novel alleles of the rice blast resistance gene Pi54

    PubMed Central

    Vasudevan, Kumar; Gruissem, Wilhelm; Bhullar, Navreet K.

    2015-01-01

    Rice blast is one of the most devastating rice diseases and continuous resistance breeding is required to control the disease. The rice blast resistance gene Pi54 initially identified in an Indian cultivar confers broad-spectrum resistance in India. We explored the allelic diversity of the Pi54 gene among 885 Indian rice genotypes that were found resistant in our screening against field mixture of naturally existing M. oryzae strains as well as against five unique strains. These genotypes are also annotated as rice blast resistant in the International Rice Genebank database. Sequence-based allele mining was used to amplify and clone the Pi54 allelic variants. Nine new alleles of Pi54 were identified based on the nucleotide sequence comparison to the Pi54 reference sequence as well as to already known Pi54 alleles. DNA sequence analysis of the newly identified Pi54 alleles revealed several single polymorphic sites, three double deletions and an eight base pair deletion. A SNP-rich region was found between a tyrosine kinase phosphorylation site and the nucleotide binding site (NBS) domain. Together, the newly identified Pi54 alleles expand the allelic series and are candidates for rice blast resistance breeding programs. PMID:26498172

  18. Allelic inclusion in the pre-B-cell line 18-81.

    PubMed Central

    Wabl, M R; Beck-Engeser, G B; Burrows, P D

    1984-01-01

    In an Abelson-virus-transformed mouse lymphoid cell line with pre-B-cell characteristics, a few cells continuously produce heavy chains from both homologs. Each chain has a different variable region. These cells thereby exhibit allelic inclusion rather than allelic exclusion. Images PMID:6322175

  19. Identification of novel alleles of the rice blast resistance gene Pi54

    NASA Astrophysics Data System (ADS)

    Vasudevan, Kumar; Gruissem, Wilhelm; Bhullar, Navreet K.

    2015-10-01

    Rice blast is one of the most devastating rice diseases and continuous resistance breeding is required to control the disease. The rice blast resistance gene Pi54 initially identified in an Indian cultivar confers broad-spectrum resistance in India. We explored the allelic diversity of the Pi54 gene among 885 Indian rice genotypes that were found resistant in our screening against field mixture of naturally existing M. oryzae strains as well as against five unique strains. These genotypes are also annotated as rice blast resistant in the International Rice Genebank database. Sequence-based allele mining was used to amplify and clone the Pi54 allelic variants. Nine new alleles of Pi54 were identified based on the nucleotide sequence comparison to the Pi54 reference sequence as well as to already known Pi54 alleles. DNA sequence analysis of the newly identified Pi54 alleles revealed several single polymorphic sites, three double deletions and an eight base pair deletion. A SNP-rich region was found between a tyrosine kinase phosphorylation site and the nucleotide binding site (NBS) domain. Together, the newly identified Pi54 alleles expand the allelic series and are candidates for rice blast resistance breeding programs.

  20. Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues

    PubMed Central

    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

    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

  1. Allelic diversification at the class II DQB locus of the mammalian major histocompatibility complex.

    PubMed Central

    Gyllensten, U B; Lashkari, D; Erlich, H A

    1990-01-01

    The allelic diversity at HLA class II loci either arose after the divergence of hominoid lineages or, alternatively, the polymorphism was present before speciation and has been maintained by selection. Here, we report the use of oligonucleotide primers to amplify, by the polymerase chain reaction, and sequence the polymorphic second exon of the DQB locus from 11 species, spanning more than 40 million years of mammalian evolution. Phylogenetic analysis reveals that of the four human DQB allelic types (DQB1-B4), three (DQB1-3) were found in chimpanzee and gorilla and two (DQB3 and -4) were identified in the rhesus monkey, suggesting that some of these types are 5-20 million years old. The ratio of replacement to silent substitutions was calculated between members of the same allelic type from different species. These results suggest that the evolution of the DQB3 allelic type is more constrained than that of the DQB1 allelic type; both evolve more slowly than the DXB locus, a linked but presumably nonexpressed locus. Further, the clustering of allelic subtypes by species in the phylogenetic tree indicates that allelic diversification has occurred subsequent to the divergence of hominoids. Finally, some haplotype combinations of DQA and DQB alleles are common to several hominoid species and may have been maintained for at least 5 million years. PMID:2308943

  2. A Novel Allele of Hap1 Causes Uninducible Expression of Hem13 in Saccharomyces Cerevisiae

    PubMed Central

    Ushinsky, S. C.; Keng, T.

    1994-01-01

    Transcription of HEM13 in Saccharomyces cerevisiae is repressed by heme and oxygen. We have isolated two mutants in which expression of HEM13 is aberrant. The mutant alleles in these strains represent two different alleles of HAP1. HAP1 encodes an activator protein whose DNA binding activity is stimulated by heme, and is required for the transcription of CYC1, ROX1 and a number of other heme-dependent genes. One of our mutant alleles confers a phenotype much like that of the hap1::LEU2 allele. Expression of HEM13 in a strain with this mutation is elevated under repressing conditions and not fully inducible in the absence of heme. The other mutant allele of HAP1 we uncovered confers a novel phenotype. A strain containing this allele exhibits heme-independent expression of CYC1 and ROX1 and uninducible expression of HEM13 and ANB1. The mutation associated with this novel allele of HAP1 was localized to a glycine to aspartate change in amino acid 235 of HAP1, between the DNA binding and heme responsive domains. DNA binding assays demonstrated that the protein made from this HAP1 allele retains the ability to bind DNA, but that unlike wild-type HAP1 protein, this binding is not stimulated by heme. PMID:8005437

  3. A Computer Simulation Study of Vntr Population Genetics: Constrained Recombination Rules Out the Infinite Alleles Model

    PubMed Central

    Harding, R. M.; Boyce, A. J.; Martinson, J. J.; Flint, J.; Clegg, J. B.

    1993-01-01

    Extensive allelic diversity in variable numbers of tandem repeats (VNTRs) has been discovered in the human genome. For population genetic studies of VNTRs, such as forensic applications, it is important to know whether a neutral mutation-drift balance of VNTR polymorphism can be represented by the infinite alleles model. The assumption of the infinite alleles model that each new mutant is unique is very likely to be violated by unequal sister chromatid exchange (USCE), the primary process believed to generate VNTR mutants. We show that increasing both mutation rates and misalignment constraint for intrachromosomal recombination in a computer simulation model reduces simulated VNTR diversity below the expectations of the infinite alleles model. Maximal constraint, represented as slippage of single repeats, reduces simulated VNTR diversity to levels expected from the stepwise mutation model. Although misalignment rule is the more important variable, mutation rate also has an effect. At moderate rates of USCE, simulated VNTR diversity fluctuates around infinite alleles expectation. However, if rates of USCE are high, as for hypervariable VNTRs, simulated VNTR diversity is consistently lower than predicted by the infinite alleles model. This has been observed for many VNTRs and accounted for by technical problems in distinguishing alleles of neighboring size classes. We use sampling theory to confirm the intrinsically poor fit to the infinite alleles model of both simulated VNTR diversity and observed VNTR polymorphisms sampled from two Papua New Guinean populations. PMID:8293988

  4. An Updated Collection of Sequence Barcoded Temperature-Sensitive Alleles of Yeast Essential Genes.

    PubMed

    Kofoed, Megan; Milbury, Karissa L; Chiang, Jennifer H; Sinha, Sunita; Ben-Aroya, Shay; Giaever, Guri; Nislow, Corey; Hieter, Philip; Stirling, Peter C

    2015-09-01

    Systematic analyses of essential gene function using mutant collections in Saccharomyces cerevisiae have been conducted using collections of heterozygous diploids, promoter shut-off alleles, through alleles with destabilized mRNA, destabilized protein, or bearing mutations that lead to a temperature-sensitive (ts) phenotype. We previously described a method for construction of barcoded ts alleles in a systematic fashion. Here we report the completion of this collection of alleles covering 600 essential yeast genes. This resource covers a larger gene repertoire than previous collections and provides a complementary set of strains suitable for single gene and genomic analyses. We use deep sequencing to characterize the amino acid changes leading to the ts phenotype in half of the alleles. We also use high-throughput approaches to describe the relative ts behavior of the alleles. Finally, we demonstrate the experimental usefulness of the collection in a high-content, functional genomic screen for ts alleles that increase spontaneous P-body formation. By increasing the number of alleles and improving the annotation, this ts collection will serve as a community resource for probing new aspects of biology for essential yeast genes. PMID:26175450

  5. An Updated Collection of Sequence Barcoded Temperature-Sensitive Alleles of Yeast Essential Genes

    PubMed Central

    Kofoed, Megan; Milbury, Karissa L.; Chiang, Jennifer H.; Sinha, Sunita; Ben-Aroya, Shay; Giaever, Guri; Nislow, Corey; Hieter, Philip; Stirling, Peter C.

    2015-01-01

    Systematic analyses of essential gene function using mutant collections in Saccharomyces cerevisiae have been conducted using collections of heterozygous diploids, promoter shut-off alleles, through alleles with destabilized mRNA, destabilized protein, or bearing mutations that lead to a temperature-sensitive (ts) phenotype. We previously described a method for construction of barcoded ts alleles in a systematic fashion. Here we report the completion of this collection of alleles covering 600 essential yeast genes. This resource covers a larger gene repertoire than previous collections and provides a complementary set of strains suitable for single gene and genomic analyses. We use deep sequencing to characterize the amino acid changes leading to the ts phenotype in half of the alleles. We also use high-throughput approaches to describe the relative ts behavior of the alleles. Finally, we demonstrate the experimental usefulness of the collection in a high-content, functional genomic screen for ts alleles that increase spontaneous P-body formation. By increasing the number of alleles and improving the annotation, this ts collection will serve as a community resource for probing new aspects of biology for essential yeast genes. PMID:26175450

  6. Genetic background alters dominance relationships between mat alleles in the ciliate Tetrahymena thermophila.

    PubMed

    Phadke, Sujal S; Paixo, Tiago; Pham, Tuan; Pham, Stephanie; Zufall, Rebecca A

    2014-01-01

    The pattern of inheritance and mechanism of sex determination can have important evolutionary consequences. We studied probabilistic sex determination in the ciliate Tetrahymena thermophila, which was previously shown to cause evolution of skewed sex ratios. We find that the genetic background alters the sex determination patterns of mat alleles in heterozygotes and that allelic interaction can differentially influence the expression probability of the 7 sexes. We quantify the dominance relationships between several mat alleles and find that A-type alleles, which specify sex I, are indeed recessive to B-type alleles, which are unable to specify that sex. Our results provide additional support for the presence of modifier loci and raise implications for the dynamics of sex ratios in populations of T. thermophila. PMID:24190504

  7. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function.

    PubMed

    Robbins, L S; Nadeau, J H; Johnson, K R; Kelly, M A; Roselli-Rehfuss, L; Baack, E; Mountjoy, K G; Cone, R D

    1993-03-26

    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 locus encodes the melanocyte-stimulating hormone (MSH) receptor. In mice, the recessive yellow allele (e) results from a frameshift that produces a prematurely terminated, nonfunctioning receptor. The sombre (Eso and Eso-3J) and tobacco darkening (Etob) alleles, which both have dominant melanizing effects, results from point mutations that produce hyperactive MSH receptors. The Eso-3J receptor is constitutively activated, while the Etob receptor remains hormone responsive and produces a greater activation of its effector, adenylyl cyclase, than does the wild-type allele. PMID:8458079

  8. Inter-allelic interactions play a major role in microsatellite evolution.

    PubMed

    Amos, William; Kosanovi?, Danica; Eriksson, Anders

    2015-11-01

    Microsatellite mutations identified in pedigrees confirm that most changes involve the gain or loss of single repeats. However, an unexpected pattern is revealed when the resulting data are plotted on standardized scales that range from the shortest to longest allele at a locus. Both mutation rate and mutation bias reveal a strong dependency on allele length relative to other alleles at the same locus. We show that models in which alleles mutate independently cannot explain these patterns. Instead, both mutation probability and direction appear to involve interactions between homologues in heterozygous individuals. Simple models in which the longer homologue in heterozygotes is more likely to mutate and/or biased towards contraction readily capture the observed trends. The exact model remains unclear in all its details but inter-allelic interactions are a vital component, implying a link between demographic history and the mode and tempo of microsatellite evolution. PMID:26511050

  9. Tools and best practices for data processing in allelic expression analysis.

    PubMed

    Castel, Stephane E; Levy-Moonshine, Ami; Mohammadi, Pejman; Banks, Eric; Lappalainen, Tuuli

    2015-01-01

    Allelic expression analysis has become important for integrating genome and transcriptome data to characterize various biological phenomena such as cis-regulatory variation and nonsense-mediated decay. We analyze the properties of allelic expression read count data and technical sources of error, such as low-quality or double-counted RNA-seq reads, genotyping errors, allelic mapping bias, and technical covariates due to sample preparation and sequencing, and variation in total read depth. We provide guidelines for correcting such errors, show that our quality control measures improve the detection of relevant allelic expression, and introduce tools for the high-throughput production of allelic expression data from RNA-sequencing data. PMID:26381377

  10. Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells.

    PubMed Central

    Reeve, A E; Sih, S A; Raizis, A M; Feinberg, A P

    1989-01-01

    Children with associated Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) frequently have a cytogenetically visible germ line deletion of chromosomal band 11p13. In accordance with the Knudson hypothesis of two-hit carcinogenesis, the absence of this chromosomal band suggests that loss of both alleles of a gene at 11p13 causes Wilms' tumor. Consistent with this model, chromosomes from sporadically occurring Wilms' tumor cells frequently show loss of allelic heterozygosity at polymorphic 11p15 loci, and therefore it has been assumed that allelic loss extends proximally to include 11p13. We report here that in samples from five sporadic Wilms' tumors, allelic loss occurred distal to the WAGR locus on 11p13. In cells from one tumor, mitotic recombination occurred distal to the gamma-globin gene on 11p15.5. Thus, allelic loss in sporadic Wilms' tumor cells may involve a second locus on 11p. Images PMID:2542777

  11. Global distribution of allele frequencies at the human dopamine D4 receptor locus

    SciTech Connect

    Chang, F.M.; Kidd, J.R.; Livak, K.J.

    1994-09-01

    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).

  12. Eastern European risk management

    SciTech Connect

    Honey, J.A. )

    1992-01-01

    Here the authors assess Eastern European risk management practices through the evaluation of the nuclear power plants in the region. This evaluation is limited to the Soviet-designed and -built VVER-440 pressurized water reactors (PWRs) that are currently operating in Bulgaria, Czechoslovakia, Hungary, Russia, and the Ukraine and until recently operated at Greifswald in the former East Germany. This evaluation is based on the basic design of the plants, a safety evaluation of the Greifswald facility by representatives from the Federal Republic of Germany and personal visits by the author to Greifswald and Loviisa.

  13. Biophotonics: a European perspective

    NASA Astrophysics Data System (ADS)

    Robin, Thierry; Cochard, Jacques; Breussin, Frédéric

    2013-03-01

    The objective of the present work is to determine the opportunities and challenges for Biophotonics business development in Europe for the next five years with a focus on sensors and systems: for health diagnostics and monitoring; for air, water and food safety and quality control. The development of this roadmap was initiated and supported by EPIC (The European Photonics Industry Consortium). We summarize the final roadmap data: market application segments and trends, analysis of the market access criteria, analysis of the technology trends and major bottlenecks and challenges per application.

  14. European drought trends

    NASA Astrophysics Data System (ADS)

    Gudmundsson, L.; Seneviratne, S. I.

    2015-06-01

    Recent climate projections suggest pronounced changes in European drought frequency. In the north, increased precipitation volumes are likely to reduce drought occurrence, whereas more frequent droughts are expected for southern Europe. To assess whether this pattern of changes in drought frequency can already be identified for the past decades, we analyse trends in a recently developed pan-European drought climatology that is based on the Standardized Precipitation Index (SPI). The index is derived on multiple time scales, ranging from 1 to 36 months, which allows the assessment of trends in both short term and multi-year droughts. Trends are quantified using the Theil-Sen trend estimator combined with an extension of the Mann-Kendal test (p < 0.05) that accounts for serial correlation. Field significance is assessed on the basis of techniques that control the false discovery rate in a multiple testing setting. The trend analysis indicates that changes in drought frequency are more pronounced on time scales of one year and longer. The analysis also reveals that there has been a tendency for decreased drought frequency in northern Europe in the past decades, whereas droughts have likely become more frequent in selected southern regions.

  15. A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration.

    PubMed

    Tanaka, K; Gregersen, N; Ribes, A; Kim, J; Kølvraa, S; Winter, V; Eiberg, H; Martinez, G; Deufel, T; Leifert, B; Santer, R; François, B; Pronicka, E; László, A; Kmoch, S; Kremensky, I; Kalaydjicva, L; Ozalp, I; Ito, M

    1997-02-01

    Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty acid metabolism. It is one of the most frequent genetic metabolic disorders among Caucasian children. The G985 allele represented 90% of all the variant alleles of the MCAD gene in an extensive series of retrospective studies. To study the distribution of the G985 allele, newborn blood samples from the following countries were tested; 3000 from Germany (1/116). 1000 each from Belgium (1/77). Poland (1/98), Czech Republic (1/240). Hungary (1/168), Bulgaria (1/91), Spain (1/141). Turkey (1/216), and 500 from Japan (none). The frequency is shown in parentheses. The haplotype of G985 alleles in 1 homozygote and 57 heterozygote samples were then analyzed using two intragenic MCAD gene polymorphisms (Iaq1 and GT-repeat). The result indicated that only 1 of the 10 known haplotypes was associated with the G985 mutation, suggesting that G985 was derived originally from a single ancestral source. We made a compilation of the G985 frequencies in these countries and those in nine other European countries studied previously. The G985 distribution was high in the area stretching from Russia to Bulgaria in the east and in all northern countries in western and middle Europe, but low in the southern part of western and middle Europe. The incidence among ethnic Basques appeared to be low. This distribution pattern and the fact that all G985 alleles belong to a single haplotype suggest that G985 mutation occurred later than the delta F508 mutation of the CFTR, possibly in the neolithic or in a later period, and was brought into Europe by IndoEuropean-speaking people. The panEuropean distribution of the G985 allele, including Slavic countries from which patients with MCAD deficiency have rarely been detected, indicates the importance of raising the level of awareness of this disease. PMID:9029639

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

    PubMed Central

    Lee, Jong-Min; Kim, Kyung-Hee; Shin, Aram; Chao, MichaelJ.; AbuElneel, Kawther; Gillis, Tammy; Mysore, JayalakshmiSrinidhi; Kaye, JuliaA.; Zahed, Hengameh; Kratter, IanH.; Daub, AaronC.; Finkbeiner, Steven; Li, Hong; Roach, JaredC.; Goodman, Nathan; Hood, Leroy; Myers, RichardH.; MacDonald, MarcyE.; Gusella, JamesF.

    2015-01-01

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

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

    PubMed

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

    2015-09-01

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

  18. A New Impetus for European Youth. European Commission White Paper.

    ERIC Educational Resources Information Center

    Commission of the European Communities, Brussels (Belgium).

    Despite their highly divergent situations, young people largely share the same values, ambitions, and difficulties. Despite the more complex social and economic context in which young Europeans are currently living, they are well equipped to adapt. National and European policymakers must facilitate this process of change by making young people

  19. High-Density Genotyping of Immune Loci in Koreans and Europeans Identifies Eight New Rheumatoid Arthritis Risk Loci

    PubMed Central

    Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong-Kyu; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung-Yoon; Shin, Hyoung Doo; Lee, Jong-Young; Han, Bok-Ghee; Nath, Swapan K.; Eyre, Steve; Bowes, John; Pappas, Dimitrios A.; Kremer, Joel M.; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; rlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothe; Liao, Katherine P.; Karlson, Elizabeth W.; Raychaudhuri, Soumya; Rantap-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K.; Worthington, Jane; Greenberg, Jeffrey D.; Plenge, Robert M.; Bae, Sang-Cheol

    2015-01-01

    Objective A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples. Results We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<510?8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusion This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. PMID:24532676

  20. Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans.

    PubMed

    Li, Ming; Wu, Dong-Dong; Yao, Yong-Gang; Huo, Yong-Xia; Liu, Jie-Wei; Su, Bing; Chasman, Daniel I; Chu, Audrey Y; Huang, Tao; Qi, Lu; Zheng, Yan; Luo, Xiong-Jian

    2016-01-01

    Natural selection has played important roles in optimizing complex human adaptations. However, schizophrenia poses an evolutionary paradox during human evolution, as the illness has strongly negative effects on fitness, but persists with a prevalence of ~0.5% across global populations. Recent studies have identified numerous risk variations in diverse populations, which might be able to explain the stable and high rate of schizophrenia morbidity in different cultures and regions, but the questions about why the risk alleles derived and maintained in human gene pool still remain unsolved. Here, we studied the evolutionary pattern of a schizophrenia risk variant rs13107325 (P < 5.010(-8) in Europeans) in the SLC39A8 gene. We found the SNP is monomorphic in Asians and Africans with risk (derived) T-allele totally absent, and further evolutionary analyses showed the T-allele has experienced recent positive selection in Europeans. Subsequent exploratory analyses implicated that the colder environment in Europe was the likely selective pressures, ie, when modern humans migrated "out of Africa" and moved to Europe mainland (a colder and cooler continent than Africa), new alleles derived due to positive selection and protected humans from risk of hypertension and also helped them adapt to the cold environment. The hypothesis was supported by our pleiotropic analyses with hypertension and energy intake as well as obesity in Europeans. Our data thus provides an intriguing example to illustrate a possible mechanism for maintaining schizophrenia risk alleles in the human gene pool, and further supported that schizophrenia is likely a product caused by pleiotropic effect during human evolution. PMID:26006263

  1. Does the parasite-mediated selection drive the MHC class IIB diversity in wild populations of European chub (Squalius cephalus)?

    PubMed

    Seifertová, Mária; Jarkovský, Jiří; Šimková, Andrea

    2016-04-01

    The genes of major histocompatibility complex (MHC) provide an excellent opportunity to study host-parasite relationships because they are expected to evolve in response to parasites and variation in parasite communities. In this study, we investigated the potential role of parasite-mediated selection acting on MHC class IIB (DAB) genes in European chub (Squalius cephalus) natural populations. We found significant differences between populations in metazoan parasites, neutral and adaptive genetic diversities. The analyses based on pairwise data revealed that populations with dissimilar MHC allelic profiles were geographically distant populations with significantly different diversity in microsatellites and a dissimilar composition of parasite communities. The results from the generalized estimating equations method (GEE) on the level of individuals revealed that metazoan parasite load in European chub was influenced by the diversity of DAB alleles as well as by the diversity of neutral genetic markers and host traits reflecting condition and immunocompetence. The multivariate co-inertia analysis showed specific associations between DAB alleles and parasite species. DAB1-like alleles were more involved in associations with ectoparasites, while DAB3-like alleles were positively associated with endoparasites which could suggest potential differences between DAB genes caused by different selection pressure. Our study revealed that parasite-mediated selection is not the only variable affecting MHC diversity in European chub; however, we strongly support the role of neutral processes as the main driver of DAB diversity across populations. In addition, our study contributes to the understanding of the evolution of MHC genes in wild living fish. PMID:26693717

  2. Polymorphic haplotypes on R408BW PKU and normal PAH chromosomes in Quebec and European populations

    SciTech Connect

    Byck, S.; Morgan, K.; Scriver, C.R.

    1994-09-01

    The R408W mutation in the phenylalanine hydroxylase gene (PAH) is associated with haplotype 2.3 (RFLP haplotype 2, VNTR 3 of the HindIII system) in most European populations. Another chromosome, first observed in Quebec and then in northwest Europe, carries R408W on haplotype 1.8. The occurrence of the R408W mutation on two different PKU chromosomes could be the result of intragenic recombination, recurrent mutation or gene conversion. In this study, we analyzed both normal and R408W chromosomes carrying 1.8 and 2.3 haplotypes in Quebec and European populations; we used the TCTA{sub (n)} short tandem repeat sequence (STR) at the 5{prime} end of the PAH gene and the HindIII VNTR system at the 3{prime} end of the PAH gene to characterize chromosomes. Fourteen of sixteen R408W chromosomes from {open_quotes}Celtic{close_quotes} families in Quebec and the United Kingdom (UK) harbor a 244 bp STR allele; the remaining two chromosomes, carry a 240 bp or 248bp STR allele. Normal chromosomes (n=18) carry the 240 bp STR allele. R408W chromosomes are different from mutant H1.8 chromosomes; mutant H2.3 carries the 240 bp STR allele (14 of 16 chromosomes) or the 236 allele (2 of 16 chromosomes). The HindIII VNTR comprises variable numbers of 30 bp repeats (cassettes); the repeats also vary in nucleotide sequence. Variation clusters toward the 3{prime} end of cassettes and VNTRs. VNTR 3 alleles on normal H2 (n=9) and mutant R408W H2 (n=19) chromosomes were identical. VNTR 8 alleles on normal H1 chromosomes (n=9) and on R408W H1 chromosomes (n=15) differ by 1 bp substitution near the 3{prime} end of the 6th cassette. In summary, the mutant H1.8 chromosome harboring the R408W mutation has unique features at both the 5{prime} and 3{prime} end of the gene that distinguish it from the mutant H2.3 and normal H1.8 and H2.3 counterparts. The explanation for the occurrence of R408W on two different PAH haplotypes is recurrent mutation affecting the CpG dinucleotide in PAH codon 408.

  3. Distinct physiological and behavioural functions for parental alleles of imprinted Grb10

    PubMed Central

    Garfield, Alastair S.; Cowley, Michael; Smith, Florentia M.; Moorwood, Kim; Stewart-Cox, Joanne E.; Gilroy, Kerry; Baker, Sian; Xia, Jing; Dalley, Jeffrey W.; Hurst, Laurence D.; Wilkinson, Lawrence S.; Isles, Anthony R.; Ward, Andrew

    2010-01-01

    Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development1, but also post-natal functions including energy homeostasis2 and behaviour3, 4. When the two parental alleles are unequally represented within a social group (when there is sex-bias in dispersal and/or variance in reproductive success)5, 6, imprinted genes may evolve to modulate social behaviour, although to date no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adapter protein that can interact with a number of receptor tyrosine kinases and downstream signalling molecules7. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10 deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus, Grb10 is to date a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, due to actions of the two parental alleles in different tissues. PMID:21270893

  4. HLA-DR4 allele frequencies on Indian and Mestizo population from Mexico.

    PubMed

    Vargas-Alarcn, G; Gamboa, R; Zuiga, J; Hernndez-Pacheco, G; Ramos-Kuri, M; Castillo, E; Gmez-Casado, E; Martnez-Laso, J; Arnaiz-Villena, A; Granados, J

    2000-03-01

    Using PCR-SSOP and sequencing, we examined DRB1*04 nucleotide polymorphism in 137 DR4-positive Mexican healthy individuals (46 Mexican Mestizos, 64 Mazatecans, and 27 Nahuas), carrying a total of 147 DR4 haplotypes. Eleven different DRB1*04 alleles were detected in Mexican Mestizo population, whereas, in the two Indian groups a restricted polymorphism was observed (5 variants in Mazatecans and 4 in Nahuas). DRB1*0407 was the most frequent allele (gf = 0.106 in Mexican Mestizos, gf = 0.281 in Mazatecans, and gf = 0.189 in Nahuas). In spite of the restriction in polymorphism, there were differences on DRB1*04 alleles found in Mexicans mainly between Mazatecan and Nahua populations. DRB1*0403 was characteristic allele in Nahua ethnic group, whereas, 0404 and 0411 were predominant alleles in Mazatecans. This data corroborates the restricted polymorphism of DRB1*04 alleles in American populations. In spite of the restriction in this polymorphism, differences in frequencies of DRB1*04 alleles could help distinguish each population. PMID:10689126

  5. Yy1 Gene Dosage Effect and Bi-Allelic Expression of Peg3

    PubMed Central

    Perera, Bambarendage P. U.; Teruyama, Ryoichi; Kim, Joomyeong

    2015-01-01

    In the current study, we tested the in vivo effects of Yy1 gene dosage on the Peg3 imprinted domain with various breeding schemes utilizing two sets of mutant alleles. The results indicated that a half dosage of Yy1 coincides with the up-regulation of Peg3 and Zim1, suggesting a repressor role of Yy1 in this imprinted domain. This repressor role of Yy1 is consistent with the observations derived from previous in vitro studies. The current study also provided an unexpected observation that the maternal allele of Peg3 is also normally expressed, and thus the expression of Peg3 is bi-allelic in the specific areas of the brain, including the choroid plexus, the PVN (Paraventricular Nucleus) and the SON (Supraoptic Nucleus) of the hypothalamus. The exact roles of the maternal allele of Peg3 in these cell types are currently unknown, but this new finding confirms the previous prediction that the maternal allele may be functional in specific cell types based on the lethality associated with the homozygotes for several mutant alleles of the Peg3 locus. Overall, these results confirm the repressor role of Yy1 in the Peg3 domain and also provide a new insight regarding the bi-allelic expression of Peg3 in mouse brain. PMID:25774914

  6. MICB Allele Genotyping on Microarrays by Improving the Specificity of Extension Primers

    PubMed Central

    Baek, In-Cheol; Jang, Jung-Pil; Choi, Eun-Jeong; Kim, Tai-Gyu

    2015-01-01

    Major histocompatibility complex (MHC) class I chain-related gene B (MICB) encodes a ligand for activating NKG2D that expressed in natural killer cells, γδ T cells, and αβ CD8+ T cells, which is associated with autoimmune diseases, cancer, and infectious diseases. Here, we have established a system for genotyping MICB alleles using allele-specific primer extension (ASPE) on microarrays. Thirty-six high quality, allele-specific extension primers were evaluated using strict and reliable cut-off values using mean fluorescence intensity (MFI), whereby an MFI >30,000 represented a positive signal and an MFI <10,000 represented a negative signal. Eight allele-specific extension primers were found to be false positives, five of which were improved by adjusting their length, and three of which were optimized by refractory modification. The MICB alleles (*002:01, *003, *005:02/*010, *005:03, *008, *009N, *018, and *024) present in the quality control panel could be exactly defined by 22 allele-specific extension primers. MICB genotypes that were identified by ASPE on microarrays were in full concordance with those identified by PCR-sequence-based typing. In conclusion, we have developed a method for genotyping MICB alleles using ASPE on microarrays; which can be applicable for large-scale single nucleotide polymorphism typing studies of population and disease associations. PMID:26569110

  7. Allelic differences in bovine kappa-CN gene which may regulate gene expression.

    PubMed

    Debeljak, M; Susnik, S; Marinsek-Logar, R; Medrano, J F; Dovc, P

    2000-01-01

    The most common kappa casein (kappa-CN) variants, kappa-CN A and kappa-CN B, are synthesised differentially in the lactating mammary gland of heterozygous animals (kappa-CN AB). In this study we evaluated several approaches for quantification of allele specific mRNA transcripts. The most consistent results were obtained using allele specific RT-PCR and capillary electrophoresis. On average, 13.4% more allele B specific than A specific transcripts were found. DNA sequencing of the proximal promoter region in several homozygous animals (kappa-CN AA, BB, EE) did not reveal any allele specific polymorphisms. Using the EMSA and DNase I footprinting we confirmed functional binding sites for three transcription factors (AP-2, NF1 and MGF) within the kappa-CN proximal promoter region. Sequence analysis of the 3'-UTR of the kappa-CN gene revealed seven allele specific sites. Two of these allelic differences were close to previously identified 3'-end regulatory sequences. In addition, allele specific differences in length between mRNAs of both variants were found. The two later findings suggest a possible post translational control determining content differences of kappa-CN in milk. PMID:10653122

  8. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer.

    PubMed

    Halabi, Najeeb M; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A; Malek, Joel A; Rafii, Arash

    2016-01-01

    Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

  9. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer

    PubMed Central

    Halabi, Najeeb M.; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G.; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A.; Malek, Joel A.; Rafii, Arash

    2016-01-01

    Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

  10. Allele-specific interactions between ttg and gl1 during trichome development in Arabidopsis thaliana.

    PubMed Central

    Larkin, J C; Walker, J D; Bolognesi-Winfield, A C; Gray, J C; Walker, A R

    1999-01-01

    Trichome development in Arabidopsis thaliana is a well-characterized model for the study of plant cell differentiation. Two genes that play an essential role in the initiation of trichome development are GL1 and TTG. Mutations in either gene prevent the initiation of most trichomes. The GL1 gene encodes a myb-related transcription factor. Mutations in TTG are pleiotropic, affecting anthocyanins, root hairs, and seed coat mucilage in addition to trichomes. Six ttg alleles were examined and shown to form a hypomorphic series. The severity of all aspects of the ttg phenotype varied in parallel in this allelic series. The weakest allele, ttg-10, causes frequent clusters of adjacent trichomes, suggesting a role for TTG in inhibiting neighboring cells from choosing the trichome fate. This allele results from a mutation in the 5'-untranslated region of ttg and creates an out-of-frame upstream AUG codon. The ttg-10 allele shows several unusual genetic interactions with the weak hypomorphic gl1-2 allele, including intergenic noncomplementation and a synthetic glabrous phenotype. These interactions are specific for the gl1-2 allele. The implication of these results for current models of trichome development is discussed. PMID:10101180

  11. Sequence Variation within the KIV-2 Copy Number Polymorphism of the Human LPA Gene in African, Asian, and European Populations

    PubMed Central

    Noureen, Asma; Fresser, Friedrich; Utermann, Gerd; Schmidt, Konrad

    2015-01-01

    Amazingly little sequence variation is reported for the kringle IV 2 copy number variation (KIV 2 CNV) in the human LPA gene. Apart from whole genome sequencing projects, this region has only been analyzed in some detail in samples of European populations. We have performed a systematic resequencing study of the exonic and flanking intron regions within the KIV 2 CNV in 90 alleles from Asian, European, and four different African populations. Alleles have been separated according to their CNV length by pulsed field gel electrophoresis prior to unbiased specific PCR amplification of the target regions. These amplicons covered all KIV 2 copies of an individual allele simultaneously. In addition, cloned amplicons from genomic DNA of an African individual were sequenced. Our data suggest that sequence variation in this genomic region may be higher than previously appreciated. Detection probability of variants appeared to depend on the KIV 2 copy number of the analyzed DNA and on the proportion of copies carrying the variant. Asians had a high frequency of so-called KIV 2 type B and type C (together 70% of alleles), which differ by three or two synonymous substitutions respectively from the reference type A. This is most likely explained by the strong bottleneck suggested to have occurred when modern humans migrated to East Asia. A higher frequency of variable sites was detected in the Africans. In particular, two previously unreported splice site variants were found. One was associated with non-detectable Lp(a). The other was observed at high population frequencies (10% to 40%). Like the KIV 2 type B and C variants, this latter variant was also found in a high proportion of KIV 2 repeats in the affected alleles and in alleles differing in copy numbers. Our findings may have implications for the interpretation of SNP analyses in other repetitive loci of the human genome. PMID:25822457

  12. Differential allele-specific accumulation of bovine kappa-casein mRNA throughout lactation.

    PubMed

    Vachon, Dominic; Britten, Michel; Morisset, Jean; Petitclerc, Denis; Robitaille, Gilles

    2004-11-01

    A differential allele-specific accumulation of kappa-casein mRNA that is not linked to the kappa-casein protein variants is described in Holstein cows. Actually, cows genotyped kappa-casein AB were a mixed population. For the first group of kappa-casein AB cows, allele A-specific kappa-casein mRNA contents within mammary epithelial cells were lower than the allele B-specific ones (cows LH), suggesting that the allele A-specific kappa-casein gene was expressed with lower efficiency in mRNA. For the other group of kappa-casein AB cows, allele A- and B-specific kappa-casein mRNA accumulated to a similar level within mammary epithelial cells (cows HH). The objective of this study was to determine whether the accumulation of allele-specific kappa-casein mRNA remained constant throughout lactation for the two groups of cows. Quantitative RT-PCR was used to monitor Holstein cows kappa-casein AB genotyped HH and LH throughout lactation for the proportion of allele B-specific mRNA accumulation relative to the total kappa-casein encoded mRNA within mammary epithelial cells: RNA was extracted from milk somatic cells known to contain a small proportion of mammary epithelial cells. Mean values of allele B-specific mRNA content were 50.6+/-0.5 and 54.0+/-0.9%, for cows HH and cows LH, respectively, and did not vary during lactation (P> 0.10). This suggests that the phenotypic expression of the genetic mutation that causes the differential allele-specific accumulation of kappa-casein mRNA was not affected by physiological and environmental factors, which tend to vary considerably throughout lactation. PMID:15605706

  13. Complex and multi-allelic copy number variation in human disease

    PubMed Central

    McCarroll, Steven A.

    2015-01-01

    Hundreds of copy number variants are complex and multi-allelic, in that they have many structural alleles and have rearranged multiple times in the ancestors who contributed chromosomes to current humans. Not only are the relationships of these multi-allelic CNVs (mCNVs) to phenotypes generally unknown, but many mCNVs have not yet been described at the basic levelsalleles, allele frequencies, structural featuresthat support genetic investigation. To date, most reported disease associations to these variants have been ascertained through candidate gene studies. However, only a few associations have reached the level of acceptance defined by durable replications in many cohorts. This likely stems from longstanding challenges in making precise molecular measurements of the alleles individuals have at these loci. However, approaches for mCNV analysis are improving quickly, and some of the unique characteristics of mCNVs may assist future association studies. Their various structural alleles are likely to have different magnitudes of effect, creating a natural allelic series of growing phenotypic impact and giving investigators a set of natural predictions and testable hypotheses about the extent to which each allele of an mCNV predisposes to a phenotype. Also, mCNVs low-to-modest correlation to individual single-nucleotide polymorphisms (SNPs) may make it easier to distinguish between mCNVs and nearby SNPs as the drivers of an association signal, and perhaps, make it possible to preliminarily screen candidate loci, or the entire genome, for the many mCNVdisease relationships that remain to be discovered. PMID:26163405

  14. Complex and multi-allelic copy number variation in human disease.

    PubMed

    Usher, Christina L; McCarroll, Steven A

    2015-09-01

    Hundreds of copy number variants are complex and multi-allelic, in that they have many structural alleles and have rearranged multiple times in the ancestors who contributed chromosomes to current humans. Not only are the relationships of these multi-allelic CNVs (mCNVs) to phenotypes generally unknown, but many mCNVs have not yet been described at the basic levels-alleles, allele frequencies, structural features-that support genetic investigation. To date, most reported disease associations to these variants have been ascertained through candidate gene studies. However, only a few associations have reached the level of acceptance defined by durable replications in many cohorts. This likely stems from longstanding challenges in making precise molecular measurements of the alleles individuals have at these loci. However, approaches for mCNV analysis are improving quickly, and some of the unique characteristics of mCNVs may assist future association studies. Their various structural alleles are likely to have different magnitudes of effect, creating a natural allelic series of growing phenotypic impact and giving investigators a set of natural predictions and testable hypotheses about the extent to which each allele of an mCNV predisposes to a phenotype. Also, mCNVs' low-to-modest correlation to individual single-nucleotide polymorphisms (SNPs) may make it easier to distinguish between mCNVs and nearby SNPs as the drivers of an association signal, and perhaps, make it possible to preliminarily screen candidate loci, or the entire genome, for the many mCNV-disease relationships that remain to be discovered. PMID:26163405

  15. SAGE - European ozonesonde comparison

    NASA Technical Reports Server (NTRS)

    Reiter, R.; Mccormick, M. P.

    1982-01-01

    Between February and December 1979, 30 correlative comparisons were conducted of ozone profiles derived from the satellite sensor SAGE and those derived from balloon-borne ozonesondes launched in Europe. The mean absolute differences between SAGE and the European sondes when ozone mixing ratio is used as the basis of comparison are listed, and ozone comparisons made at four stations in Europe are plotted as ozone mixing ratio versus altitude. The agreement is considered quite reasonable. Also shown is an April 2, 1979 Garmisch comparison where the time and space differences were very small. The agreement is found to be remarkable. For example, the ratio of SAGE to ozonesonde values at 13 out of 17 levels between 12.5 and 28.5 km lies in the range 0.92-1.06.

  16. Optranet: a European project

    NASA Astrophysics Data System (ADS)

    Jeanjean, Marie

    2003-10-01

    In a situation where curricula did not adjust at the required pace and many students are getting attracted out of science and technology, the shortage of skilled workers at the technician and engineer level is known to be a threat to development. In spite of a serious crisis in 2001, the trend of an increased presence of optical technologies remains unchanged and is bound to remain part of the landscape for decades. The level of investment required and the markets make Europe the best scale to plan for unified curricula and a global analysis of the human resources needs. There is no agreement on the definition of a trained optician, and European countries differ in the way they educate opticians, source of a lack of clarity and visibility which is detrimental to attracting good students and to the job market. Through its closely work with companies, OPTRANET will propose measures to enhance the adequacy and the visibility of the training offer.

  17. The cathepsin D gene exon 2 (C224T) polymorphism and sporadic Alzheimer's disease in European populations.

    PubMed

    Capurso, Cristiano; Solfrizzi, Vincenzo; D'Introno, Alessia; Colacicco, Anna M; Capurso, Sabrina A; Mastroianni, Franco; Liaci, Maria; Vendemiale, Gianluigi; Capurso, Antonio; Panza, Francesco

    2005-08-01

    The cathepsin D gene (CTSD) exon 2 (C224T) polymorphism has been associated with an increased risk for sporadic Alzheimer's disease (AD), but with controversial findings. We studied CTSD exon 2 (C224T) and apolipoprotein E (APOE) genotype frequencies in 168 AD patients and 218 age-matched healthy controls from Southern Italy. No statistically significant differences were found in CTSD allele or genotype frequencies between AD patients and controls, and there were no interactions with sex or APOE genotype. Furthermore, comparing our results with the findings from other European populations, the CTSD*T allele frequency showed a statistically significant increasing trend from Northern to Southern regions of Europe in AD patients and controls (z=2.51, p<.01; z=4.02, p<.001, respectively), with a concomitant inverse trend for CTSD*C allele frequency. The regional differences in CTSD allele frequencies could be related to the different patterns of association between this polymorphism and AD in various European studies. PMID:16127101

  18. Global diversity and genetic contributions of chicken populations from African, Asian and European regions.

    PubMed

    Lyimo, C M; Weigend, A; Msoffe, P L; Eding, H; Simianer, H; Weigend, S

    2014-12-01

    Genetic diversity and population structure of 113 chicken populations from Africa, Asia and Europe were studied using 29 microsatellite markers. Among these, three populations of wild chickens and nine commercial purebreds were used as reference populations for comparison. Compared to commercial lines and chickens sampled from the European region, high mean numbers of alleles and a high degree of heterozygosity were found in Asian and African chickens as well as in Red Junglefowl. Population differentiation (FST ) was higher among European breeds and commercial lines than among African, Asian and Red Junglefowl populations. Neighbour-Net genetic clustering and structure analysis revealed two main groups of Asian and north-west European breeds, whereas African populations overlap with other breeds from Eastern Europe and the Mediterranean region. Broilers and brown egg layers were situated between the Asian and north-west European clusters. structure analysis confirmed a lower degree of population stratification in African and Asian chickens than in European breeds. High genetic differentiation and low genetic contributions to global diversity have been observed for single European breeds. Populations with low genetic variability have also shown a low genetic contribution to a core set of diversity in attaining maximum genetic variation present from the total populations. This may indicate that conservation measures in Europe should pay special attention to preserving as many single chicken breeds as possible to maintain maximum genetic diversity given that higher genetic variations come from differentiation between breeds. PMID:25315897

  19. PCSK9 polymorphism in a Tunisian cohort: identification of a new allele, L8, and association of allele L10 with reduced coronary heart disease risk.

    PubMed

    Slimani, Afef; Hrira, Mohamed Yahia; Najah, Mohamed; Jomaa, Walid; Maatouk, Faouzi; Hamda, Khaldoun Ben; Abifadel, Marianne; Rabs, Jean-Pierre; Boileau, Catherine; Rouis, Mustapha; Slimane, Mohamed Naceur; Varret, Mathilde

    2015-02-01

    The c.61_63dupCTG (L10) allele of rs72555377 polymorphism in PCSK9 has been reported to be associated with low-density lipoprotein-cholesterol (LDL-C) levels and with a decreased risk of coronary artery disease (CAD). We investigated the effect of two known alleles for rs72555377, L10 and L11, on the risk of CAD in a Tunisian cohort (218 patients diagnosed by angiography and 125 control subjects). Two subgroups of patients were defined by their level of stenosis: ?50% for CAD and <50% for no-CAD. The genotypes were obtained by the size measurement of fluorescent-labeled PCR products. We identified a novel allele for the rs72555377 polymorphism: an in-frame deletion, c.61_63delCTG (L8). The frequency of the L10 allele was significantly higher in the no-CAD subgroup than in the CAD subgroup (0.210 vs 0.114, p=0.045), and than in the subgroup of CAD patients presenting a stenosis ?50% in two or three major coronary arteries (0.210 vs 0.125, p=0.028). Multiple regression analysis showed that the L10 allele was significantly associated with a reduced risk of CAD (p=0.049, OR=0.51[0.26-1.00]), and with its reduced severity (p=0.045, OR=0.44[0.20-0.98]). The L10 allele is associated with a reduced risk and severity of CAD, seemingly independently of its LDL-lowering effect, suggesting a direct effect of PCSK9 on atherogenesis. PMID:25239117

  20. European Nations Seek Compatible Degrees.

    ERIC Educational Resources Information Center

    Bollag, Burton

    1999-01-01

    After developing independently of each other for centuries, European higher-education systems are beginning serious efforts to "harmonize" their systems. The goal is to promote European integration and economic growth by making academic standards and degrees compatible across national boundaries. The Bologna Declaration of May 1999 formalizes the

  1. The European Dimension in Education.

    ERIC Educational Resources Information Center

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

    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…

  2. Adult Education and European Identity

    ERIC Educational Resources Information Center

    Negt, Oskar

    2008-01-01

    Europe is coming together. This is a historic project; for the first time in modern history, will and consciousness are used for bringing political, social and cultural unity to the European continent. In this process lifelong learning and hence adult education are gaining in importance. The European project takes place in an age characterised by…

  3. European Schoolnet: Enabling School Networking

    ERIC Educational Resources Information Center

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

    2009-01-01

    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

  4. What Audience for European Television?

    ERIC Educational Resources Information Center

    Wendelbo, Harald Arni

    This discussion of the audience for European television argues that satellite television has taken an upside-down approach, i.e., it has begun by focusing on the hardware, and then the software, before checking to see if there would be a user at the end of the line willing to pay for the whole operation. "European television" is then defined as

  5. Selection and Reduced Population Size Cannot Explain Higher Amounts of Neandertal Ancestry in East Asian than in European Human Populations

    PubMed Central

    Kim, BernardY.; Lohmueller, KirkE.

    2015-01-01

    It has been hypothesized that the greater proportion of Neandertal ancestry in East Asians than in Europeans is due to the fact that purifying selection is less effective at removing weakly deleterious Neandertal alleles from East Asian populations. Using simulations of a broad range of models of selection and demography, we have shown that this hypothesis cannot account for the higher proportion of Neandertal ancestry in East Asians than in Europeans. Instead, more complex demographic scenarios, most likely involving multiple pulses of Neandertal admixture, are required to explain the data. PMID:25683122

  6. Selection and reduced population size cannot explain higher amounts of Neandertal ancestry in East Asian than in European human populations.

    PubMed

    Kim, Bernard Y; Lohmueller, Kirk E

    2015-03-01

    It has been hypothesized that the greater proportion of Neandertal ancestry in East Asians than in Europeans is due to the fact that purifying selection is less effective at removing weakly deleterious Neandertal alleles from East Asian populations. Using simulations of a broad range of models of selection and demography, we have shown that this hypothesis cannot account for the higher proportion of Neandertal ancestry in East Asians than in Europeans. Instead, more complex demographic scenarios, most likely involving multiple pulses of Neandertal admixture, are required to explain the data. PMID:25683122

  7. An American Construction of European Education Space

    ERIC Educational Resources Information Center

    Silova, Iveta; Brehm, William C.

    2010-01-01

    The construction of the European education space has typically been attributed to European education policy makers, institutions, and networks. Rarely do scholars consider the role of outside, non-European actors in shaping the terrain of European education thought and practice. This article considers the construction of the European education

  8. An American Construction of European Education Space

    ERIC Educational Resources Information Center

    Silova, Iveta; Brehm, William C.

    2010-01-01

    The construction of the European education space has typically been attributed to European education policy makers, institutions, and networks. Rarely do scholars consider the role of outside, non-European actors in shaping the terrain of European education thought and practice. This article considers the construction of the European education…

  9. No association between an allele at the D sub 2 dopamine receptor gene (DRD2) and alcoholism

    SciTech Connect

    Gelernter, J.; Krystal, J.; Kennedy, J.L. West Haven Dept. of Veterans Affairs Medical Center, CT ); O'Malley, S.; Risch, N.; Merikangas, K.; Kidd, K.K. ); Kranzler, H.R. )

    1991-10-02

    The author attempted to replicate a positive allelic association between the A1 allele of DRD2 (the D{sub 2} dopamine receptor locus) and alcoholism that has been reported. They compared allele frequencies at the previously described Taq I restriction fragment length polymorphism system of DRD2 in alcoholics and random population controls.

  10. Identification of pologyne and mongyne fire ant colonies (Solenopsis invivta) by multiplex PCR of GP-9 alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oligonucleotide primers were designed to discriminate between the Gp-9B and Gp-9b alleles found in the two social forms (monogyne and polygyne) of Solenopsis invicta. Primers specific for the Gp-9B allele produced a 518 bp amplicon and primers specific for Gp-9b allele produced a 423 bp amplicon. ...

  11. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

    PubMed

    Earp, Madalene A; Kelemen, Linda E; Magliocco, Anthony M; Swenerton, Kenneth D; Chenevix-Trench, Georgia; Lu, Yi; Hein, Alexander; Ekici, Arif B; Beckmann, Matthias W; Fasching, Peter A; Lambrechts, Diether; Despierre, Evelyn; Vergote, Ignace; Lambrechts, Sandrina; Doherty, Jennifer A; Rossing, Mary Anne; Chang-Claude, Jenny; Rudolph, Anja; Friel, Grace; Moysich, Kirsten B; Odunsi, Kunle; Sucheston-Campbell, Lara; Lurie, Galina; Goodman, Marc T; Carney, Michael E; Thompson, Pamela J; Runnebaum, Ingo B; Drst, Matthias; Hillemanns, Peter; Drk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M; Butzow, Ralf; Bunker, Clareann H; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjr, Susanne K; Hgdall, Claus K; Hgdall, Estrid; Lundvall, Lene; Sellers, Thomas A; Fridley, Brooke L; Goode, Ellen L; Cunningham, Julie M; Vierkant, Robert A; Giles, Graham G; Baglietto, Laura; Severi, Gianluca; Southey, Melissa C; Liang, Dong; Wu, Xifeng; Lu, Karen; Hildebrandt, Michelle A T; Levine, Douglas A; Bisogna, Maria; Schildkraut, Joellen M; Iversen, Edwin S; Weber, Rachel Palmieri; Berchuck, Andrew; Cramer, Daniel W; Terry, Kathryn L; Poole, Elizabeth M; Tworoger, Shelley S; Bandera, Elisa V; Chandran, Urmila; Orlow, Irene; Olson, Sara H; Wik, Elisabeth; Salvesen, Helga B; Bjorge, Line; Halle, Mari K; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Pejovic, Tanja; Bean, Yukie T; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Wentzensen, Nicolas; Brinton, Louise A; Lissowska, Jolanta; Garcia-Closas, Montserrat; Dicks, Ed; Dennis, Joe; Easton, Douglas F; Song, Honglin; Tyrer, Jonathan P; Pharoah, Paul D P; Eccles, Diana; Campbell, Ian G; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph H; Flanagan, James M; Paul, James; Brown, Robert; Phelan, Catherine M; Risch, Harvey A; McLaughlin, John R; Narod, Steven A; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Gayther, Simon A; Ramus, Susan J; Wu, Anna H; Pearce, Celeste L; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K; Szafron, Lukasz M; Kupryjanczyk, Jolanta; Cook, Linda S; Le, Nhu D; Brooks-Wilson, Angela

    2014-05-01

    Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P<0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR=1.17, P=0.029, n=1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P=0.014, n=2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR=0.86, P=0.0043, n=892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR=0.84, P=0.0007) and LMP serous EOC risk remained statistically significant at P<0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes. PMID:24190013

  12. Genome-wide Association Study of Subtype-Specific Epithelial Ovarian Cancer Risk Alleles Using Pooled DNA

    PubMed Central

    Earp, Madalene A.; Kelemen, Linda E.; Magliocco, Anthony M.; Swenerton, Kenneth D.; Chenevix–Trench, Georgia; Lu, Yi; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Fasching, Peter A.; Lambrechts, Diether; Despierre, Evelyn; Vergote, Ignace; Lambrechts, Sandrina; Doherty, Jennifer A.; Rossing, Mary Anne; Chang-Claude, Jenny; Rudolph, Anja; Friel, Grace; Moysich, Kirsten B.; Odunsi, Kunle; Sucheston-Campbell, Lara; Lurie, Galina; Goodman, Marc T.; Carney, Michael E.; Thompson, Pamela J.; Runnebaum, Ingo B.; Dürst, Matthias; Hillemanns, Peter; Dörk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.; Butzow, Ralf; Bunker, Clareann H.; Modugno, Francesmary; Edwards, Robert P.; Ness, Roberta B.; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjær, Susanne K.; Høgdall, Claus K.; Høgdall, Estrid; Lundvall, Lene; Sellers, Thomas A.; Fridley, Brooke L.; Goode, Ellen L.; Cunningham, Julie M.; Vierkant, Robert A.; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; Southey, Melissa C.; Liang, Dong; Wu, Xifeng; Lu, Karen; Hildebrandt, Michelle A.T.; Levine, Douglas A.; Bisogna, Maria; Schildkraut, Joellen M.; Iversen, Edwin S.; Weber, Rachel Palmieri; Berchuck, Andrew; Cramer, Daniel W.; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.; Bandera, Elisa V.; Chandran, Urmila; Orlow, Irene; Olson, Sara H.; Wik, Elisabeth; Salvesen, Helga B.; Bjorge, Line; Halle, Mari K.; van Altena, Anne M.; Aben, Katja K.H.; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Pejovic, Tanja; Bean, Yukie T.; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Garcia–Closas, Montserrat; Dicks, Ed; Dennis, Joe; Easton, Douglas F.; Song, Honglin; Tyrer, Jonathan P.; Pharoah, Paul D. P.; Eccles, Diana; Campbell, Ian G.; Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph H.; Flanagan, James M.; Paul, James; Brown, Robert; Phelan, Catherine M.; Risch, Harvey A.; McLaughlin, John R.; Narod, Steven A.; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Pearce, Celeste L.; Pike, Malcolm C.; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K; Szafron, Lukasz M; Kupryjanczyk, Jolanta; Cook, Linda S.; Le, Nhu D.; Brooks–Wilson, Angela

    2014-01-01

    Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS (56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low malignant potential (LMP) serous, and 24 for invasive serous EOC), selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging 6 loci were associated with subtype-specific EOC risk at P<0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR=1.17, P=0.029, n=1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P=0.014, n=2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR=0.86, P=0.0043, n=892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR=0.84, P=0.0007) and LMP serous EOC risk remained statistically significant at P<0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes. PMID:24190013

  13. The IPD and IMGT/HLA database: allele variant databases

    PubMed Central

    Robinson, James; Halliwell, Jason A.; Hayhurst, James D.; Flicek, Paul; Parham, Peter; Marsh, StevenG.E.

    2015-01-01

    The Immuno Polymorphism Database (IPD) was developed to provide a centralized system for the study of polymorphism in genes of the immune system. Through the IPD project we have established a central platform for the curation and publication of locus-specific databases involved either directly or related to the function of the Major Histocompatibility Complex in a number of different species. We have collaborated with specialist groups or nomenclature committees that curate the individual sections before they are submitted to IPD for online publication. IPD consists of five core databases, with the IMGT/HLA Database as the primary database. Through the work of the various nomenclature committees, the HLA Informatics Group and in collaboration with the European Bioinformatics Institute we are able to provide public access to this data through the website http://www.ebi.ac.uk/ipd/. The IPD project continues to develop with new tools being added to address scientific developments, such as Next Generation Sequencing, and to address user feedback and requests. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the immunogenetics community, and the wider research and clinical communities. PMID:25414341

  14. Nucleotide sequence of a novel HLA-DRB1 allele, DRB1*0806

    SciTech Connect

    Loeffler, D.; Woelpl, A.; Eiermann, T.H.

    1995-01-01

    Human major histocompatibility complex (HLA) class II genes are organized in three subregions, DR, DQ, and DP. The genes in this region are extremely polymorphic and new alleles are continuously being identified. We report here a novel allele that was found by the amplification and direct sequencing of exon 2 of DRB1. The novel allele was found in a bone marrow transplantation patient, the mother, and two serologically identified donors. The patient was typed as DR3/DR8, the mother as DR2/DR8, and the father as DR3/DR8 heterozygote. Therefore, the patient inherited the DR3 haplotype from the father and the DR8 haplotype from the mother. At first, it was not possible to definitely determine the subtype of the DR8 allele by oligotyping. 4 refs., 1 fig.

  15. Using multi-locus allelic sequence data to estimate genetic divergence among four Lilium (Liliaceae) cultivars

    PubMed Central

    Shahin, Arwa; Smulders, Marinus J. M.; van Tuyl, Jaap M.; Arens, Paul; Bakker, Freek T.

    2014-01-01

    Next Generation Sequencing (NGS) may enable estimating relationships among genotypes using allelic variation of multiple nuclear genes simultaneously. We explored the potential and caveats of this strategy in four genetically distant Lilium cultivars to estimate their genetic divergence from transcriptome sequences using three approaches: POFAD (Phylogeny of Organisms from Allelic Data, uses allelic information of sequence data), RAxML (Randomized Accelerated Maximum Likelihood, tree building based on concatenated consensus sequences) and Consensus Network (constructing a network summarizing among gene tree conflicts). Twenty six gene contigs were chosen based on the presence of orthologous sequences in all cultivars, seven of which also had an orthologous sequence in Tulipa, used as out-group. The three approaches generated the same topology. Although the resolution offered by these approaches is high, in this case there was no extra benefit in using allelic information. We conclude that these 26 genes can be widely applied to construct a species tree for the genus Lilium. PMID:25368628

  16. Characterization of a novel B(A) allele with BBBA type at the ABO blood group.

    PubMed

    Deng, Zhi-Hui; Yu, Qiong; Liang, Yan-Lian; Wang, Da-Ming; Su, Yu-Qing; Wu, Guo-Guang

    2006-01-01

    The ABO blood group is one of the main blood group systems, and it plays an important role in transfusion medicine and transplantation. To date, most of the many ABO subgroups with a weak expression of the A or B antigen on red blood cells have been elucidated to have specific molecular genetic background with respect to the ABO gene. The ABO*B(A) allele or CisAB allele is a type of dual ABO allele which can encode glycosyltransferases responsible for the conversion of H substance to both A and B antigen. We report here our characterization of a novel B(A) allele which differs from those reported previously. PMID:16871363

  17. Genotyping of Single Nucleotide Polymorphisms by 5′ Nuclease Allelic Discrimination

    PubMed Central

    Malkki, Mari; Petersdorf, Effie W.

    2013-01-01

    Real-time quantitative PCR is an efficient method for high-throughput genotyping of single nucleotide polymorphisms (SNPs). In this chapter, we describe the 5′ nuclease allelic discrimination assay for genotyping biallelic SNPs. PMID:22665234

  18. Using multi-locus allelic sequence data to estimate genetic divergence among four Lilium (Liliaceae) cultivars.

    PubMed

    Shahin, Arwa; Smulders, Marinus J M; van Tuyl, Jaap M; Arens, Paul; Bakker, Freek T

    2014-01-01

    Next Generation Sequencing (NGS) may enable estimating relationships among genotypes using allelic variation of multiple nuclear genes simultaneously. We explored the potential and caveats of this strategy in four genetically distant Lilium cultivars to estimate their genetic divergence from transcriptome sequences using three approaches: POFAD (Phylogeny of Organisms from Allelic Data, uses allelic information of sequence data), RAxML (Randomized Accelerated Maximum Likelihood, tree building based on concatenated consensus sequences) and Consensus Network (constructing a network summarizing among gene tree conflicts). Twenty six gene contigs were chosen based on the presence of orthologous sequences in all cultivars, seven of which also had an orthologous sequence in Tulipa, used as out-group. The three approaches generated the same topology. Although the resolution offered by these approaches is high, in this case there was no extra benefit in using allelic information. We conclude that these 26 genes can be widely applied to construct a species tree for the genus Lilium. PMID:25368628

  19. Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder

    SciTech Connect

    Lim, L.C.C.; Sham, P.; Castle, D.

    1995-08-14

    We present evidence of a genetic association between bipolar disorder and alleles at 3 monoamine oxidase A (MAOA) markers, but not with alleles of a monoamine oxidase B (MAOB) polymorphism. The 3 MAOA markers, including one associated with low MAOA activity, show strong allelic association with each other but surprisingly not with MAOB. Our results are significantly only for females, though the number of males in our sample is too small to draw any definite conclusions. Our data is consistent with recent reports of reduced MAOA activity in patients with abnormal behavioral phenotypes. The strength of the association is weak, but significant, which suggests that alleles at the MAOA locus contribute to susceptibility to bipolar disorder rather than being a major determinant. 58 refs., 1 fig., 3 tabs.

  20. Random Monoallelic Expression: Regulating gene expression one allele at a time

    PubMed Central

    Eckersley-Maslin, Mlanie A.; Spector, David L.

    2014-01-01

    Monoallelic gene expression is a remarkable process in which transcription occurs from only one of two homologous alleles in a diploid cell. Interestingly, between 0.5% to 15% of autosomal genes exhibit random monoallelic gene expression, in which different cells express only one allele independently of the underlying genomic sequence, in a cell-type specific manner. Recently, genome-wide studies have increased our understanding of the cell-type specific incidence of random monoallelic gene expression, and how the imbalance in allelic expression is distinguished within the cell and potentially maintained across cell generations. Monoallelic gene expression is likely generated through stochastic independent regulation of the two alleles upon differentiation, and has varied implications for the cell and organism, in particular with respect to disease. PMID:24780084

  1. Reintroduction of a Homocysteine Level-Associated Allele into East Asians by Neanderthal Introgression.

    PubMed

    Hu, Ya; Ding, Qiliang; He, Yungang; Xu, Shuhua; Jin, Li

    2015-12-01

    In this study, we present an analysis of Neanderthal introgression at the dipeptidase 1 gene, DPEP1. A Neanderthal origin for the putative introgressive haplotypes was demonstrated using an established three-step approach. This introgression was under positive natural selection, reached a frequency of >50%, and introduced a homocysteine level- and pigmentation-associated allele (rs460879-T) into East Asians. However, the same allele was also found in non-East Asians, but not from Neanderthal introgression. It is likely that rs460879-T was lost in East Asians and was reintroduced subsequently through Neanderthal introgression. Our findings suggest that Neanderthal introgression could reintroduce an important previously existing allele into populations where the allele had been lost. This study sheds new light on understanding the contribution of Neanderthal introgression to the adaptation of non-Africans. PMID:26392408

  2. European Citizenship and European Union Expansion: Perspectives on Europeanness and Citizenship Education from Britain and Turkey

    ERIC Educational Resources Information Center

    Wilkins, Chris; Busher, Hugh; Lawson, Tony; Acun, Ismail; Goz, Nur Leman

    2010-01-01

    This article discusses some perspectives on citizenship education in Turkey and Britain in the context of current contested discourses on the nature of European identity and of the European Union (EU). It is based on data collected during an EU-funded student teacher exchange programme between three universities in Turkey and Leicester University

  3. A human-specific allelic group of the MHC DRB1 gene in primates

    PubMed Central

    2014-01-01

    Background Diversity among human leukocyte antigen (HLA) molecules has been maintained by host-pathogen coevolution over a long period of time. Reflecting this diversity, the HLA loci are the most polymorphic in the human genome. One characteristic of HLA diversity is long-term persistence of allelic lineages, which causes trans-species polymorphisms to be shared among closely related species. Modern humans have disseminated across the world after their exodus from Africa, while chimpanzees have remained in Africa since the speciation event between humans and chimpanzees. It is thought that modern humans have recently acquired resistance to novel pathogens outside Africa. In the present study, we investigated HLA alleles that could contribute to this local adaptation in humans and also studied the contribution of natural selection to human evolution by using molecular data. Results Phylogenetic analysis of HLA-DRB1 genes identified two major groups, HLA Groups A and B. Group A formed a monophyletic clade distinct from DRB1 alleles in other Catarrhini, suggesting that Group A is a human-specific allelic group. Our estimates of divergence time suggested that seven HLA-DRB1 Group A allelic lineages in humans have been maintained since before the speciation event between humans and chimpanzees, while chimpanzees possess only one DRB1 allelic lineage (Patr-DRB1*03), which is a sister group to Group A. Experimental data showed that some Group A alleles bound to peptides derived from human-specific pathogens. Of the Group A alleles, three exist at high frequencies in several local populations outside Africa. Conclusions HLA Group A alleles are likely to have been retained in human lineages for a long period of time and have not expanded since the divergence of humans and chimpanzees. On the other hand, most orthologs of HLA Group A alleles may have been lost in the chimpanzee due to differences in selective pressures. The presence of alleles with high frequency outside of Africa suggests these HLA molecules result from the local adaptations of humans. Our study helps elucidate the mechanism by which the human adaptive immune system has coevolved with pathogens over a long period of time. PMID:24928070

  4. Interrogation of allelic chromatin states in human cells by high-density ChIP-genotyping

    PubMed Central

    Light, Nicholas; Adoue, Véronique; Ge, Bing; Chen, Shu-Huang; Kwan, Tony; Pastinen, Tomi

    2014-01-01

    Allele-specific (AS) assessment of chromatin has the potential to elucidate specific cis-regulatory mechanisms, which are predicted to underlie the majority of the known genetic associations to complex disease. However, development of chromatin landscapes at allelic resolution has been challenging since sites of variable signal strength require substantial read depths not commonly applied in sequencing based approaches. In this study, we addressed this by performing parallel analyses of input DNA and chromatin immunoprecipitates (ChIP) on high-density Illumina genotyping arrays. Allele-specificity for the histone modifications H3K4me1, H3K4me3, H3K27ac, H3K27me3, and H3K36me3 was assessed using ChIP samples generated from 14 lymphoblast and 6 fibroblast cell lines. AS-ChIP SNPs were combined into domains and validated using high-confidence ChIP-seq sites. We observed characteristic patterns of allelic-imbalance for each histone-modification around allele-specifically expressed transcripts. Notably, we found H3K4me1 to be significantly anti-correlated with allelic expression (AE) at transcription start sites, indicating H3K4me1 allelic imbalance as a marker of AE. We also found that allelic chromatin domains exhibit population and cell-type specificity as well as heritability within trios. Finally, we observed that a subset of allelic chromatin domains is regulated by DNase I-sensitive quantitative trait loci and that these domains are significantly enriched for genome-wide association studies hits, with autoimmune disease associated SNPs specifically enriched in lymphoblasts. This study provides the first genome-wide maps of allelic-imbalance for five histone marks. Our results provide new insights into the role of chromatin in cis-regulation and highlight the need for high-depth sequencing in ChIP-seq studies along with the need to improve allele-specificity of ChIP-enrichment. PMID:25055051

  5. Cw*1505: A novel HLA-C allele isolated from a B*7301 haplotype

    SciTech Connect

    Vilches, C.; Pablo, R. de; Herrero, M.J.; Moreno, M.E.; Kreisler, M.

    1994-12-31

    The Cw*15 allelic family is one of the most numerous within the HLA-C locus, with four members described so far. In this report, the authors describe Cw*1505, a new allele of this group isolated from the B-LCL of Spanish Caucasoid origin LE023. Cw*1505 differs from Cw*1502 by two point changes, one at exon 1 (synonymous), and the other at codon 116 (Leu {yields} Phe). 7 refs., 1 fig.

  6. Origin and dissemination of chloroquine-resistant Plasmodium falciparum with mutant pfcrt alleles in the Philippines.

    PubMed

    Chen, Nanhua; Wilson, Danny W; Pasay, Cielo; Bell, David; Martin, Laura B; Kyle, Dennis; Cheng, Qin

    2005-05-01

    The pfcrt allelic type and adjacent microsatellite marker type were determined for 82 Plasmodium falciparum isolates from the Philippines. Mutant pfcrt allelic types P1a and P2a/P2b were dominant in different locations. Microsatellite analysis revealed that P2a/P2b evolved independently in the Philippines, while P1a shared common ancestry with Papua New Guinea chloroquine-resistant parasites. PMID:15855538

  7. Reduced expression of the normal DMPK allele in a congenital DM patient

    SciTech Connect

    Funanage, V.L.; Carango, P.; Moses, R.M.; Marks, H.G.

    1994-09-01

    Both adult-onset and congenital myotonic dystrophy (DM) are autosomal dominant disorders caused by triplet repeat expansions within the 3{prime} untranslated region of the DM protein kinase (DMPK) gene. The size of the repeat region shows a positive correlation with disease severity; in general, the triplet repeat expansions in congenital DM patients are larger than those found in adult DM individuals. In an adult DM patient, the expanded allele of 133 repeats reduced both the synthesis and processing of DMPK mRNA, whereas expression from the unexpanded allele remained unaffected. However, in both muscle and skin tissues from a congenital DM individual, DMPK mRNA expression from the unexpanded allele was also reduced. This reduced expression was maintained in fibroblasts cultured from a skin biospy of the patient; however, normal expression of the unexpanded allele occurred in cultured myoblasts established from this patient`s muscle biopsy. To determine if the expanded repeat exerts a trans effect on DMPK gene expression, we have separated the normal and mutant DMPK alleles from the cogenital DM skin fibroblasts by somatic cell hybridization. Hybrid clones containing only the normal DMPK gene still produced reduced levels of DMPK mRNA, indicating that the reduced expression from the normal allele is due to a cis effect. Cultured skin fibroblasts from the congenital DM patient were exposed to 5-azacytidine to determine if demethylation of the DMPK gene could restore proper expression of the normal allele. We are currently analyzing DMPK mRNA levels in these cells and determining if a difference in the methylation patterns of the normal DMPK alleles from adult and congenital DM patients accounts for this effect.

  8. Detection of multiple beta-casein (CASB) alleles by amplification created restriction sites (ACRS).

    PubMed

    Lien, S; Alestrm, P; Klungland, H; Rogne, S

    1992-01-01

    Direct sequencing of polymerase chain reaction (PCR) amplified DNA has been used to detect the DNA sequences for bovine beta-casein (CASB) A3 and B variants. Based on these sequences we have designed primers which create allele-specific restriction sites in the PCR product. Restriction analysis of PCR product generated in one reaction enable us to identify the A1, A2, A3 and B alleles of CASB rapidly without the use of radioactivity. PMID:1503272

  9. Detection of allelic variations of human gene expression by polymerase colonies

    PubMed Central

    Butz, James A; Yan, Hai; Mikkilineni, Venugopal; Edwards, Jeremy S

    2004-01-01

    Background Quantification of variations of human gene expression is complicated by the small differences between different alleles. Recent work has shown that variations do exist in the relative allelic expression levels in certain genes of heterozygous individuals. Herein, we describe the application of an immobilized polymerase chain reaction technique as an alternative approach to measure relative allelic differential expression. Results Herein, we report a novel assay, based on immobilized polymerase colonies, that accurately quantifies the relative expression levels of two alleles in a given sample. Mechanistically, this was accomplished by PCR amplifying a gene in a cDNA library in a thin polyacrylamide gel. By immobilizing the PCR, it is ensured that each transcript gives rise to only a single immobilized PCR colony, or "polony". Once polony amplified, the two alleles of the gene were differentially labeled by performing in situ sequencing with fluorescently labeled nucleotides. For these sets of experiments, silent single nucleotide polymorphisms (SNPs) were used to discriminate the two alleles. Finally, a simple count was then performed on the differentially labeled polonies in order to determine the relative expression levels of the two alleles. To validate this technique, the relative expression levels of PKD2 in a family of heterozygous patients bearing the 4208G/A SNP were examined and compared to the literature. Conclusions We were able to reproduce the results of allelic variation in gene expression using an accurate technology known as polymerase colonies. Therefore, we have demonstrated the utility of this method in human gene expression analysis. PMID:15040815

  10. No evidence for allelic association between bipolar disorder and monoamine oxidase A gene polymorphisms

    SciTech Connect

    Craddock, N.; Daniels, J.; Roberts, E.

    1995-08-14

    We have tested the hypothesis that DNA markers in the MAOA gene show allelic association with bipolar affective disorder. Eighty-four unrelated Caucasian patients with DSM III-R bipolar disorder and 84 Caucasian controls were typed for three markers in MAOA: a dinucleotide repeat in intron 2, a VNTR in intron 1, and an Fnu4HI RFLP in exon 8. No evidence for allelic association was observed between any of the markers and bipolar disorder. 9 refs., 1 tab.

  11. Allelic Diversity of MSP1 Gene in Plasmodium falciparum from Rural and Urban Areas of Gabon

    PubMed Central

    Mawili-Mboumba, Denise Patricia; Mbondoukwe, No; Adande, Elvire; Bouyou-Akotet, Marielle Karine

    2015-01-01

    The present study determined and compared the genetic diversity of Plasmodium falciparum strains infecting children living in 2 areas from Gabon with different malaria endemicity. Blood samples were collected from febrile children from 2008 to 2009 in 2 health centres from rural (Oyem) and urban (Owendo) areas. Genetic diversity was determined in P. falciparum isolates by analyzing the merozoite surface protein-1 (msp1) gene polymorphism using nested-PCR. Overall, 168 children with mild falciparum malaria were included. K1, Ro33, and Mad20 alleles were found in 110 (65.5%), 94 (55.9%), and 35 (20.8%) isolates, respectively, without difference according to the site (P>0.05). Allelic families frequencies were comparable between children less than 5 years old from the 2 sites; while among the older children the proportions of Ro33 and Mad20 alleles were 1.7 to 2.0 fold higher at Oyem. Thirty-three different alleles were detected, 16 (48.5%) were common to both sites, and 10 out of the 17 specific alleles were found at Oyem. Furthermore, multiple infection carriers were frequent at Oyem (57.7% vs 42.2% at Owendo; P=0.04) where the complexity of infection was of 1.88 (0.95) higher compared to that found at Owendo (1.550.75). Extended genetic diversity of P. falciparum strains infecting Gabonese symptomatic children and high multiplicity of infections were observed in rural area. Alleles common to the 2 sites were frequent; the site-specific alleles predominated in the rural area. Such distribution of the alleles should be taken into accounts when designing MSP1 or MSP2 malaria vaccine. PMID:26323839

  12. Optimization of allele-specific PCR using patient specific HIV consensus sequences for primer design

    PubMed Central

    Boltz, Valerie F.; Maldarelli, Frank; Martinson, Neil; Morris, Lynn; McIntyre, James A.; Gray, Glenda; Hopley, Mark J.; Kimura, Toshio; Mayers, Douglas L.; Robinson, Patrick; Mellors, John W.; Coffin, John M.; Palmer, Sarah E.

    2015-01-01

    Allele-specific PCR based on subtype consensus sequences is a powerful technique for detecting low frequency drug resistant mutants in HIV-1 infected patients. However, this approach can be limited by genetic variation in the region complementary to the primers, leading to variability in allele detection. The goals of this study were to quantify this effect and then to improve assay performance PMID:19948190

  13. Differential accessibility at the ?chain locus plays a role in allelic exclusion

    PubMed Central

    Goldmit, Maya; Schlissel, Mark; Cedar, Howard; Bergman, Yehudit

    2002-01-01

    Gene rearrangement in the immune system is always preceded by DNA demethylation and increased chromatin accessibility. Using a model system in which rearrangement of the endogenous immunoglobulin ?locus is prevented, we demonstrate that these epigenetic and chromatin changes actually occur on one allele with a higher probability than the other. It may be this process that, together with feedback inhibition, serves as the basis for allelic exclusion. PMID:12356741

  14. Common and Well-Documented HLA Alleles: 2012 Update to the CWD Catalogue

    PubMed Central

    Mack, Steven J.; Cano, Pedro; Hollenbach, Jill A.; He, Jun; Hurley, Carolyn Katovich; Middleton, Derek; Moraes, Maria Elisa; Pereira, Shalini E.; Kempenich, Jane H.; Reed, Elaine F.; Setterholm, Michelle; Smith, AnaJane G.; Tilanus, Marcel G.; Torres, Margareth; Varney, Michael D.; Voorter, Christien E. M.; Fischer, Gottfried F.; Fleischhauer, Katharina; Goodridge, Damian; Klitz, William; Little, Ann-Margaret; Maiers, Martin; Marsh, Steven G. E.; Mller, Carlheinz R.; Noreen, Harriet; Rozemuller, Erik H.; Sanchez-Mazas, Alicia; Senitzer, David; Trachtenberg, Elizabeth; Fernandez-Vina, Marcelo

    2013-01-01

    We have updated the catalogue of common and well-documented (CWD) HLA alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and DPB1 loci in IMGT/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being common (having known frequencies) and 707 as being well-documented on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Programs bioinformatics web pages. PMID:23510415

  15. Analysis of FBN1 allele expression by dermal fibroblasts from Marfan syndrome patients

    SciTech Connect

    Putman, E.A.; Cao, S.N.; Milewicz, D.M.

    1994-09-01

    Screening for mutations in the FBN1 cDNA from Marfan patient cell strains has detected mutations in only 10-15% of patients. In an attempt to explain this poor detection rate, we examined FBN1 allele expression and fibrillin synthesis by 26 cell strains from Marfan patients. DNA from the patients and 10 controls was assessed for the presence of a polymorphic Rsa I restriction site in the 3{prime} untranslated region of the FBN1 gene. Twelve of 26 patient and 5 of 10 control DNAs were heterozygous. Fibroblast RNA from the heterozygous cell strains was reverse-transcribed and subsequently PCR amplified using a [{sup 32}P]-labelled primer, digested with Rsa I and analyzed. Although 3 samples showed no transcript from one allele by ethidium bromide staining, a Betagen scanner detected low levels (10-15%) of that allele. In addition, there was unequal expression of the two alleles in three other patients; for example, only 30% expression from one allele. The remaining patients and the controls had equal expression of each allele. Fibrillin protein synthesis by fibroblasts from these heterozygous patients was also examined. After a 30 minute pulse with [{sup 35}S]-cysteine, cell lysates were collected and proteins analyzed by SDS-PAGE. The amount of fibrillin produced relative to a reference protein was determined using a Betagen scanner. Fibrillin protein synthesis was reduced in 2 of the 3 patients with very low RNA production from one of the FBN1 alleles. All other Marfan and control cell strains showed normal amounts of fibrillin synthesized. The low expression levels from one allele may contribute to, but not fully account for, the low detection rate of FBN1 mutations. Interestingly, protein synthesis levels were not affected in 4 of 6 cell strains demonstrating low levels of RNA expression.

  16. Gene Behavior Interaction of Depressive Symptoms and the Apolipoprotein E ?4 Allele on Cognitive Decline

    PubMed Central

    Rajan, Kumar B.; Wilson, Robert S.; Skarupski, Kimberly A.; de Leon, Carlos Mendes; Evans, Denis A.

    2014-01-01

    Objective Depressive symptoms and the APOE ?4 allele are independent risk factors for cognitive decline. However, it is not clear whether the presence of both depressive symptoms and the APOE ?4 allele increases cognitive decline. Methods A prospective study of a population-based sample of 4,150 (70% African American and 63% women) participants, aged 65 years and older, who were interviewed at 3-year intervals. Depressive symptoms were measured using the 10-item version of the Center for Epidemiologic Studies Depression scale, with each item coded as presence or absence of a symptom. The APOE genotype was ascertained by DNA samples collected during follow-up. Cognitive function was assessed at the initial and follow-up interviews (average follow-up of 9.2 years), using a standardized global cognitive score. Results There were 1405 (34%) participants with one or more copies of the APOE ?4 allele. In participants with no depressive symptoms, cognitive function decreased by 0.0412-unit per year among those with no copies and 0.0704-unit per year among those with one or more copies of the APOE ?4 allele. For each additional symptom of depression, cognitive decline increased by 0.0021-unit per year among those with no copies and 0.0051-unit per year among those with one or more copies of the APOE ?4 allele. The three-way interaction of depressive symptoms, APOE ?4 allele, and time was significant (p=0.021). Conclusions The association of depressive symptoms on cognitive decline was increased among participants with one or more copies of the APOE ?4 allele compared to those without the allele. PMID:24434953

  17. Combination of Eight Alleles at Four Quantitative Trait Loci Determines Grain Length in Rice

    PubMed Central

    Zeng, Yuxiang; Ji, Zhijuan; Wen, Zhihua; Liang, Yan; Yang, Changdeng

    2016-01-01

    Grain length is an important quantitative trait in rice (Oryza sativa L.) that influences both grain yield and exterior quality. Although many quantitative trait loci (QTLs) for grain length have been identified, it is still unclear how different alleles from different QTLs regulate grain length coordinately. To explore the mechanisms of QTL combination in the determination of grain length, five mapping populations, including two F2 populations, an F3 population, an F7 recombinant inbred line (RIL) population, and an F8 RIL population, were developed from the cross between the U.S. tropical japonica variety ‘Lemont’ and the Chinese indica variety ‘Yangdao 4’ and grown under different environmental conditions. Four QTLs (qGL-3-1, qGL-3-2, qGL-4, and qGL-7) for grain length were detected using both composite interval mapping and multiple interval mapping methods in the mapping populations. In each locus, there was an allele from one parent that increased grain length and another allele from another parent that decreased it. The eight alleles in the four QTLs were analyzed to determine whether these alleles act additively across loci, and lead to a linear relationship between the predicted breeding value of QTLs and phenotype. Linear regression analysis suggested that the combination of eight alleles determined grain length. Plants carrying more grain length-increasing alleles had longer grain length than those carrying more grain length-decreasing alleles. This trend was consistent in all five mapping populations and demonstrated the regulation of grain length by the four QTLs. Thus, these QTLs are ideal resources for modifying grain length in rice. PMID:26942914

  18. A genome-wide association study of severe teenage acne in European Americans

    PubMed Central

    Zhang, Mingfeng; Qureshi, Abrar A.; Hunter, David J.; Han, Jiali

    2013-01-01

    Despite the family aggregation of severe teenage acne, the genetic basis of this common skin condition remains unclear. We conducted a genome-wide association study (GWAS) on severe teenage acne in 928 European Americans. The SNP rs4133274 on chromosome 8q24 (72kb upstream of MYC) revealed the most significant association with severe teenage acne (p-value = 1.710?6). The variant allele of this SNP (G allele) was associated with an increased risk of severe teenage acne with odds ratio of 2.44 (95% confidence interval = 1.753.41). Upon further replication, our findings suggest new genetic basis of acne and may explain the association between acne and cancer risk observed in the epidemiological studies. PMID:24114350

  19. Europeans: an endangered species?

    PubMed

    Von Cube, A

    1986-10-01

    Below replacement fertility has become the norm in 21 of Europe's 27 countries. Their average total fertility rate is 1.69. This trend has raised concerns about insufficient numbers in the economically active population and prospective personnel shortages in the military. In the Federal Republic of Germany, fertility has been below replacement for the past 17 years and its 1985 total fertility rate of 1.28 is a record low. Only a few European countries (Bulgaria, France, and Romania) have explicitly pronatalist policies. Other nations (Belgium, Finland, Luxembourg, and the German Democratic Republic) have instituted a progressive system of child allowances, increasing payments with each additional birth. Ironically, policies that seek to promote social opportunities for women, such as participation in the labor force, are likely to reduce fertility even farther. Without increased services such as reasonably priced housing, child care centers, and economic incentives to compensate women for lost opportunity costs in the labor market, policies that seek to increase fertility will not succeed. Policy options that were once available to increase fertility (for example, prohibiting abortion) are no longer socially acceptable. New policies will have to be developed through research on the determinants of fertility behavior in postindustrial societies. PMID:12315251

  20. The distribution of HLA alleles revealed a founder effect in the geographically isolated Chinese population, Drung.

    PubMed

    Chen, Shangwu; Hu, Qingsong; Liu, Zehuan; Fu, Yonggui; Lin, Jianghai; Tao, Hong; Wu, Yuping; Xu, Anlong

    2007-03-01

    The Drung ethnic minority is one of the smallest ethnic groups of China, geographically isolated by mountains and rivers. Before 1949, Drung society maintained many vestiges of the primitive commune system. The origin and migration of the Drung and their genetic background are still unknown because of limited records about this population. Here, we for the first time demonstrated the unique distribution of HLA alleles in the Drung by high-resolution sequence-based typing (SBT) method. Number of alleles detected is obviously less than expected and only a few alleles with a high homozygosity in each locus are predominant in this minority. The characteristics of HLA allele distribution in the Drung could reflect founder effects, suggesting the Drung probably descended from very few ancestors. The statistical analysis based on allele frequencies indicated that the Drung was an isolated ethnic group, but it also provided the clue that the Drung was genetically related to Chinese southwestern ethnic groups. Significant reduced allelic diversity and genetic isolate in the Drung make it an ideal homogeneous population and very useful model to study the evolution of HLA and the origin and migration of Chinese ethnic groups. The research paved a way to elucidate the genetic background of this mysterious minority and disease predisposition. PMID:17069887

  1. Imprinting control regions (ICRs) are marked by mono-allelic bivalent chromatin when transcriptionally inactive.

    PubMed

    Maupetit-Mhouas, Stphanie; Montibus, Bertille; Nury, David; Tayama, Chiharu; Wassef, Michel; Kota, Satya K; Fogli, Anne; Cerqueira Campos, Fabiana; Hata, Kenichiro; Feil, Robert; Margueron, Raphael; Nakabayashi, Kazuhiko; Court, Franck; Arnaud, Philippe

    2016-01-29

    Parental allele-specific expression of imprinted genes is mediated by imprinting control regions (ICRs) that are constitutively marked by DNA methylation imprints on the maternal or paternal allele. Mono-allelic DNA methylation is strictly required for the process of imprinting and has to be faithfully maintained during the entire life-span. While the regulation of DNA methylation itself is well understood, the mechanisms whereby the opposite allele remains unmethylated are unclear. Here, we show that in the mouse, at maternally methylated ICRs, the paternal allele, which is constitutively associated with H3K4me2/3, is marked by default by H3K27me3 when these ICRs are transcriptionally inactive, leading to the formation of a bivalent chromatin signature. Our data suggest that at ICRs, chromatin bivalency has a protective role by ensuring that DNA on the paternal allele remains unmethylated and protected against spurious and unscheduled gene expression. Moreover, they provide the proof of concept that, beside pluripotent cells, chromatin bivalency is the default state of transcriptionally inactive CpG island promoters, regardless of the developmental stage, thereby contributing to protect cell identity. PMID:26400168

  2. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

    PubMed

    Cochran, Rory L; Cidado, Justin; Kim, Minsoo; Zabransky, Daniel J; Croessmann, Sarah; Chu, David; Wong, Hong Yuen; Beaver, Julia A; Cravero, Karen; Erlanger, Bracha; Parsons, Heather; Heaphy, Christopher M; Meeker, Alan K; Lauring, Josh; Park, Ben Ho

    2015-09-22

    Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk. PMID:26246475

  3. FcalphaRI (CD89) alleles determine the proinflammatory potential of serum IgA.

    PubMed

    Wu, Jianming; Ji, Chuanyi; Xie, Fenglong; Langefeld, Carl D; Qian, Kun; Gibson, Andrew W; Edberg, Jeffrey C; Kimberly, Robert P

    2007-03-15

    The human IgA FcR (FcalphaRI; CD89) mediates a variety of immune system functions including degranulation, endocytosis, phagocytosis, cytokine synthesis, and cytokine release. We have identified a common, nonsynonymous, single nucleotide polymorphism (SNP) in the coding region of CD89 (844A-->G) (rs16986050), which changes codon 248 from AGC (Ser(248)) to GGC (Gly(248)) in the cytoplasmic domain of the receptor. The two different alleles demonstrate significantly different FcalphaRI-mediated intracellular calcium mobilization and degranulation in rat basophilic leukemia cells and cytokine production (IL-6 and TNF-alpha) in murine macrophage P388D1 cells. In the absence of FcR gamma-chain association in P388D1 cells, the Ser(248)-FcalphaRI allele does not mediate cytokine production, but the Gly(248)-FcalphaRI allele retains the capacity to mediate a robust production of proinflammatory cytokine. This allele-dependent difference is also seen with FcalphaRI-mediated IL-6 cytokine release by human neutrophils ex vivo. These findings and the enrichment of the proinflammatory Gly(248)-FcalphaRI allele in systemic lupus erythematosus populations in two ethnic groups compared with their respective non-systemic lupus erythematosus controls suggest that FcalphaRI (CD89) alpha-chain alleles may affect receptor-mediated signaling and play an important role in the modulation of immune responses in inflammatory diseases. PMID:17339498

  4. Identification of the new HLA-DRB1{sup *}0812 allele detected by sequencing based typing

    SciTech Connect

    Versluis, L.F.; Zwan, A.W. van der; Tilanus, M.G.J.; Savelkoul, P.H.M.; Berg-Loonen, E.M. van den

    1996-12-31

    HLA-DRB typing by polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing based typing (SBT) was studied within the framework of the Antigen and Haplotype Society 11 and the Sequencing Based Typing Component of the Twelfth International HLA workshop. Sequencing was performed as described by McGinnis and co-workers in 1995 on coded samples, including most DR2 subtypes, resulting in high resolution HLA-DR typing. Sequences were compared with a database containing 107 DRB1, four DRB3, and five DRB5 alleles in a similar way as described for HLA-DPB. One sample showed a new DR8 sequence, indicating the presence of a new allele. This individual (4390) is of Indonesian origin. The specific amplification of the DR8 allele and subsequent sequencing resulted in a sequence which did not match the database and new polymorphism was identified. The complementary strand was sequenced and confirmed the presence of a new DRB1 allele. Cloning and subsequent sequencing of the polymerase chain reaction fragment resulted in confirmation of the direct sequence data. Later this variant was officially named DRB1{sup *}0812. The complete nucleotide sequence of exon 2 of this new allele is shown. This allele differs from DRB1{sup *}0810 by one nucleotide at codon 85, resulting in an alanine (GTT), whereas DRB1{sup *}0810 carries a valine (GCT). 5 refs., 1 fig.

  5. A new DRB1 allele (DRB1*0811) identified in Native Americans

    SciTech Connect

    McAuley, J.D.; Williams, T.M.; Wu, J.; Foutz, T.; Troup, G.M.

    1994-12-31

    A novel DRB1 allele was identified in a potential bone marrow transplantation recipient and her father. Both are Native Americans of Navajo descent. Class II serologic typing of the patient demonstrated the presence of DR8, DR14, DR52, and DQ3. Sequence specific polymerase chain reaction (PCR) amplification of genomic DNA was consistent with the DRB1 alleles *08 and *14. Direct DNA sequencing of PCR products prepared from genomic DNA demonstrated that the patient`s class II alleles included the novel allele, DRB1*1402, DRB3*0101, DQB1*0301, and DQB1*0402. Analysis of the siblings and the father of this individual revealed that the new allele was transmitted on the haplotype A2, Cw7, B39, DQB1*0402, while the DRB1*1402 allele was transmitted on the haplotype A24, Cw4, B35, DRB3*0101, DQB1*0301. 4 refs., 1 fig., 1 tab.

  6. In-frame single codon deletion in the Mmalton deficiency allele of alpha 1-antitrypsin.

    PubMed Central

    Fraizer, G C; Harrold, T R; Hofker, M H; Cox, D W

    1989-01-01

    A deficiency of the plasma protease inhibitor alpha 1-antitrypsin (alpha 1AT) is usually a consequence of the PI*Z allele. Mmalton is another deficiency allele which, like Z alpha 1AT, is associated with hepatocyte inclusions and impaired secretion. We report here the sequence of the PI Mmalton allele, which contains a 3-bp deletion coding for one of two adjacent phenylalanine residues (amino acid 51 or 52 of the mature protein). Using oligonucleotide hybridization of polymerase chain reaction-amplified DNA, we have demonstrated cosegregation of the PI Mmalton protein and the 3-bp deletion in the family in which this allele was originally described and in three other, unrelated kindreds. This deletion is found exclusively in PI Mmalton alleles and not in the normal M2 alleles from which, to judge on the basis of haplotype data, the Mmalton mutation must have been derived. In polyacrylamide isoelectric focusing (PIEF) gels, the isoelectric point of Mmalton is only slightly more cathodal than M2, a finding consistent with the loss of a single uncharged amino acid. To judge on the basis of X-ray crystallography data for the normal alpha 1AT protein, the deletion of aa 51/52 would shorten one strand of the beta sheet, B6, apparently preventing normal processing and secretion. Images Figure 2 Figure 3 PMID:2786335

  7. Balancing Selection at a Frog Antimicrobial Peptide Locus: Fluctuating Immune Effector Alleles?

    PubMed Central

    Blouin, Michael S.

    2008-01-01

    Balancing selection is common on many defense genes, but it has rarely been reported for immune effector proteins such as antimicrobial peptides (AMPs). We describe genetic diversity at a brevinin-1 AMP locus in three species of leopard frogs (Rana pipiens, Rana blairi, and Rana palustris). Several highly divergent allelic lineages are segregating at this locus. That this unusual pattern results from balancing selection is demonstrated by multiple lines of evidence, including a ratio of nonsynonymous/synonymous polymorphism significantly higher than 1, the ZnS test, incongruence between the number of segregating sites and haplotype diversity, and significant Tajima's D values. Our data are more consistent with a model of fluctuating selection in which alleles change frequencies over time than with a model of stable balancing selection such as overdominance. Evidence for fluctuating selection includes skewed allele frequencies, low levels of synonymous variation, nonneutral values of Tajima's D within allelic lineages, an inverse relationship between the frequency of an allelic lineage and its degree of polymorphism, and divergent allele frequencies among populations. AMP loci could be important sites of adaptive genetic diversity, with consequences for hostpathogen coevolution and the ability of species to resist disease epidemics. PMID:18799711

  8. Cytokine SNPs: Comparison of Allele Frequencies by Race & Implications for Future Studies

    PubMed Central

    Van Dyke, Alison L.; Cote, Michele L.; Wenzlaff, Angie S.; Land, Susan; Schwartz, Ann G.

    2009-01-01

    The role of inflammation is being considered in chronic diseases. Previous studies have examined SNPs in a few key inflammatory genes and have included small numbers of African American participants. Variation in the frequencies of inflammatory pathway SNPs may help to explain racial disparities in disease risk. Through a population-based study of 103 African American and 380 Caucasian unrelated, healthy women, we examined the relationships between race and allele frequencies of 70 cytokine and cytokine receptor SNPs. The associations between genotypic and haplotype frequencies and race were also analyzed. Allelic frequencies for 52 out of the 70 SNPs meeting criteria for analysis differed significantly by race. Of the 32 pro-inflammatory and 20 anti-inflammatory SNPs for which the allele frequencies varied significantly by race, variant allele frequency differences between Caucasians and African Americans ranged between 6%37% and 7%53% for pro-inflammatory SNPs and anti-inflammatory SNPs, respectively. Our findings suggest that while allele frequencies do vary by race, racial groups are not simplistically represented by a pro-inflammatory or anti-inflammatory genetic profile. Given the racial variability in allele frequencies in inflammatory gene SNPs, studies examining the association between these SNPs and disease should at least incorporate self-reported race in their analyses. PMID:19356949

  9. Long-term persistence of crop alleles in weedy populations of wild radish (Raphanus raphanistrum).

    PubMed

    Snow, A A; Culley, T M; Campbell, L G; Sweeney, P M; Hegde, S G; Ellstrand, N C

    2010-04-01

    *Hybridization allows transgenes and other crop alleles to spread to wild/weedy populations of related taxa. Researchers have debated whether such alleles will persist because low hybrid fitness and linkage to domestication traits could severely impede introgression. *To examine variation in the fates of three unlinked crop alleles, we monitored four experimental, self-seeding, hybrid populations of Raphanus raphanistrum x Raphanus sativus (radish) in Michigan, USA, over a decade. We also compared the fecundity of advanced-generation hybrid plants with wild plants in a common garden experiment. *Initially, F(1) hybrids had reduced fitness, but the populations quickly evolved wild-type pollen fertility. In Year 10, the fecundity of plants from the experimental populations was similar to that of wild genotypes. Crop-specific alleles at the three loci persisted for 10 yr in all populations, and their frequencies varied among loci, populations and years. *This research provides a unique case study of substantial variation in the rates and patterns of crop allele introgression after a single hybridization event. Our findings demonstrate that certain crop alleles can introgress easily while others remain rare, supporting the assumption that neutral or beneficial transgenes that are not linked to maladaptive traits can persist in the wild. PMID:20122132

  10. Imprinting control regions (ICRs) are marked by mono-allelic bivalent chromatin when transcriptionally inactive

    PubMed Central

    Maupetit-Méhouas, Stéphanie; Montibus, Bertille; Nury, David; Tayama, Chiharu; Wassef, Michel; Kota, Satya K.; Fogli, Anne; Cerqueira Campos, Fabiana; Hata, Kenichiro; Feil, Robert; Margueron, Raphael; Nakabayashi, Kazuhiko; Court, Franck; Arnaud, Philippe

    2016-01-01

    Parental allele-specific expression of imprinted genes is mediated by imprinting control regions (ICRs) that are constitutively marked by DNA methylation imprints on the maternal or paternal allele. Mono-allelic DNA methylation is strictly required for the process of imprinting and has to be faithfully maintained during the entire life-span. While the regulation of DNA methylation itself is well understood, the mechanisms whereby the opposite allele remains unmethylated are unclear. Here, we show that in the mouse, at maternally methylated ICRs, the paternal allele, which is constitutively associated with H3K4me2/3, is marked by default by H3K27me3 when these ICRs are transcriptionally inactive, leading to the formation of a bivalent chromatin signature. Our data suggest that at ICRs, chromatin bivalency has a protective role by ensuring that DNA on the paternal allele remains unmethylated and protected against spurious and unscheduled gene expression. Moreover, they provide the proof of concept that, beside pluripotent cells, chromatin bivalency is the default state of transcriptionally inactive CpG island promoters, regardless of the developmental stage, thereby contributing to protect cell identity. PMID:26400168

  11. Natural selection for the Duffy-null allele in the recently admixed people of Madagascar

    PubMed Central

    Hodgson, Jason A.; Pickrell, Joseph K.; Pearson, Laurel N.; Quillen, Ellen E.; Prista, Antnio; Rocha, Jorge; Soodyall, Himla; Shriver, Mark D.; Perry, George H.

    2014-01-01

    While gene flow between distantly related populations is increasingly recognized as a potentially important source of adaptive genetic variation for humans, fully characterized examples are rare. In addition, the role that natural selection for resistance to vivax malaria may have played in the extreme distribution of the protective Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, is controversial. We address both these issues by investigating the evolution of the Duffy-null allele in the Malagasy, a recently admixed population with major ancestry components from both East Asia and mainland sub-Saharan Africa. We used genome-wide genetic data and extensive computer simulations to show that the high frequency of the Duffy-null allele in Madagascar can only be explained in the absence of positive natural selection under extreme demographic scenarios involving high genetic drift. However, the observed genomic single nucleotide polymorphism diversity in the Malagasy is incompatible with such extreme demographic scenarios, indicating that positive selection for the Duffy-null allele best explains the high frequency of the allele in Madagascar. We estimate the selection coefficient to be 0.066. Because vivax malaria is endemic to Madagascar, this result supports the hypothesis that malaria resistance drove fixation of the Duffy-null allele in mainland sub-Saharan Africa. PMID:24990677

  12. Structural and functional distinctiveness of HLA-A2 allelic variants.

    PubMed

    Chen, Kenneth Yuanxiang; Liu, Jingxian; Ren, Ee Chee

    2012-09-01

    Human leukocyte antigen (HLA) class I molecules are involved in the presentation of antigenic peptides to CD8(+) cytotoxic T lymphocytes (CTLs), which is important for the development of cellular immunity during viral infections and in cancers. HLA-A2 is one of the most frequent HLA class I specificities and thus is extensively studied structurally and functionally. Since its discovery, more than 300 allelic variants of this HLA specificity have been recorded. Among the HLA-A2 allelic variants, HLA-A*02:01 is the most prevalent, hence commonly used as a model to study HLA-A2-restricted CTL responses. However, HLA-A2 alleles are unevenly distributed globally such that HLA-A2 allelic variants besides A*02:01 are expressed at considerably high frequencies in Asian and African populations. Furthermore, increasing evidence of variations in the peptide-binding repertoire and CTL responses among HLA-A2 allelic variants suggests the need to understand these differences among various frequently expressed HLA-A2 molecules. In this review, the structural and functional distinctiveness of HLA-A2 allelic variants will be discussed. PMID:22434516

  13. Activation of the Arabidopsis thaliana immune system by combinations of common ACD6 alleles.

    PubMed

    Todesco, Marco; Kim, Sang-Tae; Chae, Eunyoung; Bomblies, Kirsten; Zaidem, Maricris; Smith, Lisa M; Weigel, Detlef; Laitinen, Roosa A E

    2014-07-01

    A fundamental question in biology is how multicellular organisms distinguish self and non-self. The ability to make this distinction allows animals and plants to detect and respond to pathogens without triggering immune reactions directed against their own cells. In plants, inappropriate self-recognition results in the autonomous activation of the immune system, causing affected individuals to grow less well. These plants also suffer from spontaneous cell death, but are at the same time more resistant to pathogens. Known causes for such autonomous activation of the immune system are hyperactive alleles of immune regulators, or epistatic interactions between immune regulators and unlinked genes. We have discovered a third class, in which the Arabidopsis thaliana immune system is activated by interactions between natural alleles at a single locus, ACCELERATED CELL DEATH 6 (ACD6). There are two main types of these interacting alleles, one of which has evolved recently by partial resurrection of a pseudogene, and each type includes multiple functional variants. Most previously studies hybrid necrosis cases involve rare alleles found in geographically unrelated populations. These two types of ACD6 alleles instead occur at low frequency throughout the range of the species, and have risen to high frequency in the Northeast of Spain, suggesting a role in local adaptation. In addition, such hybrids occur in these populations in the wild. The extensive functional variation among ACD6 alleles points to a central role of this locus in fine-tuning pathogen defenses in natural populations. PMID:25010663

  14. Natural selection for the Duffy-null allele in the recently admixed people of Madagascar.

    PubMed

    Hodgson, Jason A; Pickrell, Joseph K; Pearson, Laurel N; Quillen, Ellen E; Prista, António; Rocha, Jorge; Soodyall, Himla; Shriver, Mark D; Perry, George H

    2014-08-22

    While gene flow between distantly related populations is increasingly recognized as a potentially important source of adaptive genetic variation for humans, fully characterized examples are rare. In addition, the role that natural selection for resistance to vivax malaria may have played in the extreme distribution of the protective Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, is controversial. We address both these issues by investigating the evolution of the Duffy-null allele in the Malagasy, a recently admixed population with major ancestry components from both East Asia and mainland sub-Saharan Africa. We used genome-wide genetic data and extensive computer simulations to show that the high frequency of the Duffy-null allele in Madagascar can only be explained in the absence of positive natural selection under extreme demographic scenarios involving high genetic drift. However, the observed genomic single nucleotide polymorphism diversity in the Malagasy is incompatible with such extreme demographic scenarios, indicating that positive selection for the Duffy-null allele best explains the high frequency of the allele in Madagascar. We estimate the selection coefficient to be 0.066. Because vivax malaria is endemic to Madagascar, this result supports the hypothesis that malaria resistance drove fixation of the Duffy-null allele in mainland sub-Saharan Africa. PMID:24990677

  15. Impact of the Mdm2(SNP309-G) allele on a murine model of colorectal cancer.

    PubMed

    Zhang, X; Pageon, L; Post, S M

    2015-08-13

    A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2(SNP309-G)) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case-control studies indicate the Mdm2(SNP309-)(G) allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2(SNP309-)(G) allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2(SNP309-G/G) mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2(SNP309-G/G) colons had significant changes in the expression of genes that regulate Mdm2 transcription (ER? and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2(SNP309-)(G) allele significantly impacts CRC through mechanisms outside the p53 pathway. PMID:25435368

  16. S-genotype identification based on allele-specific PCR in Japanese pear

    PubMed Central

    Nashima, Kenji; Terakami, Shingo; Nishio, Sogo; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Yamamoto, Toshiya

    2015-01-01

    Gametophytic self-incompatibility in Japanese pear (Pyrus pyrifolia Nakai) is controlled by the single, multi-allelic S-locus. Information about the S-genotypes is important for breeding and the selection of pollen donors for fruit production. Rapid and reliable S-genotype identification system is necessary for efficient breeding of new cultivars in Japanese pear. We designed S allele-specific PCR primer pairs for ten previously reported S-RNase alleles (S1S9 and Sk) as simple and reliable method. Specific nucleotide sequences were chosen to design the primers to amplify fragments of only the corresponding S alleles. The developed primer pairs were evaluated by using homozygous S-genotypes (S1/S1S9/S9 and S4sm/S4sm) and 14 major Japanese pear cultivars, and found that S allele-specific primer pairs can identify S-genotypes effectively. The S allele-specific primer pairs developed in this study will be useful for efficient S-genotyping and for marker-assisted selection in Japanese pear breeding programs. PMID:26175617

  17. Allelic diversity and molecular characterization of puroindoline genes in five diploid species of the Aegilops genus.

    PubMed

    Cuesta, Susana; Guzmn, Carlos; Alvarez, Juan B

    2013-11-01

    Grain hardness is an important quality trait in wheat. This trait is related to the variation in, and the presence of, puroindolines (PINA and PINB). This variation can be increased by the allelic polymorphism present in the Aegilops species that are related to wheat. This study evaluated allelic Pina and Pinb gene variability in five diploid species of the Aegilops genus, along with the molecular characterization of the main allelic variants found in each species. This polymorphism resulted in 16 alleles for the Pina gene and 24 alleles for the Pinb gene, of which 10 and 17, respectively, were novel. Diverse mutations were detected in the deduced mature proteins of these alleles, which could influence the hardness characteristics of these proteins. This study shows that the diploid species of the Aegilops genus could be a good source of genetic variability for both Pina and Pinb genes, which could be used in breeding programmes to extend the range of different textures in wheat. PMID:24058161

  18. Interspecific Backcross Mice Show Sex-Specific Differences in Allelic Inheritance

    PubMed Central

    Siracusa, L. D.; Alvord, W. G.; Bickmore, W. A.; Jenkins, N. A.; Copeland, N. G.

    1991-01-01

    Transmission distortion is identified as a difference in transmission frequency of two alleles from the normal 1:1 Mendelian segregation in diploid organisms. Transmission distortion can extend over part or all of a chromosome. The recent development of interspecific mouse backcrosses has provided a powerful method for multilocus mapping of entire chromosomes in a single cross, and consequently for identifying distortions in allelic inheritance. We used an interspecific backcross of [(C57BL/6J X Mus spretus)F(1) X C57BL/6J] mice to map molecular loci to mouse chromosome 2 and had previously found that the distal region of the chromosome showed distortions in allelic inheritance. We now report the mapping of five loci (Actc-1, D2Hgu1, His-1, Hox-4.1 and Neb) to chromosome 2, which, in addition to the Abl, Ada, B2m, Bmp-2a, Hc, Emv-15, Fshb, Hck-1, Pax-1, Pck-1, Spna-2 and Vim loci previously mapped in our interspecific backcross, serve as markers to measure allelic inheritance along ~75% of mouse chromosome 2. Statistical analyses are used to identify and delimit chromosomal regions showing transmission distortion and to determine whether there are sex-specific differences in allelic inheritance. These studies provide evidence for sex-specific differences in allelic inheritance for chromosome 2 and suggest biological explanations for this form of transmission distortion. PMID:1916246

  19. Isolation of two alleles of the b locus of Ustilago maydis.

    PubMed

    Kronstad, J W; Leong, S A

    1989-02-01

    The basidiomycete Ustilago maydis is the causative agent of the disease corn smut. To be pathogenic, strains of U. maydis must be heterozygous for a locus called "b," which appears to control both pathogenicity and sexual development. Two alleles of the b locus of U. maydis were isolated by complementation and hybridization. The clones have the specificities of b1 and b2 alleles as demonstrated by their effects on the colony morphology and pathogenicity of haploid and diploid strains upon transformation. For example, nonpathogenic haploid and diploid strains of U. maydis carrying b2 alleles became pathogenic when transformed with the cloned b1 allele. Furthermore, an a2 b2 haploid strain could be transformed to an a2 b1 genotype by gene replacement using a DNA fragment containing a b1 allele and a selectable marker. The isolation of b alleles represents an important step toward understanding the control of dicaryon formation, dicaryon maintenance, and pathogenicity in U. maydis. PMID:2915990

  20. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes

    PubMed Central

    Cochran, Rory L.; Cidado, Justin; Kim, Minsoo; Zabransky, Daniel J.; Croessmann, Sarah; Chu, David; Wong, Hong Yuen; Beaver, Julia A.; Cravero, Karen; Erlanger, Bracha; Parsons, Heather; Heaphy, Christopher M.; Meeker, Alan K.; Lauring, Josh; Park, Ben Ho

    2015-01-01

    Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk. PMID:26246475

  1. Multiple and independent origins of short seeded alleles of GS3 in rice

    PubMed Central

    Takano-Kai, Noriko; Jiang, Hui; Powell, Adrian; McCouch, Susan; Takamure, Itsuro; Furuya, Naruto; Doi, Kazuyuki; Yoshimura, Atsushi

    2013-01-01

    GRAIN SIZE 3 (GS3) is a cloned gene that is related to seed length. Here we report the discovery of new deletion alleles at the GS3 locus, each of which confer short seed. We selected ten short seeded cultivars from a collection of 282 diverse cultivars. Sequence analysis across the GS3 gene in these ten cultivars identified three novel alleles and a known allele that contain several independent deletion(s) in the fifth exon of GS. These independent deletion variants each resulted in a frameshift mutation that caused a premature stop codon, and they were functionally similar to one another. Each coded for a truncated gene product that behaved as an incomplete dominant allele and conferred a short seeded phenotype. Haplotype analysis of these sequence variants indicated that two of the variants were of japonica origin, and two were from indica. Transformation experiments demonstrated that one of the deletion alleles of GS3 decrease the cell number in the upper epidermis of the glume, resulting in a significant reduction in seed length. The multiple and independent origins of these short seeded alleles indicate that farmers and early breeders imposed artificial selection favoring short seeds. PMID:23641184

  2. Apolipoprotein E ?4 allele and malondialdehyde level are independent risk factors for Alzheimers disease

    PubMed Central

    Lpez-Riquelme, Natividad; Alom-Poveda, Jordi; Viciano-Morote, Nuria; Llinares-Ibor, Isabel; Tormo-Daz, Consuelo

    2016-01-01

    Background: The ?4 allele of Apolipoprotein E is involved in lipid metabolism. Oxidative stress produces an increase in lipid peroxidation that has been implicated in the pathogenic cascade in Alzheimers disease. This study estimated the effect of the ?4 allele, malondialdehyde and lipid levels on the risk for Alzheimers disease. Methods: A total of 41 control subjects and 73 patients with Alzheimers disease were recruited. The Apolipoprotein E genotype was determined by amplification of exon 4 of the Apolipoprotein E by polymerase chain reaction?(PCR); malondialdehyde concentration was determined by high-pressure liquid chromatography, and serum lipids were measured by routine photometric techniques. Results: Malondialdehyde levels were significantly higher in Alzheimers disease patients independent of the Apolipoprotein E genotype and ?4 allele. The ?4 allele increases the risk of Alzheimers disease by 5.114 times and elevated malondialdehyde levels increase the risk by 9.342. Conclusion: The presence of ?4 allele and elevated malondialdehyde levels are independent risk factors for Alzheimers disease. These findings support the hypothesis that lipid peroxidation and ?4 allele contribute to the pathogenic cascade in Alzheimers disease by different pathways. PMID:26835020

  3. Frequencies of HK?? and anti-HK?? Alleles in Chinese Carriers of Silent Deletional ?-Thalassemia.

    PubMed

    Wu, Man-Yu; Li, Jian; Li, Shu-Chen; Li, Yan; Li, Dong-Zhi

    2015-12-01

    The HK?? (HongKong??) allele is an unusual rearrangement of the ?-globin gene cluster containing both the -?(3.7) (rightward) and ???(anti 4.2) crossover deletion/duplication. The anti-HK?? (anti-HongKong??) allele is the reciprocal product containing both the -?(4.2) (leftward) and ???(anti 3.7) unequal crossover deletion/duplication. In clinical practice of thalassemia screening, gap-polymerase chain reaction (gap-PCR) approaches are used to detect the common -?(3.7) and -?(4.2) deletions of ?-thalassemia (?-thal). Because the HK?? and anti-HK?? alleles also contain the single ?-globin gene deletion, individuals with these alleles would be misdiagnosed as -?(3.7) or -?(4.2) carriers. This would likely produce misleading or incorrect information in genetic counseling. In this study, we investigated the HK?? and anti-HK?? alleles in Chinese carriers of silent deletional ?-thal, and reported their frequencies to be 2.27 and 0.35% in -?(3.7) and -?(4.2) carriers, respectively. Given the rarity of the HK?? and anti-HK?? alleles, a routine screening for these two rearrangements are unlikely to be necessary on most occasions. PMID:26287669

  4. Association of DLA-DQB1 alleles with exocrine pancreatic insufficiency in Pembroke Welsh Corgis.

    PubMed

    Evans, J M; Tsai, K L; Starr-Moss, A N; Steiner, J M; Clark, L A

    2015-08-01

    Exocrine pancreatic insufficiency (EPI) is a digestive disorder resulting from the insufficient secretion of enzymes from the pancreas. In dogs, this condition is often attributed to pancreatic acinar atrophy, wherein the enzyme-producing acinar cells are believed to be destroyed through an autoimmune process. Although EPI affects many diverse breeds, to date, molecular studies have been limited to the German Shepherd dog. A recent study of major histocompatibility genes in diseased and healthy German Shepherd dogs identified both risk and protective haplotypes. Herein, we genotyped DLA-DQB1 in Pembroke Welsh Corgis to determine whether dog leukocyte antigen alleles contribute to the pathogenesis of EPI across dog breeds. We evaluated 14 affected and 43 control Pembroke Welsh Corgis, which were selected based on an age of onset similar to German Shepherd dogs. We identified one protective allele (odds ratio = 0.13, P-value = 0.044) and one risk allele (odds ratio = 3.8, P-value = 0.047). As in German Shepherd dogs, the risk allele is a duplication of DLA-DQB1 (alleles DQB1*013:03 and 017:01); however, Pembroke Welsh Corgis have acquired a single polymorphism on DQB1*017:01. Thus, the DLA-DQB1 duplication is a risk allele for EPI in at least two breeds. PMID:26095904

  5. Grouping of class I HLA alleles using electrostatic distribution maps of the peptide binding grooves.

    PubMed

    Kangueane, Pandjassarame; Sakharkar, Meena Kishore

    2007-01-01

    Human leukocyte antigen (HLA) molecules involved in immune function by binding to short peptides (8-20 residues) have different sequences in different individuals belonging to distinct ethnic population. Hence, the peptide-binding function of HLA alleles is specific. Class I HLA alleles (alternative forms of a gene) are associated with CD8+ T cells, and their allele-specific sequence information is available at the IMGT/HLA database. The available sequences are one-dimensional (ID), and the peptide-binding functional inference often requires 3-dimensional (3D) structural models of respective alleles. Hence, 3D structures were constructed for 1,000 class I HLA alleles (310 A, 570 B, and 120 C) using MODELLER (a comparative protein modeling program for modeling protein structures). The electrostatic distribution maps were generated for each modeled structure using Deep View (Swiss PDB Viewer Version 3.7). The 1,000 models were then grouped into different categories by visual inspection of their electrostatic distribution maps in the peptide binding grooves. The distribution of the models based on electrostatic distribution was 30% negative (300), 1% positive (12), 8% neutral (84), and 60% (604) mixed (random mixture of negative, positive, and neutral). This grouping provides insight toward the inference for functional overlap among HLA alleles. PMID:18450000

  6. Self-incompatibility of Prunus tenella and evidence that reproductively isolated species of Prunus have different SFB alleles coupled with an identical S-RNase allele.

    PubMed

    Surbanovski, Nada; Tobutt, Kenneth R; Konstantinovi?, Miroslav; Maksimovi?, Vesna; Sargent, Daniel J; Stevanovi?, Vladimir; Boskovi?, Radovan I

    2007-05-01

    Many species of Prunus display an S-RNase-based gametophytic self-incompatibility (SI), controlled by a single highly polymorphic multigene complex termed the S-locus. This comprises tightly linked stylar- and pollen-expressed genes that determine the specificity of the SI response. We investigated SI of Prunus tenella, a wild species found in small, isolated populations on the Balkan peninsula, initially by pollination experiments and identifying stylar-expressed RNase alleles. Nine P. tenella S-RNase alleles (S(1)-S(9)) were cloned; their sequence analysis showed a very high ratio of non-synonymous to synonymous nucleotide substitutions (K(a)/K(s)) and revealed that S-RNase alleles of P. tenella, unlike those of Prunus dulcis, show positive selection in all regions except the conserved regions and that between C2 and RHV. Remarkably, S(8)-RNase, was found to be identical to S(1)-RNase from Prunus avium, a species that does not interbreed with P. tenella and, except for just one amino acid, to S(11) of P. dulcis. However, the corresponding introns and S-RNase-SFB intergenic regions showed considerable differences. Moreover, protein sequences of the pollen-expressed SFB alleles were not identical, harbouring 12 amino-acid replacements between those of P. tenella SFB(8) and P. avium SFB(1). Implications of this finding for hypotheses about the evolution of new S-specificities are discussed. PMID:17461794

  7. Distribution of HLA-DQA1 alleles in Arab and Pakistani individuals from Dubai, United Arab Emirates.

    PubMed

    Tahir, M A; al Khayat, A Q; al Shamali, F; Budowle, B; Novick, G E

    1997-03-14

    PCR-based typing of the HLA-DQA1 locus, using allele specific oligonucleotide (ASO) probes and reverse dot blot methodology was used to determine allelic distributions and construct a database for Arab and Pakistani individuals living in Dubai. Genotype and allelic frequencies were calculated, and the data were tested for departures from Hardy-Weinberg (HWE) equilibrium. The most frequent HLA-DQA1 alleles among Dubaian Arabs are DQA1 4 and 1.2. Among Pakistanis, the most frequent allele is also DQA1 4. No significant deviations from HWE were detected. PMID:9149406

  8. Genetic diversity comparison of the DQA gene in European rabbit (Oryctolagus cuniculus) populations.

    PubMed

    Magalhes, Vanessa; Abrantes, Joana; Munz-Pajares, Antonio Jess; Esteves, Pedro J

    2015-10-01

    The European rabbit (Oryctolagus cuniculus) natural populations within the species native region, the Iberian Peninsula, are considered a reservoir of genetic diversity. Indeed, the Iberia was a Pleistocene refuge to the species and currently two subspecies are found in the peninsula (Oryctolagus cuniculus cuniculus and Oryctolagus cuniculus algirus). The genes of the major histocompatibility complex (MHC) have been substantially studied in wild populations due to their exceptional variability, believed to be pathogen driven. They play an important function as part of the adaptive immune system affecting the individual fitness and population viability. In this study, the MHC variability was assessed by analysing the exon 2 of the DQA gene in several European rabbit populations from Portugal, Spain and France and in domestic breeds. Twenty-eight DQA alleles were detected, among which 18 are described for the first time. The Iberian rabbit populations are well differentiated from the French population and domestic breeds. The Iberian populations retained the higher allelic diversity with the domestic breeds harbouring the lowest; in contrast, the DQA nucleotide diversity was higher in the French population. Signatures of positive selection were detected in four codons which are putative peptide-binding sites and have been previously detected in other mammals. The evolutionary relationships showed instances of trans-species polymorphism. Overall, our results suggest that the DQA in European rabbits is evolving under selection and genetic drift. PMID:26307416

  9. The ROP18 and ROP5 gene allele types are highly predictive of virulence in mice across globally distributed strains of Toxoplasma gondii.

    PubMed

    Shwab, Elliot Keats; Jiang, Tiantian; Pena, Hilda F J; Gennari, Solange M; Dubey, Jitender P; Su, Chunlei

    2016-02-01

    The protozoan parasite Toxoplasma gondii is one of the most successful known eukaryotic pathogens on Earth. Virulence of T. gondii strains varies greatly in mice, and mounting evidence suggests that such variations may be relevant to the manifestation of human toxoplasmosis. Polymorphic rhoptry-secreted kinases and pseudokinases (ROP) have been demonstrated to account for murine virulence among the archetypal clonal parasite lineages that dominate the populations of North America and Europe. However, the distribution of virulence gene alleles in natural populations and the broad influence of these allele combinations on T. gondii virulence have not been examined in depth. In the present study, we performed PCR-RFLP genotyping analysis on a diverse array of globally distributed T. gondii strains at four ROP gene loci including ROP18, ROP5, ROP16 and ROP17 that were previously implicated in influencing T. gondii virulence and pathogenesis. We demonstrated through correlation with published virulence data that the combination of ROP18 and ROP5 allele types is highly predictive of T. gondii virulence across a broad range of global T. gondii isolates. These findings indicate that the importance of ROP18 and ROP5 in determining strain virulence is not limited to the North American/European archetypal lineages most commonly used in molecular studies, but also appears to apply to diverse isolates from South/central America and Asia. Restriction fragment length polymorphism analysis of these loci may thus serve as a valuable tool in determining the potential virulence of uncharacterized T. gondii strains in future studies. PMID:26699401

  10. The ADA*2 allele of the adenosine deaminase gene (20q13.11) and recurrent spontaneous abortions: an age-dependent association

    PubMed Central

    Nunes, Daniela Prudente Teixeira; Spegiorin, Lígia Cosentino Junqueira Franco; de Mattos, Cinara Cássia Brandão; Oliani, Antonio Helio; Vaz-Oliani, Denise Cristina Mós; de Mattos, Luiz Carlos

    2011-01-01

    OBJECTIVE: Adenosine deaminase acts on adenosine and deoxyadenosine metabolism and modulates the immune response. The adenosine deaminase G22A polymorphism (20q.11.33) influences the level of adenosine deaminase enzyme expression, which seems to play a key role in maintaining pregnancy. The adenosine deaminase 2 phenotype has been associated with a protective effect against recurrent spontaneous abortions in European Caucasian women. The aim of this study was to investigate whether the G22A polymorphism of the adenosine deaminase gene is associated with recurrent spontaneous abortions in Brazilian women. METHODS: A total of 311 women were recruited to form two groups: G1, with a history of recurrent spontaneous abortions (N = 129), and G2, without a history of abortions (N = 182). Genomic DNA was extracted from peripheral blood with a commercial kit and PCR-RFLP analysis was used to identify the G22A genetic polymorphism. Fisher's exact test and odds ratio values were used to compare the proportions of adenosine deaminase genotypes and alleles between women with and without a history of recurrent spontaneous abortion (p<0.05). The differences between mean values for categorical data were calculated using unpaired t tests. The Hardy-Weinberg equilibrium was assessed with a chi-square test. RESULTS: Statistically significant differences were identified for the frequencies of adenosine deaminase genotypes and alleles between the G1 and G2 groups when adjusted for maternal age. CONCLUSIONS: The results suggest that the adenosine deaminase *2 allele is associated with a low risk for recurrent spontaneous abortions, but this association is dependent on older age. PMID:22086524

  11. Immunogenetics of three novel HLA-Class II alleles: DRB1*03:112, DQB1*03:02:16 and DQB1*03:139.

    PubMed

    Street, J; Johnson, J; Lemin, A J; Harvey, C; Darke, C

    2016-02-01

    Three novel HLA-Class II alleles, DRB1*03:112, DQB1*03:02:16 and DQB1*03:139, are described with predicted bearing haplotypes of A*02:01, B*40:01, C*03:04, DRB1*03:112, DQB1*02:01; A*23:01, B*15:01, C*03:03, DRB1*04:01, DQB1*03:02:16 andA*01:01, B*44:02, C*05:01/03, DRB1*04:01, DQB1*03:139. Serological tests showed that the DRB1*03:112 and DQB1*03:139 specificities failed to react as expected with some well-documented monoclonal antibodies. Subsequent examination of published HLA-Class II epitopes and inspection of amino acid motifs suggested that epitopes exist that include the positions of their single substitutions (F31C between DRB1*03:01:01:01 and DRB1*03:112, and R48P between DQB1*03:01:01:01 and DQB1*03:139 specificities). This suggests that the reactivity of the monoclonal antibodies used was dependent on these epitopes and that their loss from these rare allele products resulted in their aberrant serology. The new alleles were found after the sequence-based typing of 32530 random UK European routine blood donors suggesting that each has a maximum carriage frequency of 0.0031% in the blood donor population resident in Wales. PMID:26684212

  12. FRIGIDA LIKE 2 Is a Functional Allele in Landsberg erecta and Compensates for a Nonsense Allele of FRIGIDA LIKE 11[W][OA

    PubMed Central

    Schlppi, Michael R.

    2006-01-01

    The Landsberg erecta (Ler) accession of Arabidopsis (Arabidopsis thaliana) has a weak allele of the floral inhibitor FLOWERING LOCUS C (FLC). FLC-Ler is weakly up-regulated by the active San Feliu-2 (Sf2) allele of FRIGIDA (FRI-Sf2), resulting in a moderately late-flowering phenotype. By contrast, the Columbia (Col) allele of FLC is strongly up-regulated by FRI-Sf2, resulting in a very late-flowering phenotype. In Col, the FRI-related gene FRI LIKE 1 (FRL1) is required for FRI-mediated up-regulation of FLC. It is shown here that in Ler, the FRL1-related gene FRI LIKE 2 (FRL2), but not FRL1, is required for FRI-mediated up-regulation of FLC. FRL1-Ler is shown to be a nonsense allele of FRL1 due to a naturally occurring premature stop codon in the middle of the conceptual protein sequence, suggesting that FRL1-Ler is nonfunctional. Compared to FRL2-Col, FRL2-Ler has two amino acid changes in the conceptual protein sequence. Plants homozygous for FRI-Sf2, FLC-Ler, FRL1-Ler, and FRL2-Col have no detectable FLC expression, resulting in an extremely early flowering phenotype. Transformation of a genomic fragment of FRL2-Ler, but not of FRL2-Col, into a recombinant inbred line derived from these plants restores both FRI-mediated up-regulation of FLC expression and a late-flowering phenotype, indicating that FRL2-Ler is the functional allele of FRL2. Taken together, these results suggest that in the two different Arabidopsis accessions Col and Ler, either FRL1 or FRL2, but not both, is functional and required for FRI-mediated up-regulation of FLC. PMID:17056759

  13. DIIIa and DIII Type 5 are encoded by the same allele and are associated with altered RHCE*ce alleles: clinical implications

    PubMed Central

    Westhoff, Connie M.; Vege, Sunitha; Halter-Hipsky, Christine; Whorley, Trina; Hue-Roye, Kim; Lomas-Francis, Christine; Reid, Marion E.

    2010-01-01

    BACKGROUND The partial D phenotype DIIIa was originally reported to be associated with 455A>C in Exon 3, 602C>G in Exon 4, and 667T>G in Exon 5. Other alleles with these changes were subsequently identified and designated DIII Types 5, 6, and 7, as they had additional alterations. The observation that DNA samples associated with the DIIIa phenotype had more changes than those originally reported motivated us to reanalyze the DIIIa probands (BP and DJ) from the original study. We also studied additional DIIIa samples to clarify the RHD background and establish the associated RHCE. STUDY DESIGN AND METHODS Hemagglutination testing was performed by standard methods. RHD and RHCE were analyzed by combinations of polymerase chain reactionrestriction fragment length polymorphism, exon-specific sequencing, cloning, or direct sequencing of Rh-cDNAs. RESULTS The RHD alleles from BP, DJ, and 58 additional DIIIa samples had the three reported nucleotide changes as well as 186G>T, 410C>T, and 819G>A. The DIIIa allele was associated with several altered RHCE*ce-alleles, the prominent one being ceS (48C, 733G, 1006T). CONCLUSION The DIIIa phenotype is associated with six RHD changes, five of which encode amino acid changes, and partial DIIIa and DIII Type 5 are encoded by the same RHD allele. In all samples, RHD*DIIIa was inherited with altered RHCE*ce. Patients with partial DIIIa are at risk for production of alloanti-D, but they are also at risk for alloanti-e, -c, or antibodies to high-prevalence Rh antigens if there is no conventional RHCE*ce in trans. Among 39 patients studied, 16 had alloanti-D and 27 had alloanti-e or anti-hrB. PMID:20088832

  14. Structure of the gene for the F allele of complement receptor type 1 and sequence of the coding region unique to the S allele

    SciTech Connect

    Vik, D.P. ); Wong, W.W. )

    1993-12-01

    The genes for human complement receptor type 1 (CR1) F and S alleles have been cloned and span a region of 133-160 kb on chromosome 1. The F allele was found to comprise 39 exons and the S allele contain and additional 8 exons. The leader sequence and 5[prime]-untranslated region are contained in one exon. Each of the long homologous repeats (LHR), which contain seven short consensus repeats (SCR), is composed of 8 exons. Within a LHR, SCR 1,5, and 7 are each encoded by a single exon, SCR 2 and 6 are each encoded by 2 exons, and a single exon codes for SCR 3 and 4. The transmembrane region is encoded by 2 exons and the cytoplasmic domain and the 3[prime]-untranslated regions are coded for by separate exons. The sequences of the eight S allele-specific exons were very similar to those from LHR-A and -B, as was predicted by comparison of the genomic restriction maps. It had previously been suggested that the alleles of CR1 have arisen by a mechanism of unequal crossover. A comparison of intron sequences from LHR-A, -B, -C indicated that the crossover event between LHR-A and -C that gave rise to LHR-B probably occurred within the fourth exon of these LHR. Likewise, the crossover event between LHR-A and -B that produced LHR-S probably occurred within a 383 bp region around the sixth exon. Analysis of RNA from peripheral blood cells by the S1 nuclease assay indicated that the transcription start site is 111 bp upstream of the translation initiation codon ATG. The 5[prime] rapid amplification of cDNA ends confirmed this position as a transcription start site and revealed another possible start site 29 bp further upstream. 46 refs., 7 figs., 3 tabs.

  15. Microevolution of S-allele frequencies in wild cherry populations: respective impacts of negative frequency dependent selection and genetic drift.

    PubMed

    Stoeckel, Solenn; Klein, Etienne K; Oddou-Muratorio, Sylvie; Musch, Brigitte; Mariette, Stphanie

    2012-02-01

    Negative frequency dependent selection (NFDS) is supposed to be the main force controlling allele evolution at the gametophytic self-incompatibility locus (S-locus) in strictly outcrossing species. Genetic drift also influences S-allele evolution. In perennial sessile organisms, evolution of allelic frequencies over two generations is mainly shaped by individual fecundities and spatial processes. Using wild cherry populations between two successive generations, we tested whether S-alleles evolved following NFDS qualitative and quantitative predictions. We showed that allelic variation was negatively correlated with parental allelic frequency as expected under NFDS. However, NFDS predictions in finite population failed to predict more than half S-allele quantitative evolution. We developed a spatially explicit mating model that included the S-locus. We studied the effects of self-incompatibility and local drift within populations due to pollen dispersal in spatially distributed individuals, and variation in male fecundity on male mating success and allelic frequency evolution. Male mating success was negatively related to male allelic frequency as expected under NFDS. Spatial genetic structure combined with self-incompatibility resulted in higher effective pollen dispersal. Limited pollen dispersal in structured distributions of individuals and genotypes and unequal pollen production significantly contributed to S-allele frequency evolution by creating local drift effects strong enough to counteract the NFDS effect on some alleles. PMID:22276543

  16. The Burden of JAK2V617F Mutated Allele in Turkish Patients With Myeloproliferative Neoplasms

    PubMed Central

    Yonal-Hindilerden, Ipek; Daglar-Aday, Aynur; Akadam-Teker, Basak; Yilmaz, Ceylan; Nalcaci, Meliha; Yavuz, Akif Selim; Sargin, Deniz

    2015-01-01

    Background Studies regarding the impact of JAK2V617F allele burden on phenotypic properties and clinical course in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) have reported variable results. We aimed to analyze the association of mutated JAK2V617F allele burden with laboratory characteristics and clinical phenotype in Turkish patients (107 essential thrombocythemia (ET) and 77 primary myelofibrosis (PMF)). Methods Peripheral blood samples of 184 patients with Ph-negative MPNs were analyzed for JAK2V617F allele status and burden. JAK2 MutaScreen assay (Ipsogen, Luminy Biotech, Marseille, France) was used to detect the JAK2V617F status and quantitative JAK2V617F allele burdens in genomic DNA using TaqMan allelic discrimination. Results Frequency of JAK2V617F-positive patients with high mutation load (allele burden > 50%) was higher in PMF compared to ET (23.4% and 4.7%, respectively; P = 0.001). We found significant association between ET patients with high JAK2V617F allele burden and lower hemoglobin (Hgb) and hematocrit (Hct), higher LDH levels and more prevalent massive splenomegaly (P = 0.001, P = 0.001, P = 0.012 and P = 0.015, respectively). ET patients with high mutation load displayed higher prevalence of bleeding compared to low mutation load and wild-type mutational status (P = 0.003). Rate of DVT was significantly higher in ET patients with mutant allele burden in upper half compared to lower half and wild-type (P = 0.029). We observed significant association between PMF patients with high JAK2V617F allele burden and higher Hgb, Hct levels and leukocyte counts (P = 0.003, P = 0.021 and P = 0.001, respectively). Conclusions Our study demonstrated JAK2V617F allele burden correlates with clinical features in ET and PMF. We conclude quantification of JAK2V617F mutation contributes to the workup of Ph-negative MPNs. PMID:25584101

  17. Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population

    PubMed Central

    Williams, Susan E.I.; Whigham, Benjamin T.; Liu, Yutao; Carmichael, Trevor R.; Qin, Xuejun; Schmidt, Silke; Ramsay, Michele; Hauser, Michael A.

    2010-01-01

    Purpose To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an ancestral population from South Africa. Methods Black South African subjects with XFG, POAG, and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto, Johannesburg, South Africa, using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of LOXL1 was sequenced using the PCR-based Sanger method. The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fishers exact test. Results A large number of coding variants were identified, including rs1048661 (R141L), rs3825942 (G153D), S159A, S161L, rs41435250 (A320A), rs13329473 (F489F), and T567A. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p=5.210?13 and 1.710?5, respectively). The G allele for rs1048661 (encoding arginine) was the risk allele which is similar to other populations. The A allele of rs3825942 (encoding aspartic acid) was the risk allele, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in LOXL1 between POAG and control subjects. Conclusions This represents the first genetic association study of LOXL1 in an ancestral African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown causal variants of LOXL1 contribute to the genetic risk of XFG. PMID:20431720

  18. Enhanced low-template DNA analysis conditions and investigation of allele dropout patterns.

    PubMed

    Hedell, Ronny; Dufva, Charlotte; Ansell, Ricky; Mostad, Petter; Hedman, Johannes

    2015-01-01

    Forensic DNA analysis applying PCR enables profiling of minute biological samples. Enhanced analysis conditions can be applied to further push the limit of detection, coming with the risk of visualising artefacts and allele imbalances. We have evaluated the consecutive increase of PCR cycles from 30 to 35 to investigate the limitations of low-template (LT) DNA analysis, applying the short tandem repeat (STR) analysis kit PowerPlex ESX 16. Mock crime scene DNA extracts of four different quantities (from around 8-84 pg) were tested. All PCR products were analysed using 5, 10 and 20 capillary electrophoresis (CE) injection seconds. Bayesian models describing allele dropout patterns, allele peak heights and heterozygote balance were developed to assess the overall improvements in EPG quality with altered PCR/CE settings. The models were also used to evaluate the impact of amplicon length, STR marker and fluorescent label on the risk for allele dropout. The allele dropout probability decreased for each PCR cycle increment from 30 to 33 PCR cycles. Irrespective of DNA amount, the dropout probability was not affected by further increasing the number of PCR cycles. For the 42 and 84 pg samples, mainly complete DNA profiles were generated applying 32 PCR cycles. For the 8 and 17 pg samples, the allele dropouts decreased from 100% using 30 cycles to about 75% and 20%, respectively. The results for 33, 34 and 35 PCR cycles indicated that heterozygote balance and stutter ratio were mainly affected by DNA amount, and not directly by PCR cycle number and CE injection settings. We found 32 and 33 PCR cycles with 10 CE injection seconds to be optimal, as 34 and 35 PCR cycles did not improve allele detection and also included CE saturation problems. We find allele dropout probability differences between several STR markers. Markers labelled with the fluorescent dyes CXR-ET (red in electropherogram) and TMR-ET (shown as black) generally have higher dropout risks compared with those labelled with JOE (green) and fluorescein (blue). Overall, the marker D10S1248 has the lowest allele dropout probability and D8S1179 the highest. The marker effect is mainly pronounced for 30-32 PCR cycles. Such effects would not be expected if the amplification efficiencies were identical for all markers. Understanding allele dropout risks and the variability in peak heights and balances is important for correct interpretation of forensic DNA profiles. PMID:25282604

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

    PubMed Central

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

    2009-01-01

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

  20. North European Transect

    NASA Astrophysics Data System (ADS)

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

    2010-05-01

    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.

  1. European MEMS foundries

    NASA Astrophysics Data System (ADS)

    Salomon, Patric R.

    2003-01-01

    According to the latest release of the NEXUS market study, the market for MEMS or Microsystems Technology (MST) is predicted to grow to $68B by the year 2005, with systems containing these components generating even higher revenues and growth. The latest advances in MST/MEMS technology have enabled the design of a new generation of microsystems that are smaller, cheaper, more reliable, and consume less power. These integrated systems bring together numerous analog/mixed signal microelectronics blocks and MEMS functions on a single chip or on two or more chips assembled within an integrated package. In spite of all these advances in technology and manufacturing, a system manufacturer either faces a substantial up-front R&D investment to create his own infrastructure and expertise, or he can use design and foundry services to get the initial product into the marketplace fast and with an affordable investment. Once he has a viable product, he can still think about his own manufacturing efforts and investments to obtain an optimized high volume manufacturing for the specific product. One of the barriers to successful exploitation of MEMS/MST technology has been the lack of access to industrial foundries capable of producing certified microsystems devices in commercial quantities, including packaging and test. This paper discusses Multi-project wafer (MPW) runs, requirements for foundries and gives some examples of foundry business models. Furthermore, this paper will give an overview on MST/MEMS services that are available in Europe, including pure commercial activities, European project activities (e.g. Europractice), and some academic services.

  2. CYP46A1 T/C polymorphism associated with the APOE ε4 allele increases the risk of Alzheimer's disease.

    PubMed

    Li, Ling; Yin, Zegang; Liu, Juan; Li, Gongbo; Wang, Yanjiang; Yan, Jiachuan; Zhou, Huadong

    2013-07-01

    Studies of the relationship between Alzheimer's disease (AD) and single nucleotide polymorphism (SNP) T/C in intron 2 of the cholesterol-24S-hydroxylase gene (CYP46A1) have reported inconsistent results. To confirm the association between the CYP46A1 T/C polymorphism and AD risk, a meta-analysis containing 4,875 AD cases and 4,874 controls from 21 case-control studies was performed. There were 16 studies involving Europeans, four studies with Asians and one study with Africans. The combined results of overall analysis showed that the CYP46A1 T/C polymorphism increased the risk of AD significantly in recessive model [CC versus CT + TT, odds ratio (OR) = 1.20, 95 % confidence interval (CI) = 1.04-1.38, p = 0.01]. On subgroup analysis by ethnicity, similarly significant differences in recessive model were also found in Europeans. Another analysis of the synergistic effect of the CYP46A1 T/C polymorphism and the ε4 allele of the apolipoprotein E gene (APOE ε4) was performed in eight studies with available stratified information. The results revealed that the presence of APOE ε4 allele could strengthen the effect of CC genotype on AD risk, and the reverse was also true. In conclusion, our meta-analysis has successfully proved that CC genotype of the CYP46A1 T/C polymorphism could increase the risk of AD, and this effect would be weakened in APOE ε4 non-carriers and strengthened in APOE ε4 carriers. PMID:23070465

  3. European strategies for mental health.

    PubMed

    Di Fiandra, Teresa

    2009-01-01

    The most recent developments of strategies and policies in the mental health field in Europe are related to the World Health Organization (WHO) Declaration and Action Plan on Mental Health signed by all the Ministers of Health of all Member States in the European Region (2005). The Action Plan proposes ways and means of developing comprehensive mental health policies, listing 12 areas in which challenges are indicated and detailed actions are required. Afterwards the Green Paper on Mental Health has been launched by the European Commission for the definition of an European strategy. The more precise European Pact for Mental Health and Well-being has been presented in 2008. Many other international bodies (OECD, Council of Europe, etc.) have actively worked to stress the mental health issue. All are clearly referring to the Italian model, started 30 years ago. PMID:19567979

  4. Papillomatosis in a European bison.

    PubMed

    Literk, I; Tomita, Y; Ogawa, T; Shirasawa, H; Smd, B; Novotny, L; Adamec, M

    2006-01-01

    Five European bison (Bison bonasus) from three European zoos were shipped to the Bukovsk Vrchy Hills (Slovakia) in June 2004 and kept together in an acclimatization enclosure. The European bison were released into the wild in December 2004. At that time, papillomas were found at the medial canthus of the left eye of a 12-yr-old female bison. Cutaneous papillomatosis was confirmed histologically. Negative stain transmission electron microscopic examination revealed papillomavirus in the papillomas, and papillomavirus DNA also was detected using the polymerase chain reaction with FAP59 and FAP64 primers. The amplified 413 bp DNA sequence was identical to that of BAPV2 bovine papillomavirus. This paper is the first report of papillomatosis in European bison. PMID:16699157

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

    NASA Astrophysics Data System (ADS)

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

    2012-08-01

    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.

  6. MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India.

    PubMed

    Delgado, J C; Yunis, D E; Bozón, M V; Salazar, M; Deulofeut, R; Turbay, D; Mehra, N K; Pasricha, J S; Raval, R S; Patel, H; Shah, B K; Bhol, K; Alper, C A; Ahmed, A R; Yunis, E J

    1996-12-01

    Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P < 0.0001), DQA1*0101 (P = 0.001), and DQB1*0503 (P < 0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB1*1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p < 0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB1*0302 (p = 0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67-74 of the beta domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles. PMID:9008309

  7. HLA alleles associated with the adaptive immune response to smallpox vaccine: a replication study.

    PubMed

    Ovsyannikova, Inna G; Pankratz, V Shane; Salk, Hannah M; Kennedy, Richard B; Poland, Gregory A

    2014-09-01

    We previously reported HLA allelic associations with vaccinia virus (VACV)-induced adaptive immune responses in a cohort of healthy individuals (n = 1,071 subjects) after a single dose of the licensed smallpox (Dryvax) vaccine. This study demonstrated that specific HLA alleles were significantly associated with VACV-induced neutralizing antibody (NA) titers (HLA-B*13:02, *38:02, *44:03, *48:01, and HLA-DQB1*03:02, *06:04) and cytokine (HLA-DRB1*01:03, *03:01, *10:01, *13:01, *15:01) immune responses. We undertook an independent study of 1,053 healthy individuals and examined associations between HLA alleles and measures of adaptive immunity after a single dose of Dryvax-derived ACAM2000 vaccine to evaluate previously discovered HLA allelic associations from the Dryvax study and determine if these associations are replicated with ACAM2000. Females had significantly higher NA titers than male subjects in both study cohorts [median ID50 discovery cohort 159 (93, 256) vs. 125 (75, 186), p < 0.001; replication cohort 144 (82, 204) vs. 110 (61, 189), p = 0.024]. The association between the DQB1*03:02 allele (median ID50 discovery cohort 152, p = 0.015; replication cohort 134, p = 0.010) and higher NA titers was replicated. Two HLA associations of comparable magnitudes were consistently found between DRB1*04:03 and DRB1*08:01 alleles and IFN-? ELISPOT responses. The association between the DRB1*15:01 allele with IFN-? secretion was also replicated (median pg/mL discovery cohort 182, p = 0.052; replication cohort 203, p = 0.014). Our results suggest that smallpox vaccine-induced adaptive immune responses are significantly influenced by HLA gene polymorphisms. These data provide information for functional studies and design of novel candidate smallpox vaccines. PMID:24880604

  8. Allele-Specific Expression of Angiotensinogen in Human Subcutaneous Adipose Tissue

    PubMed Central

    Park, Sungmi; Lu, Ko-Ting; Liu, Xuebo; Chatterjee, Tapan K.; Rudich, Steven M.; Weintraub, Neal L.; Kwitek, Anne E.; Sigmund, Curt D.

    2013-01-01

    The angiotensinogen gene is genetically linked with hypertension, but the mechanistic basis for association of sequence variants in the promoter and coding region of the gene remains unclear. An E-box at position ?20 has been hypothesized to control the level of angiotensinogen expression, but its mechanistic importance for angiotensinogen expression in human tissues is uncertain. We developed an allele-specific PCR-based assay to distinguish between angiotensinogen mRNA derived from variants at the ?20 position (rs5050) in the angiotensinogen promoter in adipose tissues obtained during surgery. The assay takes advantage of linkage disequilibrium between the rs5050 (located in the promoter) and rs4762 (located in the coding region) single nucleotide polymorphisms. This strategy allowed us to assess the level of allele-specific expression in A-20C heterozygous subjects comparing the relative proportion of each allele to the total, thus eliminating the problem of variability in the level of total angiotensinogen mRNA among subjects. We show that 1) angiotensinogen mRNA derived from the ?20C allele is expressed significantly higher than that derived from the ?20A allele in subcutaneous adipose tissue, and 2) increased expression correlates with enriched chromatin binding of upstream stimulatory factor 2 to the ?20C E-box compared with ?20A. This may be depot selective because we were unable to detect these differences in omental adipose. This provides the first data directly comparing expression of angiotensinogen mRNA and differential transcription factor binding derived from two variant alleles in human tissue where the ratio of expression of one allele to another can be accurately determined. PMID:23648704

  9. Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene.

    PubMed Central

    Pena, S D; de Souza, K T; de Andrade, M; Chakraborty, R

    1994-01-01

    At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the small alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, we observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of "cooperative" changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes. Images Fig. 1 PMID:8290589

  10. Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene

    SciTech Connect

    Pena, S.D.J.; De Souza, K.T. ); De Andrade, M.; Chakraborty, R. )

    1994-01-18

    At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the same alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, the authors observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of cooperative changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes.

  11. Protective effect of the APOE-e3 allele in Alzheimer's disease.

    PubMed

    de-Almada, B V P; de-Almeida, L D; Camporez, D; de-Moraes, M V D; Morelato, R L; Perrone, A M S; Belcavello, L; Louro, I D; de-Paula, F

    2012-01-01

    Although several alleles of susceptibility to Alzheimer's disease (AD) have been studied in the last decades, few polymorphisms have been considered as risk factors for the disease. Among them, the APOE-e4 allele appears to be the major genetic risk factor for the onset of the disease. However, it is important to confirm the potential susceptibility of these genetic variants in different populations in order to establish a genetic profile for the disease in specific communities. This study analyzed the APOE polymorphisms regarding susceptibility to AD in a sample of 264 individuals (primarily Caucasians; 82 cases and 182 controls) in the population from Vitória, ES, Brazil, by PCR restriction fragment length polymorphism (PCR-RFLP) methods. The patients were selected according to clinical criteria for probable AD. Whereas the e4 allele showed statistically significant positive association with susceptibility to AD (OR = 3.01, 95%CI = 1.96-4.61; P < 0.0001), the e2 allele did not. The results of the e4 allele confirm the role of this polymorphism as a risk factor for AD in the sample studied as observed in other populations. Although the e3 allele has been considered neutral in several studies, our results suggest that it acts as a protective factor against AD in the population studied (OR = 0.46, 95%CI = 0.30-0.67; P < 0.0001). This study may provide a new insight into the role of the APOE-e3 allele in the etiology of AD and might help to establish a profile of risk for AD in the population from Vitória, ES. PMID:22068907

  12. Protective effect of the APOE-e3 allele in Alzheimer's disease

    PubMed Central

    de-Almada, B.V.P.; de-Almeida, L.D.; Camporez, D.; de-Moraes, M.V.D.; Morelato, R.L.; Perrone, A.M.S.; Belcavello, L.; Louro, I.D.; de-Paula, F.

    2011-01-01

    Although several alleles of susceptibility to Alzheimer's disease (AD) have been studied in the last decades, few polymorphisms have been considered as risk factors for the disease. Among them, the APOE-e4 allele appears to be the major genetic risk factor for the onset of the disease. However, it is important to confirm the potential susceptibility of these genetic variants in different populations in order to establish a genetic profile for the disease in specific communities. This study analyzed the APOE polymorphisms regarding susceptibility to AD in a sample of 264 individuals (primarily Caucasians; 82 cases and 182 controls) in the population from Vitória, ES, Brazil, by PCR restriction fragment length polymorphism (PCR-RFLP) methods. The patients were selected according to clinical criteria for probable AD. Whereas the e4 allele showed statistically significant positive association with susceptibility to AD (OR = 3.01, 95%CI = 1.96-4.61; P < 0.0001), the e2 allele did not. The results of the e4 allele confirm the role of this polymorphism as a risk factor for AD in the sample studied as observed in other populations. Although the e3 allele has been considered neutral in several studies, our results suggest that it acts as a protective factor against AD in the population studied (OR = 0.46, 95%CI = 0.30-0.67; P < 0.0001). This study may provide a new insight into the role of the APOE-e3 allele in the etiology of AD and might help to estabilish a profile of risk for AD in the population from Vitória, ES. PMID:22068907

  13. Allelic Analysis of Sheath Blight Resistance with Association Mapping in Rice

    PubMed Central

    Jia, Limeng; Yan, Wengui; Zhu, Chengsong; Agrama, Hesham A.; Jackson, Aaron; Yeater, Kathleen; Li, Xiaobai; Huang, Bihu; Hu, Biaolin; McClung, Anna; Wu, Dianxing

    2012-01-01

    Sheath blight (ShB) caused by the soil-borne pathogen Rhizoctonia solani is one of the most devastating diseases in rice world-wide. Global attention has focused on examining individual mapping populations for quantitative trait loci (QTLs) for ShB resistance, but to date no study has taken advantage of association mapping to examine hundreds of lines for potentially novel QTLs. Our objective was to identify ShB QTLs via association mapping in rice using 217 sub-core entries from the USDA rice core collection, which were phenotyped with a micro-chamber screening method and genotyped with 155 genome-wide markers. Structure analysis divided the mapping panel into five groups, and model comparison revealed that PCA5 with genomic control was the best model for association mapping of ShB. Ten marker loci on seven chromosomes were significantly associated with response to the ShB pathogen. Among multiple alleles in each identified loci, the allele contributing the greatest effect to ShB resistance was named the putative resistant allele. Among 217 entries, entry GSOR 310389 contained the most putative resistant alleles, eight out of ten. The number of putative resistant alleles presented in an entry was highly and significantly correlated with the decrease of ShB rating (r = −0.535) or the increase of ShB resistance. Majority of the resistant entries that contained a large number of the putative resistant alleles belonged to indica, which is consistent with a general observation that most ShB resistant accessions are of indica origin. These findings demonstrate the potential to improve breeding efficiency by using marker-assisted selection to pyramid putative resistant alleles from various loci in a cultivar for enhanced ShB resistance in rice. PMID:22427867

  14. The effect of the Neolithic expansion on European molecular diversity

    PubMed Central

    Currat, Mathias; Excoffier, Laurent

    2005-01-01

    We performed extensive and realistic simulations of the colonization process of Europe by Neolithic farmers, as well as their potential admixture and competition with local Palaeolithic huntergatherers. We find that minute amounts of gene flow between Palaeolithic and Neolithic populations should lead to a massive Palaeolithic contribution to the current gene pool of Europeans. This large Palaeolithic contribution is not expected under the demic diffusion (DD) model, which postulates that agriculture diffused over Europe by a massive migration of individuals from the Near East. However, genetic evidence in favour of this model mainly consisted in the observation of allele frequency clines over Europe, which are shown here to be equally probable under a pure DD or a pure acculturation model. The examination of the consequence of range expansions on single nucleotide polymorphism (SNP) diversity reveals that an ascertainment bias consisting of selecting SNPs with high frequencies will promote the observation of genetic clines (which are not expected for random SNPs) and will lead to multimodal mismatch distributions. We conclude that the different patterns of molecular diversity observed for Y chromosome and mitochondrial DNA can be at least partly owing to an ascertainment bias when selecting Y chromosome SNPs for studying European populations. PMID:15870030

  15. Cytochrome P450 2D6 variants in a Caucasian population: Allele frequencies and phenotypic consequences

    SciTech Connect

    Sachse, C.; Brockmoeller, J.; Bauer, S.; Roots, I.

    1997-02-01

    Cytochrome P450 2D6 (CYP2D6) metabolizes many important drugs. CYP2D6 activity ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different known alleles. Their frequencies were determined in 589 unrelated German volunteers and correlated with enzyme activity measured by phenotyping with dextromethorphan or debrisoquine. For genotyping, nested PCR-RFLP tests from a PCR amplificate of the entire CYP2D6 gene were developed. The frequency of the CYP2D6*1 allele coding for extensive metabolizer (EM) phenotype was .364. The alleles coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity (intermediate metabolizer phenotype [IM]) showed frequencies of .324, .018, and .015, respectively. By use of novel PCR tests for discrimination, CYP2D6 gene duplication alleles were found with frequencies of.005 (*1 x 2), .013 (* 2 x 2), and .001 (*4 x 2). Frequencies of alleles with complete deficiency (poor metabolizer phenotype [PM]) were .207 (*4), .020 (*3 and *5), .009 (*6), and .001 (*7, *15, and *16). The defective CYP2D6 alleles *8, *11, *12, *13, and *14 were not found. All 41 PMs (7.0%) in this sample were explained by five mutations detected by four PCR-RFLP tests, which may suffice, together with the gene duplication test, for clinical prediction of CYP2D6 capacity. Three novel variants of known CYP2D6 alleles were discovered: *1C (T{sub 1957}C), *2B (additional C{sub 2558}T), and *4E (additional C{sub 2938}T). Analysis of variance showed significant differences in enzymatic activity measured by the dextromethorphan metabolic ratio (MR) between carriers of EN/PM (mean MR = .006) and IM/PM (mean MR = .014) alleles and between carriers of one (mean MR = .009) and two (mean MR = .003) functional alleles. The results of this study provide a solid basis for prediction of CYP2D6 capacity, as required in drug research and routine drug treatment. 35 refs., 4 figs., 5 tabs.

  16. Multi-allelic phenotyping A systematic approach for the simultaneous analysis of multiple induced mutations?

    PubMed Central

    Dooley, Christopher M.; Scahill, Catherine; Fnyes, Fruzsina; Kettleborough, Ross N.W.; Stemple, Derek L.; Busch-Nentwich, Elisabeth M.

    2013-01-01

    The zebrafish mutation project (ZMP) aims to generate a loss of function allele for every protein-coding gene, but importantly to also characterise the phenotypes of these alleles during the first five days of development. Such a large-scale screen requires a systematic approach both to identifying phenotypes, and also to linking those phenotypes to specific mutations. This phenotyping pipeline simultaneously assesses the consequences of multiple alleles in a two-step process. First, mutations that do not produce a visible phenotype during the first five days of development are identified, while a second round of phenotyping focuses on detailed analysis of those alleles that are suspected to cause a phenotype. Allele-specific PCR single nucleotide polymorphism (SNP) assays are used to genotype F2 parents and individual F3 fry for mutations known to be present in the F1 founder. With this method specific phenotypes can be linked to induced mutations. In addition a method is described for cryopreserving sperm samples of mutagenised males and their subsequent use for in vitro fertilisation to generate F2 families for phenotyping. Ultimately this approach will lead to the functional annotation of the zebrafish genome, which will deepen our understanding of gene function in development and disease. PMID:23624102

  17. Allele-specific copy-number discovery from whole-genome and whole-exome sequencing

    PubMed Central

    Wang, WeiBo; Wang, Wei; Sun, Wei; Crowley, James J.; Szatkiewicz, Jin P.

    2015-01-01

    Copy-number variants (CNVs) are a major form of genetic variation and a risk factor for various human diseases, so it is crucial to accurately detect and characterize them. It is conceivable that allele-specific reads from high-throughput sequencing data could be leveraged to both enhance CNV detection and produce allele-specific copy number (ASCN) calls. Although statistical methods have been developed to detect CNVs using whole-genome sequence (WGS) and/or whole-exome sequence (WES) data, information from allele-specific read counts has not yet been adequately exploited. In this paper, we develop an integrated method, called AS-GENSENG, which incorporates allele-specific read counts in CNV detection and estimates ASCN using either WGS or WES data. To evaluate the performance of AS-GENSENG, we conducted extensive simulations, generated empirical data using existing WGS and WES data sets and validated predicted CNVs using an independent methodology. We conclude that AS-GENSENG not only predicts accurate ASCN calls but also improves the accuracy of total copy number calls, owing to its unique ability to exploit information from both total and allele-specific read counts while accounting for various experimental biases in sequence data. Our novel, user-friendly and computationally efficient method and a complete analytic protocol is freely available at https://sourceforge.net/projects/asgenseng/. PMID:25883151

  18. Differential alleleic expression of the type II collagen gene (COL2A2) in osteoarthritic cartilage

    SciTech Connect

    Loughlin, J.; Irven, C.; Sykes, B.; Athanasou, N.; Carr, A.

    1995-05-01

    Osteoarthritis (OA) is a common debilitating disease resulting from the degeneration of articular cartilage. The major protein of cartilage is type II collagen, which is encoded by the COL2A1 gene. Mutations at this locus have been discovered in several individuals with inherited disorders of cartilage. We have identified 27 primary OA patients who are heterozygous for sequence dimorphisms located in the coding region of COL2A1. These dimorphisms were used to distinguish the mRNA output from each of the two COL2A1 alleles in articular cartilage obtained from each patient. Three patients demonstrated differential allelic expression and produced <12% of the normal level of mRNA from one of their COL2A1 alleles. The same allele shows reduced expression in a well-defined OA population than in a control group, suggesting the possible existence of a rare COL2A1 allele that predisposes to OA. 31 refs., 4 figs., 3 tabs.

  19. Antagonistic effects of a Mhc class I allele on malaria-infected house sparrows.

    PubMed

    Loiseau, Claire; Zoorob, Rima; Garnier, Stphane; Birard, Julien; Federici, Pierre; Julliard, Romain; Sorci, Gabriele

    2008-03-01

    Genes of the Major Histocompatibility Complex (Mhc) play a fundamental role during the immune response because MHC molecules expressed on cell surface allow the recognition and presentation of antigenic peptides to T-lymphocytes. Although Mhc alleles have been found to correlate with pathogen resistance in several host-parasite systems, several studies have also reported associations between Mhc alleles and an accrued infection risk or an accelerated disease progression. The existence of these susceptibility alleles is puzzling, as the cost generated by the infection should rapidly eliminate them from the population. Here, we show that susceptibility alleles may be maintained in a population of house sparrows (Passer domesticus) if they have antagonistic effects on different malaria parasites. We found that one Mhc class I allele was associated with a 2.5-fold increase in the risk to be infected with a Plasmodium strain, but with a 6.4-fold reduction in the risk to harbour a Haemoproteus strain. We suggest that this antagonistic effect might arise because Mhc genes can alter the competitive interactions between malaria parasites within the host. PMID:18070099

  20. Generation of a Conditional Allele for the Mouse Endothelial Nitric Oxide Synthase Gene

    PubMed Central

    Jiang, Rosie; Wang, Suwan; Takahashi, Keiko; Fujita, Hiroki; Fruci, Christopher R.; Breyer, Matthew D.; Harris, Raymond C; Takahashi, Takamune

    2012-01-01

    Mice with endothelial nitric oxide synthase (eNOS) deletions have defined the crucial role of eNOS in vascular development, homeostasis, and pathology. However, cell specific eNOS function has not been determined, although an important role of eNOS has been suggested in multiple cell types. Here we have generated a floxed eNOS allele in which exons 9–12, encoding the sites essential to eNOS activity, are flanked with loxP sites. Mice homozygous for the floxed allele showed normal eNOS protein levels and no overt phenotype. Conversely, homozygous mice with Cre-deleted alleles displayed truncated eNOS protein, lack of vascular nitric oxide production, and exhibited similar phenotype to eNOS knockout mice, including hypertension, low heart rate, and focal renal scar. These findings demonstrate that the floxed allele is normal and it can be converted to a non-functional eNOS allele through Cre recombination. This mouse will allow time and cell specific eNOS deletion. PMID:22467476

  1. ALDH2*2 Allele is a Negative Risk Factor for Cerebral Infarction in Chinese Women.

    PubMed

    Li, Qiao-Yan; Zhao, Ning-Min; Ma, Jian-Jun; Duan, Hong-Fei; Ma, Yong-Cheng; Zhang, Wei; Zhao, Hong-Wei; Qin, Yu-Hua

    2015-10-01

    Unlike its reported role in the cardiovascular diseases, little information is available for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the cerebrovascular function. We investigated the different effects of ALDH2 genotypes on the risk of cerebral infarction between the genders, because different genders had different smoking and/or dinking status which are also risk factors for cerebral infarction. 247 healthy Chinese Han people (controls, group 1), 287 Chinese Han male patients with cerebral infarction (group 2), and 82 Chinese Han female patients with cerebral infarction (group 3) were involved in this study. The frequencies of the ALDH2*2 allele in group 3 were significantly higher than those in other groups (with P=0.001 and P=0.002, respectively). The difference of ALDH2*2 allele frequency between group 1 and group 2 was not significant (P=0.652). After adjustment for smoking and drinking status, the male patients without smoking or drinking status (group 4) had higher ALDH2*2 allele frequency than group 1, but the difference was still not significant (P=0.139). Thus, we conclude that ALDH2*2 allele may be a significant negative risk factor for cerebral infarction in Chinese women [odds ratio (OR)=2.207, 95% CI 1.416-3.439]. But for Chinese male patients, the negative effects of ALDH2*2 allele on cerebral infarction which might be concealed by other risk factors were not significant. PMID:26142243

  2. Rapid, efficient and precise allele replacement in the fission yeast Schizosaccharomycespombe.

    PubMed

    Gao, Jun; Kan, Fengling; Wagnon, Jacy L; Storey, Aaron J; Protacio, Reine U; Davidson, Mari K; Wahls, Wayne P

    2014-05-01

    Gene targeting provides a powerful tool to modify endogenous loci to contain specific mutations, insertions and deletions. Precise allele replacement, with no other chromosomal changes (e.g., insertion of selectable markers or heterologous promoters), maintains physiologically relevant context. Established methods for precise allele replacement in fission yeast employ two successive rounds of transformation and homologous recombination and require genotyping at each step. The relative efficiency of homologous recombination is low and a high rate of false positives during the second round of gene targeting further complicates matters. We report that pop-in, pop-out allele replacement circumvents these problems. We present data for 39 different allele replacements, involving simple and complex modifications at seven different target loci, that illustrate the power and utility of the approach. We also developed and validated a rapid, efficient process for precise allele replacement that requires only one round each of transformation and genotyping. We show that this process can be applied in population scale to an individual target locus, without genotyping, to identify clones with an altered phenotype (targeted forward genetics). It is therefore suitable for saturating, in situ, locus-specific mutation screens (e.g., of essential or non-essential genes and regulatory DNA elements) within normal chromosomal context. PMID:24026504

  3. Alleles versus genotypes: Genetic interactions and the dynamics of selection in sexual populations

    NASA Astrophysics Data System (ADS)

    Neher, Richard

    2010-03-01

    Physical interactions between amino-acids are essential for protein structure and activity, while protein-protein interactions and regulatory interactions are central to cellular function. As a consequence of these interactions, the combined effect of two mutations can differ from the sum of the individual effects of the mutations. This phenomenon of genetic interaction is known as epistasis. However, the importance of epistasis and its effects on evolutionary dynamics are poorly understood, especially in sexual populations where recombination breaks up existing combinations of alleles to produce new ones. Here, we present a computational model of selection dynamics involving many epistatic loci in a recombining population. We demonstrate that a large number of polymorphic interacting loci can, despite frequent recombination, exhibit cooperative behavior that locks alleles into favorable genotypes leading to a population consisting of a set of competing clones. As the recombination rate exceeds a certain critical value this ``genotype selection'' phase disappears in an abrupt transition giving way to ``allele selection'' - the phase where different loci are only weakly correlated as expected in sexually reproducing populations. Clustering of interacting sets of genes on a chromosome leads to the emergence of an intermediate regime, where localized blocks of cooperating alleles lock into genetic modules. Large populations attain highest fitness at a recombination rate just below critical, suggesting that natural selection might tune recombination rates to balance the beneficial aspect of exploration of genotype space with the breaking up of synergistic allele combinations.

  4. Targeting Alzheimer's disease genes with RNA interference: an efficient strategy for silencing mutant alleles.

    PubMed

    Miller, Victor M; Gouvion, Cynthia M; Davidson, Beverly L; Paulson, Henry L

    2004-01-01

    Tau and amyloid precursor protein (APP) are key proteins in the pathogenesis of sporadic and inherited Alzheimer's disease. Thus, developing ways to inhibit production of these proteins is of great research and therapeutic interest. The selective silencing of mutant alleles, moreover, represents an attractive strategy for treating inherited dementias and other dominantly inherited disorders. Here, using tau and APP as model targets, we describe an efficient method for producing small interfering RNA (siRNA) against essentially any targeted region of a gene. We then use this approach to develop siRNAs that display optimal allele-specific silencing against a well-characterized tau mutation (V337M) and the most widely studied APP mutation (APPsw). The allele-specific RNA duplexes identified by this method then served as templates for constructing short hairpin RNA (shRNA) plasmids that successfully silenced mutant tau or APP alleles. These plasmids should prove useful in experimental and therapeutic studies of Alzheimer's disease. Our results suggest guiding principles for the production of allele-specific siRNA, and the general method described here should facilitate the production of gene-specific siRNAs. PMID:14754988

  5. Molecular Basis for Allelic Polymorphism of the Maize Globulin-1 Gene

    PubMed Central

    Belanger, F. C.; Kriz, A. L.

    1991-01-01

    An abundant protein in maize (Zea mays L.) embryos is a storage globulin encoded by the polymorphic Glb1 gene. Several Glb1 protein size alleles and a null allele have been described. Here we report the isolation and nucleotide sequence analysis of genomic clones corresponding to two Glb1 size alleles (Glb1-L and Glb1-S) and to the Glb1-0 null allele. The Glb1-L and Glb1-0 alleles differ from Glb1-S by the presence of small nucleotide insertions which are imperfect or perfect duplications, respectively, of adjacent sequences. In the case of Glb1-L, the insertion is in-frame and results in a protein larger than that encoded by Glb1-S, whereas in Glb1-0 the insertion causes a translational frameshift which introduces a premature termination codon. Although steady-state levels of Glb1-0 transcripts are extremely low in Glb1-0/0 embryos, nuclear transcription assays indicate that the Glb1-0 gene is transcribed at a level comparable to that of Glb1-L. This suggests that the low amounts of Glb1-0 transcripts in the cytoplasm may be due to mRNA instability. PMID:1752424

  6. ADZE: a rarefaction approach for counting alleles private to combinations of populations

    PubMed Central

    Szpiech, Zachary A.; Jakobsson, Mattias; Rosenberg, Noah A.

    2008-01-01

    Motivation: Analysis of the distribution of alleles across populations is a useful tool for examining population diversity and relationships. However, sample sizes often differ across populations, sometimes making it difficult to assess allelic distributions across groups. Results: We introduce a generalized rarefaction approach for counting alleles private to combinations of populations. Our method evaluates the number of alleles found in each of a set of populations but absent in all remaining populations, considering equal-sized subsamples from each population. Applying this method to a worldwide human microsatellite dataset, we observe a high number of alleles private to the combination of African and Oceanian populations. This result supports the possibility of a migration out of Africa into Oceania separate from the migrations responsible for the majority of the ancestry of the modern populations of Asia, and it highlights the utility of our approach to sample size correction in evaluating hypotheses about population history. Availability: We have implemented our method in the computer pro-gram ADZE, which is available for download at http://rosenberglab.bioinformatics.med.umich.edu/adze.html. Contact: szpiechz@umich.edu PMID:18779233

  7. Predisposition towards urolithiasis associated with the NQO1 null-allele.

    PubMed

    Schulz, W A; Krummeck, A; Rösinger, I; Schmitz-Dräger, B J; Sies, H

    1998-10-01

    The distribution of two alleles of the NQO1 gene encoding NADP(H):quinone oxidoreductase was studied in 140 urolithiasis patients and 271 control individuals. The minor allele encoding a protein lacking quinone reductase activity was significantly more frequent (q = 0.214) among these patients than in control individuals (P = 0.135) indicating an increased risk for kidney stone formation among heterozygotes (odds ratio 1.83, confidence interval 1.17-2.86) and homozygotes for the null-allele (odds ratio 2.97, confidence interval 0.78-11.33). Since NADP(H):quinone oxidoreductase is thought to participate in activation of vitamin K for protein gamma-carboxylation, decreased activity of the enzyme in heterozygotes or in null-allele homozygotes may disturb the post-translational modification of urinary calcium-binding proteins protective against kidney stone formation. The NQO1 null-allele might therefore be a determinant in enhanced risk of urolithiasis. PMID:9825838

  8. Allelic diversity is generated by intraexon sequence exchange at the DRB1 locus of primates.

    PubMed Central

    Gyllensten, U B; Sundvall, M; Erlich, H A

    1991-01-01

    The loci encoding the class II cell surface antigens HLA-DR, -DQ, and -DP exhibit a remarkable degree of allelic polymorphism. Most of the class II allelic diversity is localized to the second exon, which encodes a beta-pleated sheet followed by an alpha-helical domain. Here, phylogenetic analysis of 39 human DRB1 alleles and 21 DRB1 alleles obtained by polymerase chain reaction (PCR) amplification from a set of closely related primates reveals that sequences encoding the beta-pleated sheet and those encoding the alpha-helix of the second domain have different evolutionary histories. The polymorphisms in the beta-pleated sheet have been conserved between species and appear to reflect the ancestral relationships among haplotypes, whereas polymorphic segments encoding the alpha-helical domain appear to have been inserted by interallelic sequence exchange into the framework of different ancestral DRB1 sequences. Allelic polymorphism at the DRB1 locus may thus have been generated in part by combining different variants of the two structural domains. PMID:2023919

  9. Ancestral Alleles in the Human Genome Based on Population Sequencing Data

    PubMed Central

    Park, Leeyoung

    2015-01-01

    Ancestral allele information is useful for genetics studies. Previously, the identification of ancestral alleles was primarily based on sequence alignments between species. Alternative ways to identify ancestral alleles were proposed in this study based on population sequencing data. The methods described here utilized the diversity between haplotypes harboring ancestral and newly emerged alleles. Simulations showed that these methods were reliable for identifying ancestral alleles when the variants had not aged too greatly. Application to the human genome sequencing data suggested the role of indels in maintaining the GC content in the human genome. The deletion-to-insertion ratios and GC proportions were correlated depending on the sizes of insertions and deletions in the direction of increasing GC content. There were GC-biased fixations in single base-pair insertions and AT-biased fixations in single base-pair deletions in the results based on the proposed methods. In the current study, GC-biased gene conversions in nucleotide substitutions were very slight or insignificant. In the variants of several quantitative trait loci (QTLs), slight GC-biased gene conversion was observed in nucleotide substitutions. For the QTL indels, insertions were observed more often than deletions, and deletion-biased fixation was observed, providing new insights into the evolution of functional genes. PMID:26020928

  10. Predicting Carriers of Ongoing Selective Sweeps without Knowledge of the Favored Allele

    PubMed Central

    Zakov, Shay; Rosenberg, Noah A.; Bafna, Vineet

    2015-01-01

    Methods for detecting the genomic signatures of natural selection have been heavily studied, and they have been successful in identifying many selective sweeps. For most of these sweeps, the favored allele remains unknown, making it difficult to distinguish carriers of the sweep from non-carriers. In an ongoing selective sweep, carriers of the favored allele are likely to contain a future most recent common ancestor. Therefore, identifying them may prove useful in predicting the evolutionary trajectory—for example, in contexts involving drug-resistant pathogen strains or cancer subclones. The main contribution of this paper is the development and analysis of a new statistic, the Haplotype Allele Frequency (HAF) score. The HAF score, assigned to individual haplotypes in a sample, naturally captures many of the properties shared by haplotypes carrying a favored allele. We provide a theoretical framework for computing expected HAF scores under different evolutionary scenarios, and we validate the theoretical predictions with simulations. As an application of HAF score computations, we develop an algorithm (PreCIOSS: Predicting Carriers of Ongoing Selective Sweeps) to identify carriers of the favored allele in selective sweeps, and we demonstrate its power on simulations of both hard and soft sweeps, as well as on data from well-known sweeps in human populations. PMID:26402243

  11. Allele-specific copy number profiling by next-generation DNA sequencing.

    PubMed

    Chen, Hao; Bell, John M; Zavala, Nicolas A; Ji, Hanlee P; Zhang, Nancy R

    2015-02-27

    The progression and clonal development of tumors often involve amplifications and deletions of genomic DNA. Estimation of allele-specific copy number, which quantifies the number of copies of each allele at each variant loci rather than the total number of chromosome copies, is an important step in the characterization of tumor genomes and the inference of their clonal history. We describe a new method, falcon, for finding somatic allele-specific copy number changes by next generation sequencing of tumors with matched normals. falcon is based on a change-point model on a bivariate mixed Binomial process, which explicitly models the copy numbers of the two chromosome haplotypes and corrects for local allele-specific coverage biases. By using the Binomial distribution rather than a normal approximation, falcon more effectively pools evidence from sites with low coverage. A modified Bayesian information criterion is used to guide model selection for determining the number of copy number events. Falcon is evaluated on in silico spike-in data and applied to the analysis of a pre-malignant colon tumor sample and late-stage colorectal adenocarcinoma from the same individual. The allele-specific copy number estimates obtained by falcon allows us to draw detailed conclusions regarding the clonal history of the individual's colon cancer. PMID:25477383

  12. Diversity of Lactase Persistence Alleles in Ethiopia: Signature of a Soft Selective Sweep

    PubMed Central

    Jones, BryonyL.; Raga, TamiruO.; Liebert, Anke; Zmarz, Pawel; Bekele, Endashaw; Danielsen, E.Thomas; Olsen, AndersKrger; Bradman, Neil; Troelsen, JesperT.; Swallow, DallasM.

    2013-01-01

    The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (?13910?T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (?13907?G, rs41525747; ?13915?G, rs41380347; ?14010?C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, ?14009T>G (ss 820486563), is significantly associated with lactose-digester status, and invitro functional tests confirm that the ?14009?G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spread through several ethnic groups, and we report a greater genetic diversity in lactose digesters than in nondigesters. By examining flanking markers to control for the effects of mutation and demography, we further describe, from empirical evidence, the signature of a soft selective sweep. PMID:23993196

  13. Female sticklebacks count alleles in a strategy of sexual selection explaining MHC polymorphism.

    PubMed

    Reusch, T B; Hberli, M A; Aeschlimann, P B; Milinski, M

    2001-11-15

    The origin and maintenance of polymorphism in major histocompatibility complex (MHC) genes in natural populations is still unresolved. Sexual selection, frequency-dependent selection by parasites and pathogens, and heterozygote advantage have been suggested to explain the maintenance of high allele diversity at MHC genes. Here we argue that there are two (non-exclusive) strategies for MHC-related sexual selection, representing solutions to two different problems: inbreeding avoidance and parasite resistance. In species prone to inadvertent inbreeding, partners should prefer dissimilar MHC genotypes to similar ones. But if the goal is to maximize the resistance of offspring towards potential infections, the choosing sex should prefer mates with a higher diversity of MHC alleles. This latter strategy should apply when there are several MHC loci, as is the case in most vertebrates. We tested the relative importance of an 'allele counting' strategy compared to a disassortative mating strategy using wild-caught three-spined sticklebacks (Gasterosteus aculeatus) from an interconnected system of lakes. Here we show that gravid female fish preferred the odour of males with a large number of MHC class-IIB alleles to that of males with fewer alleles. Females did not prefer male genotypes dissimilar to their own. PMID:11713527

  14. Probe-free allele-specific copy number detection and analysis of tumors.

    PubMed

    Zhu, Ailin; Guan, Xiaowei; Gu, Xinbin; Xie, Guiqin

    2016-03-15

    Cancer development and progression frequently involve nucleotide mutations as well as amplifications and deletions of genomic segments. Quantification of allele-specific copy number is an important step in characterizing tumor genomes for precision medicine. Despite advances in approaches to high-throughput genomic DNA analysis, inexpensive and simple methods for analyzing complex nucleotide and copy number variants are still needed. Real-time polymerase chain reaction (PCR) methods for discovering and genotyping single nucleotide polymorphisms are becoming increasingly important in genetic analysis. In this study, we describe a simple, single-tube, probe-free method that combines SYBR Green I-based quantitative real-time PCR and quantitative melting curve analysis both to detect specific nucleotide variants and to quantify allele-specific copy number variants of tumors. The approach is based on the quantification of the targets of interest and the relative abundance of two alleles in a single tube. The specificity, sensitivity, and utility of the assay were demonstrated in detecting allele-specific copy number changes critical for carcinogenesis and therapeutic intervention. Our approach would be useful for allele-specific copy number analysis or precise genotyping. PMID:26743720

  15. Osteogensis imperfecta type I is commonly due to a COLIAI null allel of type I collagen

    SciTech Connect

    Willing, M.C.; Pruchno, C.J. ); Atkinson, M.; Byers, P.H. )

    1992-09-01

    Dermal fibroblasts from most individuals with osteogenesis imperfecta (OI) type I produce about half the normal amount of type I procollagen, as a result of decreased synthesis of one of its constituent chains, pro[alpha](I). To test the hypothesis that decreased synthesis of pro[alpha](I) chains results from mutations in the COL1A1 gene, the authors used primer extension with nucleotide-specific chain termination to measure the contribution of individual COL1A1 alleles to the mRNA pool in fibroblasts from affected individuals. A polymorphic Mn/I restriction endonuclease site in the 3'-untranslated region of COL1A1 was used to distinguish the transcripts of the two alleles in heterozygous individuals. Twenty-three individuals from 21 unrelated families were studied. In each case there was marked diminution in steady-state mRNA levels from one COL1A2 allele. Loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Primer extension with nucleotide-specific chain termination allows identification of the mutant COL1A1 allele in cell strains that are heterozygous for an expressed polymorphism. It is applicable to sporadic cases, to small families, and to large families in whom key individuals are uninformative at the polymorphic sites used in linkage analysis, making it a useful adjunct to the biochemical screening of collagenous proteins for OI. 40 refs., 3 figs., 1 tab.

  16. Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep.

    PubMed

    Jones, Bryony L; Raga, Tamiru O; Liebert, Anke; Zmarz, Pawel; Bekele, Endashaw; Danielsen, E Thomas; Olsen, Anders Krger; Bradman, Neil; Troelsen, Jesper T; Swallow, Dallas M

    2013-09-01

    The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (-13910(?)T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (-13907(?)G, rs41525747; -13915(?)G, rs41380347; -14010(?)C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, -14009T>G (ss 820486563), is significantly associated with lactose-digester status, and invitro functional tests confirm that the -14009(?)G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spre