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Sample records for european ccr5-delta32 allele

  1. 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-?32) raises interesting questions for evolutionary biologists. We had suggested first that, in the past, the European colonizers, principally Romans, might have been instrumental of a progressively decrease of the frequencies southwards. Indeed, statistical analyses suggested strong negative correlations between the allele frequency and historical parameters including the colonization dates by Mediterranean civilisations. The gene flows from colonizers to native populations were extremely low but colonizers are responsible of the spread of several diseases suggesting that the dissemination of parasites in naive populations could have induced a breakdown rupture of the fragile pathocenosis changing the balance among diseases. The new equilibrium state has been reached through a negative selection of the null allele. Results Most of the human diseases are zoonoses and cat might have been instrumental in the decrease of the allele frequency, because its diffusion through Europe was a gradual process, due principally to Romans; and that several cat zoonoses could be transmitted to man. The possible implication of a feline lentivirus (FIV) which does not use CCR5 as co-receptor is discussed. This virus can infect primate cells in vitro and induces clinical signs in macaque. Moreover, most of the historical regions with null or low frequency of CCR5-?32 allele coincide with historical range of the wild felid species which harbor species-specific FIVs. Conclusion We proposed the hypothesis that the actual European CCR5 allelic frequencies are the result of a negative selection due to a disease spreading. A cat zoonosis, could be the most plausible hypothesis. Future studies could provide if CCR5 can play an antimicrobial role in FIV pathogenesis. Moreover, studies of ancient DNA could provide more evidences regarding the implications of zoonoses in the actual CCR5-?32 distribution. PMID:18925940

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

    PubMed Central

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

    1998-01-01

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

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

    PubMed

    de Farias, Josileide Duarte; Santos, Marlene Guimarães; de França, Andonai Krauze; Delani, Daniel; Tada, Mauro Shugiro; Casseb, Almeida Andrade; Simões, 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 Candelária/Bate-Estaca (1.8%), whereas a fourth, from the Research Center on Tropical Medicine/CEPEM (0.6%), was composed of malaria patients under treament. The fifth sample (3.4%) came from the inland Quilombola village of Pedras Negras. Two homozygous individuals (CCR5?32/CCR5?32) were detected among the HB Mother samples. The frequency of this allele was heterogeneous and higher where the European inflow was more pronounced. The presence of the allele in Pedras Negras revealed European miscegenation in a community largely comprising Quilombolas. PMID:22481870

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

    PubMed Central

    de Farias, Josileide Duarte; Santos, Marlene Guimarães; de França, Andonai Krauze; Delani, Daniel; Tada, Mauro Shugiro; Casseb, Almeida Andrade; Simões, 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 Candelária/Bate-Estaca (1.8%), whereas a fourth, from the Research Center on Tropical Medicine/CEPEM (0.6%), was composed of malaria patients under treament. The fifth sample (3.4%) came from the inland Quilombola village of Pedras Negras. Two homozygous individuals (CCR5?32/CCR5?32) were detected among the HB Mother samples. The frequency of this allele was heterogeneous and higher where the European inflow was more pronounced. The presence of the allele in Pedras Negras revealed European miscegenation in a community largely comprising Quilombolas. PMID:22481870

  5. 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

  6. Effects of the Chemokine Receptor 5 (CCR5)-Delta32 Mutation on Hepatitis C Virus-Specific Immune Responses and Liver Tissue Pathology in HCV Infected Patients

    PubMed Central

    Yilmaz, Abdulkerim; Alagozlu, Hakan; Ozdemir, Ozturk; Arici, Sema

    2014-01-01

    Background: The specific antiviral T cells provide CC chemokine receptor 5 (CCR5) for the immune response during the hepatitis C virus (HCV) infection. Heterogenous and/or homozygous 32 base pair deletion in CCR5 gene (CCR5?32 bpdel) leads to reduced protein expression. Objectives: In the current case control study, we aimed to compare the histopathological findings of liver to the CCR5?32 bpdel mutation profiles, expression and some other clinical findings in patients with chronic HCV infection. Materials and Methods: Multiple Strip Assay reverse hybridisation and Real Time PCR techniques were used to determine the germline CCR5 mutations and immunohistochemical technique was used to evaluate the gene expression in targer tissue biopsies. Results: Target CCR5 WT/WT, WT/?32, and ?32/?32 genotypes were observed in 91.4%, 8.6% and 0.0% for HCV positive patients and 98.3%, 1.7% and 0.0% for control group respectively. The histologic activity index (HAI) was significantly lower (4.0 ± 1.0) in the mutated group than the non-mutated group (5.7 ± 1.0). Decreased fibrosis levels were detected in HCV positive mutated group. Conclusions: Results showed that CCR5 polymorphism was more frequent in HCV positive patients than in healthy population in Turkish population. Current results also showed that mutated CCR5 signalling pathway due to CCR5-Delta32 may potentially result in subtle reduction of HCV specifity to the drug responses due to the positive impact on liver inflammation, fibrosis levels and liver destruction in HCV infection. PMID:25067937

  7. 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 Inácio; Hacker, Mariana A; Morgado, Mariza Gonçalves

    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

  8. 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

  9. Comparison of allele frequencies of eight STR loci from Argentinian Amerindian and European populations.

    PubMed

    Sala, A; Penacino, G; Corach, D

    1998-10-01

    Eight STR systems (THO1, FABP, VWA, FES/FPS, HPRTB, F13A1, CSF1PO, and D6S366) were investigated in different ethnic groups of Argentina. Allele and genotype frequencies, power of exclusion, and discriminative power were investigated. Hardy-Weinberg expectations were calculated from heterozygosity levels. FST and G tests demonstrated that significant differences exist among the investigated populations for some of the eight STRs markers. The Wichi Indians are clearly separated from the Mapuche and Tehuelche, who in turn are closer to the European population, suggesting non-Amerindian admixture. PMID:9780520

  10. 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

  11. 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

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

    PubMed

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

    2013-11-01

    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

  13. [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

  14. Triglyceride associated polymorphisms of the APOA5 gene have very different allele frequencies in Pune, India compared to Europeans

    PubMed Central

    Chandak, Giriraj R; Ward, Kirsten J; Yajnik, Chittaranjan S; Pandit, Anand N; Bavdekar, Ashish; Joglekar, Charu V; Fall, Caroline HD; Mohankrishna, P; Wilkin, Terence J; Metcalf, Bradley S; Weedon, Michael N; Frayling, Timothy M; Hattersley, Andrew T

    2006-01-01

    Background The APOA5 gene variants, -1131T>C and S19W, are associated with altered triglyceride concentrations in studies of subjects of Caucasian and East Asian descent. There are few studies of these variants in South Asians. We investigated whether the two APOA5 variants also show similar association with various lipid parameters in Indian population as in the UK white subjects. Methods We genotyped 557 Indian adults from Pune, India, and 237 UK white adults for -1131T>C and S19W variants in the APOA5 gene, compared their allelic and genotype frequency and determined their association with fasting serum triglycerides, total cholesterol, HDL and LDL cholesterol levels using univariate general linear analysis. APOC3 SstI polymorphism was also analyzed in 175 Pune Indian subjects for analysis of linkage disequilibrium with the APOA5 variants. Results The APOA5 -1131C allele was more prevalent in Indians from Pune (Pune Indians) compared to UK white subjects (allele frequency 20% vs. 4%, p = 0.00001), whereas the 19W allele was less prevalent (3% vs. 6% p = 0.0015). Patterns of linkage disequilibrium between the two variants were similar between the two populations and confirmed that they occur on two different haplotypes. In Pune Indians, the presence of -1131C allele and the 19W allele was associated with a 19% and 15% increase respectively in triglyceride concentrations although only -1131C was significant (p = 0.0003). This effect size was similar to that seen in the UK white subjects. Analysis of the APOC3 SstI polymorphism in 175 Pune Indian subjects showed that this variant is not in appreciable linkage disequilibrium with the APOA5 -1131T>C variant (r2 = 0.07). Conclusion This is the first study to look at the role of APOA5 in Asian Indian subjects that reside in India. The -1131C allele is more prevalent and the 19W allele is less prevalent in Pune Indians compared to UK Caucasians. We confirm that the APOA5 variants are associated with triglyceride levels independent of ethnicity and that this association is similar in magnitude in Asian Indians and Caucasians. The -1131C allele is present in 36% of the Pune Indian population making it a powerful marker for looking at the role of elevated triglycerides in important conditions such as pancreatitis, diabetes and coronary heart disease. PMID:17032446

  15. 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

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

    PubMed Central

    López, Saioa; García, Óscar; Yurrebaso, Iñaki; Flores, Carlos; Acosta-Herrera, Marialbert; Chen, Hua; Gardeazabal, Jesús; Careaga, Jesús María; Boyano, María Dolores; Sánchez, Ana; Ratón-Nieto, Juan Antonio; Sevilla, Arrate; Smith-Zubiaga, Isabel; de Galdeano, Alicia García; Martinez-Cadenas, Conrado; Izagirre, Neskuts; de la Rúa, Concepción; 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

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

    PubMed

    Krüttli, Annina; Bouwman, Abigail; 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

  18. 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

  19. 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

  20. 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

  1. Break zones in the distributions of alleles and species in alpine plants

    E-print Network

    ORIGINAL ARTICLE Break zones in the distributions of alleles and species in alpine plants Conny We test for the congruence between allele-based range boundaries (break zones) in silicicolous alpine plants and species-based break zones in the silicicolous flora of the European Alps. We also ask whether

  2. 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)

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

    PubMed Central

    Balboa-Beltrán, 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. allele.freq.plot Plots population allele frequencies per locus represented by dots of varying size

    E-print Network

    Borges, Rita

    allele.freq.plot Plots population allele frequencies per locus represented by dots of varying size Description For each locus a plot is constructed in a new window. Allele frequencies are represented by dots of varying diameter. Allele codes are indicated on the x axis and populations on the y axis Usage allele.freq.plot

  5. 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

  6. 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

  7. 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.

  8. Characterization of the treefrog null allele, 1991

    SciTech Connect

    Guttman, S.I.

    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.

  9. 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

  10. 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

  11. Allele Workbench: transcriptome pipeline and interactive graphics for allele-specific expression.

    PubMed

    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

  12. 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

  13. 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

  14. 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

  15. Demographic history and rare allele sharing among human populations

    PubMed Central

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

    2011-01-01

    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

  16. Independent Introduction of Two Lactase-Persistence Alleles into Human Populations Reflects Different History of Adaptation to Milk Culture

    PubMed Central

    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 ? (HNF1?). High selection coefficient (s) ?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

  17. HLA-B alleles of the Cayapa of Ecuador: New B39 and B15 alleles

    SciTech Connect

    Garber, T.L.; Butler, L.M.; Watkins, D.I.

    1995-05-01

    Recent data suggest that HLA-B locus alleles can evolve quickly in native South American populations. To investigate further this phenomenon of new HLA-B variants among Amerindians, we studied samples from another South American tribe, the Cayapa from Ecuador. We selected individuals for HLA-B molecular typing based upon their HLA class II typing results. Three new variants of HLA-B39 and one new variant of HLA-B15 were found in the Cayapa: HLA-B*3905, HLA-B*3906, HLA-B*3907, and HLA-B*1522. A total of thirteen new HLA-B alleles have now been found in the four South American tribes studied. Each of these four tribes studied, including the Cayapa, had novel alleles that were not found in any of the other tribes, suggesting that many of these new HLA-B alleles may have evolved since the Paleo-Indians originally populated South America. Each of these 13 new alleles contained predicted amino acid replacements that were located in the peptide binding site. These amino acid replacements may affect the sequence motif of the bound peptides, suggesting that these new alleles have been maintained by selection. New allelic variants have been found for all common HLA-B locus antigenic groups present in South American tribes with the exception of B48. In spite of its high frequency in South American tribes, no evidence for variants of B48 has been found in all the Amerindians studied, suggesting that B48 may have unique characteristics among the B locus alleles. 70 refs., 2 figs., 2 tabs.

  18. Fundamentals of Population Genetics Mechanisms of Allele Frequency Changes

    E-print Network

    Qiu, Weigang

    Genetics and Evolution Definition Evolution = Divergence Between Populations = Fixation of New AllelesFundamentals of Population Genetics Mechanisms of Allele Frequency Changes Case Studies Chapter 4. Population Genetics Weigang Qiu Department of Biological Sciences Hunter College BIOL 375 Molecular Evolution

  19. Do Heliconius butterfly species exchange mimicry alleles?

    PubMed Central

    Smith, Joel; Kronforst, Marcus R.

    2013-01-01

    Hybridization has the potential to transfer beneficial alleles across species boundaries, and there are a growing number of examples in which this has apparently occurred. Recent studies suggest that Heliconius butterflies have transferred wing pattern mimicry alleles between species via hybridization, but ancestral polymorphism could also produce a signature of shared ancestry around mimicry genes. To distinguish between these alternative hypotheses, we measured DNA sequence divergence around putatively introgressed mimicry loci and compared this with the rest of the genome. Our results reveal that putatively introgressed regions show strongly reduced sequence divergence between co-mimetic species, suggesting that their divergence times are younger than the rest of the genome. This is consistent with introgression and not ancestral variation. We further show that this signature of introgression occurs at sites throughout the genome, not just around mimicry genes. PMID:23864282

  20. Mutant maize variety containing the glt1-1 allele

    DOEpatents

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

    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.

  1. 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.

  2. Allelic variation contributes to bacterial host specificity.

    PubMed

    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

  3. 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

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

    PubMed Central

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

    2011-01-01

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

  5. Update on allele nomenclature for human cytochromes P450 and the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Database.

    PubMed

    Sim, Sarah C; Ingelman-Sundberg, Magnus

    2013-01-01

    Interindividual variability in xenobiotic metabolism and drug response is extensive and genetic factors play an important role in this variation. A majority of clinically used drugs are substrates for the cytochrome P450 (CYP) enzyme system and interindividual variability in expression and function of these enzymes is a major factor for explaining individual susceptibility for adverse drug reactions and drug response. Because of the existence of many polymorphic CYP genes, for many of which the number of allelic variants is continually increasing, a universal and official nomenclature system is important. Since 1999, all functionally relevant polymorphic CYP alleles are named and published on the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Web site (http://www.cypalleles.ki.se). Currently, the database covers nomenclature of more than 660 alleles in a total of 30 genes that includes 29 CYPs as well as the cytochrome P450 oxidoreductase (POR) gene. On the CYP-allele Web site, each gene has its own Webpage, which lists the alleles with their nucleotide changes, their functional consequences, and links to publications identifying or characterizing the alleles. CYP2D6, CYP2C9, CYP2C19, and CYP3A4 are the most important CYPs in terms of drug metabolism, which is also reflected in their corresponding highest number of Webpage hits at the CYP-allele Web site.The main advantage of the CYP-allele database is that it offers a rapid online publication of CYP-alleles and their effects and provides an overview of peer-reviewed data to the scientific community. Here, we provide an update of the CYP-allele database and the associated nomenclature. PMID:23475683

  6. Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics.

    PubMed

    Izaabel, H; Garchon, H J; Beaurain, G; Biga, M; Akhayat, O; Bach, J F; Caillat-Zucman, S

    1996-09-01

    HLA class II polymorphism in Moroccan IDDM patients has not been investigated so far. In this study, HLA-DRB1, -DQA1, and -DQB1 allele and haplotype frequencies were analyzed in 125 unrelated Moroccan IDDM patients and 93 unrelated healthy controls, all originating from the Souss region and mostly of Berber origin. Some common features with other Caucasian groups were observed, in particular, a predisposing effect of the DRB1*03-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 alleles or allelic combinations. The Moroccan IDDM group also presented with more specific characteristics. Among DRB1*04 subtypes, DRB1*0405 was associated with susceptibility to and DRB1*0406 with protection from the disease. The haplotype and the relative predispositional effect (RPE) analyses indicated that the DRB1*08-DQA1*0401-DQB1*0402 haplotype was also associated with susceptibility to IDDM. Interestingly, the DRB1*09-DQA1*0301-DQB1*0201 haplotype, completely absent from the control group and very rare in North African populations, was observed in 7.2% of the Moroccan diabetics. Conversely, the DRB1*07-DQA1*0201-DQB1*0201 and DRB1*15-DQA1*0102-DQB1*0602 haplotypes were associated with protection from IDDM. Finally, we observed an age-dependent genetic heterogeneity of IDDM, the frequencies of predisposing alleles being higher and those of protective alleles lower in childhood- than in adult-onset diabetics. Our data on Moroccan diabetics, together with data on European and Northern Mediterranean patients, suggest a gradient of various HLA class II predisposing and protective markers that link these populations. PMID:8872168

  7. Distribution of CYP2D6 alleles and phenotypes in the Brazilian population.

    PubMed

    Friedrich, Deise C; Genro, Júlia P; Sortica, Vinicius A; Suarez-Kurtz, Guilherme; de Moraes, Maria Elizabete; Pena, Sergio D J; dos Santos, Andrea K Ribeiro; Romano-Silva, Marco A; Hutz, Mara H

    2014-01-01

    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

  8. 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

  9. Biased Gene Conversion Skews Allele Frequencies in Human Populations, Increasing the Disease Burden of Recessive Alleles

    PubMed Central

    Lachance, Joseph; Tishkoff, Sarah A.

    2014-01-01

    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

  10. 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

  11. 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

  12. 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, Céline; Migliorini, Paola; Bombardieri, Stefano; Balsa, Alejandro; Westhovens, René; Barrera, Pilar; Radstake, Timothy R D J; Alves, Helena; Bardin, Thomas; Prum, Bernard; Emmrich, Frank; Cornelis, François; 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

  13. 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, Céline; Migliorini, Paola; Bombardieri, Stefano; Balsa, Alejandro; Westhovens, René; Barrera, Pilar; Radstake, Timothy R. D. J.; Alves, Helena; Bardin, Thomas; Prum, Bernard; Emmrich, Frank; Cornelis, François

    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

  14. 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, François; 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

  15. [Polymorphism of SSR alleles in pear cultivars grown in Belarus].

    PubMed

    Urbanovich, O Iu; Kozlovskaia, Z A; Iakimovich, O A; Kartel', N A

    2011-03-01

    Using SSR markers designed for Malus x domestica Borkh, genetic polymorphism of 43 pear accessions cultivated in Belarus was examined. A total of 217 alleles were identified with the mean number of 12.8 alleles per marker. The mean PIC value was 0.81; the mean number of informative alleles, 6.49. The heterozygosity level ranged from 0.30 to 0.84. Genetic diversity of SSR alleles in pear and apple genomes was compared. A method of identification of commercial pear cultivars using a set of six SSR markers was suggested. PMID:21542305

  16. 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

  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; Sánchez, 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.; Alarcón-Riquelme, Marta; Looger, Loren L.; Nath, Swapan K.; Acevedo, Eduardo; Acevedo, Eduardo; La Torre, Ignacio García-De; Maradiaga-Ceceña, Marco A.; Cardiel, Mario H.; Esquivel-Valerio, Jorge A.; Rodriguez-Amado, Jacqueline; Moctezuma, José 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 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

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

    PubMed

    Picanço, Juliane Bentes; Raimann, Paulo Eduardo; da Motta, Carlos Henrique Ares Silveira; Rodenbusch, Rodrigo; Gusmão, 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

  19. 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

  20. 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

  1. Implementing a Student Allele Database via the World Wide Web

    E-print Network

    Newberg, Heidi

    and implementation of the Human Genome Diver- sity Project's Student Allele Database Facility and its interface via Diversity project which we describe in this section. The Human Genome Diversity--Student Allele Database that illustrates many facets of the Human Genome Project. The project is centered around a hands-on laboratory

  2. Genome-wide mapping of allele-specific protein-

    E-print Network

    Cai, Long

    they lead to allele-specific gene expression remains to be determined. Dosage compensation regulates another that monoallelic expression of autosomal genes is not limited to genes linked to the immune or nervous systems of allele-specific gene expression. Mammalian somatic cells typically contain two copies of every gene

  3. Supplementary Information Measurement of the human allele frequency spectrum demonstrates

    E-print Network

    Keinan, Alon

    Supplementary Information Measurement of the human allele frequency spectrum demonstrates greater and validations based on Hinds et al. 36 6) Impact of length of bottleneck on modeling 39 7) Derived allele state filtering and balancing of SNPs from different sources: We eliminated SNPs that did not pass HapMap

  4. Tyrosinase and Tyrosinase Related Protein 1 Alleles Specify Domestic Cat

    E-print Network

    Eizirik, Eduardo

    Tyrosinase and Tyrosinase Related Protein 1 Alleles Specify Domestic Cat Coat Color Phenotypes in domestic cat coat color, we determined the complete nucleotide coding sequence of the domestic cat genes microsatellite, previously found to be fixed in a cat breed selected for the chocolate (b) allele of the B locus

  5. Demographic history and rare allele sharing among human populations

    E-print Network

    Keinan, Alon

    Demographic history and rare allele sharing among human populations Simon Gravela , Brenna M. Henna technology enables population-level surveys of human genomic variation. Here, we examine the joint allele that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations

  6. 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

  7. 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

  8. Distribution of human leukocyte antigens-E alleles in Thailand.

    PubMed

    Kimkong, Ingorn; Mutirangura, Apiwat; Pimtanothai, Nattiya

    2003-06-01

    The aim of this study was to investigate the distribution of human leukocyte antigens (HLA) -E alleles in Thailand. HLA-E alleles were assigned by using a polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method and direct sequencing in 200 healthy individuals. They comprised 100 Thai, 50 Chinese and 50 Thai-Chinese. From the results, three alleles of HLA-E could be detected in these populations. The E*0101 was the most common allele in Thai and Thai-Chinese with allelic frequencies of 42.5 per cent and 38 per cent, respectively. The other HLA-E allele frequencies of Thai origin were 33 per cent for E*01031 and 24.5 per cent for E*01032, respectively. Among Thai-Chinese, the allele frequencies of HLA-E were 31 per cent for E*01031 and E*01032, respectively. Whereas, the E*01031 was the predominant allele in Chinese origin with a frequency of 39 per cent, followed by E*0101 and E*01032 with 32 per cent and 29 per cent, respectively. No E*01033, E*0102 and E*0104 could be detected in all individuals. When comparing the distribution of HLA-E alleles between each of the populations (Thai vs Chinese, Thai vs Thai-Chinese and Chinese vs Thai-Chinese), no significant difference could be found among these populations. In addition, there was no significant difference of the distribution of HLA-E alleles between the study populations and other populations from Asian countries, reported previously. However, there were significant differences between the populations (Thai, Chinese and Thai-Chinese) and Danish (chi2 = 15.64, p = 0.0004; chi2 = 24.58, p = 0.0000046; chi2 = 14.69, p = 0.00065, respectively). PMID:12929994

  9. Characterization of phenylalanine hydroxylase alleles in untreated phenylketonuria patients from Victoria, Australia: origin of alleles and haplotypes.

    PubMed Central

    Ramus, S J; Treacy, E P; Cotton, R G

    1995-01-01

    Mutations in the phenylalanine hydroxylase (PAH) gene were identified in a group of untreated phenylketonuria patients from Victoria, Australia. Ninety-eight percent of the alleles were identified, and a total of 26 different mutations were detected on 83 independent chromosomes. The three most prevalent mutations--R408W, I65T, and IVS12nt1--together accounted for 54% of the alleles. A number of alleles were demonstrated, by genealogical studies, to be of Irish or Scottish origin, including a newly described mutation 1197/1198 del A. The distribution and relative frequencies of the more common alleles in this population parallel observed frequencies in the British Isles and are consistent with the known history of Caucasian settlement of this region of Australia. We have analyzed the haplotype and polymorphic short tandem-repeat allele of the mutant chromosomes and describe a number of new associations. Images Figure 2 PMID:7726156

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

    PubMed Central

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

    2013-01-01

    Background Polyploidy is a major component of eukaryote evolution. Estimation of allele copy numbers for molecular markers has long been considered a challenge for polyploid species, while this process is essential for most genetic research. With the increasing availability and whole-genome coverage of single nucleotide polymorphism (SNP) markers, it is essential to implement a versatile SNP genotyping method to assign allelic configuration efficiently in polyploids. Scope This work evaluates the usefulness of the KASPar method, based on competitive allele-specific PCR, for the assignment of SNP allelic configuration. Citrus was chosen as a model because of its economic importance, the ongoing worldwide polyploidy manipulation projects for cultivar and rootstock breeding, and the increasing availability of SNP markers. Conclusions Fifteen SNP markers were successfully designed that produced clear allele signals that were in agreement with previous genotyping results at the diploid level. The analysis of DNA mixes between two haploid lines (Clementine and pummelo) at 13 different ratios revealed a very high correlation (average = 0·9796; s.d. = 0·0094) between the allele ratio and two parameters [? angle = tan?1 (y/x) and y? = y/(x + y)] derived from the two normalized allele signals (x and y) provided by KASPar. Separated cluster analysis and analysis of variance (ANOVA) from mixed DNA simulating triploid and tetraploid hybrids provided 99·71 % correct allelic configuration. Moreover, triploid populations arising from 2n gametes and interploid crosses were easily genotyped and provided useful genetic information. This work demonstrates that the KASPar SNP genotyping technique is an efficient way to assign heterozygous allelic configurations within polyploid populations. This method is accurate, simple and cost-effective. Moreover, it may be useful for quantitative studies, such as relative allele-specific expression analysis and bulk segregant analysis. PMID:23422023

  11. 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 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at ?29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity?allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices. PMID:24690327

  12. Allelic Diversity and Its Implications for the Rate of Adaptation

    PubMed Central

    Caballero, Armando; García-Dorado, Aurora

    2013-01-01

    Genetic variation is usually estimated empirically from statistics based on population gene frequencies, but alternative statistics based on allelic diversity (number of allelic types) can provide complementary information. There is a lack of knowledge, however, on the evolutionary implications attached to allelic-diversity measures, particularly in structured populations. In this article we simulated multiple scenarios of single and structured populations in which a quantitative trait subject to stabilizing selection is adapted to different fitness optima. By forcing a global change in the optima we evaluated which diversity variables are more strongly correlated with both short- and long-term adaptation to the new optima. We found that quantitative genetic variance components for the trait and gene-frequency-diversity measures are generally more strongly correlated with short-term response to selection, whereas allelic-diversity measures are more correlated with long-term and total response to selection. Thus, allelic-diversity variables are better predictors of long-term adaptation than gene-frequency variables. This observation is also extended to unlinked neutral markers as a result of the information they convey on the demographic population history. Diffusion approximations for the allelic-diversity measures in a finite island model under the infinite-allele neutral mutation model are also provided. PMID:24121776

  13. Recurrence of the R408W Mutation in the Phenylalanine Hydroxylase Locus in Europeans

    PubMed Central

    Eisensmith, Randy C.; Goltsov, Alexei A.; O'Neill, Charles; Tyfield, Linda A.; Schwartz, Eugene I.; Kuzmin, Alexei I.; Baranovskaya, Svetlana S.; Tsukerman, Gennady L.; Treacy, Eileen; Scriver, Charles R.; Güttler, Flemming; Guldberg, Per; Eiken, Hans G.; Apold, Jaran; Svensson, Elisabeth; Naughten, Eileen; Cahalane, Seamus F.; Croke, David T.; Cockburn, Forrester; Woo, Savio L. C.

    1995-01-01

    The relative frequency of the common phenylalanine hydroxylase (PAH) mutation R408W and its associations with polymorphic RFLP, VNTR, and short-tandem-repeat (STR) sites in the PAH gene were examined in many European populations and one representative North American population of defined European descent. This mutation was found to cluster in two regions: in northwest Europe among Irish and Scottish peoples, and in eastern Europe, including the Commonwealth of Independent States. This allele was significantly less frequent in intervening populations. In eastern European populations, the R408W mutation is strongly associated with RFLP haplotype 2, the three-copy VNTR allele (VNTR 3), and the 240-bp STR allele. In northwestern European populations, it is strongly associated with RFLP haplotype 1, the VNTR allele containing eight repeats (VNTR 8), and the 244-bp STR allele. An examination of the linkage between the R408W mutation and highly polymorphic RFLP, VNTR, and STR haplotypes suggests that recurrence is the most likely mechanism to account for the two different major haplotype associations of R408W in Europe. ImagesFigure 1Figure 2 PMID:7825588

  14. Allelic exclusion of immunoglobulin genes: models and mechanisms

    PubMed Central

    Vettermann, Christian; Schlissel, Mark S.

    2010-01-01

    Summary The allelic exclusion of immunoglobulin (Ig) genes is one of the most evolutionarily conserved features of the adaptive immune system and underlies the monospecificity of B cells. While much has been learned about how Ig allelic exclusion is established during B-cell development, the relevance of monospecificity to B-cell function remains enigmatic. Here, we review the theoretical models that have been proposed to explain the establishment of Ig allelic exclusion and focus on the molecular mechanisms utilized by developing B cells to ensure the monoallelic expression of Ig? and Ig? light chain genes. We also discuss the physiological consequences of Ig allelic exclusion and speculate on the importance of monospecificity of B cells for immune recognition. PMID:20727027

  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. 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.

  18. 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.

  19. HLA alleles and haplotypes in the Turkish population: relatedness to Kurds, Armenians and other Mediterraneans.

    PubMed

    Arnaiz-Villena, A; Karin, M; Bendikuze, N; Gomez-Casado, E; Moscoso, J; Silvera, C; Oguz, F S; Sarper Diler, A; De Pacho, A; Allende, L; Guillen, J; Martinez Laso, J

    2001-04-01

    Turkish and Kurdish HLA profiles are studied for the first time. The comparative study of their allele frequencies, characteristic haplotypes, genetic distances with other Mediterraneans is complemented by neighbor-joining dendrograms and correspondence analyses. Turks, Kurds, Armenians, Iranians, Jews, Lebanese and other (Eastern and Western) Mediterranean groups seem to share a common ancestry: the older "Mediterranean" substratum. No sign of the postulated Indo-European (Aryan) invasion (1200 B.C.) is detected by our genetic analysis. It is concluded that this invasion, if occurred, had a relatively few invaders in comparison to the already settled populations, i.e. Anatolian Hittite and Hurrian groups (older than 2000 B.C.). These may have given rise to present-day Kurdish, Armenian and Turkish populations. PMID:11380939

  20. APOE ?4, 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 ?4 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 ?4 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, ?4 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

  1. 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 Crohn’s 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 Crohn’s 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

  2. Hematopoietic Cell Transplantation with Cord Blood for Cure of HIV Infections

    PubMed Central

    Petz, Lawrence; Redei, Istvan; Bryson, Yvonne; Regan, Donna; Kurtzberg, Joanne; Shpall, Elizabeth; Gutman, Jonathan; Querol, Sergio; Clark, Pamela; Tonai, Richard; Santos, Sarah; Bravo, Aide; Spellman, Stephen; Boo, Michael; Gragert, Loren; Rossi, John; Li, Shirley; Li, Haitang; Senitzer, David; Zaia, John; Forman, Stephen; Chow, Robert

    2015-01-01

    Hematopoietic cell transplantation (HCT) using CCR5-?32/?32 stem cells from an adult donor has resulted in the only known cure of HIV infection. However, it is not feasible to repeat this procedure except rarely because of the low incidence of the CCR5-delta 32 allele, the availability of only a small number of potential donors for most patients and the need for a very close HLA match between donor and recipient. In contrast, cord blood (CB) transplants require significantly less stringent HLA matching. Therefore, our hypothesis is that cure of HIV infections by HCT can be accomplished much more readily using umbilical cord blood stem cells obtained from a modestly sized inventory of cryopreserved CCR5-?32/?32 CB units. To test this hypothesis we have developed a screening program for cord blood units and are developing an inventory of CCR5-?32/?32 cryopreserved units available for HCT. 300 such units are projected to provide for Caucasian pediatric patients a 73.6% probability of finding an adequately HLA matched unit with a cell dose of ? 2.5 x 107TNC/kg and a 27.9% probability for Caucasian adults. With a cell dose of ? 1 x 107TNC/kg the corresponding projected probabilities are 85.6% and 82.1%. The projected probabilities are lower for ethnic minorities. Impetus for using CB HCT was provided by a transplant of an adult with acute myelogenous leukemia who was not HIV infected. The HCT was performed with a CCR5-?32/?32 CB unit, and post-transplant in vitro studies indicated that the patient’s peripheral blood mononuclear cells (PBMCs) were resistant to HIV infection. PMID:23089564

  3. Definitive high resolution typing of HLA-E allelic polymorphisms: Identifying potential errors in existing allele data.

    PubMed

    Grimsley, C; Kawasaki, A; Gassner, C; Sageshima, N; Nose, Y; Hatake, K; Geraghty, D E; Ishitani, A

    2002-09-01

    A set of robust PCR-SSP reactions were developed for each of the five polymorphic sites that define the five alleles of the HLA class Ib gene, HLA-E. This method was developed using 28 homozygous cell lines and further tested in a sample of African-Americans, a sample of Japanese, and a core panel of cell lines compiled for the 13th International Histocompatibility Workshop. Three alleles were found in each of these four sample groups, HLA-E*0101 (64.29, 50.00, 32.00 and 56.58%, respectively), *01031 (5.36, 20.65, 39.00 and 18.42%) and *01032 (30.35, 29.35, 29.00, and 25.00%). HLA-E*0102 was not detected in any of these samples nor in the cell line, LCL 722.221, in which this allele was originally described. HLA-E*0104 was not found either. This latter allele was originally reported in Japanese at a frequency of 1/22 (4.5%), which should have been high enough to have resulted in multiple occurrences of the *0104 allele in the samples tested in this study. We propose that the existence of the HLA-E*0102 and E*0104 alleles should be questioned. PMID:12445303

  4. European Space Agency European Space Exploration

    E-print Network

    Crawford, Ian

    European Space Agency Aurora European Space Exploration Programme EXECUTIVE SUMMARY #12;2 Aurora Programme EXECUTIVE SUMMARY 1. What is Aurora? A European Space Exploration Programme based on a road map economically and politically as a leading world power, it cannot leave space exploration to the other space

  5. 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

  6. theoretical population biology 50, 91 104 (1996) The Sampling Theory of Neutral Alleles in an

    E-print Network

    1996-01-01

    theoretical population biology 50, 91 104 (1996) The Sampling Theory of Neutral Alleles, New Haven, Connecticut 06520-8104 Received July 24, 1995 The sampling distribution of neutral alleles of allele types in a sample of N individuals from an island when the allele frequen- cies among immigrants

  7. Allele-Dependent Barley Grain ?-Amylase Activity1

    PubMed Central

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

    1998-01-01

    The wild ancestor of cultivated barley, Hordeum vulgare subsp. spontaneum (K. Koch) A. & Gr. (H. spontaneum), is a source of wide genetic diversity, including traits that are important for malting quality. A high ?-amylase trait was previously identified in H. spontaneum strains from Israel, and transferred into the backcross progeny of a cross with the domesticated barley cv Adorra. We have used Southern-blot analysis and ?-amy1 gene characterization to demonstrate that the high ?-amylase trait in the backcross line is co-inherited with the ?-amy1 gene from the H. spontaneum parent. We have analyzed the ?-amy1 gene organization in various domesticated and wild-type barley strains and identified three distinct ?-amy1 alleles. Two of these ?-amy1 alleles were present in modern barley, one of which was specifically found in good malting barley cultivars. The third allele, linked with high grain ?-amylase activity, was found only in a H. spontaneum strain from the Judean foothills in Israel. The sequences of three isolated ?-amy1 alleles are compared. The involvement of specific intron III sequences, in particular a 126-bp palindromic insertion, in the allele-dependent expression of ?-amylase activity in barley grain is proposed. PMID:9625721

  8. Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans.

    PubMed

    Du, Mengmeng; Auer, Paul L; Jiao, Shuo; Haessler, Jeffrey; Altshuler, David; Boerwinkle, Eric; Carlson, Christopher S; Carty, Cara L; Chen, Yii-Der Ida; Curtis, Keith; Franceschini, Nora; Hsu, Li; Jackson, Rebecca; Lange, Leslie A; Lettre, Guillaume; Monda, Keri L; Nickerson, Deborah A; Reiner, Alex P; Rich, Stephen S; Rosse, Stephanie A; Rotter, Jerome I; Willer, Cristen J; Wilson, James G; North, Kari; Kooperberg, Charles; Heard-Costa, Nancy; Peters, Ulrike

    2014-12-15

    Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain <10% of the phenotypic variance in height. We searched for novel associations between height and common (minor allele frequency, MAF ?5%) or infrequent (0.5% < MAF < 5%) variants across the exome in African Americans. Using a reference panel of 1692 African Americans and 471 Europeans from the National Heart, Lung, and Blood Institute's (NHLBI) Exome Sequencing Project (ESP), we imputed whole-exome sequence data into 13 719 African Americans with existing array-based GWAS data (discovery). Variants achieving a height-association threshold of P < 5E-06 in the imputed dataset were followed up in an independent sample of 1989 African Americans with whole-exome sequence data (replication). We used P < 2.5E-07 (=0.05/196 779 variants) to define statistically significant associations in meta-analyses combining the discovery and replication sets (N = 15 708). We discovered and replicated three independent loci for association: 5p13.3/C5orf22/rs17410035 (MAF = 0.10, ? = 0.64 cm, P = 8.3E-08), 13q14.2/SPRYD7/rs114089985 (MAF = 0.03, ? = 1.46 cm, P = 4.8E-10) and 17q23.3/GH2/rs2006123 (MAF = 0.30; ? = 0.47 cm; P = 4.7E-09). Conditional analyses suggested 5p13.3 (C5orf22/rs17410035) and 13q14.2 (SPRYD7/rs114089985) may harbor novel height alleles independent of previous GWAS-identified variants (r(2) with GWAS loci <0.01); whereas 17q23.3/GH2/rs2006123 was correlated with GWAS-identified variants in European and African populations. Notably, 13q14.2/rs114089985 is infrequent in African Americans (MAF = 3%), extremely rare in European Americans (MAF = 0.03%), and monomorphic in Asian populations, suggesting it may be an African-American-specific height allele. Our findings demonstrate that whole-exome imputation of sequence variants can identify low-frequency variants and discover novel variants in non-European populations. PMID:25027330

  9. Apolipoprotein E alleles in women with severe pre-eclampsia.

    PubMed Central

    Nagy, B; Rigó, J; Fintor, L; Karádi, I; Tóth, T

    1998-01-01

    This study investigated the frequency of apolipoprotein E (apoE) alleles among women with severe pre-eclampsia. The presence of the three most common apoE alleles (epsilon 2, epsilon 3, epsilon 4) was determined by polymerase chain reaction-restriction fragment length polymorphism in three groups of white women: non-pregnant healthy (n = 101), pregnant healthy (n = 52), and pregnant with a diagnosis of severe pre-eclampsia (n = 54). The frequency of apo epsilon 2 was highest among women with severe pre-eclampsia (16.6%) followed by non-pregnant women (12.9%), and those experiencing a healthy pregnancy (10.6%). The higher frequency of the apo epsilon 2 allele detected among women with severe pre-eclampsia suggests that apoE may play a role in the development of pre-eclampsia. PMID:9659248

  10. 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.

  11. 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

  12. 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

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

    PubMed

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

    2015-09-01

    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

  14. 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.

  15. 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

  16. Genetic Diversity and Population Structure Analysis of European Hexaploid Bread Wheat (Triticum aestivum L.)

    E-print Network

    Schierup, Mikkel Heide

    Genetic Diversity and Population Structure Analysis of European Hexaploid Bread Wheat (Triticum. Here, Diversity Array Technology (DArT) was used to characterize a population of 94 bread wheat. Our data provides an overview of the allele composition of bread wheat varieties anchored to DAr

  17. Nonfrequent but well-documented, rare and very rare HLA alleles observed in the Croatian population.

    PubMed

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

    2014-12-01

    The aim of the study was to evaluate the presence of nonfrequent, rare and very rare alleles among Croats and to estimate whether they are associated with specific alleles at other human leukocyte antigen (HLA) loci. This retrospective study included the typing results from the last 10?years; total number of individuals included was approximately 45,000. Among 17 alleles so far observed only once in our population, 6 (A*24:41, B*07:02:28, B*35:03:03, B*39:40N, DRB1*13:23 and DRB1*14:111) belong to very rare alleles, 2 (B*44:16 and DRB1*01:31) belong to rare alleles according to the 'Rare Alleles Detector' tool ( www.allelefrequencies.net), while for the B*35:101:01 allele published data exist only in the IMGT/HLA database. The remaining eight HLA alleles observed only once among Croats are considered as frequent according to the 'Rare Alleles Detector'. Those 17 HLA alleles are not declared as common well defined (CWD) alleles in the CWD allele catalogue 2.0.0. Haplotype analysis of nonfrequent alleles detected in our sample supports the idea that different populations, although similar in some aspects regarding HLA allele and haplotype distribution, still have some unique characteristics. This is the case for A*01:02, B*39:10 and DRB1*13:32 which form haplotypes unreported to date among our subjects. PMID:25413106

  18. 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

  19. 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

  20. 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 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

  1. 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...

  2. PUTATIVE ALLELES FOR INCREASED YIELD FROM SOYBEAN PLANT INTRODUCTIONS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Improving seed yield of soybean [Glycine max (L.) Merr.] cultivars is an important goal of breeding programs. The objective of this study was to evaluate two soybean plant introductions (PIs) as sources of alleles for the enhancement of seed yield in North American cultivars. A soybean population ...

  3. 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

  4. 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...

  5. Distribution of forensic marker allelic frequencies in Pernambuco, Northestern Brazil.

    PubMed

    Santos, S M; Souza, C A; Rabelo, K C N; Souza, P R E; Moura, R R; Oliveira, T C; Crovella, S

    2015-01-01

    Pernambuco is one of the 27 federal units of Brazil, ranking seventh in the number of inhabitants. We examined the allele frequencies of 13 short tandem repeat loci (CFS1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, vWA, and TPOX), the minimum recommended by the Federal Bureau of Investigation and commonly used in forensic genetics laboratories in Brazil, in a sample of 609 unrelated individuals from all geographic regions of Pernambuco. The allele frequencies ranged from 5 to 47.2%. No significant differences for any loci analyzed were observed compared with other publications in other various regions of Brazil. Most of the markers observed were in Hardy-Weinberg equilibrium. The occurrence of the allele 47.2 (locus FGA) and alleles 35.1 and 39 (locus D21S11), also described in a single study of the Brazilian population, was observed. The other forensic parameters analyzed (matching probability, power of discrimination, polymorphic information content, paternity exclusion, complement factor I, observed heterozygosity, expected heterozygosity) indicated that the studied markers are very informative for human forensic identification purposes in the Pernambuco population. PMID:25966202

  6. 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.

  7. 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.

  8. Extensive allele-specific translational regulation in hybrid 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

  9. 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

  10. Simple allelic-phenotype diversity and differentiation statistics for allopolyploids

    E-print Network

    Jiggins, Francis

    RB, UK The analysis of genetic diversity within and between populations is a routine task share alleles. As a result, analysis of genetic diversity patterns in allopolyploids has tended to rely: disomic inheritance; FDASH; FST; genetic differentiation; genetic diversity; polyploidy Introduction

  11. Cancer Cell Allele-Specific p53 Mutant Reactivation

    E-print Network

    Vazquez, Alexei

    Cancer Cell Article Allele-Specific p53 Mutant Reactivation Xin Yu,1,4,6 Alexei Vazquez,1 Rescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Using as either DNA contact mutants (e.g., p53R273H ) when the mutation occurs in a DNA binding residue

  12. INVESTIGATION Evidence for a Natural Allelic Series at the Maize

    E-print Network

    Doebley, John

    typically biallelic, like Mendel's classic loci, or do genes often harbor allelic series, i.e., multiple at the teosinte branched1 (tb1) gene in natural populations of teosinte (Zea mays ssp. parviglumis, Z. mays ssp populations as defined by number of genes involved and the effect sizes of these genes (Tanksley 1993; Mackay

  13. Segregation of male-sterility alleles across a species boundary.

    PubMed

    Weller, S G; Sakai, A K; Culley, T M; Duong, L; Danielson, R E

    2014-02-01

    Hybrid zones may serve as bridges permitting gene flow between species, including alleles influencing the evolution of breeding systems. Using greenhouse crosses, we assessed the likelihood that a hybrid zone could serve as a conduit for transfer of nuclear male-sterility alleles between a gynodioecious species and a hermaphroditic species with very rare females in some populations. Segregation patterns in progeny of crosses between rare females of hermaphroditic Schiedea menziesii and hermaphroditic plants of gynodioecious Schiedea salicaria heterozygous at the male-sterility locus, and between female S. salicaria and hermaphroditic plants from the hybrid zone, were used to determine whether male-sterility was controlled at the same locus in the parental species and the hybrid zone. Segregations of females and hermaphrodites in approximately equal ratios from many of the crosses indicate that the same nuclear male-sterility allele occurs in the parent species and the hybrid zone. These rare male-sterility alleles in S. menziesii may result from gene flow from S. salicaria through the hybrid zone, presumably facilitated by wind pollination in S. salicaria. Alternatively, rare male-sterility alleles might result from a reversal from gynodioecy to hermaphroditism in S. menziesii, or possibly de novo evolution of male sterility. Phylogenetic analysis indicates that some species of Schiedea have probably evolved separate sexes independently, but not in the lineage containing S. salicaria and S. menziesii. High levels of selfing and expression of strong inbreeding depression in S. menziesii, which together should favour females in populations, argue against a reversal from gynodioecy to hermaphroditism in S. menziesii. PMID:24417506

  14. Nomenclature for alleles of the thiopurine methyltransferase gene

    PubMed Central

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

    2013-01-01

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

  15. Nomenclature for alleles of the thiopurine methyltransferase gene.

    PubMed

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

    2013-04-01

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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

    PubMed

    Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

    2015-10-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. PMID:26291516

  1. Apolipoprotein ?4-allele as a significant risk factor for conversion from mild cognitive impairment to Alzheimer's disease: a meta-analysis of prospective studies.

    PubMed

    Fei, Ma; Jianhua, Wang

    2013-06-01

    Recent studies of the relationship between progression from mild cognitive impairment (MCI) to Alzheimer disease (AD) and APOE ?4-allele revealed inconsistent results. To estimate the risk posed by APOE ?4-allele for developing AD in MCI subjects using meta-analysis and identify possible sources of heterogeneity between studies, we reviewed longitudinal epidemiological studies of the presence of APOE ?4-allele on risk for progression to dementia in MCI subjects, and conducted meta-analyses of the results from these studies. Our study was derived from 315 positive-outcome events and 461 negative-outcome events from 8 prospective studies. The pooled RR was statistically significant (pooled RR?=?2.09; 95 % CI, 1.52-2.88). The Q statistics indicated high heterogeneity across studies (Q?=?14.21, p?=?0.003). RR were significantly related to the ethnicity of the sample (z?=?3.58, p?=?0.024). No significant heterogeneity was observed after stratification in four European-population studies (?²?=?0.67, p?=?0.880), but it remained in four American-population studies (?²?=?18.52, p?=?0.003). Heterogeneity markedly reduced after excluding one specific study (Q?=?4.9, p?=?0.009; I²?=?39 %). APOE ?4-allele conferred increased risk for progression to dementia in MCI subjects. Ethnicity is a critical factor to yield heterogeneity. Further studies using larger sample sizes are required. PMID:23242623

  2. 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

  3. Attenuated APC alleles produce functional protein from internal translation initiation

    PubMed Central

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

    2002-01-01

    Some truncating mutations of the APC tumor suppressor gene are associated with an attenuated phenotype of familial adenomatous polyposis coli (AAPC). This work demonstrates that APC alleles with 5? mutations produce APC protein that down-regulates ?-catenin, inhibits ?-catenin/T cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrate that cap-independent translation is initiated internally at an AUG at codon 184 of APC. Furthermore, APC coding sequence between AAPC mutations and AUG 184 permits internal ribosome entry in a bicistronic vector. These data suggest that AAPC alleles in vivo may produce functional APC by internal initiation and establish a functional correlation between 5? APC mutations and their associated clinical phenotype. PMID:12034871

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

    PubMed Central

    Chen, Hua; Slatkin, Montgomery

    2013-01-01

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

  5. [Phenotypic effects of puroindoline gene alleles of bread wheat].

    PubMed

    Chebotar, S V; Kurakina, K O; Khokhlov, O M; Chebotar, H O; Syvolap, Iu M

    2012-01-01

    85 winter bread wheat varieties and lines that have been developed mostly in Ukraine were analyzed with NIR for parameters of hardness and protein content. The hardness data were compared with the data of puroindoline gene alleles analysis done earlier and the published data. Significant variation of parameters of hardness was revealed when there was low polymorphism of puroindoline genes indicating the presence of additional genes that influence the hardness parameters. PMID:23074957

  6. 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

  7. Large multi-allelic copy number variations in humans

    PubMed Central

    Handsaker, Robert E.; Van Doren, Vanessa; Berman, Jennifer R.; Genovese, Giulio; Kashin, Seva; Boettger, Linda M.; McCarroll, Steven A.

    2015-01-01

    Thousands of genome segments appear to be present in widely varying copy number in different human genomes. We developed ways to use increasingly abundant whole genome sequence data to identify the copy numbers, alleles and haplotypes present at most large, multi-allelic CNVs (mCNVs). We analyzed 849 genomes sequenced by the 1000 Genomes Project to identify most large (>5 kb) mCNVs, including 3,878 duplications, of which 1,356 appear to have three or more segregating alleles. We find that mCNVs give rise to most human gene-dosage variation – exceeding sevenfold the contribution of deletions and biallelic duplications – and that this variation in gene dosage generates abundant variation in gene expression. We describe “runaway duplication haplotypes” in which genes, including HPR and ORM1, have mutated to high copy number on specific haplotypes. We describe partially successful initial strategies for analyzing mCNVs via imputation and provide an initial data resource to support such analyses. PMID:25621458

  8. 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.

  9. A versatile transgenic allele for mouse overexpression studies.

    PubMed

    Dolatshad, Hamid; Biggs, Daniel; Diaz, Rebeca; Hortin, Nicole; Preece, Christopher; Davies, Benjamin

    2015-12-01

    For the analysis of gene function in vivo, gene overexpression in the mouse provides an alternative to loss-of-function knock-out approaches and can help reveal phenotypes where compensatory mechanisms are at play. Furthermore, when multiple lines overexpressing a gene-of-interest at varying levels are studied, the consequences of differences in gene dosage can be explored. Despite these advantages, inherent shortcomings in the methodologies used for the generation of gain-of-function transgenic mouse models have limited their application to functional gene analysis, and the necessity for multiple lines comes at a significant animal and financial cost. The targeting of transgenic overexpression constructs at single copy into neutral genomic loci is the preferred method for the generation of such models, which avoids the unpredictable outcomes associated with conventional random integration. However, despite the increased reliability that targeted transgenic methodologies provide, only one expression level results, as defined by the promoter used. Here, we report a new versatile overexpression allele, the promoter-switch allele, which couples PhiC31 integrase-targeted transgenesis with Flp recombinase promoter switching and Cre recombinase activation. These recombination switches allow the conversion of different overexpression alleles, combining the advantages of transgenic targeting with tunable transgene expression. With this approach, phenotype severity can be correlated with transgene expression in a single mouse model, providing a cost-effective solution amenable to systematic gain-of-function studies. PMID:26369329

  10. Genetic relationships of Asians and Northern Europeans, revealed by Y-chromosomal DNA analysis.

    PubMed Central

    Zerjal, T; Dashnyam, B; Pandya, A; Kayser, M; Roewer, L; Santos, F R; Schiefenhövel, W; Fretwell, N; Jobling, M A; Harihara, S; Shimizu, K; Semjidmaa, D; Sajantila, A; Salo, P; Crawford, M H; Ginter, E K; Evgrafov, O V; Tyler-Smith, C

    1997-01-01

    We have identified a new T-->C transition on the human Y chromosome. C-allele chromosomes have been found only in a subset of the populations from Asia and northern Europe and reach their highest frequencies in Yakut, Buryats, and Finns. Examination of the microsatellite haplotypes of the C-allele chromosomes suggests that the mutation occurred recently in Asia. The Y chromosome thus provides both information about population relationships in Asia and evidence for a substantial paternal genetic contribution of Asians to northern European populations such as the Finns. Images Figure 1 Figure 3 Figure 4 PMID:9150165

  11. 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

  12. Autoantibodies, autoimmune risk alleles and clinical associations in rheumatoid arthritis cases and non-RA controls in the electronic medical records

    PubMed Central

    Liao, Katherine P.; Kurreeman, Fina; Li, Gang; Duclos, Grant; Murphy, Shawn; Raul Guzman, P; Cai, Tianxi; Gupta, Namrata; Gainer, Vivian; Schur, Peter; Cui, Jing; Denny, Joshua C.; Szolovits, Peter; Churchill, Susanne; Kohane, Isaac; Karlson, Elizabeth W.; Plenge, Robert M.

    2012-01-01

    Objectives The significance of non-RA autoantibodies in patients with rheumatoid arthritis (RA) is unclear. We studied associations between autoimmune risk alleles and autoantibodies in RA cases and non-RA controls, and autoantibodies and clinical diagnoses from the electronic medical records (EMR). Methods We studied 1,290 RA cases and 1,236 non-RA controls of European genetic ancestry from the EMR from two large academic centers. We measured antibodies to citrullinated peptides (ACPA), anti-nuclear antibodies (ANA), antibodies to tissue transglutaminase (anti-tTG), antibodies to thyroid peroxidase (anti-TPO). We genotyped subjects for autoimmune risk alleles, and studied the association between number of autoimmune risk alleles and number of types of autoantibodies present. We conducted a phenome-wide association study (PheWAS) to study potential associations between autoantibodies and clinical diagnoses among RA cases and controls. Results Mean age was 60.7 in RA and 64.6 years in controls, and both were 79% female. The prevalence of ACPA and ANA was higher in RA cases compared to controls (p<0.0001, both); we observed no difference in anti-TPO and anti-tTG. Carriage of higher numbers of autoimmune risk alleles was associated with increasing types of autoantibodies in RA cases (p=4.4x10?6) and controls (p=0.002). From the PheWAS, ANA was significantly associated with Sjogren’s/siccain RA cases. Conclusion The increased frequency of autoantibodies in RA cases and controls was associated with the number of autoimmune risk alleles carried by an individual. PheWAS analyses within the EMR linked to blood samples provide a novel method to test for the clinical significance of biomarkers in disease. PMID:23233247

  13. 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

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

    PubMed

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

    2014-04-01

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

  15. 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; Unterländer, 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 pathways—HERC2, SLC45A2, and TYR—using allele frequency estimates from Eneolithic, Bronze Age, and modern Eastern European samples and forward simulations. Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2–10% per generation. Our results provide direct evidence that strong selection favoring lighter skin, hair, and eye pigmentation has been operating in European populations over the last 5,000 y. PMID:24616518

  16. 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

  17. 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

    Juárez-Martín, Ana Itzel; González-Sobrino, Blanca Zoila; Olvera, Ángel Eduardo Camarena; Falfán-Valencia, Ramcés

    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

  18. 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

  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 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

  20. 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.; Vilá, Luis M.; Alarcón, 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?=?2.7×10?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

  1. 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

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

    PubMed Central

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

    2013-01-01

    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

  3. 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

  4. 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.

  5. COORDINATING EUROPEAN UNION ENVIRONMENTAL POLICY

    E-print Network

    Bateman, Ian J.

    COORDINATING EUROPEAN UNION ENVIRONMENTAL POLICY: SHIFTING FROM PASSIVE TO ACTIVE COORDINATION in the European Union (EU). The integration (or `mainstreaming') of environmental objectives into `non coordination. Keywords: Governance; coordination; European Union; environmental policy integration

  6. 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.

  7. 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

  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. 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)

  10. Allele specific expression in worker reproduction genes in the bumblebee Bombus terrestris

    PubMed Central

    Nathanael, Despina

    2015-01-01

    Methylation has previously been associated with allele specific expression in ants. Recently, we found methylation is important in worker reproduction in the bumblebee Bombus terrestris. Here we searched for allele specific expression in twelve genes associated with worker reproduction in bees. We found allele specific expression in Ecdysone 20 monooxygenase and IMP-L2-like. Although we were unable to confirm a genetic or epigenetic cause for this allele specific expression, the expression patterns of the two genes match those predicted for imprinted genes. PMID:26213649

  11. Creation and functional analysis of new Puroindoline alleles in Triticum aestivum.

    PubMed

    Feiz, L; Martin, J M; Giroux, M J

    2009-01-01

    The Hardness (Ha) locus controls grain texture and affects many end-use properties of wheat (Triticum aestivum L.). The Ha locus is functionally comprised of the Puroindoline a and b genes, Pina and Pinb, respectively. The lack of Pin allelic diversity is a major factor limiting Ha functional analyses and wheat quality improvement. In order to create new Ha alleles, a 630 member M(2) population was produced in the soft white spring cultivar Alpowa using ethylmethane sulfonate mutagenesis. The M(2) population was screened to identify new alleles of Pina and Pinb. Eighteen new Pin alleles, including eight missense alleles, were identified. F(2) populations for four of the new Pin alleles were developed after crossing each back to non-mutant Alpowa. Grain hardness was then measured on F(2:3) seeds and the impact of each allele on grain hardness was quantified. The tested mutations were responsible for between 28 and 94% of the grain hardness variation and seed weight and vigor of all mutation lines was restored among the F(2) populations. Selection of new Pin alleles following direct phenotyping or direct sequencing is a successful approach to identify new Ha alleles useful in improving wheat product quality and understanding Ha locus function. PMID:18846362

  12. 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.

  13. New York State TrueAllele® Casework Validation Study*

    PubMed Central

    Perlin, Mark W; Belrose, Jamie L; Duceman, Barry W

    2013-01-01

    DNA evidence can pose interpretation challenges, particularly with low-level or mixed samples. It would be desirable to make full use of the quantitative data, consider every genotype possibility, and objectively produce accurate and reproducible DNA match results. Probabilistic genotype computing is designed to achieve these goals. This validation study assessed TrueAllele® probabilistic computer interpretation on 368 evidence items in 41 test cases and compared the results with human review of the same data. Whenever there was a human result, the computer's genotype was concordant. Further, the computer produced a match statistic on 81 mixture items (for 87 inferred matching genotypes) in the test cases, while human review reported a statistic on 25 of these items (30.9%). Using match statistics to quantify information, probabilistic genotyping was shown to be sensitive, specific, and reproducible. These results demonstrate that objective probabilistic genotyping of biological evidence can reliably preserve DNA identification information. PMID:23865896

  14. Associations of HLA alleles with specific language impairment

    PubMed Central

    2014-01-01

    Background Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals affected by language impairment. Methods We perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types. Results Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD). Conclusion These preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders. PMID:24433325

  15. 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

  16. The European Fusion Programme

    SciTech Connect

    Antidormi, R.; Bartlett, D.; Bruhns, H.

    2004-03-15

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

  17. Association between rs2431697 T allele on 5q33.3 and systemic lupus erythematosus: case-control study and meta-analysis.

    PubMed

    Tang, Zhao-Ming; Wang, Ping; Chang, Pan-Pan; Hasahya, Tony; Xing, Hui; Wang, Jin-Ping; Hu, Li-Hua

    2015-11-01

    rs2431697 is located on 5q33.3, between pituitary tumor-transforming gene 1 and miR-146a. Several studies have estimated the association between rs2431697 and systemic lupus erythematosus risk. However, the results were inconsistent. A case-control study was carried out to explore the association between rs2431697 and systemic lupus erythematosus risk in a central Chinese population. Meta-analyses combining present with previous studies were conducted to further explore the association. Our case-control study included 322 cases and 353 controls. rs2431697 T allele was associated with increased risk of systemic lupus erythematosus (odds ratios (ORs)?=?1.461, 95 % confidence intervals (CI) 1.091-1.957, P?=?0.011). The association was stronger between T allele and the risk of anti-double-stranded DNA (dsDNA)-positive systemic lupus erythematosus (OR?=?2.510, 95 % CI 1.545-4.077, P?allele had an overall OR of 1.262 (95 % CI 1.205-1.323, P?allele had an OR of 1.213 (95 % CI 1.145-1.284, P?European descendant and 1.365 (95 % CI 1.259-1.480, P?allele had an OR of 1.337 (95 % CI 1.162-1.539, P?allele significantly associates with the increased risk of systemic lupus erythematosus. PMID:26251230

  18. Allelic Variation in KIR2DL3 Generates a KIR2DL2-like Receptor with Increased Binding to Its HLA-C Ligand12

    PubMed Central

    Frazier, William R.; Steiner, Noriko; Hou, Lihua; Dakshanamurthy, Sivanesan; Hurley, Carolyn Katovich

    2013-01-01

    Although extensive homology exists between their extracellular domains, natural killer cell inhibitory receptors KIR2DL2*001 and KIR2DL3*001 have previously been shown to differ substantially in their HLA-C binding avidity. To explore the largely uncharacterized impact of allelic diversity, the most common KIR2DL2/3 allelic products in European American and African American populations were evaluated for surface expression and binding affinity to their HLA-C group 1 and 2 ligands. Although no significant differences in the degree of cell membrane localization were detected in a transfected human NKL cell line by flow cytometry, surface plasmon resonance and KIR binding to a panel of HLA allotypes demonstrated that KIR2DL3*005 differed significantly from other KIR2DL3 allelic products in its ability to bind HLA-C. The increased affinity and avidity of KIR2DL3*005 for its ligand was also demonstrated to have a larger impact on the inhibition of IFN-? production by the human KHYG-1 NK cell line compared to KIR2DL3*001, a low affinity allelic product. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 in KIR2DL3*005 were critical to the observed phenotype. Although these residues are distal to the KIR/HLA-C interface, molecular modeling suggests that alteration in the interdomain hinge angle of KIR2DL3*005 towards that found in KIR2DL2*001, another strong receptor of the KIR2DL2/3 family, may be the cause of this increased affinity. The regain of inhibitory capacity by KIR2DL3*005 suggests that the rapidly evolving KIR locus may be responding to relatively recent selective pressures placed upon certain human populations. PMID:23686481

  19. 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

  20. 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

  1. Burden of risk alleles for Hypertension Increases Risk of Intracerebral Hemorrhage

    PubMed Central

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

    2012-01-01

    SUMMARY Background and Purpose Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (SNPs) associated with blood pressure (BP) levels have been identified. We sought to determine whether the cumulative burden of BP-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods Prospective multicenter case-control study in 2272 subjects of European descent (1025 cases and 1247 controls). Thirty-nine SNPs reported to be associated with BP levels were identified from the National Human Genome Research Institute GWAS catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results No single SNP was associated with either ICH or pre-ICH HTN. The BP-based unweighted genetic risk score was associated with risk of ICH (odds ratio [OR] = 1.11, 95% confidence interval [CI] 1.02–1.21, p=0.01) and the subset of ICH in deep regions (OR=1.18, 95%CI 1.07–1.30, p=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among controls (OR=1.17, 95%CI 1.04–1.31, p=0.009) and ICH cases (OR=1.15, 95%CI 1.01–1.31, p=0.04). Similar results were obtained when using a weighted score. Conclusion Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. PMID:22933587

  2. 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.

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

    PubMed Central

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

    2015-01-01

    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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. Suppression among alleles encoding nucleotide-binding-leucine-rich repeat resistance proteins interferes with resistance in F1 hybrid and allele-pyramided wheat plants.

    PubMed

    Stirnweis, Daniel; Milani, Samira D; Brunner, Susanne; Herren, Gerhard; Buchmann, Gabriele; Peditto, David; Jordan, Tina; Keller, Beat

    2014-09-01

    The development of high-yielding varieties with broad-spectrum durable disease resistance is the ultimate goal of crop breeding. In plants, immune receptors of the nucleotide-binding-leucine-rich repeat (NB-LRR) class mediate race-specific resistance against pathogen attack. When employed in agriculture this type of resistance is often rapidly overcome by newly adapted pathogen races. The stacking of different resistance genes or alleles in F1 hybrids or in pyramided lines is a promising strategy for achieving more durable resistance. Here, we identify a molecular mechanism which can negatively interfere with the allele-pyramiding approach. We show that pairwise combinations of different alleles of the powdery mildew resistance gene Pm3 in F1 hybrids and stacked transgenic wheat lines can result in suppression of Pm3-based resistance. This effect is independent of the genetic background and solely dependent on the Pm3 alleles. Suppression occurs at the post-translational level, as levels of RNA and protein in the suppressed alleles are unaffected. Using a transient expression system in Nicotiana benthamiana, the LRR domain was identified as the domain conferring suppression. The results of this study suggest that the expression of closely related NB-LRR resistance genes or alleles in the same genotype can lead to dominant-negative interactions. These findings provide a molecular explanation for the frequently observed ineffectiveness of resistance genes introduced from the secondary gene pool into polyploid crop species and mark an important step in overcoming this limitation. PMID:24942051

  9. Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: description of the new alleles and review of the literature.

    PubMed

    Adamek, Martina; Klages, Cornelia; Bauer, Manuela; Kudlek, Evelina; Drechsler, Alina; Leuser, Birte; Scherer, Sabine; Opelz, Gerhard; Tran, Thuong Hien

    2015-01-01

    The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms. HLA-B*41:21, HLA-DQB1*02:10 and HLA-DQA1*01:12 likely emerged from the common alleles of their groups by point mutations, all of which caused non-synonymous amino acid substitutions. In contrast, a deletion of one nucleotide leading to a frame shift with subsequent generation of a stop codon is responsible for the appearance of a null allele, HLA-A*01:123N. Whereas HLA-B*35:231 and HLA-B*53:31 were probably products of intralocus gene conversion between HLA-B alleles, HLA-C*07:294 presumably evolved by interlocus gene conversion between an HLA-C and an HLA-B allele. Our analysis of these novel alleles illustrates the different mechanisms which may have contributed to the evolution of HLA polymorphism. PMID:25500251

  10. allele dropout allele dropout

    E-print Network

    . More and more labs are attempting to process lower amounts of DNA, many without realizing with improved PCR master mixes and more robust DNA polymerases. This can potentially lead to labs pushing Biosystems, Foster City, CA) and PowerPlex® 16 HS (Promega Corporation, Madison, WI) PCR amplification kits

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

    PubMed

    Herrmann, D C; Wibbelt, G; Götz, 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

  12. 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

  13. 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

  14. 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.

  15. 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 wheat–rye (Secale cereale L.) t...

  16. Adaptive Mutation with Fitness and Allele Distribution Correlation for Genetic Algorithms

    E-print Network

    Yang, Shengxiang

    Adaptive Mutation with Fitness and Allele Distribution Correlation for Genetic Algorithms 34469 Istanbul, Turkey etaner@cs.itu.edu.tr ABSTRACT In this paper, a new gene based adaptive mutation and on gene based allele distribution statistics are correlated to explicitly adapt the mutation probability

  17. 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

  18. Stem Cell Reports Single-Cell Analysis of Proxy Reporter Allele-Marked Epithelial Cells

    E-print Network

    Jensen, Shane T.

    Stem Cell Reports Resource Single-Cell Analysis of Proxy Reporter Allele-Marked Epithelial Cells Establishes Intestinal Stem Cell Hierarchy Ning Li,1 Maryam Yousefi,1,5 Angela Nakauka-Ddamba,1 Rajan Jain,2 development of targeted murine reporter alleles as proxies for intestinal stem cell activity has led

  19. Theoretical Population Biology 52, 216 223 (1997) On the Genealogy of a Rare Allele

    E-print Network

    1997-01-01

    Theoretical Population Biology 52, 216 223 (1997) On the Genealogy of a Rare Allele Bruce Rannala 31, 1996 The gene genealogy is derived for a rare allele that is descended from a mutant ancestor is described for rapidly simulating these coalescence times. The relationship between the genealogical

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

    PubMed

    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

  1. Variation of Herbivore-Induced Volatile Terpenes among Arabidopsis Ecotypes Depends on Allelic Differences

    E-print Network

    Tholl, Dorothea

    Variation of Herbivore-Induced Volatile Terpenes among Arabidopsis Ecotypes Depends on Allelic Differences and Subcellular Targeting of Two Terpene Synthases, TPS02 and TPS031[W][OA] Mengsu Huang-duplicated terpene synthase genes, TPS02 and TPS03. The Ws genome contains a functional allele of TPS02

  2. Dynamics of insecticide resistance alleles in house fly populations from New York and Florida.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The frequency of insecticide resistance alleles for two genes (Vssc1 and CYP6D1) was studied in field collected populations of house flies from two different climates. While the frequency of these resistance alleles in flies at dairies from four states has recently been reported, there is no infor...

  3. Independent recruitment of Igh alleles in V(D)J recombination

    PubMed Central

    Alves-Pereira, Clara F.; de Freitas, Raquel; Lopes, Telma; Gardner, Rui; Marta, Filipa; Vieira, Paulo; Barreto, Vasco M.

    2014-01-01

    How the vast majority of B cells express only one of the two alleles at their immunoglobulin loci remains a biological puzzle. Here, in mice reconstituted with a single haematopoietic stem cell, we demonstrate that each of the two immunoglobulin heavy chain (Igh) alleles has a similar probability to be the first to undergo VH to DJH rearrangement. We also observe this similar probability in clones from multipotent and common lymphoid precursors. The extreme biases in the expression of the alleles that we find in more differentiated subsets are mostly due to constraints imposed by early rearrangements. Our data demonstrate that each of the two Igh alleles in a B cell behaves independently of the other, up to the moment when a successful rearrangement in one allele triggers a feedback mechanism that prevents further recombination. PMID:25517887

  4. No effect of the alpha1-antichymotrypsin A allele in Alzheimer's disease.

    PubMed

    Didierjean, O; Martinez, M; Campion, D; Hannequin, D; Dubois, B; Martin, C; Puel, M; Thomas Anterion, C; Pasquier, F; Moreau, O; Babron, M C; Penet, C; Agid, Y; Clerget-Darpoux, F; Frebourg, T; Brice, A

    1997-07-01

    The apolipoprotein E (ApoE)-epsilon4 allele is associated in a dose dependent manner to an increased risk for Alzheimer's disease. However, the ApoE-epsilon4 allele effect does not account for all patients with Alzheimer's disease, and the existence of other genetic risk factors has been postulated. Kamboh et al reported an association between Alzheimer's disease and the A allele of alpha1-antichymotrypsin (Aact) gene, which was not confirmed in a larger series more recently analysed. The ApoE and Aact genotypes were analysed in 314 patients with Alzheimer's disease and 173 healthy controls, confirming the dose dependent effect of the ApoE-epsilon4 allele. Nevertheless, even using odds ratios adjusted for age and sex, there was no significant effect of the Aact genotype on Alzheimer's disease or on the ApoE-epsilon4 allele associated risk for Alzheimer's disease. PMID:9221977

  5. No association between the alpha 1-antichymotrypsin A allele and Alzheimer's disease.

    PubMed

    Murphy, G M; Sullivan, E V; Gallagher-Thompson, D; Thompson, L W; van Duijn, C M; Forno, L S; Ellis, W G; Jagust, W J; Yesavage, J; Tinklenberg, J R

    1997-05-01

    The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD. PMID:9153464

  6. No effect of the ?1-antichymotrypsin A allele in Alzheimer's disease

    PubMed Central

    Didierjean, O; Martinez, M; Campion, D; Hannequin, D; Dubois, B; Martin, C; Puel, M; Anterion, C; Pasquier, F; Moreau, O; Babron, M; Penet, C; Agid, Y; Clerget-Darpoux, F; Frebourg, T; Brice, A

    1997-01-01

    The apolipoprotein E (ApoE)-?4 allele is associated in a dose dependent manner to an increased risk for Alzheimer's disease. However, the ApoE-?4 allele effect does not account for all patients with Alzheimer's disease, and the existence of other genetic risk factors has been postulated. Kamboh et al reported an association between Alzheimer's disease and the A allele of ?1-antichymotrypsin (Aact) gene, which was not confirmed in a larger series more recently analysed. The ApoE and Aact genotypes were analysed in 314 patients with Alzheimer's disease and 173 healthy controls, confirming the dose dependent effect of the ApoE-?4 allele. Nevertheless, even using odds ratios adjusted for age and sex, there was no significant effect of the Aact genotype on Alzheimer's disease or on the ApoE-?4 allele associated risk for Alzheimer's disease.?? PMID:9221977

  7. 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).

  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. Comparative analysis of type 2 diabetes-associated SNP alleles identifies allele-specific DNA-binding proteins for the KCNQ1 locus.

    PubMed

    Hiramoto, Masaki; Udagawa, Haruhide; Watanabe, Atsushi; Miyazawa, Keisuke; Ishibashi, Naoko; Kawaguchi, Miho; Uebanso, Takashi; Nishimura, Wataru; Nammo, Takao; Yasuda, Kazuki

    2015-07-01

    Although recent genome-wide association studies (GWAS) have been extremely successful, it remains a big challenge to functionally annotate disease?associated single nucleotide polymorphisms (SNPs), as the majority of these SNPs are located in non?coding regions of the genome. In this study, we described a novel strategy for identifying the proteins that bind to the SNP?containing locus in an allele?specific manner and successfully applied this method to SNPs in the type 2 diabetes mellitus susceptibility gene, potassium voltage?gated channel, KQT?like subfamily Q, member 1 (KCNQ1). DNA fragments encompassing SNPs, and risk or non?risk alleles were immobilized onto the novel nanobeads and DNA?binding proteins were purified from the nuclear extracts of pancreatic ? cells using these DNA?immobilized nanobeads. Comparative analysis of the allele-specific DNA-binding proteins indicated that the affinities of several proteins for the examined SNPs differed between the alleles. Nuclear transcription factor Y (NF?Y) specifically bound the non?risk allele of the SNP rs2074196 region and stimulated the transcriptional activity of an artificial promoter containing SNP rs2074196 in an allele?specific manner. These results suggest that SNP rs2074196 modulates the affinity of the locus for NF?Y and possibly induces subsequent changes in gene expression. The findings of this study indicate that our comparative method using novel nanobeads is effective for the identification of allele?specific DNA?binding proteins, which may provide important clues for the functional impact of disease?associated non?coding SNPs. PMID:25955334

  10. Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus.

    PubMed

    Fraser, Louise D; Zhao, Yuan; Lutalo, Pamela M K; D'Cruz, David P; Cason, John; Silva, Joselli S; Dunn-Walters, Deborah K; Nayar, Saba; Cope, Andrew P; Spencer, Jo

    2015-08-01

    The principles of allelic exclusion state that each B cell expresses a single light and heavy chain pair. Here, we show that B cells with both kappa and lambda light chains (Ig? and Ig?) are enriched in some patients with the systemic autoimmune disease systemic lupus erythematosus (SLE), but not in the systemic autoimmune disease control granulomatosis with polyangiitis. Detection of dual Ig? and Ig? expression by flow cytometry could not be abolished by acid washing or by DNAse treatment to remove any bound polyclonal antibody or complexes, and was retained after two days in culture. Both surface and intracytoplasmic dual light chain expression was evident by flow cytometry and confocal microscopy. We observed reduced frequency of rearrangements of the kappa-deleting element (KDE) in SLE and an inverse correlation between the frequency of KDE rearrangement and the frequency of dual light chain expressing B cells. We propose that dual expression of Ig? and Ig? by a single B cell may occur in some patients with SLE when this may be a consequence of reduced activity of the KDE. PMID:26036683

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

    PubMed

    McLarren, Keith W; Severson, Tesa M; du Souich, Christèle; 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

  12. 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 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

  13. 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

  14. Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction

    E-print Network

    Thormaehlen, Aenne S.

    A fundamental challenge to contemporary genetics is to distinguish rare missense alleles that disrupt protein functions from the majority of alleles neutral on protein activities. High-throughput experimental tools to ...

  15. 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.

  16. 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

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

    PubMed

    Vargas-Alarcón, G; Gamboa, R; Zuñiga, J; Hernández-Pacheco, G; Ramos-Kuri, M; Castillo, E; Gómez-Casado, E; Martínez-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

  18. The frequency of HLA alleles in a population of Inuit women of northern Quebec

    PubMed Central

    Metcalfe, Stephanie; Roger, Michel; Faucher, Marie-Claude; Coutlée, François; Franco, Eduardo L.; Brassard, Paul

    2013-01-01

    Background Human leukocyte antigen (HLA) alleles code for proteins that are involved in the recognition of foreign antigens and activation of the immune system. The frequency of HLA alleles varies across different populations. Objective To describe the frequency of HLA alleles in a population of Inuit women of Nunavik, Quebec, Canada. Design A cohort of women was recruited from 4 different communities between January 2002 and December 2007. HLA-B*07, HLA-DQB1*03, DQB1*06:02, DRB1*13 and DRB1*15:01 alleles were typed by PCR sequence-specific primers (PCR-SSP) and HLA-E and G alleles were type by DNA-sequencing procedures. Results We obtained data on 524 participants. The most frequent HLA alleles in this population were HLA-E*01:03, HLA-G*01:04:01 and HLA-DQB1*03, and they were found in 89, 75 and 94% of the population, respectively. Conclusions The distribution of HLA alleles in Nunavik, Quebec is unique when compared to other populations in Canada or around the world. PMID:23986892

  19. 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

  20. 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, ?? T cells, and ?? 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

  1. European security and France

    SciTech Connect

    deRose, A.

    1985-01-01

    A French authority on security argues for new European initiatives in the face of the ''danger represented by Soviet military power deployed in support of an imperialistic ideology.'' His proposals, including the strengthening of conventional forces without abandoning the option of the first use of nuclear weapons, are meant to give substance to President Mitterrand's declaration in 1983: ''The European nations now need to realize that their defense is also their responsibility....'' A part of the increasingly important debate in France over defense policy in Europe.

  2. 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 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

  3. 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

  4. Allelic-specific expression in relation to Bombyx mori resistance to Bt toxin.

    PubMed

    Chen, Yazhou; Li, Muwang; Islam, Iftakher; You, Lang; Wang, Yueqiang; Li, Zhiqian; Ling, Lin; Zeng, Baosheng; Xu, Jun; Huang, Yongping; Tan, Anjiang

    2014-11-01

    Understanding the mechanism of Bt resistance is one of the key elements of the effective application of Bt in pest control. The lepidopteran model insect, the silkworm, demonstrates qualities that make it an ideal species to use in achieving this understanding. We screened 45 strains of silkworm (Bombyx mori) using a Cry1Ab toxin variant. The sensitivity levels of the strains varied over a wide range. A resistant strain (P50) and a phylogenetically related susceptible strain (Dazao) were selected to profile the expressions of 12 Bt resistance-related genes. The SNPs in these genes were detected based on EST analysis and were validated by allelic-specific PCR. A comparison of allelic-specific expression between P50 and Dazao showed that the transcript levels of heterozygous genes containing two alleles rather than an imbalanced allelic expression contribute more to the resistance of P50 against Bt. The responses of the allelic-specific expression to Bt in hybrid larvae were then investigated. The results showed that the gene expression pattern of an ATP-binding cassette transporter C2 (ABCC2) and an aminopeptidase N (APN3), changed in an allelic-specific manner, with the increase of the resistant allele expression correlated with larval survival. The results suggest that a trans-regulatory mechanism in ABCC2 and APN3 allelic-specific expression is involved in the insect's response to the Bt toxin. The potential role of allelic-specific gene regulation in insect resistance to Bt toxins is discussed. PMID:25123097

  5. Detection of cystic brosis alleles from single cells using molecular beacons and a novel method of asymmetric

    E-print Network

    Wangh, Lawrence J.

    Detection of cystic ®brosis alleles from single cells using molecular beacons and a novel method-stranded amplicon is carried out in real time, using allele-speci®c molecular beacons. The LATE-PCR method permits with molecular beacons to identify the normal and DF508 alleles of cystic ®brosis in single human cells

  6. 205. POPULATION GENETICS Evolution can be defined as the change in allele frequencies in a population. For this definition to

    E-print Network

    Antonovics, Janis

    in a population. For this definition to be useful, we must also define the terms "allele frequency205. POPULATION GENETICS Evolution can be defined as the change in allele frequencies" and "population". A population is a group of freely interbreeding individuals. Alleles are different forms

  7. 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.

  8. Impact of ABCB1 allelic variants on QTc interval prolongation

    PubMed Central

    Sissung, Tristan M.; Gardner, Erin R.; Piekarz, Richard L.; Howden, Reuben; Chen, Xaiohong; Woo, Sukyung; Franke, Ryan; Clark, James A.; Miller-DeGraff, Laura; Steinberg, Seth M.; Venzon, David; Liewehr, David; Kleeberger, Steven R.; Bates, Susan E.; Price, Douglas K.; Rosing, Douglas R.; Cabell, Christopher; Sparreboom, Alex; Figg, William D.

    2010-01-01

    Purpose While the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e. blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT-prolongation and cardiotoxicity. Experimental design ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (?/?) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced QTc prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. Results Here, we demonstrate that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT-prolongation from baseline (?QTc) over time. Consistent with this observation, we also demonstrate that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ?QTc following a single dose of romidepsin. Conclusions To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT-prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT-prolongation following the administration of ABCB1-substrate drugs. PMID:21106724

  9. 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 < 5.0×10(-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

  10. 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; Rabès, 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

  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. 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...

  13. Fourth Conference European Chapter

    E-print Network

    for Computational Linguistics Order copies of this and other ACL proceedings from: Donald E. Walker (ACL) Bell for many forms of moral and material support. Don Walker and the officials of the European Chapter, Maghi Hammond John McNaught Jeanette Pugh Harold Somers Mary McGee Wood Referees Lars Ahrenberg (Linkdping

  14. 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…

  15. European Student Guide Mathematics

    E-print Network

    Harman, Neal.A.

    most of the UK Gateway to the Gower Peninsula, Britain's first area of Outstanding Natural BeautyEuropean Student Guide Mathematics www.swansea.ac.uk/maths www.swansea.ac.uk in the UK for overall research quality Safe and friendly multicultural city with lower living costs than

  16. 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…

  17. 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…

  18. European Commission Agriculture and

    E-print Network

    European Commission Agriculture and Rural Development Good practice guidance on the sustainable Commission (EC) DG Agriculture and Rural Development 130, Rue de la Loi B ­ 1049 Brussels, Belgium Phone: +32 (0) 2-2969909 Fax: +32 (0) 2-29211 33 E-mail: info@ec.europa.eu Web: https://www.ec.europa.eu/agriculture

  19. 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.

  20. 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

  1. 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; 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

    2014-05-01

    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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. Modified bases enable high-efficiency oligonucleotide-mediated allelic replacement via mismatch repair evasion

    E-print Network

    Wang, Harris H.

    Genome engineering using single-stranded oligonucleotides is an efficient method for generating small chromosomal and episomal modifications in a variety of host organisms. The efficiency of this allelic replacement strategy ...

  8. Prevalence of HLA-B*57:01 allele in Argentinean HIV-1 infected patients.

    PubMed

    Moragas, M; Belloso, W H; Baquedano, M S; Gutierrez, M I; Bissio, E; Larriba, J M; Fay, F; Aulicino, P; Gurevich, J M; Yaunguzian, M F; Maldonado, A C; Falistocco, C; Sen, L; Mangano, A

    2015-07-01

    Hypersensitivity reaction to abacavir (ABC hypersensitivity syndrome, AHS) is strongly associated with the presence of the HLA-B*57:01 allele. This study was designed to estimate the prevalence of HLA-B*57:01 allele in Argentinean HIV-1 infected patients. We analyzed the presence of HLA-B*57:01 allele in 1646 HIV-1 infected patients from different regions of Argentina. This allele was detected in 81 patients; most of them corresponded to patients living in the central region of the country. The prevalence of HLA-B*57:01 was 4.9%, similar to other Caucasian populations and higher than other data reported for South American populations. This strongly supports screening for the presence of HLA-B*57:01 in abacavir treatment of HIV-1 in our country. PMID:25922880

  9. 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

  10. Extent of differential allelic expression of candidate breast cancer genes is similar in blood and breast

    E-print Network

    Maia, Ana-Teresa; Spiteri, Inmaculada; Lee, Alvin J X; O'Reilly, Martin; Jones, Linda; Caldas, Carlos; Ponder, Bruce A J

    2009-12-10

    . Differential allelic expression (DAE) in heterozygote individuals could be used to develop a new approach to discover regulatory breast cancer susceptibility loci. As access to large numbers of fresh breast tissue to perform such studies is difficult, a...

  11. 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

  12. Stacking Pima S-6 fiber length alleles in a Tamcot 2111 background 

    E-print Network

    Souder, Christopher Lee

    2003-01-01

    Molecular markers can be used to stack fiber quality alleles among recombinant inbred lines and thus, aid in the development of unique genotypes. The objective of this study was to determine the potential for stacking Gossypium barbadense (Pima S-6...

  13. Genetic Dissection of the Drosophila melanogaster Female Head Transcriptome Reveals Widespread Allelic Heterogeneity

    E-print Network

    King, Elizabeth G.; Sanderson, Brian J.; McNeil, Casey Lee; Long, Anthony D.; Macdonald, Stuart J.

    2014-05-08

    explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume...

  14. Gametophytic self-incompatibility in Lycium parishii (Solanaceae): allelic diversity, genealogical

    E-print Network

    Miller, Jill S.

    Gametophytic self-incompatibility in Lycium parishii (Solanaceae): allelic diversity, genealogical controlling self- incompatibility (SI) for a population of Lycium parishii (Solanaceae) from Organ Pipe. andersonii. Gameto- phytic SI is well characterized for Solanaceae and although balancing selection

  15. Genomic Analysis of Parent-of-Origin Allelic Expression in Arabidopsis thaliana Seeds

    E-print Network

    Gehring, Mary

    Differential expression of maternally and paternally inherited alleles of a gene is referred to as gene imprinting, a form of epigenetic gene regulation common to flowering plants and mammals. In plants, imprinting primarily ...

  16. Sunflower domestication alleles support single domestication center in eastern North America

    E-print Network

    Rieseberg, Loren

    Sunflower domestication alleles support single domestication center in eastern North America conflicting hypotheses about evolutionary history or process. In sunflower, two genes have previously been to address a recent, controversial hypothesis about the origin of cultivated sunflower. Although

  17. Random Monoallelic Expression: Regulating gene expression one allele at a time

    PubMed Central

    Eckersley-Maslin, Mélanie 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

  18. G-allele of Intronic rs10830963 in MTNR1B Confers Increased Risk of Impaired Fasting Glycemia and Type 2 Diabetes Through an Impaired Glucose-Stimulated Insulin Release

    PubMed Central

    Sparsø, Thomas; Bonnefond, Amélie; Andersson, Ehm; Bouatia-Naji, Nabila; Holmkvist, Johan; Wegner, Lise; Grarup, Niels; Gjesing, Anette P.; Banasik, Karina; Cavalcanti-Proença, Christine; Marchand, Marion; Vaxillaire, Martine; Charpentier, Guillaume; Jarvelin, Marjo-Riitta; Tichet, Jean; Balkau, Beverley; Marre, Michel; Lévy-Marchal, Claire; Færch, Kristine; Borch-Johnsen, Knut; Jørgensen, Torben; Madsbad, Sten; Poulsen, Pernille; Vaag, Allan; Dina, Christian; Hansen, Torben; Pedersen, Oluf; Froguel, Philippe

    2009-01-01

    OBJECTIVE Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461). RESULTS The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 × 10?31) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 × 10?11) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017). CONCLUSIONS The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of ?-cell dysfunction and hepatic insulin resistance. PMID:19324940

  19. Hunting for the LCT-13910*T allele between the Middle Neolithic and the Middle Ages suggests its absence in dairying LBK people entering the Kuyavia region in the 8th millennium BP.

    PubMed

    Witas, Henryk W; P?oszaj, Tomasz; J?drychowska-Da?ska, Krystyna; Witas, Piotr J; Mas?owska, Alicja; Jerszy?ska, Blandyna; Koz?owski, Tomasz; Osipowicz, Grzegorz

    2015-01-01

    Populations from two medieval sites in Central Poland, Stary Brze?? Kujawski-4 (SBK-4) and Gruczno, represented high level of lactase persistence (LP) as followed by the LCT-13910*T allele's presence (0.86 and 0.82, respectively). It was twice as high as in contemporaneous Cedynia (0.4) and ?ródka (0.43), both located outside the region, higher than in modern inhabitants of Poland (0.51) and almost as high as in modern Swedish population (0.9). In an attempt to explain the observed differences its frequency changes in time were followed between the Middle Neolithic and the Late Middle Ages in successive dairying populations on a relatively small area (radius ?60km) containing the two sites. The introduction of the T allele to Kuyavia 7.4 Ka BP by dairying LBK people is not likely, as suggested by the obtained data. It has not been found in any of Neolithic samples dated between 6.3 and 4.5 Ka BP. The identified frequency profile indicates that both the introduction and the beginning of selection could have taken place approx. 4 millennia after first LBK people arrived in the region, shifting the value of LP frequency from 0 to more than 0.8 during less than 130 generations. We hypothesize that the selection process of the T allele was rather rapid, starting just after its introduction into already milking populations and operated via high rates of fertility and mortality on children after weaning through life-threatening conditions, favoring lactose-tolerant individuals. Facing the lack of the T allele in people living on two great European Neolithization routes, the Danubian and Mediterranean ones, and based on its high frequency in northern Iberia, its presence in Scandinavia and estimated occurrence in Central Poland, we propose an alternative Northern Route of its spreading as very likely. None of the successfully identified nuclear alleles turned out to be deltaF508 CFTR. PMID:25853887

  20. Microsatellite allele sizes: a simple test to assess their significance on genetic differentiation.

    PubMed

    Hardy, Olivier J; Charbonnel, Nathalie; Fréville, Hélène; Heuertz, Myriam

    2003-04-01

    The mutation process at microsatellite loci typically occurs at high rates and with stepwise changes in allele sizes, features that may introduce bias when using classical measures of population differentiation based on allele identity (e.g., F(ST), Nei's Ds genetic distance). Allele size-based measures of differentiation, assuming a stepwise mutation process [e.g., Slatkin's R(ST), Goldstein et al.'s (deltamu)(2)], may better reflect differentiation at microsatellite loci, but they suffer high sampling variance. The relative efficiency of allele size- vs. allele identity-based statistics depends on the relative contributions of mutations vs. drift to population differentiation. We present a simple test based on a randomization procedure of allele sizes to determine whether stepwise-like mutations contributed to genetic differentiation. This test can be applied to any microsatellite data set designed to assess population differentiation and can be interpreted as testing whether F(ST) = R(ST). Computer simulations show that the test efficiently identifies which of F(ST) or R(ST) estimates has the lowest mean square error. A significant test, implying that R(ST) performs better than F(ST), is obtained when the mutation rate, mu, for a stepwise mutation process is (a) >/= m in an island model (m being the migration rate among populations) or (b) >/= 1/t in the case of isolated populations (t being the number of generations since population divergence). The test also informs on the efficiency of other statistics used in phylogenetical reconstruction [e.g., Ds and (deltamu)(2)], a nonsignificant test meaning that allele identity-based statistics perform better than allele size-based ones. This test can also provide insights into the evolutionary history of populations, revealing, for example, phylogeographic patterns, as illustrated by applying it on three published data sets. PMID:12702690

  1. Microsatellite allele sizes: a simple test to assess their significance on genetic differentiation.

    PubMed Central

    Hardy, Olivier J; Charbonnel, Nathalie; Fréville, Hélène; Heuertz, Myriam

    2003-01-01

    The mutation process at microsatellite loci typically occurs at high rates and with stepwise changes in allele sizes, features that may introduce bias when using classical measures of population differentiation based on allele identity (e.g., F(ST), Nei's Ds genetic distance). Allele size-based measures of differentiation, assuming a stepwise mutation process [e.g., Slatkin's R(ST), Goldstein et al.'s (deltamu)(2)], may better reflect differentiation at microsatellite loci, but they suffer high sampling variance. The relative efficiency of allele size- vs. allele identity-based statistics depends on the relative contributions of mutations vs. drift to population differentiation. We present a simple test based on a randomization procedure of allele sizes to determine whether stepwise-like mutations contributed to genetic differentiation. This test can be applied to any microsatellite data set designed to assess population differentiation and can be interpreted as testing whether F(ST) = R(ST). Computer simulations show that the test efficiently identifies which of F(ST) or R(ST) estimates has the lowest mean square error. A significant test, implying that R(ST) performs better than F(ST), is obtained when the mutation rate, mu, for a stepwise mutation process is (a) >/= m in an island model (m being the migration rate among populations) or (b) >/= 1/t in the case of isolated populations (t being the number of generations since population divergence). The test also informs on the efficiency of other statistics used in phylogenetical reconstruction [e.g., Ds and (deltamu)(2)], a nonsignificant test meaning that allele identity-based statistics perform better than allele size-based ones. This test can also provide insights into the evolutionary history of populations, revealing, for example, phylogeographic patterns, as illustrated by applying it on three published data sets. PMID:12702690

  2. 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.

  3. 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.

  4. Allelic Diversity of MSP1 Gene in Plasmodium falciparum from Rural and Urban Areas of Gabon

    PubMed Central

    Mawili-Mboumba, Denise Patricia; Mbondoukwe, Noé; 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 (1.55±0.75). 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

  5. 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

  6. 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.; Müller, 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 Program’s bioinformatics web pages. PMID:23510415

  7. Detection of multiple beta-casein (CASB) alleles by amplification created restriction sites (ACRS).

    PubMed

    Lien, S; Aleström, 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

  8. HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities.

    PubMed

    Strong, Roland K; Holmes, Margaret A; Li, Pingwei; Braun, Laura; Lee, Ni; Geraghty, Daniel E

    2003-02-14

    Previous studies of HLA-E allelic polymorphism have indicated that balancing selection may be acting to maintain two major alleles in most populations, indicating that a functional difference may exist between the alleles. The alleles differ at only one amino acid position, where an arginine at position 107 in HLA-E*0101 (E(R)) is replaced by a glycine in HLA-E*0103 (E(G)). To investigate possible functional differences, we have undertaken a study of the physical and biochemical properties of these two proteins. By comparing expression levels, we found that whereas steady-state protein levels were similar, the two alleles did in fact differ with respect to cell surface levels. To help explain this difference, we undertook studies of the relative differences in peptide affinity, complex stability, and three-dimensional structure between the alleles. The crystal structures for HLA-E(G) complexed with two distinct peptides were determined, and both were compared with the HLA-E(R) structure. No significant differences in the structure of HLA-E were induced as a result of binding different peptides or by the allelic substitution at position 107. However, there were clear differences in the relative affinity for peptide of each heavy chain, which correlated with and may be explained by differences between their thermal stabilities. These differences were completely consistent with the relative levels of the HLA-E alleles on the cell surface and may indeed correlate with functional differences. This in turn may help explain the apparent balancing selection acting on this locus. PMID:12411439

  9. 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

  10. Molecular characterisation of indigenous Swedish apple cultivars based on SSR and S-allele analysis.

    PubMed

    Garkava-Gustavsson, L; Kolodinska Brantestam, A; Sehic, J; Nybom, H

    2008-06-01

    Trees of 68 apple cultivars, aimed for preservation by the 'National Program for diversity of cultivated plants' as mandate cultivars, were analysed using a set of 10 SSR (simple sequence repeat) primer pairs and the self-incompatibility (S-)locus to evaluate genetic diversity and reveal inter-cultivar relationships. The 12 polymorphic SSR loci exhibited 2 to 15 alleles, with expected heterozygozity (H(e)) ranging from 0.36 to 0.88 and a mean of 0.74. Numerous alleles were classified as rare or unique (35% and 18% respectively). For the S-locus, a total of 14 alleles were identified in this study. Five alleles, S1-S3, S5 and S7 had frequencies ranging from 11 to 18%, whereas the remaining 9 alleles were below 6%. All sexually obtained cultivars could be distinguished with the set of SSR loci. Sports were identical with their progenitors in two cases, but differed in one SSR allele in a third case. An SSR-based dendrogram, based on Roger's genetic distances, did not reveal any clear pattern of clustering. The genetic distances were, however, correlated with a corresponding matrix obtained in a previously conducted RAPD-based study of the same cultivars. Non-mandate parents of Swedish mandate cultivars together with some other reference cultivars were included in this study to check the accuracy of allele scoring, verify parentage and compare the results of this study with those presented in previously published studies. Some discrepancies in allele sizing were revealed and the possibilities of avoiding this problem are discussed. PMID:18667000

  11. 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

  12. Selection and Reduced Population Size Cannot Explain Higher Amounts of Neandertal Ancestry in East Asian than in European Human Populations

    PubMed Central

    Kim, Bernard Y.; Lohmueller, Kirk E.

    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

  13. 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

  14. Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants.

    PubMed

    Kassner, Ursula; Salewsky, Bastian; Wühle-Demuth, Marion; Szijarto, Istvan Andras; Grenkowitz, Thomas; Binner, Priska; März, Winfried; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja

    2015-09-01

    Rare monogenic hyperchylomicronemia is caused by loss-of-function mutations in genes involved in the catabolism of triglyceride-rich lipoproteins, including the lipoprotein lipase gene, LPL. Clinical hallmarks of this condition are eruptive xanthomas, recurrent pancreatitis and abdominal pain. Patients with LPL deficiency and severe or recurrent pancreatitis are eligible for the first gene therapy treatment approved by the European Union. Therefore the precise molecular diagnosis of familial hyperchylomicronemia may affect treatment decisions. We present a 57-year-old male patient with excessive hypertriglyceridemia despite intensive lipid-lowering therapy. Abdominal sonography showed signs of chronic pancreatitis. Direct DNA sequencing and cloning revealed two novel missense variants, c.1302A>T and c.1306G>A, in exon 8 of the LPL gene coexisting on the same allele. The variants result in the amino-acid exchanges p.(Lys434Asn) and p.(Gly436Arg). They are located in the carboxy-terminal domain of lipoprotein lipase that interacts with the glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) and are likely of functional relevance. No further relevant mutations were found by direct sequencing of the genes for APOA5, APOC2, LMF1 and GPIHBP1. We conclude that heterozygosity for damaging mutations of LPL may be sufficient to produce severe hypertriglyceridemia and that chylomicronemia may be transmitted in a dominant manner, at least in some families. PMID:25585702

  15. 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

  16. 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.

  17. 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

  18. Activation of the Arabidopsis thaliana Immune System by Combinations of Common ACD6 Alleles

    PubMed Central

    Todesco, Marco; Kim, Sang-Tae; Chae, Eunyoung; Bomblies, Kirsten; Zaidem, Maricris; Smith, Lisa M.; Weigel, Detlef; Laitinen, Roosa A. E.

    2014-01-01

    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

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

    PubMed Central

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

    2014-01-01

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

  20. ACE-II genotype and I allele predicts ischemic stroke among males in south India

    PubMed Central

    Vijayan, Murali; Chinniah, Rathika; Ravi, Padma Malini; Mosses Joseph, Arun Kumar; Vellaiappan, Neethi Arasu; Krishnan, Jeyaram Illiayaraja; Karuppiah, Balakrishnan

    2014-01-01

    Two hundred ischemic stroke patients and 193 age and sex matched healthy controls were studied for the presence of Angiotensin Converting Enzyme Insertion/Deletion (ACE I/D) gene polymorphism. The PCR studies revealed that ACE ‘II’ (OR = 2.055; p = 0.004) genotype and ‘I’ (OR = 1.411; p = 0.018) alleles were significantly associated with IS patients. Gender specific analysis revealed a strong association of ‘II’ (OR = 2.044; p = 0.014) genotype and ‘I’ (OR = 1.531; p = 0.011) allele with male sex. Classification of patients based on TOAST criteria, revealed a significant association for ‘II’ genotype (OR = 1.713; p = 0.043) and ‘I’ (OR = 1.382; p = 0.039) allele in LVD patients only. When the data was stratified based on age and sex, a statistically significant association was observed for ACE ‘II’ genotype (OR = 2.288; p = 0.006) and ‘I’ allele (OR = 1.395; p = 0.054) in IS male patients of > 50 years of age. The ACE ‘D’ allele was found to be increased in controls (OR = 0.709; p = 0.018) than IS patients. Multivariate logistic regression analysis showed that smoking and diabetes were the most powerful independent risk factor in LVD type of stroke. Thus, we presented here an evidence for a strong association of ACE ‘II’ genotype and ‘I’ allele compounded by factors such as smoking and diabetes among south Indian IS patients. PMID:25606450

  1. Rapid Microarray-Based Identification of Different mecA Alleles in Staphylococci

    PubMed Central

    Müller, Elke; Schwarz, Stefan; Hotzel, Helmut; Ehricht, Ralf

    2012-01-01

    To screen isolates and to identify mecA alleles, published mecA sequences were analyzed, and a microarray for the rapid discrimination of mecA alleles was designed. A GenBank analysis yielded 135 full-length gene sequences annotated as mecA. These sequences clustered into 32 different alleles corresponding to 28 unique amino acid sequences and to 15 distinct hybridization patterns on this microarray. A collection of 78 clinical and veterinary isolates of Staphylococcus spp. was characterized using this assay. Nine of the 15 expected patterns, as well as one as-yet-unknown pattern, were identified. These patterns were detected in various epidemic methicillin-resistant Staphylococcus aureus strains, in S. pseudintermedius, and in coagulase-negative species such as S. epidermidis, S. fleurettii, or S. haemolyticus. There was no correlation between the different mecA hybridization patterns and the SCCmec type. Determination of MICs showed that mecA alleles corresponding to only four of these nine patterns were associated with ?-lactam resistance. The mecA alleles that did not confer ?-lactam resistance were largely restricted to coagulase-negative staphylococci of animal origin, such as S. sciuri and S. vitulinus. Because of the diversity of sequences and the different impact on ?-lactam susceptibility, the existence of different mecA alleles needs to be taken into account when designing diagnostic assays for the detection of mecA. PMID:22890767

  2. 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 (S1–S9 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/S1–S9/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

  3. Allelic diversity and molecular characterization of puroindoline genes in five diploid species of the Aegilops genus.

    PubMed

    Cuesta, Susana; Guzmán, 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

  4. 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

  5. Low and high expressing alleles of the LMNA gene: implications for laminopathy disease development.

    PubMed

    Rodríguez, Sofía; Eriksson, Maria

    2011-01-01

    Today, there are at least a dozen different genetic disorders caused by mutations within the LMNA gene, and collectively, they are named laminopathies. Interestingly, the same mutation can cause phenotypes with different severities or even different disorders and might, in some cases, be asymptomatic. We hypothesized that one possible contributing mechanism for this phenotypic variability could be the existence of high and low expressing alleles in the LMNA locus. To investigate this hypothesis, we developed an allele-specific absolute quantification method for lamin A and lamin C transcripts using the polymorphic rs4641(C/T)LMNA coding SNP. The contribution of each allele to the total transcript level was investigated in nine informative human primary dermal fibroblast cultures from Hutchinson-Gilford progeria syndrome (HGPS) and unaffected controls. Our results show differential expression of the two alleles. The C allele is more frequently expressed and accounts for ?70% of the lamin A and lamin C transcripts. Analysis of samples from six patients with Hutchinson-Gilford progeria syndrome showed that the c.1824C>T, p.G608G mutation is located in both the C and the T allele, which might account for the variability in phenotype seen among HGPS patients. Our method should be useful for further studies of human samples with mutations in the LMNA gene and to increase the understanding of the link between genotype and phenotype in laminopathies. PMID:21980471

  6. S-genotype identification based on allele-specific PCR in Japanese pear.

    PubMed

    Nashima, Kenji; Terakami, Shingo; Nishio, Sogo; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Yamamoto, Toshiya

    2015-06-01

    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 (S (1)-S (9) and S (k)) 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 (S (1)/S (1)-S (9)/S (9) and S (4sm)/S (4sm)) 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

  7. Allele-Selective Inhibition of Mutant Huntingtin Expression with Antisense Oligonucleotides Targeting the Expanded CAG Repeat

    PubMed Central

    Gagnon, Keith T.; Pendergraff, Hannah M.; Deleavey, Glen F.; Swayze, Eric E.; Potier, Pierre; Randolph, John; Roesch, Eric B.; Chattopadhyaya, Jyoti; Damha, Masad J.; Bennett, C. Frank; Montaillier, Christophe; Lemaitre, Marc; Corey, David R.

    2010-01-01

    Huntington's disease (HD) is a currently incurable neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat within the huntingtin (HTT) gene. Therapeutic approaches include selectively inhibiting the expression of the mutated HTT allele while conserving function of the normal allele. We have evaluated a series of antisense oligonucleotides (ASOs) targeted to the expanded CAG repeat within HTT mRNA for their ability to selectively inhibit expression of mutant HTT protein. Several ASOs incorporating a variety of modifications, including bridged nucleic acids and phosphorothioate internucleotide linkages, exhibited allele-selective silencing in patient-derived fibroblasts. Allele-selective ASOs did not affect the expression of other CAG repeat-containing genes and selectivity was observed in cell lines containing minimal CAG repeat lengths representative of most HD patients. Allele-selective ASOs left HTT mRNA intact and did not support ribonuclease H activity in vitro. We observed cooperative binding of multiple ASO molecules to CAG repeat-containing HTT mRNA transcripts in vitro. These results are consistent with a mechanism involving inhibition at the level of translation. ASOs targeted to the CAG repeat of HTT provide a starting point for the development of oligonucleotide-based therapeutics that can inhibit gene expression with allelic discrimination in patients with HD. PMID:21028906

  8. HLA Genes in the Chuvashian Population from European Russia: Admixture of Central European and Mediterranean Populations

    E-print Network

    Arnaiz-Villena, Antonio; Martinez-Laso, Jorge; Moscoso, Juan; Livshits, Gregory; Zamora, Jorge; Gomez-Casado, Eduardo; Silvera-Redondo, Carlos; Melvin, Kristin L.; Crawford, Michael H.

    2003-06-01

    HLA alleles have been determined for the first time in individuals from the Chuvashian population by DNA typing and sequencing. HLA-A, -B, -DR, and -DQ allele frequencies and extended haplotypes have also been determined, and the results compared...

  9. BMI-Associated Alleles Do Not Constitute Risk Alleles for Polycystic Ovary Syndrome Independently of BMI: A Case-Control Study

    PubMed Central

    Louwers, Yvonne V.; Rayner, Nigel W.; Herrera, Blanca M.; Stolk, Lisette; Groves, Christopher J.; Barber, Thomas M.; Uitterlinden, Andre G.; Franks, Stephen

    2014-01-01

    Introduction Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration. Methods Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles. Results None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed. Conclusion In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI. PMID:24498077

  10. 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 reaction–restriction 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

  11. 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

  12. 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

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

    PubMed Central

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

    2013-01-01

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

  14. Genetic diversity comparison of the DQA gene in European rabbit (Oryctolagus cuniculus) populations.

    PubMed

    Magalhães, Vanessa; Abrantes, Joana; Munõz-Pajares, Antonio Jesús; 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

  15. 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.

  16. Polarisation of Major Histocompatibility Complex II Host Genotype with Pathogenesis of European Brown Hare Syndrome Virus

    PubMed Central

    Iacovakis, Christos; Mamuris, Zissis; Moutou, Katerina A.; Touloudi, Antonia; Hammer, Anne Sofie; Valiakos, George; Giannoulis, Themis; Stamatis, Costas; Spyrou, Vassiliki; Athanasiou, Labrini V.; Kantere, Maria; Asferg, Tommy; Giannakopoulos, Alexios; Salomonsen, Charlotte M.; Bogdanos, Dimitrios; Birtsas, Periklis; Petrovska, Liljana; Hannant, Duncan; Billinis, Charalambos

    2013-01-01

    A study was conducted in order to determine the occurrence of European Brown Hare Syndrome virus (EBHSV) in Denmark and possible relation between disease pathogenesis and Major Histocompatibility Complex (MHC) host genotype. Liver samples were examined from 170 brown hares (hunted, found sick or dead), collected between 2004 and 2009. Macroscopical and histopathological findings consistent with EBHS were detected in 24 (14.1%) hares; 35 (20.6%) had liver lesions not typical of the syndrome, 50 (29.4%) had lesions in other tissues and 61 (35.9%) had no lesions. Sixty five (38.2%) of 170 samples were found to be EBHSV-positive (RT-PCR, VP60 gene). In order to investigate associations between viral pathogenesis and host genotype, variation within the exon 2 DQA gene of MHC was assessed. DQA exon 2 analysis revealed the occurrence of seven different alleles in Denmark. Consistent with other populations examined so far in Europe, observed heterozygosity of DQA (Ho?=?0.1180) was lower than expected (He?=?0.5835). The overall variation for both nucleotide and amino acid differences (2.9% and 14.9%, respectively) were lower in Denmark than those assessed in other European countries (8.3% and 16.9%, respectively). Within the peptide binding region codons the number of nonsynonymous substitutions (dN) was much higher than synonymous substitutions (dS), which would be expected for MHC alleles under balancing selection. Allele frequencies did not significantly differ between EBHSV-positive and -negative hares. However, allele Leeu-DQA*30 was detected in significantly higher (P?=?0.000006) frequency among the positive hares found dead with severe histopathological lesions than among those found sick or apparently healthy. In contrast, the latter group was characterized by a higher frequency of the allele Leeu-DQA*14 as well as the proportion of heterozygous individuals (P?=?0.000006 and P?=?0.027). These data reveal a polarisation between EBHSV pathogenesis and MHC class II genotype within the European brown hare in Denmark. PMID:24069299

  17. The apolipoprotein E epsilon4 allele and incident Alzheimer's disease in persons with mild cognitive impairment.

    PubMed

    Aggarwal, Neelum T; Wilson, Robert S; Beck, Todd L; Bienias, Julia L; Berry-Kravis, Elizabeth; Bennett, David A

    2005-02-01

    Possession of one or more copies of the apolipoprotein E (APOE) epsilon4 allele is a known risk factor for Alzheimer's disease (AD), but it is uncertain whether the epsilon4 allele is associated with disease incidence among persons with mild cognitive impairment (MCI). We addressed this issue with data from the Religious Orders Study. Participants were 181 older Catholic clergy members who met criteria for MCI based on a uniform structured clinical evaluation; 56 (30.9%) had at least one epsilon4 allele. Clinical evaluations, which included clinical classification of dementia and AD, were repeated annually. During a mean of 5.7 years of observation, 79 persons (43.6%) developed AD. In a proportional hazards model that controlled for age, sex, and education, possession of an epsilon4 allele was associated with a 93% increase in the risk of developing Alzheimer's disease (95% CI; 1.02, 2.63). There was a marginally significant reduction in the effect of epsilon4 in older compared to younger participants (p=.053). The results suggest that possession of an epsilon4 allele does increase risk of AD in persons with MCI. PMID:15804918

  18. A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: Implications for carrier screening

    SciTech Connect

    Triggs-Raine, B.L.; Akerman, B.R.; Gravel, R.A. ); Mules, E.H.; Thomas, G.H.; Dowling, C.E. ); Kaback, M.M.; Lim-Steele, J.S.T. ); Natowicz, M.R. ); Grebner, E.E. ); Navon, R.R. ); Welch, J.P. ); Greenberg, C.R. )

    1992-10-01

    Deficiency of [beta]-hexosaminidase A (Hex A) activity typically results in Tay-Sachs disease. However, healthy subjects found to be deficient in Hex A activity (i.e., pseudodeficient) by means of in vitro biochemical tests have been described. The authors analyzed the HEXA gene of one pseudodeficient subject and identified both a C[sub 739]-to-T substitution that changes Arg[sub 247][yields]Trp on one allele and a previously identified Tay-Sachs disease mutation of the second allele. Six additional pseudodeficient subjects were found to have the C[sub 739]-to-T but for none of 36 Jewish enzyme-defined carries who did not have one of three known mutations common to this group. The C[sub 739]-to-T allele, together with a [open quotes]true[close quotes] Tay-Sachs disease allele, causes Hex A pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and that standard biochemical screening cannot differentiate between heterozygotes for the C[sub 739]-to-T mutations and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. This could prevent unnecessary or incorrect prenatal diagnoses. 40 refs., 3 figs., 4 tabs.

  19. Allelic Dropout Can Cause False-Positive Results for Prader-Willi and Angelman Syndrome Testing

    PubMed Central

    Hussain Askree, Syed; Hjelm, Lawrence N.; Ali Pervaiz, Muhammad; Adam, Margaret; Bean, Lora J.H.; Hedge, Madhuri; Coffee, Bradford

    2011-01-01

    The diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing. Our laboratory uses a standard methylation-sensitive PCR (MSP) to target the differentially methylated SNRPN gene to test for Prader-Willi syndrome (PWS) and Angelman syndrome. One patient, a 27-month-old female, who lacked the classical clinical features of PWS, but had a molecular diagnosis of PWS by MSP by another laboratory, had repeat testing in our laboratory. Testing by MSP in our laboratory also identified an apparent loss of the unmethylated paternal allele, consistent with a diagnosis of PWS. Confirmatory testing using Southern blot analysis with a methylation-sensitive restriction enzyme showed a normal pattern of methylation, detecting both the methylated maternal and unmethylated paternal alleles. To investigate these discrepant results, we amplified and sequenced the SNRPN locus in this patient and identified a single nucleotide change within the binding site for the unmethylated DNA-specific primer. These results indicate this nucleotide change led to allelic dropout in the MSP analysis, yielding the false-positive result. Subsequently, MSP analysis using an alternate primer set that was developed by our laboratory detected both methylated and unmethylated alleles. These findings illustrate that allelic dropout due to the presence of rare polymorphisms can cause false-positive results in commonly used MSP assays and lead to molecular misdiagnosis. PMID:21227401

  20. Antagonistic effects of a Mhc class I allele on malaria-infected house sparrows.

    PubMed

    Loiseau, Claire; Zoorob, Rima; Garnier, Stéphane; 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

  1. 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

  2. Predicting Carriers of Ongoing Selective Sweeps without Knowledge of the Favored Allele.

    PubMed

    Ronen, Roy; Tesler, Glenn; Akbari, Ali; Zakov, Shay; Rosenberg, Noah A; Bafna, Vineet

    2015-09-01

    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

  3. Spatial heterogeneity in the strength of selection against deleterious alleles and the mutation load

    PubMed Central

    Roze, D

    2012-01-01

    According to current estimates of genomic deleterious mutation rates (which are often of the order 0.1–1) the mutation load (defined as a reduction in the average fitness of a population due to the presence of deleterious alleles) may be important in many populations. In this paper, I use multilocus simulations to explore the effect of spatial heterogeneity in the strength of selection against deleterious alleles on the mutation load (for example, it has been suggested that stressful environments may increase the strength of selection). These simulations show contrasted results: in some situations, spatial heterogeneity may greatly reduce the mutation load, due to the fact that migrants coming from demes under stronger selection carry relatively few deleterious alleles, and benefit from a strong advantage within demes under weaker selection (where individuals carry many more deleterious alleles); in other situations, however, deleterious alleles accumulate within demes under stronger selection, due to migration pressure from demes under weaker selection, leading to fitness erosion within those demes. This second situation is more frequent when the productivity of the different demes is proportional to their mean fitness. The effect of spatial heterogeneity is greatly reduced, however, when the response to environmental differences is inconsistent across loci. PMID:22588129

  4. Association between HLA-DRB1 alleles and tuberculosis: a meta-analysis.

    PubMed

    Chen, B F; Wang, R; Chen, Y J; Zhu, Y; Ding, L; Wen, Y F

    2015-01-01

    Although a number of studies have reported that human leukocyte antigen (HLA)-DRB1 alleles may be correlated with tuberculosis (TB), most were based on small samples or inconsistent and unclear results. Here, we present a meta-analysis to investigate the relationship between HLA-DRB1 alleles and TB susceptibility. We gathered relevant information from published studies on the association between HLA?DRB1 alleles and TB susceptibility through a systematic research. Data from eligible fifteen studies were included in the meta-analyses. Each dataset was statistically analyzed to evaluate the HLA?DRB1 alleles by calculating the respective odds ratios (ORs) and 95% confidence intervals (CIs). The results revealed that frequencies of two DRB1 alleles were significantly decreased in TB: DRB1*03 (P = 0.016, OR = 0.78, 95%CI = 0.67?0.95) and DRB1*07 (P = 0.017, OR = 0.81, 95%CI = 0.68?0.96). Thus, our data indicate that DRB1*03 and DRB1*07 may provide protective effects against TB susceptibility. However, well?designed studies with large sample sizes are required for better understanding of this association. PMID:26634553

  5. Natural allelic variations in glutathione peroxidase-1 affect its subcellular localization and function*

    PubMed Central

    Bera, Soumen; Weinberg, Frank; Ekoue, Dede N.; Ansenberger-Fricano, Kristine; Mao, Mao; Bonini, Marcelo G.; Diamond, Alan M.

    2014-01-01

    Glutathione peroxidase 1 (GPx-1) has been implicated in the etiology of several common diseases due to the association between specific allelic variations and cancer risk. The most common among these variations are the codon 198 polymorphism that results in either a leucine or proline and the number of alanine repeat codons in the coding sequence. The molecular and biological consequences of these variations remain to be characterized. Towards achieving this goal, we have examined the cellular location of GPx-1 encoded by allelic variants by ectopically expressing these genes in MCF-7 human breast carcinoma cells that produce undetectable levels of GPx-1, thus achieving exclusive expression in the same cellular environment. A differential distribution between the cytoplasm and mitochondria was observed, with the allele expressing the leucine-198 polymorphism and 7 alanine repeats being more cytoplasmically located than the other alleles examined. To assess whether the distribution of GPx-1 between the cytoplasm and mitochondria had a biological consequence, we engineered derivative GPx-1 proteins that were targeted to the mitochondria by the addition of a mitochondria targeting sequence and expressed these proteins in MCF-7 cells. These cells were examined for their response to oxidative stress, energy metabolism and impact on cancer-associated signaling molecules. The results obtained indicated that both primary GPx-1 sequence and cellular location have a profound impact on cellular biology and offer feasible hypotheses as to how expression of distinct GPx-1 alleles can impact cancer risk. PMID:25047527

  6. 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

  7. 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

  8. 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.

  9. Resistance allele frequency to bt cotton in field populations of helicoverpa armigera (Lepidoptera: Noctuidae) in China.

    PubMed

    Liu, Fengyi; Xu, Zhiping; Chang, Juhua; Chen, Jin; Meng, Fengxia; Zhu, Yu Cheng; Shen, Jinliang

    2008-06-01

    Resistance evolution in target insects to Bacillus thurningiensis (Bt) cotton, Gossypium hirsutum L., is a main threat to Bt cotton technology. An increasing trend of population density of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) has been observed since 2001 in Qiuxian County (Hebei, China), where Bt cotton has been planted dominantly since 1998. This region was selected in 2006 and 2007 for estimating frequency of gene alleles conferring resistance to Bt cotton by screening the F1 progeny from single-pair cross between field-collected male and laboratory female of the Bt-resistant strain of H. armigera (F1 screen). F1 offspring from each single-pair line were screened for resistance alleles based on larval growth, development, and survival on Bt cotton leaves for 5 d. Two-year results indicated that approximately equal to 20% of field-collected males carried resistance alleles. The conservative estimate of the resistance allele frequency was 0.094 (95% CI, 0.044-0.145) for 2006 and 0.107 (95% CI, 0.055-0.159) for 2007. This is the first report of resistance allele frequency increase to such a high level in the field in China. Long-term adoption of Bt sprays, dominant planting of single-toxin-producing Bt cotton, and lack of conventional cotton refuge system might accelerate the resistance evolution in the region. PMID:18613597

  10. Two steps forward, one step back: the pleiotropic effects of favoured alleles.

    PubMed Central

    Otto, Sarah P.

    2004-01-01

    Pleiotropy is one of the most commonly observed attributes of genes. Yet the extent and influence of pleiotropy have been underexplored in population genetics models. In this paper, I quantify the extent to which pleiotropy inhibits the spread of alleles in response to directional selection on a focal trait. Under the assumption that pleiotropic effects are extensive and deleterious, the fraction of alleles that are beneficial overall is severely limited by pleiotropy and rises nearly linearly with the strength of directional selection on the focal trait. Over a broad class of distribution of pleiotropic effects, the mean selective effect of those alleles that are beneficial overall is halved, on average, by pleiotropy. The fraction of new mutant alleles that are beneficial overall and that succeed in fixing within a population is even more severely limited when directional selection is weak, but it rises quadratically with the strength of directional selection. Finally, the mean selective effect of mutant alleles that are beneficial and succeed in fixing is reduced by one-third, on average, by pleiotropy. These results help to shape our understanding of the evolutionary inertia caused by pleiotropy. PMID:15209104

  11. A case of DNA analysis of ABO blood group variant allele A2.

    PubMed

    Mitani, T; Tsujita, H; Kobayashi, T; Yokota, M; Akane, A

    2000-12-01

    The ABO phenotype of a bloodstain (B) on a knife that was used as a weapon in an attempted murder case was found to be different from that of the Peruvian victim's blood (AB). Serological analysis showed that the A-antigenicity was much weaker than B antigenicity, suggesting that the victim's phenotype was A(2)B or A(3)B. So, the ABO genotypes of the knife bloodstain and the victim's blood were determined by DNA analysis. The 261st G deletion, specific to the O(1) allele, was not detected in the specimens by restriction fragment length polymorphism analysis. Also, the 871st A, specific to the A(3) allele, was not found by the allele-specific amplification method. Amplified product length polymorphism and direct sequencing methods finally demonstrated that the typical B sequence was found in one allele and a single C deletion in the 1,059th-1,061st C stretch in the other allele, indicating that the ABO phenotype of the bloodstain and victim's blood were A(2)B. PMID:12935705

  12. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles

    PubMed Central

    1993-01-01

    Naturally processed peptides were acid extracted from immunoaffinity- purified HLA-DR2, DR3, DR4, DR7, and DR8. Using the complementary techniques of mass spectrometry and Edman microsequencing, > 200 unique peptide masses were identified from each allele, ranging from 1,200 to 4,000 daltons (10-34 residues in length), and a total of 201 peptide sequences were obtained. These peptides were derived from 66 different source proteins and represented sets nested at both the amino- and carboxy-terminal ends with an average length of 15-18 amino acids. Strikingly, most of the peptides (> 85%) were derived from endogenous proteins that intersect the endocytic/class II pathway, even though class II molecules are thought to function mainly in the presentation of exogenous foreign peptide antigens. The predominant endogenous peptides were derived from major histocompatibility complex-related molecules. A few peptides derived from exogenous bovine serum proteins were also bound to every allele. Four prominent promiscuous self- peptide sets (capable of binding to multiple HLA-DR alleles) as well as 84 allele-specific peptide sets were identified. Binding experiments confirmed that the promiscuous peptides have high affinity for the binding groove of all HLA-DR alleles examined. A potential physiologic role for these endogenous self-peptides as immunomodulators of the cellular immune response is discussed. PMID:8315383

  13. 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.

  14. European Union: Constraints vs. Opportunities

    E-print Network

    Kahiha, Nguvitjita

    2007-12-17

    constraints for U.S. firms entering the market; and (b) facilitate 5 individual U.S. firms to operate within the European Union. In other words, the European institutional framework eliminates internal trade barriers and creates strict regulations... to the market with three more nations on the waiting list. Table 1: European Enlargement Year Countries No. of countries Population as of 2005 in millions 1957 Germany, France, Belgium, Netherlands, Italy, Luxemburg 6 228.8 1973 Denmark, Ireland...

  15. 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.

  16. A novel genetic screen identifies checkpoint-defective alleles of Schizosaccharomyces pombe chk1.

    PubMed

    Wan, S; Walworth, N C

    2001-01-01

    The protein kinase Chk1 is required in the fission yeast Schizosaccharomyces pombe for delaying cell cycle progression in response to DNA damage. Chk1 becomes phosphorylated when DNA is damaged by a variety of agents, including the anti-tumor drug camptothecin. To further characterize the behavior of Chk1 in response to DNA damage, we used PCR-based mutagenesis of the chk1 gene coupled with in vivo gap repair to generate mutant alleles. Of 44 chk1 mutants recovered, six encode full-length proteins that confer a DNA damage-sensitive phenotype. All of the alleles render cells checkpoint-defective, but confer subtle differences in sensitivity to camptothecin or UV light. Mutant alleles were sequenced and served to identify regions of the protein that are critical for checkpoint function. PMID:11270571

  17. Genomic analysis of hybrid rice varieties reveals numerous superior alleles that contribute to heterosis.

    PubMed

    Huang, Xuehui; Yang, Shihua; Gong, Junyi; Zhao, Yan; Feng, Qi; Gong, Hao; Li, Wenjun; Zhan, Qilin; Cheng, Benyi; Xia, Junhui; Chen, Neng; Hao, Zhongna; Liu, Kunyan; Zhu, Chuanrang; Huang, Tao; Zhao, Qiang; Zhang, Lei; Fan, Danlin; Zhou, Congcong; Lu, Yiqi; Weng, Qijun; Wang, Zi-Xuan; Li, Jiayang; Han, Bin

    2015-01-01

    Exploitation of heterosis is one of the most important applications of genetics in agriculture. However, the genetic mechanisms of heterosis are only partly understood, and a global view of heterosis from a representative number of hybrid combinations is lacking. Here we develop an integrated genomic approach to construct a genome map for 1,495 elite hybrid rice varieties and their inbred parental lines. We investigate 38 agronomic traits and identify 130 associated loci. In-depth analyses of the effects of heterozygous genotypes reveal that there are only a few loci with strong overdominance effects in hybrids, but a strong correlation is observed between the yield and the number of superior alleles. While most parental inbred lines have only a small number of superior alleles, high-yielding hybrid varieties have several. We conclude that the accumulation of numerous rare superior alleles with positive dominance is an important contributor to the heterotic phenomena. PMID:25651972

  18. Natural Selection VS. Random Drift: Evidence from Temporal Variation in Allele Frequencies in Nature

    PubMed Central

    Mueller, Laurence D.; Barr, Lorraine G.; Ayala, Francisco J.

    1985-01-01

    We have obtained monthly samples of two species, Drosophila pseudoobscura and Drosophila persimilis, in a natural population from Napa County, California. In each species, about 300 genes have been assayed by electrophoresis for each of seven enzyme loci in each monthly sample from March 1972 to June 1975. Using statistical methods developed for the purpose, we have examined whether the allele frequencies at different loci vary in a correlated fashion. The methods used do not detect natural selection when it is deterministic (e.g., overdominance or directional selection), but only when alleles at different loci vary simultaneously in response to the same environmental variations. Moreover, only relatively large fitness differences (of the order of 15%) are detectable. We have found strong evidence of correlated allele frequency variation in 13–20% of the cases examined. We interpret this as evidence that natural selection plays a major role in the evolution of protein polymorphisms in nature. PMID:4054608

  19. Allelic association at the D14S43 locus in early onset Alzheimer`s disease

    SciTech Connect

    Brice, A.; Tardieu, S.; Campion, D.; Martinez, M.

    1995-04-24

    The D14S43 marker is closely linked to the major gene for early onset autosomal dominant Alzheimer`s disease on chromosome 14. Allelic frequencies at the D14S43 locus were compared in 113 familial and isolated cases of early onset Alzheimer`s disease (<60 years of age at onset) (EOAD) and 109 unaffected individuals of the same geographic origin. Allele 7 was significantly (P = 0.033) more frequent in type 1 EOAD patients (13.2%), defined by the presence of at least another first degree relative with EOAD, than in controls (4.1%). Since an autosomal dominant gene is probably responsible for type 1 patients, allelic association may reflect linkage disequilibrium at the D14S43 locus. This would mean that some patients share a common ancestral mutation. However, since multiple tests were carried out, this result must be interpreted with caution, and needs confirmation in an independent sample. 16 refs., 2 tabs.

  20. Genotyping bovine milk proteins using allele discrimination by primer length and automated DNA sizing technology.

    PubMed

    Lindersson, M; Lundén, A; Andersson, L

    1995-04-01

    A method for genotyping kappa-casein (A, B, E), beta-casein (A1, A2, A3, A5, B) and beta-lactoglobulin (A, B) simultaneously by the use of allele discrimination by primer length combined with automated detection of fragments with a sequencing instrument is described. Seven different mutations within the milk protein genes were analysed in order to distinguish between the alleles examined. The samples were amplified in two separate multiplex polymerase chain reactions (PCRs), which were then pooled and separated according to size in a single lane on the gel. By using stringent PCR conditions, we have been able to achieve allele-specific amplifications and minimize amplification of mis-matched primer for all seven mutations. PMID:7733509

  1. Analysis of an "off-ladder" allele at the Penta D short tandem repeat locus.

    PubMed

    Yang, Y L; Wang, J G; Wang, D X; Zhang, W Y; Liu, X J; Cao, J; Yang, S L

    2015-01-01

    Kinship testing of a father and his son from Guangxi, China, the location of the Zhuang minority people, was performed using the PowerPlex® 18D System with a short tandem repeat typing kit. The results indicated that both the father and his son had an off-ladder allele at the Penta D locus, with a genetic size larger than that of the maximal standard allelic ladder. To further identify this locus, monogenic amplification, gene cloning, and genetic sequencing were performed. Sequencing analysis demonstrated that the fragment size of the Penta D-OL locus was 469 bp and the core sequence was [AAAGA]21, also called Penta D-21. The rare Penta D-21 allele was found to be distributed among the Zhuang population from the Guangxi Zhuang Autonomous Region of China; therefore, this study improved the range of DNA data available for this locus and enhanced our ability for individual identification of gene loci. PMID:26634472

  2. Transgene- and locus-dependent imprinting reveals allele-specific chromosome conformations.

    PubMed

    Lonfat, Nicolas; Montavon, Thomas; Jebb, David; Tschopp, Patrick; Nguyen Huynh, Thi Hanh; Zakany, Jozsef; Duboule, Denis

    2013-07-16

    When positioned into the integrin ?-6 gene, an Hoxd9lacZ reporter transgene displayed parental imprinting in mouse embryos. While the expression from the paternal allele was comparable with patterns seen for the same transgene when present at the neighboring HoxD locus, almost no signal was scored at this integration site when the transgene was inherited from the mother, although the Itga6 locus itself is not imprinted. The transgene exhibited maternal allele-specific DNA hypermethylation acquired during oogenesis, and its expression silencing was reversible on passage through the male germ line. Histone modifications also corresponded to profiles described at known imprinted loci. Chromosome conformation analyses revealed distinct chromatin microarchitectures, with a more compact structure characterizing the maternally inherited repressed allele. Such genetic analyses of well-characterized transgene insertions associated with a de novo-induced parental imprint may help us understand the molecular determinants of imprinting. PMID:23818637

  3. Establishing the Limits of TrueAllele® Casework: A Validation Study.

    PubMed

    Greenspoon, Susan A; Schiermeier-Wood, Lisa; Jenkins, Brad C

    2015-09-01

    The limits of the expert system, TrueAllele® Casework (TA), were explored using challenging mock casework profiles that included 17 single-source and 18 two-, 15 three- and 7 four-person DNA mixtures. The sensitivity (ability to detect a minor contributor) of the TA analysis process was examined by challenging the system with mixture DNA samples that exhibited allelic and locus dropout and other stochastic effects. The specificity (ability to exclude nondonors) was rigorously tested by interrogating TA derived genotypes with 100 nondonor profiles. The accuracy with which TA estimated mixture weights of contributors to the two-person mixtures was examined. Finally, first-degree relatives of donors were used to assess the ability of the system to exclude close relatives. TA demonstrated great accuracy, sensitivity, and specificity. TA correctly assigned mixture weights and excluded nearly all first-degree relatives. This study demonstrates the analysis power of the TrueAllele® Casework system. PMID:26258391

  4. 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…

  5. 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…

  6. Mechanisms for dominance: Adh heterodimer formation in heterozygotes between ENU or x-ray induced null alleles and normal alleles in drosophila melanogaster

    SciTech Connect

    Jiang, J.C.; Lee, W.R.; Chang, S.H.; Silverman, H. )

    1992-01-01

    To study mechanisms for dominance of phenotype, eight ENU- and four x-ray-induced mutations at the alcohol dehydrogenase (Adh) locus were analyzed for partial dominance in their interaction with normal alleles. All ENU and one of the x-ray mutations were single base substitutions; the other three x-ray mutations were 9-21 base deletions. All but one of the 12 mutant alleles were selected for this study because they produced detectable mutant polypeptides, but seven of the 11 producing a peptide could not form dimers with the normal peptide and the enzyme activity of heterozygotes was about half that of normal homozygotes. Four mutations formed dimers with a decreased catalytic efficiency and two of these were near the limit of detectability; these two also inhibited the formation of normal homodimers. The mutant alleles therefore show multiple mechanisms leading to partial enzyme expression in heterozygotes and a wide range of dominance ranging from almost complete recessive to nearly dominant. All amino acid changes in mutant peptides that form dimers are located between amino acids 182 and 194, so this region is not critical for dimerization. It may, however, be an important surface domain for catalyzation. 34 refs., 8 figs., 2 tabs.

  7. Frequency detection of imidacloprid resistance allele in Aphis gossypii field populations by real-time PCR amplification of specific-allele (rtPASA).

    PubMed

    Zhang, Jing; Cui, Li; Xu, Xibao; Rui, Changhui

    2015-11-01

    The Aphis gossypii Glover (Hemiptera: Aphididae) is one of the most serious pests worldwide, and imidacloprid has been widely used to control this insect pest. Just like other classes of insecticides, the resistance to imidacloprid has been found in A. gossypii. An amino acid mutation (R81T) in the nicotinic acetylcholine receptor (nAChR) beta1 subunit was detected in the imidacloprid-resistant A. gossypii collected from Langfang (LF) and Dezhou (DZ) cities. To estimate the R81T mutation frequency of A. gossypii field populations, a simple, rapid and accurate rtPASA (real-time PCR amplification of specific allele) protocol was developed. The performance of the rtPASA protocol was evaluated by comparing with the data generated by a cPASA (competitive PCR amplification of specific allele) method from 50 individual genotypes. The R81T allele frequencies of the LF population (34.7%±1.3%) and DZ population (45.2%±5.2%) estimated by the rtPASA protocol matched the frequencies (LF 38.1%, DZ 48.2%) deduced by the cPASA method in specimens. The results indicated that the rtPASA format was applicable for the detection of mutation associated with imidacloprid resistance and will allow rapid and efficient monitoring of A. gossypii resistance in field populations in a high throughput format. PMID:26615144

  8. Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in ?-spectrin–deficient red cells

    PubMed Central

    Robledo, Raymond F.; Lambert, Amy J.; Birkenmeier, Connie S.; Cirlan, Marius V.; Cirlan, Andreea Flavia M.; Campagna, Dean R.; Lux, Samuel E.

    2010-01-01

    Five spontaneous, allelic mutations in the ?-spectrin gene, Spna1, have been identified in mice (spherocytosis [sph], sph1J, sph2J, sph2BC, sphDem). All cause severe hemolytic anemia. Here, analysis of 3 new alleles reveals previously unknown consequences of red blood cell (RBC) spectrin deficiency. In sph3J, a missense mutation (H2012Y) in repeat 19 introduces a cryptic splice site resulting in premature termination of translation. In sphIhj, a premature stop codon occurs (Q1853Stop) in repeat 18. Both mutations result in markedly reduced RBC membrane spectrin content, decreased band 3, and absent ?-adducin. Reevaluation of available, previously described sph alleles reveals band 3 and adducin deficiency as well. In sph4J, a missense mutation occurs in the C-terminal EF hand domain (C2384Y). Notably, an equally severe hemolytic anemia occurs despite minimally decreased membrane spectrin with normal band 3 levels and present, although reduced, ?-adducin. The severity of anemia in sph4J indicates that the highly conserved cysteine residue at the C-terminus of ?-spectrin participates in interactions critical to membrane stability. The data reinforce the notion that a membrane bridge in addition to the classic protein 4.1-p55-glycophorin C linkage exists at the RBC junctional complex that involves interactions between spectrin, adducin, and band 3. PMID:20056793

  9. Myotonic Dystrophy: Increased expression of the normal allele in CDM infants muscle

    SciTech Connect

    Radvanyi, H.H.; Gourdon, G.; Junien, C. |

    1994-09-01

    Myotonic dystrophy (DM) is an autosomal dominant multisystemic disorder characterized by a highly variable clinical phenotype. The mutation has been identified as an unstable trinucleotide CTG repeat in the 3{prime} untranslated region of the myotonin-protein kinase (MT-PK) gene. Congenital myotonic dystrophy (CDM), which represents the most severe phenotype, is exclusively maternally inherited. Recent studies, analysis by Northern blots and RT-PCR provided apparently conflicting results on the mutated allele expression in samples from congenitally affected children. The level of expression of the mutant allele depends on the extent of the repeat in the adult form and is no longer expressed when over 800-1300 repeats, whether in adult forms or in CDM. Could this decrease account for the late onset forms? However, the differences between the two phenotypes cannot be explained by the same mechanism. Alternatively, these differences could be due to differences in expression of the normal allele. We analyzed by quantitative RT-PCR the expression of the MT-PK gene in muscle samples from four CDM infants and two aged-matched normal controls. In two of these, the mutant allele (3.3 and 8 kb) was undetectable on Northern blots. We observed an increased expression of the MT-PK gene (10- to 20-fold) in tissues of severely affected congenital patients which can be attributed to the normal allele. Since expression of the normal allele is either normal or slightly decreased in the adult form, the dramatic increase in the congenital form could reflect a disturbance in muscle differentiation. Expression studies of MT-PK at different stages of development and, especially after the 20th week, are therefore required.

  10. Molecular Dynamics Simulation Reveals the Selective Binding of Human Leukocyte Antigen Alleles Associated with Behçet's Disease

    PubMed Central

    Kongkaew, Sirilak; Yotmanee, Pathumwadee; Rungrotmongkol, Thanyada; Kaiyawet, Nopporn; Meeprasert, Arthitaya; Kaburaki, Toshikatsu; Noguchi, Hiroshi; Takeuchi, Fujio; Kungwan, Nawee; Hannongbua, Supot

    2015-01-01

    Behçet’s disease (BD), a multi-organ inflammatory disorder, is associated with the presence of the human leukocyte antigen (HLA) HLA-B*51 allele in many ethnic groups. The possible antigen involvement of the major histocompatibility complex class I chain related gene A transmembrane (MICA-TM) nonapeptide (AAAAAIFVI) has been reported in BD symptomatic patients. This peptide has also been detected in HLA-A*26:01 positive patients. To investigate the link of BD with these two specific HLA alleles, molecular dynamics (MD) simulations were applied on the MICA-TM nonapeptide binding to the two BD-associated HLA alleles in comparison with the two non-BD-associated HLA alleles (B*35:01 and A*11:01). The MD simulations were applied on the four HLA/MICA-TM peptide complexes in aqueous solution. As a result, stabilization for the incoming MICA-TM was found to be predominantly contributed from van der Waals interactions. The P2/P3 residue close to the N-terminal and the P9 residue at the C-terminal of the MICA-TM nonapeptide served as the anchor for the peptide accommodated at the binding groove of the BD associated HLAs. The MM/PBSA free energy calculation predicted a stronger binding of the HLA/peptide complexes for the BD-associated HLA alleles than for the non-BD-associated ones, with a ranked binding strength of B*51:01 > B*35:01 and A*26:01 > A*11:01. Thus, the HLAs associated with BD pathogenesis expose the binding efficiency with the MICA-TM nonapeptide tighter than the non-associated HLA alleles. In addition, the residues 70, 73, 99, 146, 147 and 159 of the two BD-associated HLAs provided the conserved interaction for the MICA-TM peptide binding. PMID:26331842

  11. Comparative molecular dynamics analysis of tapasin-dependent and -independent MHC class I alleles.

    SciTech Connect

    Sieker, Florian; Springer, Sebastian; Zacharias, Martin W.

    2007-02-01

    The research described in this product was performed in part in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the Department of Energy's Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory. MHC class I molecules load antigenic peptides in the endoplasmic reticulum and present them at the cell surface. Efficiency of peptide loading depends on the class I allele and can involve interaction with tapasin and other proteins of the loading complex. Allele HLA-B*4402 (Asp at position 116) depends on tapasin for efficient peptide loading, whereas HLA-B*4405 (identical to B*4402 except for Tyr116) can efficiently load peptides in the absence of tapasin. Both alleles adopt very similar structures in the presence of the same peptide. Comparative unrestrained molecular dynamics simulations on the 1/2 peptide binding domains performed in the presence of bound peptides resulted in structures in close agreement with experiments for both alleles. In the absence of peptides, allele-specific conformational changes occurred in the first segment of the 2-helix that flanks the peptide C-terminal binding region (F-pocket) and contacts residue 116. This segment is also close to the proposed tapasin contact region. For B*4402, a shift toward an altered F-pocket structure deviating significantly from the bound form was observed. Subsequent free energy simulations on induced F-pocket opening in B*4402 confirmed a conformation that deviated significantly from the bound structure. For B*4405, a free energy minimum close to the bound structure was found. The simulations suggest that B*4405 has a greater tendency to adopt a peptide receptive conformation in the absence of peptide, allowing tapasin-independent peptide loading. A possible role of tapasin could be the stabilization of a peptide-receptive class I conformation for HLA-B*4402 and other tapasin-dependent alleles.

  12. Allelic Variation in a Willow Warbler Genomic Region Is Associated with Climate Clines

    PubMed Central

    Larson, Keith W.; Liedvogel, Miriam; Addison, BriAnne; Kleven, Oddmund; Laskemoen, Terje; Lifjeld, Jan T.; Lundberg, Max; Åkesson, Susanne; Bensch, Staffan

    2014-01-01

    Local adaptation is an important process contributing to population differentiation which can occur in continuous or isolated populations connected by various amounts of gene flow. The willow warbler (Phylloscopus trochilus) is one of the most common songbirds in Fennoscandia. It has a continuous breeding distribution where it is found in all forested habitats from sea level to the tree line and therefore constitutes an ideal species for the study of locally adapted genes associated with environmental gradients. Previous studies in this species identified a genetic marker (AFLP-WW1) that showed a steep north-south cline in central Sweden with one allele associated with coastal lowland habitats and the other with mountainous habitats. It was further demonstrated that this marker is embedded in a highly differentiated chromosome region that spans several megabases. In the present study, we sampled 2,355 individuals at 128 sites across all of Fennoscandia to study the geographic and climatic variables associated with the allele frequency distributions of WW1. Our results demonstrate that 1) allele frequency patterns significantly differ between mountain and lowland populations, 2) these allele differences coincide with extreme temperature conditions and the short growing season in the mountains, and milder conditions in coastal areas, and 3) the northern-allele or “altitude variant” of WW1 occurs in willow warblers that occupy mountainous habitat regardless of subspecies. Finally these results suggest that climate may exert selection on the genomic region associated with these alleles and would allow us to develop testable predictions for the distribution of the genetic marker based on climate change scenarios. PMID:24788148

  13. Breed Distribution of SOD1 Alleles Previously Associated with Canine Degenerative Myelopathy

    PubMed Central

    Zeng, R; Coates, JR; Johnson, GC; Hansen, L; Awano, T; Kolicheski, A; Ivansson, E; Perloski, M; Lindblad-Toh, K; O'Brien, DP; Guo, J; Katz, ML; Johnson, GS

    2014-01-01

    Background Previous reports associated 2 mutant SOD1 alleles (SOD1:c.118A and SOD1:c.52T) with degenerative myelopathy in 6 canine breeds. The distribution of these alleles in other breeds has not been reported. Objective To describe the distribution of SOD1:c.118A and SOD1:c.52T in 222 breeds. Animals DNA from 33,747 dogs was genotyped at SOD1:c.118, SOD1:c.52, or both. Spinal cord sections from 249 of these dogs were examined. Methods Retrospective analysis of 35,359 previously determined genotypes at SOD1:c.118G>A or SOD1:c.52A>T and prospective survey to update the clinical status of a subset of dogs from which samples were obtained with a relatively low ascertainment bias. Results The SOD1:c.118A allele was found in cross-bred dogs and in 124 different canine breeds whereas the SOD1:c.52T allele was only found in Bernese Mountain Dogs. Most of the dogs with histopathologically confirmed degenerative myelopathy were SOD1:c.118A homozygotes, but 8 dogs with histopathologically confirmed degenerative myelopathy were SOD1:c.118A/G heterozygotes and had no other sequence variants in their SOD1 amino acid coding regions. The updated clinical conditions of dogs from which samples were obtained with a relatively low ascertainment bias suggest that SOD1:c.118A homozygotes are at a much higher risk of developing degenerative myelopathy than are SOD1:c.118A/G heterozygotes. Conclusions and Clinical Importance We conclude that the SOD1:c.118A allele is widespread and common among privately owned dogs whereas the SOD1:c.52T allele is rare and appears to be limited to Bernese Mountain Dogs. We also conclude that breeding to avoid the production of SOD1:c.118A homozygotes is a rational strategy. PMID:24524809

  14. Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates

    PubMed Central

    Paternoster, Lavinia; Kemp, John P.; McMahon, George; Munafò, Marcus; Whitfield, John B.; Medland, Sarah E.; Montgomery, Grant W.; Timpson, Nicholas J.; St. Pourcain, Beate; Lawlor, Debbie A.; Martin, Nicholas G.; Dehghan, Abbas; Hirschhorn, Joel; Davey Smith, George

    2013-01-01

    It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections. PMID:24204319

  15. Mining the human phenome using allelic scores that index biological intermediates.

    PubMed

    Evans, David M; Brion, Marie Jo A; Paternoster, Lavinia; Kemp, John P; McMahon, George; Munafò, Marcus; Whitfield, John B; Medland, Sarah E; Montgomery, Grant W; Timpson, Nicholas J; St Pourcain, Beate; Lawlor, Debbie A; Martin, Nicholas G; Dehghan, Abbas; Hirschhorn, Joel; Smith, George Davey

    2013-10-01

    It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections. PMID:24204319

  16. Functional characterization of ABCC2 promoter polymorphisms and allele-specific expression.

    PubMed

    Nguyen, T D; Markova, S; Liu, W; Gow, J M; Baldwin, R M; Habashian, M; Relling, M V; Ratain, M J; Kroetz, D L

    2013-10-01

    Multidrug resistance protein 2 (MRP2, ABCC2) is an efflux membrane transporter highly expressed in liver, kidney and intestine with important physiological and pharmacological roles. The goal of this study was to investigate the functional significance of promoter region polymorphisms in ABCC2 and potential allele-specific expression. Twelve polymorphisms in the 1.6?kb region upstream of the translation start site were identified by resequencing 247 DNA samples from ethnically diverse individuals. Luciferase reporter gene assays showed that ABCC2 -24C>T both alone and as part of a common haplotype (-24C>T/-1019A>G/-1549G>A) increased promoter function 35% compared with the reference sequence (P<0.0001). No other common variants or haplotypes affected ABCC2 promoter activity. Allele-specific expression was also investigated as a mechanism to explain reported associations of the synonymous ABCC2 3972C>T variant with pharmacokinetic phenotypes. In Caucasian liver samples (n=41) heterozygous for the 3972C>T polymorphism, the 3972C allele was preferentially transcribed relative to the 3972T allele (P<0.0001). This allelic imbalance was particularly apparent in samples with haplotypes containing two or three promoter/untranslated region variants (-1549G>A, -1019A>G and -24C>T). The observed allelic imbalance was not associated with hepatic or renal ABCC2 mRNA expression. Additional mechanisms will need to be explored to account for the interindividual variation in ABCC2 expression and MRP2 function. PMID:22664480

  17. Imputation of TPMT defective alleles for the identification of patients with high-risk phenotypes

    PubMed Central

    Almoguera, Berta; Vazquez, Lyam; Connolly, John J.; Bradfield, Jonathan; Sleiman, Patrick; Keating, Brendan; Hakonarson, Hakon

    2014-01-01

    Background: The activity of thiopurine methyltransferase (TPMT) is subject to genetic variation. Loss-of-function alleles are associated with various degrees of myelosuppression after treatment with thiopurine drugs, thus genotype-based dosing recommendations currently exist. The aim of this study was to evaluate the potential utility of leveraging genomic data from large biorepositories in the identification of individuals with TPMT defective alleles. Material and methods: TPMT variants were imputed using the 1000 Genomes Project reference panel in 87,979 samples from the biobank at The Children's Hospital of Philadelphia. Population ancestry was determined by principal component analysis using HapMap3 samples as reference. Frequencies of the TPMT imputed alleles, genotypes and the associated phenotype were determined across the different populations. A sample of 630 subjects with genotype data from Sanger sequencing (N = 59) and direct genotyping (N = 583) (12 samples overlapping in the two groups) was used to check the concordance between the imputed and observed genotypes, as well as the sensitivity, specificity and positive and negative predictive values of the imputation. Results: Two SNPs (rs1800460 and rs1142345) that represent three TPMT alleles (*3A, *3B, and *3C) were imputed with adequate quality. Frequency for the associated enzyme activity varied across populations and 89.36–94.58% were predicted to have normal TPMT activity, 5.3–10.31% intermediate and 0.12–0.34% poor activities. Overall, 98.88% of individuals (623/630) were correctly imputed into carrying no risk alleles (553/553), heterozygous (45/46) and homozygous (25/31). Sensitivity, specificity and predictive values of imputation were over 90% in all cases except for the sensitivity of imputing homozygous subjects that was 80.64%. Conclusion: Imputation of TPMT alleles from existing genomic data can be used as a first step in the screening of individuals at risk of developing serious adverse events secondary to thiopurine drugs. PMID:24860591

  18. FUNCTIONAL CHARACTERIZATION OF ABCC2 PROMOTER POLYMORPHISMS AND ALLELE SPECIFIC EXPRESSION

    PubMed Central

    Nguyen, Tan D.; Markova, Svetlana; Liu, Wanqing; Gow, Jason M.; Baldwin, R. Michael; Habashian, Mahnoush; Relling, Mary V.; Ratain, Mark J.; Kroetz, Deanna L.

    2012-01-01

    Multidrug resistance protein 2 (MRP2, ABCC2) is an efflux membrane transporter highly expressed in liver, kidney and intestine with important physiological and pharmacological roles. The goal of this study was to investigate the functional significance of promoter region polymorphisms in ABCC2 and potential allele specific expression. Twelve polymorphisms in the 1.6 kb region upstream of the translation start site were identified by resequencing 247 DNA samples from ethnically diverse individuals. Luciferase reporter gene assays showed that ABCC2 -24C>T both alone and as part of a common haplotype (-24C>T/-1019A>G/-1549G>A) increased promoter function 35% compared to the reference sequence (P < 0.0001). No other common variants or haplotypes affected ABCC2 promoter activity. Allele specific expression was also investigated as a mechanism to explain reported associations of the synonymous ABCC2 3972C>T variant with pharmacokinetic phenotypes. In Caucasian liver samples (n=41) heterozygous for the 3972C>T polymorphism, the 3972C allele was preferentially transcribed relative to the 3972T allele (P < 0.0001). This allelic imbalance was particularly apparent in samples with haplotypes containing two or three promoter/UTR variants (-1549G>A, -1019A>G and -24C>T). The observed allelic imbalance was not associated with hepatic or renal ABCC2 mRNA expression. Additional mechanisms will need to be explored to account for the interindividual variation in ABCC2 expression and MRP2 function. PMID:22664480

  19. Existence of the rdl mutant alleles among the anopheles malaria vector in Indonesia

    PubMed Central

    2012-01-01

    Background The gamma-aminobutyric acid (GABA) receptor-chloride channel complex is known to be the target site of dieldrin, a cyclodiene insecticide. GABA-receptors, with a naturally occurring amino acid substitution, A302S/G in the putative ion-channel lining region, confer resistance to cyclodiene insecticides that includes aldrin, chlordane, dieldrin, heptachlor, endrin and endosulphan. Methods A total of 154 mosquito samples from 10 provinces of malaria-endemic areas across Indonesia (Aceh, North Sumatra, Bangka Belitung, Lampung, Central Java, East Nusa Tenggara, West Nusa Tenggara, West Sulawesi, Molucca and North Molucca) were obtained and identified by species, using morphological characteristic. The DNA was individually extracted using chelex-ion exchanger and the DNA obtained was used for analyses using sequencing method. Results Molecular analysis indicated 11% of the total 154 Anopheles samples examined, carried Rdl mutant alleles. All of the alleles were found in homozygous form. Rdl 302S allele was observed in Anopheles vagus (from Central Java, Lampung, and West Nusa Tenggara), Anopheles aconitus (from Central Java), Anopheles barbirostris (from Central Java and Lampung), Anopheles sundaicus (from North Sumatra and Lampung), Anopheles nigerrimus (from North Sumatra), whereas the 302 G allele was only found in Anopheles farauti from Molucca. Conclusion The existence of the Rdl mutant allele indicates that, either insecticide pressure on the Anopheles population in these areas might still be ongoing (though not directly associated with the malaria control programme) or that the mutant form of the Rdl allele is relatively stable in the absence of insecticide. Nonetheless, the finding suggests that integrated pest management is warranted in malaria-endemic areas where insecticides are widely used for other purposes. PMID:22364613

  20. Identification of the novel HLA-DPB1*5801 allele detected by sequenced based typing

    SciTech Connect

    Versluis, L.F.; Zwan, A.W. van der; Tilanus, M.G.J.; Daly, L.N.; Degli-Esposti, M.A.; Dawkins, R.L.

    1995-01-11

    Within the framework of HLA-DPB typing of the Fourth Asia-Oceanic Histocompatibility workshop (4AOH) we have typed the A, B, and E panels representing 101 samples. Sequenced based typing (SBT) was used as the method for typing described by Versluis and co-workers, but the sequencing chemistry was modified; in this study we have used the Sequenase enzyme instead of the thermal stable Taq enzyme. Sequences obtained were compared to a database containing all known 55 HLA-DPB1 alleles. One sample showed a new heterozygous sequence, indicating the presence of a new allele. 4 refs., 1 fig.

  1. The Plasmodium gaboni genome illuminates allelic dimorphism of immunologically important surface antigens in P. falciparum.

    PubMed

    Roy, Scott William

    2015-12-01

    In the deadly human malaria parasite Plasmodium falciparum, several major merozoite surface proteins (MSPs) show a striking pattern of allelic diversity called allelic dimorphism (AD). In AD, the vast majority of observed alleles fall into two highly divergent allelic classes, with recombinant alleles being rare or not observed, presumably due to repression by natural selection (recombination suppression, or RS). The three AD loci, merozoite surface proteins (MSPs) 1, 2, and 6, along with MSP3, which also exhibits RS among four allelic classes, can be collectively called AD/RS. The causes of AD/RS and the evolutionary history of allelic diversity at these loci remain mysterious. The few available sequences from a single closely related chimpanzee parasite, P. reichenowi, have suggested that for 3/4 loci, AD/RS is an ancient state that has been retained in P. falciparum since well before the P. falciparum-P. reichenowi ancestor. On the other hand, based on comparative sequence analysis, we recently suggested that (i) AD/RS P. falciparum loci have undergone interallelic recombination over longer evolutionary times (on the timescale of recent speciation events), and thus (ii) AD/RS may be a recent phenomenon. The recent publication of genomic sequencing efforts for P. gaboni, an outgroup to P. falciparum and P. reichenowi, allows for improved reconstruction of the evolutionary history of these loci. In this work, I report genic sequence for P. gaboni for all four AD/RS P. falciparum loci (MSP1, 2, 3, and 6). Comparison of these sequences with available P. falciparum and P. reichenowi data strengthens the evidence for interallelic recombination over the evolutionary history of these species and also strengthens the case that AD/RS at these loci is ancient. Combined with previous results, these data provide evidence that AD/RS at different loci has evolved at several different times in the evolutionary history of P. falciparum: (i) before the P. gaboni-P. falciparum divergence, for much of MSP1 and MSP3; (ii) between the P. gaboni-P. falciparum and P. reichenowi-P. falciparum divergences, for the 5' end of the AD region of MSP6 and block 3 of MSP1; (iii) near the P. reichenowi-P. falciparum divergence, for the 3' end of the AD region of MSP6; and (iv) after the P. reichenowi-P. falciparum divergence, for MSP2. Based on these results, I suggest a new hypothesis for long-term evolutionary maintenance of AD/RS by recombination within allelic groups. PMID:26296605

  2. WASP: allele-specific software for robust molecular quantitative trait locus discovery.

    PubMed

    van de Geijn, Bryce; McVicker, Graham; Gilad, Yoav; Pritchard, Jonathan K

    2015-11-01

    Allele-specific sequencing reads provide a powerful signal for identifying molecular quantitative trait loci (QTLs), but they are challenging to analyze and are prone to technical artifacts. Here we describe WASP, a suite of tools for unbiased allele-specific read mapping and discovery of molecular QTLs. Using simulated reads, RNA-seq reads and chromatin immunoprecipitation sequencing (ChIP-seq) reads, we demonstrate that WASP has a low error rate and is far more powerful than existing QTL-mapping approaches. PMID:26366987

  3. Characterization of Tn6238 with a new allele of aac(6')-Ib-cr.

    PubMed

    Quiroga, María P; Orman, Betina; Errecalde, Laura; Kaufman, Sara; Centrón, Daniela

    2015-05-01

    Here, we report that the genetic structure of Tn1331 remained conserved in Argentina from 1989 to 2013 (72 of 73 isolates), with the exception being the plasmid-borne Tn1331-like transposon Tn6238 containing a new aac(6')-Ib-cr allele recovered from a colistin-resistant Klebsiella pneumoniae clinical isolate. A bioinformatic analysis of aac(6')-Ib-like gene cassettes suggests that this new aac(6')-Ib-cr allele emerged through mutation or homologous recombination in the Tn1331 genetic platform. Tn6238 is a novel platform for the dissemination of aminoglycoside and fluoroquinolone resistance determinants. PMID:25691640

  4. Somatic Mutation Allelic Ratio Test Using ddPCR (SMART-ddPCR): An Accurate Method for Assessment of Preferential Allelic Imbalance in Tumor DNA

    PubMed Central

    de Smith, Adam J.; Walsh, Kyle M.; Hansen, Helen M.; Endicott, Alyson A.; Wiencke, John K.; Metayer, Catherine; Wiemels, Joseph L.

    2015-01-01

    The extent to which heritable genetic variants can affect tumor development has yet to be fully elucidated. Tumor selection of single nucleotide polymorphism (SNP) risk alleles, a phenomenon called preferential allelic imbalance (PAI), has been demonstrated in some cancer types. We developed a novel application of digital PCR termed Somatic Mutation Allelic Ratio Test using Droplet Digital PCR (SMART-ddPCR) for accurate assessment of tumor PAI, and have applied this method to test the hypothesis that heritable SNPs associated with childhood acute lymphoblastic leukemia (ALL) may demonstrate tumor PAI. These SNPs are located at CDKN2A (rs3731217) and IKZF1 (rs4132601), genes frequently lost in ALL, and at CEBPE (rs2239633), ARID5B (rs7089424), PIP4K2A (rs10764338), and GATA3 (rs3824662), genes located on chromosomes gained in high-hyperdiploid ALL. We established thresholds of AI using constitutional DNA from SNP heterozygotes, and subsequently measured allelic copy number in tumor DNA from 19–142 heterozygote samples per SNP locus. We did not find significant tumor PAI at these loci, though CDKN2A and IKZF1 SNPs showed a trend towards preferential selection of the risk allele (p = 0.17 and p = 0.23, respectively). Using a genomic copy number control ddPCR assay, we investigated somatic copy number alterations (SCNA) underlying AI at CDKN2A and IKZF1, revealing a complex range of alterations including homozygous and hemizygous deletions and copy-neutral loss of heterozygosity, with varying degrees of clonality. Copy number estimates from ddPCR showed high agreement with those from multiplex ligation-dependent probe amplification (MLPA) assays. We demonstrate that SMART-ddPCR is a highly accurate method for investigation of tumor PAI and for assessment of the somatic alterations underlying AI. Furthermore, analysis of publicly available data from The Cancer Genome Atlas identified 16 recurrent SCNA loci that contain heritable cancer risk SNPs associated with a matching tumor type, and which represent candidate PAI regions warranting further investigation. PMID:26575185

  5. What can I do with a degree in European and European Union Studies?

    E-print Network

    Hickman, Mark

    What can I do with a degree in European and European Union Studies? ARTS Planning your career to www.canterbury.ac.nz/liaison/best_prep.shtml What is European and European Union Studies? The European's leading political and trading blocs, with 28 member states and over 495 million people. European Union

  6. EUROPEAN SWALLOW RESEARCH: JOINT VENTURE

    E-print Network

    de Villiers, Marienne

    EUROPEAN SWALLOW RESEARCH: JOINT VENTURE William Scott P O Box 2680, Potchefstrcom 2520 After of theirfield trip collecting data andblood samples ofEuropean Swallows and other swallow and martin species my help in locating swallow roosts and help with their capture. Henk Bouwman, who had previously met

  7. 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…

  8. Recognising European pastoral farming systems

    E-print Network

    Oñate, Juan J.

    Recognising European pastoral farming systems and understanding their ecology: a necessity number 23 #12;Recognising European pastoral farming systems and understanding their ecology A necessity of low-intensity land use that are well adapted to the local limitations of the environment. A good

  9. European Red Mite Pest Introduction

    E-print Network

    New Hampshire, University of

    important fruit pests in the U.S. and Canada. Undersized fruit, foliage loss and weakened fruit buds canTree Fruit European Red Mite Pest Fact Sheet 6 Introduction This non-insect pest is a European native which was first discovered in the U.S. in 1911. Since that time, it has become one of the most

  10. Hunting for the LCT-13910*T Allele between the Middle Neolithic and the Middle Ages Suggests Its Absence in Dairying LBK People Entering the Kuyavia Region in the 8th Millennium BP

    PubMed Central

    Witas, Henryk W.; P?oszaj, Tomasz; J?drychowska-Da?ska, Krystyna; Witas, Piotr J.; Mas?owska, Alicja; Jerszy?ska, Blandyna; Koz?owski, Tomasz; Osipowicz, Grzegorz

    2015-01-01

    Populations from two medieval sites in Central Poland, Stary Brze?? Kujawski-4 (SBK-4) and Gruczno, represented high level of lactase persistence (LP) as followed by the LCT-13910*T allele’s presence (0.86 and 0.82, respectively). It was twice as high as in contemporaneous Cedynia (0.4) and ?ródka (0.43), both located outside the region, higher than in modern inhabitants of Poland (0.51) and almost as high as in modern Swedish population (0.9). In an attempt to explain the observed differences its frequency changes in time were followed between the Middle Neolithic and the Late Middle Ages in successive dairying populations on a relatively small area (radius ?60km) containing the two sites. The introduction of the T allele to Kuyavia 7.4 Ka BP by dairying LBK people is not likely, as suggested by the obtained data. It has not been found in any of Neolithic samples dated between 6.3 and 4.5 Ka BP. The identified frequency profile indicates that both the introduction and the beginning of selection could have taken place approx. 4 millennia after first LBK people arrived in the region, shifting the value of LP frequency from 0 to more than 0.8 during less than 130 generations. We hypothesize that the selection process of the T allele was rather rapid, starting just after its introduction into already milking populations and operated via high rates of fertility and mortality on children after weaning through life-threatening conditions, favoring lactose-tolerant individuals. Facing the lack of the T allele in people living on two great European Neolithization routes, the Danubian and Mediterranean ones, and based on its high frequency in northern Iberia, its presence in Scandinavia and estimated occurrence in Central Poland, we propose an alternative Northern Route of its spreading as very likely. None of the successfully identified nuclear alleles turned out to be deltaF508 CFTR. PMID:25853887

  11. Allelic Differences within and among Sister Spores of the Arbuscular Mycorrhizal Fungus Glomus etunicatum Suggest Segregation at Sporulation

    PubMed Central

    St-Arnaud, Marc; Hijri, Mohamed

    2013-01-01

    Arbuscular mycorrhizal fungi (AMF) are root-inhabiting fungi that form mutualistic symbioses with their host plants. AMF are made up of coenocytic networks of hyphae through which nuclei and organelles can freely migrate. In this study, we investigated the possibility of a genetic bottleneck and segregation of allelic variation at sporulation for a low-copy Polymerase1-like gene, PLS. Specifically, our objectives were (1) to estimate what allelic diversity is passed on to a single spore (2) to determine whether this diversity is less than the total amount of variation found in all spores (3) to investigate whether there is any differential segregation of allelic variation. We inoculated three tomato plants with a single spore of Glomus etunicatum each and after six months sampled between two and three daughter spores per tomato plant. Pyrosequencing PLS amplicons in eight spores revealed high levels of allelic diversity; between 43 and 152 alleles per spore. We corroborated the spore pyrosequencing results with Sanger- and pyrosequenced allele distributions from the original parent isolate. Both sequencing methods retrieved the most abundant alleles from the offspring spore allele distributions. Our results indicate that individual spores contain only a subset of the total allelic variation from the pooled spores and parent isolate. Patterns of allele diversity between spores suggest the possibility for segregation of PLS alleles among spores. We conclude that a genetic bottleneck could potentially occur during sporulation in AMF, with resulting differences in genetic variation among sister spores. We suggest that the effects of this bottleneck may be countered by anastomosis (hyphal fusion) between related hyphae. PMID:24386173

  12. Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent.

    PubMed

    Dudakova, Lubica; Palos, Michalis; Jirsova, Katerina; Stranecky, Viktor; Krepelova, Anna; Hysi, Pirro G; Liskova, Petra

    2015-10-01

    Corneal ectasias, among which keratoconus (KC) is the single most common entity, are one of the most frequent reasons for corneal grafting in developed countries and a threatening complication of laser in situ keratomileusis. Genome-wide association studies have previously found lysyl oxidase (LOX) and hepatocyte growth factor (HGF) associated with susceptibility to KC development. The aim of our study was to validate the effects of seven single-nucleotide polymorphisms (SNPs) within LOX and HGF over KC. Unrelated Czech cases with KC of European descent (108 males and 57 females, 165 cases in total) and 193 population and gender-matched controls were genotyped using Kompetitive Allele Specific PCR assays. Fisher's exact tests were used to assess the strength of associations. Evidence for association was found for both of the tested loci. It was strongest for rs3735520:G>A near HGF (allelic test odds ratio (OR)=1.45; 95% confidence interval (CI), 1.06-1.98; P=0.018) with A allele being a risk factor and rs2956540:G>C (OR=0.69; 95% CI, 0.50-0.96; P=0.024) within LOX with C allele having a protective effect. This first independent association validation of rs2956540:G>C and rs3735520:G>A suggests that these SNPs may serve as genetic risk markers for KC in individuals of European descent. PMID:25735481

  13. The ABCB1 3435 T allele does not increase the risk of paclitaxel-induced neurotoxicity

    PubMed Central

    ÖFVERHOLM, ANNA; EINBEIGI, ZAKARIA; MANOUCHEHRPOUR, SHOKOUFEH; ALBERTSSON, PER; SKRTIC, STANKO; ENERBÄCK, CHARLOTTA

    2010-01-01

    Paclitaxel is a frequently used anticancer drug with considerable inter-individual variability in terms of drug efficiency and toxicity. The reasons for this variability have not been fully explained. The purpose of this study was to evaluate the possible relationship between paclitaxel-induced neurotoxicity and the distribution of genetic variations with reported functional significance in the ABCB1, CYP2C8 and CYP3A4 genes that are all implicated in taxol metabolism. Women (n=36) experiencing paclitaxel-induced neurotoxicity were included in the study, and the ABCB1 G2677A/T and C3435T as well as CYP2C8*3 and CYP3A4*1b allele frequencies were determined using PCR-RFLP and DNA sequence analysis. We showed that the ABCB1 3435T allele, previously reported as a risk allele for neurotoxicity, did not correlate with the occurrence of neurotoxicity in our patient sample (Chi-square test, p=0.61). Furthermore, we showed that neither the CYP2C8*3 nor CYP3A4*1b alleles, that both lead to diminished enzyme activity, correlated with paclitaxel-induced neurotoxicity. The occurrence and variation in severity of neurotoxicity in our Swedish patient sample could therefore not be explained by the reported functional polymorphisms in the ABCB1, CYP2C8 and CYP3A4 genes. PMID:22966274

  14. Specific alleles of bitter receptor genes influence human sensitivity to the bitterness of aloin and saccharin.

    PubMed

    Pronin, Alexey N; Xu, Hong; Tang, Huixian; Zhang, Lan; Li, Qing; Li, Xiaodong

    2007-08-21

    Variation in human taste is a well-known phenomenon. However, little is known about the molecular basis for it. Bitter taste in humans is believed to be mediated by a family of 25 G protein-coupled receptors (hT2Rs, or TAS2Rs). Despite recent progress in the functional expression of hT2Rs in vitro, up until now, hT2R38, a receptor for phenylthiocarbamide (PTC), was the only gene directly linked to variations in human bitter taste. Here we report that polymorphism in two hT2R genes results in different receptor activities and different taste sensitivities to three bitter molecules. The hT2R43 gene allele, which encodes a protein with tryptophan in position 35, makes people very sensitive to the bitterness of the natural plant compounds aloin and aristolochic acid. People who do not possess this allele do not taste these compounds at low concentrations. The same hT2R43 gene allele makes people more sensitive to the bitterness of an artificial sweetener, saccharin. In addition, a closely related gene's (hT2R44's) allele also makes people more sensitive to the bitterness of saccharin. We also demonstrated that some people do not possess certain hT2R genes, contributing to taste variation between individuals. Our findings thus reveal new examples of variations in human taste and provide a molecular basis for them. PMID:17702579

  15. Patent Ductus Venosus and Dioxin Resistance in Mice Harboring a Hypomorphic Arnt Allele*

    E-print Network

    Bradfield, Christopher A.

    Patent Ductus Venosus and Dioxin Resistance in Mice Harboring a Hypomorphic Arnt Allele* Received: the toxicological response to compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and the de- velopmental a patent ductus venosus, identical to that observed in the Ahr null mice. Parallel dioxin toxicity studies

  16. Long-term persistence of crop alleles in weedy populations of wild radish (Raphanus raphanistrum)

    E-print Network

    Snow, Allison A.

    Long-term persistence of crop alleles in weedy populations of wild radish (Raphanus raphanistrum) A­wild hybridization, gene flow, introgression, rapid evolution, transgene escape, weed evolution, wild radish-seeding, hybrid populations of Raphanus raphani- strum · Raphanus sativus (radish) in Michigan, USA, over a decade

  17. Allele substitution at a flower colour locus produces a pollinator shift in monkeyflowers.

    PubMed

    Bradshaw, H D; Schemske, Douglas W

    2003-11-13

    The role of major mutations in adaptive evolution has been debated for more than a century. The classical view is that adaptive mutations are nearly infinite in number with infinitesimally small phenotypic effect, but recent theory suggests otherwise. To provide empirical estimates of the magnitude of adaptive mutations in wild plants, we conducted field studies to determine the adaptive value of alternative alleles at a single locus, YELLOW UPPER (YUP). YUP controls the presence or absence of yellow carotenoid pigments in the petals of pink-flowered Mimulus lewisii, which is pollinated by bumblebees, and its red-flowered sister species M. cardinalis, which is pollinated by hummingbirds. We bred near-isogenic lines (NILs) in which the YUP allele from each species was substituted into the other. M. cardinalis NILs with the M. lewisii YUP allele had dark pink flowers and received 74-fold more bee visits than the wild type, whereas M. lewisii NILs with the M. cardinalis yup allele had yellow-orange flowers and received 68-fold more hummingbird visits than the wild type. These results indicate that an adaptive shift in pollinator preference may be initiated by a single major mutation. PMID:14614505

  18. Evidence of Allelic Suppression for Transcripts Expressed in Day 30 Pig Embryos by SNP Genotyping

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic imprinting results in alleles being differentially expressed in a parent-of-origin specific manner. Parthenogenetic and biparental pig embryo gene expression profiles were compared using three cDNA microarray platforms. Comparison of the profiles of the two tissue types indicated different...

  19. INVOLVEMENT OF THE FGFR4 Arg388 ALLELE IN HEAD AND NECK SQUAMOUS CELL CARCINOMA

    E-print Network

    Ullrich, Axel

    INVOLVEMENT OF THE FGFR4 Arg388 ALLELE IN HEAD AND NECK SQUAMOUS CELL CARCINOMA Sylvia STREIT 1/Arg polymorphism (388) in head and neck squamous cell carcinomas (HNSCCs) of the oral cavity and the oropharynx in human HNSCC. © 2004 Wiley-Liss, Inc. Key words: fibroblast growth factor receptor 4; head and neck

  20. Alleles conferring improved fiber quality from EMS mutagenesis of elite cotton genotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The elite gene pool of cotton (Gossypium spp.) has less diversity than those of most other major crops, making identification of novel alleles important to ongoing crop improvement. A total of 3,164 M5 lines resulting from ethyl methanesulfonate mutagenesis of two G. hirsutum breeding lines, TAM 94L...

  1. Two Distinct Waxy Alleles Impact the Granule-Bound Starch Synthase in Sorghum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The granule-bound starch synthase (GBSS) is the enzyme responsible for amylose synthesis in starch granules. Loss of GBSS activity results in starch granules containing mostly amylopectin and little or no amylose, a phenotype described as waxy. Previously, two phenotypic classes of waxy alleles we...

  2. Fitness evolution and the rise of mutator alleles in experimental Escherichia coli populations.

    PubMed Central

    Shaver, Aaron C; Dombrowski, Peter G; Sweeney, Joseph Y; Treis, Tania; Zappala, Renata M; Sniegowski, Paul D

    2002-01-01

    We studied the evolution of high mutation rates and the evolution of fitness in three experimental populations of Escherichia coli adapting to a glucose-limited environment. We identified the mutations responsible for the high mutation rates and show that their rate of substitution in all three populations was too rapid to be accounted for simply by genetic drift. In two of the populations, large gains in fitness relative to the ancestor occurred as the mutator alleles rose to fixation, strongly supporting the conclusion that mutator alleles fixed by hitchhiking with beneficial mutations at other loci. In one population, no significant gain in fitness relative to the ancestor occurred in the population as a whole while the mutator allele rose to fixation, but a substantial and significant gain in fitness occurred in the mutator subpopulation as the mutator neared fixation. The spread of the mutator allele from rarity to fixation took >1000 generations in each population. We show that simultaneous adaptive gains in both the mutator and wild-type subpopulations (clonal interference) retarded the mutator fixation in at least one of the populations. We found little evidence that the evolution of high mutation rates accelerated adaptation in these populations. PMID:12399371

  3. NOTICE OF RELEASE OF HARD KERNEL PUROINDOLINE ALLELE NEAR-ISOGENIC LINE HEXAPLOID WHEAT GENETIC STOCKS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Agricultural Research Service, U.S. Department of Agriculture announces the release of seven hard kernel puroindoline allele near-isogenic line (NIL) hexaploid wheat (Triticum aestivum L.) genetic stocks (PI xxxxxx – PI xxxxxx) developed by Dr. Craig F. Morris at the USDA-ARS Western Wheat Quali...

  4. Registration of hard kernel puroindoline allele nearisogenic line hexaploid wheat genetic stocks.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Seven puroindoline allele near-isogenic line (NIL) hexaploid wheat (Triticum aestivum L.) genetic stocks (GS-xxxx – GS-xxxx; PI 644080 – PI 644086) were developed by Dr. Craig F. Morris at the USDA-ARS Western Wheat Quality Laboratory, Pullman, Washington. As they incorporate the first seven known ...

  5. Structural analysis of substitution patterns in alleles of human immunoglobulin VH genes.

    PubMed

    Romo-González, Tania; Vargas-Madrazo, Enrique

    2005-05-01

    The diversity in repertoires of antibodies (Abs) needed in response to the antigen challenge is produced by evolutionary and somatic processes. The mechanisms operating at a somatic level have been studied in great detail. In contrast, neither the mechanisms nor the strategies of diversification at an evolutionary level have yet been understood in similar detail. Particularly, the substitution patterns in alleles of immunoglobulin genes (Igs) have not been systematically studied. Furthermore, there is a scarcity of studies which link the analysis at a genetic level of the diversification of repertoires with the structural consequences at the protein level of the changes in DNA information. For the purpose of systematically characterizing the strategies of evolutionary diversification through sequence variation at alleles, in this work, we built a database for all the alleles of the IGHV locus in humans reported until now. Based on these data, we performed diverse analyses of substitution patterns and linked these results with studies at the protein level. We found that the sequence diversification in different alleles does not operate with equal intensity for all V genes. Our studies, both of the number of substitutions and of the type of amino acid change per sub-segment of the V-REGION evidenced differences in the selective pressure to which these regions are exposed. The implications of these results for understanding the evolutionary diversification strategies, as well as for the somatic generation of antibody repertoires are discussed. PMID:15829298

  6. TOWARDS POSITIONAL CLONING OF THE HIGH BETA-CAROTENE OR (ORANGE) ALLELE OF CAULIFLOWER

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cauliflower (Brassica oleracea L. var. botrytis) Or allele confers the accumulation of high levels of beta-carotene in various tissues that normally are devoid of carotenoids. Early work revealed that the Or gene appeared not to exert its effect via direct up-regulation of genes that encode enz...

  7. Expression regulation triggers oncogenicity of xmrk alleles in the Xiphophorus melanoma system.

    PubMed

    Regneri, Janine; Schartl, Manfred

    2012-01-01

    The Xiphophorus melanoma model has gained attention in biomedical research as a genetic model for tumor formation. Melanoma development in interspecific hybrids of Xiphophorus is connected to pigment cell specific overexpression of the mutationally activated receptor tyrosine kinase Xmrk. In purebred fish the oncogenic function of xmrk is suppressed by a so far unknown regulator locus R. To test the hypothesis that R is involved in transcriptional regulation of xmrk and consequently acts upstream of the xmrk signal, we performed a quantitative analysis of xmrk transcript levels in normal and melanoma tissues of different Xiphophorus genotypes carrying either a highly tumorigenic or a non-tumorigenic xmrk allele. Our results demonstrate that expression of the tumorigenic xmrk allele is highly increased in malignant melanomas compared to benign lesions, macromelanophore spots, and healthy skin. Transcription of the non-tumorigenic xmrk allele in pigment cells, in contrast, is not influenced by the presence or absence of R. These findings strongly indicate that differential transcriptional regulation of the xmrk promoter determines the tumorigenic potential of xmrk alleles in the Xiphophorus melanoma system, thereby supporting the hypothesis that R suppresses the oncogenic function of xmrk on the level of transcriptional control. PMID:21527356

  8. Highly efficient bi-allelic mutation rates using TALENs in Xenopus tropicalis

    E-print Network

    Amaya, Enrique

    Highly efficient bi-allelic mutation rates using TALENs in Xenopus tropicalis Shoko Ishibashi investigated the efficiency of transcription activator-like effector nucleases (TALENs) for generating targeted injected mRNA encoding TALENs targeting the first exon of the tyr gene into two-cell-stage embryos

  9. Always look on both sides: Phylogenetic information conveyed by simple sequence repeat allele sequences

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Simple sequence repeat (SSR) markers are widely used tools for inferences about genetic diversity, phylogeography and spatial genetic structure. Their applications assume that variation among alleles is essentially caused by an expansion or contraction of the number of repeats and that, accessorily,...

  10. MOLECULAR AND BIOCHEMICAL CHARACTERIZATION OF PUROINDOLINE A AND B ALLELES IN CHINESE LANDRACES AND HISTORICAL CULTIVARS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Kernel hardness that is conditioned by puroindoline genes has a profound effect on milling, baking and end-use quality of bread wheat. In this study, 219 landraces and 166 historical cultivars from China and 12 introduced wheats were investigated for their kernel hardness and puroindoline alleles, ...

  11. Incompletely Penetrant PKD1 Alleles Mimic the Renal Manifestations of ARPKD

    PubMed Central

    Vujic, Mihailo; Heyer, Christina M.; Ars, Elisabet; Hopp, Katharina; Markoff, Arseni; Örndal, Charlotte; Rudenhed, Bengt; Nasr, Samih H.; Torres, Vicente E.; Torra, Roser

    2010-01-01

    Autosomal dominant polycystic kidney disease (ADPKD), caused by mutation in PKD1 or PKD2, is usually an adult-onset disorder but can rarely manifest as a neonatal disease within a family characterized by otherwise typical ADPKD. Coinheritance of a hypomorphic PKD1 allele in trans with an inactivating PKD1 allele is one mechanism that can cause early onset ADPKD. Here, we describe two pedigrees without a history of cystic kidney disease that each contain two patients with onset of massive PKD in utero. The presentations were typical of autosomal recessive PKD (ARPKD) but they were not linked to the known ARPKD gene, PKHD1. Mutation analysis of the ADPKD genes provided strong evidence that both families inherited, in trans, two incompletely penetrant PKD1 alleles. These patients illustrate that PKD1 mutations can manifest as a phenocopy of ARPKD with respect to renal involvement and highlight the perils of linkage-based diagnostics in ARPKD without positive PKHD1 mutation data. Furthermore, the phenotypic overlap between ARPKD and these patients resulting from incomplete penetrant PKD1 alleles support a common pathogenesis for these diseases. PMID:20558538

  12. New Markers from Sugar Metabolism ESTs: Tagging Positive Alleles from Saccharum spontaneum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Limited genetic gains, obtained from breeding for sugar content in different breeding programs worldwide suggest that a plateau has been reached for this trait. One way to overcome this obstacle would be to identify and introduce into commercial germplasm alternative alleles controlling sugar metab...

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

    E-print Network

    Announcement of Population Data Allele frequencies for 70 autosomal SNP loci with U.S. Caucasian nucleotide polymorphisms (SNPs). For each sample, the 70 SNP markers were typed in 11 unique 6-plexes-Weinberg equilibrium indicated a statistically significant result. In order to evaluate the minimum number of SNP loci

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

    E-print Network

    Cai, Long

    SNP discovery and allele frequency estimation by deep sequencing of reduced representation S Sonstegard1 High-density single-nucleotide polymorphism (SNP) arrays have revolutionized the ability genotyping assays with broad utility. We describe an economical, efficient, single- step method for SNP

  15. SNP Calling, Genotype Calling, and Sample Allele Frequency Estimation from New-Generation Sequencing

    E-print Network

    Nielsen, Rasmus

    SNP Calling, Genotype Calling, and Sample Allele Frequency Estimation from New, and show how the method can be used for genotype calling and SNP calling. We also show how the method can. Citation: Nielsen R, Korneliussen T, Albrechtsen A, Li Y, Wang J (2012) SNP Calling, Genotype Calling

  16. Genome-wide allele-and strand-specific expression Julien Gagneur1

    E-print Network

    Sinha, Himanshu

    , and the degree to which this variation is transcribed conditions its impact on phenotype. Up to 90% of the genomeREPORT Genome-wide allele- and strand-specific expression profiling Julien Gagneur1 , Himanshu@embl.de Received 4.2.09; accepted 27.4.09 Recent reports have shown that most of the genome is transcribed

  17. Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism

    SciTech Connect

    Noble, E.P.; Blum, K.; Ritchie, T.; Montgomery, A.; Sheridan, P.J. )

    1991-07-01

    The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and non-alcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (lambda hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd (binding affinity) and Bmax (number of binding sites)) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover, a progressively reduced Bmax was found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.

  18. Single-Stranded RNAs Use RNAi to Potently and Allele-Selectively Inhibit Mutant Huntingtin Expression

    PubMed Central

    Yu, Dongbo; Pendergraff, Hannah; Liu, Jing; Kordasiewicz, Holly B.; Cleveland, Don W.; Swayze, Eric E.; Lima, Walt F.; Crooke, Stanley T.; Prakash, Thazha P.; Corey, David R.

    2012-01-01

    Mutant huntingtin (HTT) protein causes Huntington’s Disease (HD), an incurable neurological disorder. Silencing mutant HTT using nucleic acids would eliminate the root cause of HD. Developing nucleic acid drugs is challenging, and an ideal clinical approach to gene silencing would combine the simplicity of single-stranded antisense oligonucleotides with the efficiency of RNAi. Here we describe RNAi by single-stranded silencing RNAs (ss-siRNAs). ss-siRNAs are potent (>100-fold more than unmodified RNA) and allele-selective (>30-fold) inhibitors of mutant HTT expression in cells derived from HD patients. Strategic placement of mismatched bases mimics micro-RNA recognition and optimizes discrimination between mutant and wild-type alleles. ss-siRNAs require argonaute protein and function through the RNAi pathway. Intraventricular infusion of ss-siRNA produced selective silencing of the mutant HTT allele throughout the brain in a mouse HD model. These data demonstrate that chemically modified ss-siRNAs function through the RNAi pathway and provide allele-selective compounds for clinical development. PMID:22939619

  19. What phylogeny and gene genealogy analyses reveal about homoplasy in citrus microsatellite alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sixty-five microsatellite alleles from three Simple Sequence Repeat (SSR) loci (cAGG9, CCT01 and GT03) of various Citrus, Fortunella or Poncirus accessions were cloned and sequenced to determine their mode of evolution. This data was used to assess sequence variation by calculating the average numb...

  20. Association of the Apolipoprotein E 2 Allele with Concurrent Occurrence of Endometrial Hyperplasia and Endometrial Carcinoma

    PubMed Central

    Ivanova, Tatiana I.; Krikunova, Ludmila I.; Ryabchenko, Nikolay I.; Mkrtchyan, Liana S.; Khorokhorina, Vera A.; Salnikova, Lyubov E.

    2015-01-01

    Genes encoding proteins with antioxidant properties may influence susceptibility to endometrial hyperplasia (EH) and endometrial carcinoma (ECa). Patients with EH (n = 89), EH concurrent with ECa (n = 76), ECa (n = 186), and healthy controls (n = 1110) were genotyped for five polymorphic variants in the genes involved in metabolism of lipoproteins (APOE Cys112Arg and Arg158Cys), iron (HFE Cys282Tyr and His63Asp), and catecholamines (COMT Val158Met). Patients and controls were matched by ethnicity (all Caucasians), age, body mass index (BMI), and incidence of hypertension and diabetes. The frequency of the APOE E 2 allele (158Cys) was higher in patients with EH + ECa than in controls (P = 0.0012, PBonferroni = 0.018, OR = 2.58, 95% CI 1.49–4.45). The APOE E 4 allele (112Arg) was more frequently found in patients with EH than in controls and HFE minor allele G (63Asp) had a protective effect in the ECa group, though these results appeared to be nonsignificant after correction for multiple comparisons. The results of the study indicate that E 2 allele might be associated with concurrent occurrence of EH and ECa. PMID:25741405

  1. A high-throughput Taqman approach for the discrimination of HLA-E alleles.

    PubMed

    Paquay, M M; Schellekens, J; Tilanus, M G J

    2009-12-01

    An association between human leukocyte antigen (HLA) molecules and the incidence of various diseases has been recognized for years. Molecules of the HLA system also exert an important role on the clinical outcome after transplantation such as stem cell transplantation. The conventional HLA typing method is sequence based typing (SBT) which is reliable but laborious. The goal of this study was to develop a high-throughput Taqman assay to screen large panels for HLA-E alleles. Two functional HLA-E alleles, *0101 and *0103, have been identified. We set up the Taqman assay with genomic DNA as template to discriminate the three HLA-E genotypes: homozygous HLA-E*0101, heterozygous *0101, *0103 and homozygous *0103. This Taqman approach was validated by the comparison of results obtained with the typing results acquired by sequenced base typing (SBT). Additional screening of a large panel showed the pronounced discriminative capacity of the Taqman assay for HLA-E allele typing. The Taqman assay is a fast, reliable and consistent HLA-E allele typing method, especially useful to screen large panels. PMID:19845911

  2. Genetic Heterogeneity within Electrophoretic "Alleles" of Xanthine Dehydrogenase in DROSOPHILA PSEUDOOBSCURA

    PubMed Central

    Singh, R. S.; Lewontin, R. C.; Felton, A. A.

    1976-01-01

    An experimental plan for an exhaustive determination of genic variation at structural gene loci is presented. In the initial steps of this program, 146 isochromosomal lines from 12 geographic populations of D. pseudoobscura were examined for allelic variation of xanthine dehydrogenase by the serial use of 4 different electrophoretic conditions and a heat stability test. The 5 criteria revealed a total of 37 allelic classes out of the 146 genomes examined where only 6 had been previously revealed by the usual method of gel electrophoresis. This immense increase in genic variation also showed previously unsuspected population differences between the main part of the species distribution and the isolated population of Bogotá, Colombia, in conformity with the known partial reproductive isolation of the Bogotá population. The average heterozygosity at the Xdh locus is at least 72% in natural populations. This result, together with the very large number of alleles segregating and the pattern of allelic frequencies, has implications for theories of genetic polymorphism which are discussed. PMID:1001881

  3. Natural allelic variation identies new genes in the Arabidopsis circadian system

    E-print Network

    Millar, Andrew J.

    Natural allelic variation identi®es new genes in the Arabidopsis circadian system Kamal Swarup1 the circadian rhythm of Arabidopsis thaliana leaf movements in the accession Cvi from the Cape Verde Islands the period of the circadian clock. Near-isogenic lines (NILs) that contain a QTL in a small, de®ned chromo

  4. Digital RNA allelotyping reveals tissue-specific and allele-specific gene expression in human

    E-print Network

    Church, George M.

    Digital RNA allelotyping reveals tissue-specific and allele-specific gene expression in human Kun Aach2, Emily M Leproust6, Kevin Eggan5 & George M Church2 We developed a digital RNA allelotyping recently been used in the digital characterization of transcriptome and alternatively spliced transcripts9

  5. A new strategy to reduce allelic bias in RNA-Seq readmapping

    E-print Network

    that mapping to this enhanced reference reduced the read-mapping biases, leading to more reliable estimates numbers of reads obtained from individual tran- scripts. However, multiple sources of bias inherent significant difference in the number of reads carrying the two alleles indicates ASE. Reliable estimation

  6. Precision-engineering the Pseudomonas aeruginosa genome with two-step allelic exchange.

    PubMed

    Hmelo, Laura R; Borlee, Bradley R; Almblad, Henrik; Love, Michelle E; Randall, Trevor E; Tseng, Boo Shan; Lin, Chuyang; Irie, Yasuhiko; Storek, Kelly M; Yang, Jaeun Jane; Siehnel, Richard J; Howell, P Lynne; Singh, Pradeep K; Tolker-Nielsen, Tim; Parsek, Matthew R; Schweizer, Herbert P; Harrison, Joe J

    2015-11-01

    Allelic exchange is an efficient method of bacterial genome engineering. This protocol describes the use of this technique to make gene knockouts and knock-ins, as well as single-nucleotide insertions, deletions and substitutions, in Pseudomonas aeruginosa. Unlike other approaches to allelic exchange, this protocol does not require heterologous recombinases to insert or excise selective markers from the target chromosome. Rather, positive and negative selections are enabled solely by suicide vector-encoded functions and host cell proteins. Here, mutant alleles, which are flanked by regions of homology to the recipient chromosome, are synthesized in vitro and then cloned into allelic exchange vectors using standard procedures. These suicide vectors are then introduced into recipient cells by conjugation. Homologous recombination then results in antibiotic-resistant single-crossover mutants in which the plasmid has integrated site-specifically into the chromosome. Subsequently, unmarked double-crossover mutants are isolated directly using sucrose-mediated counter-selection. This two-step process yields seamless mutations that are precise to a single base pair of DNA. The entire procedure requires ?2 weeks. PMID:26492139

  7. Dexamethasone Promotes Hypertension by Allele-specific Regulation of the Human Angiotensinogen Gene*S

    E-print Network

    Abraham, Nader G.

    Dexamethasone Promotes Hypertension by Allele-specific Regulation of the Human Angiotensinogen Gene, Valhalla, New York, 10595 Background: Glucocorticoids modulate the RAS and cause hypertension. Results to dexamethasone with tissue-specific up-regulation of hAGT, increased plasma AngII, and hypertension. Conclusion

  8. Increased frequency of the alpha-1-antichymotrypsin T allele in cerebral amyloid angiopathy.

    PubMed

    Durany, N; Ravid, R; Riederer, P; Cruz-Sánchez, F F

    2000-09-01

    Cerebral amyloid angiopathy (CAA) is a process of unknown etiology characterized by amyloid deposition in the wall of small cerebral and meningeal blood vessels. CAA is also a feature of Alzheimer's disease (AD) and of a subgroup of elderly people. Alpha-1-Antichymotrypsin (ACT) is a serum glycoprotein frequently associated with vascular and senile plaque amyloid. The ACT gene is known to have a bi-allele polymorphism that causes a simple amino acid substitution. In an attempt to clarify the possible role of ACT polymorphism in AD and in cases of CAA, the ACT genotype was investigated in AD, CAA, and intellectually intact controls. Representative brain areas (cerebral cortex, hippocampus, putamen, white matter, and gyrus cinguli) from all cases were studied using classical histologic staining techniques (hematoxylin-eosin (HE), Mallory's thrichromic or alkaline congo red stain), and immunohistochemistry for tau and beta-amyloid proteins. There was a significantly increased T allele and TT genotype frequency in the CAA group, but not in the AD group, suggesting a role for the ACT genotype in the development of vascular lesions. The presence of the apolipoprotein E4 allele (ApoE4) did not correlate with the ACT-A allele, as previously reported, and appeared to be independent of the risk for developing AD. PMID:11132933

  9. Rapid Publication A Mouse Model for the AF508 Allele of Cystic Fibrosis

    E-print Network

    Capecchi, Mario R.

    Rapid Publication A Mouse Model for the AF508 Allele of Cystic Fibrosis Bernhardt G. Zeiher,* Ernst College ofMedicine, Salt Lake City, Utah 84112 Abstract The most common cause of cystic fibrosis is a mutation that deletes phenylalanine 508 in cystic fibrosis transmembrane conductance regulator (CFTR

  10. Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline.

    PubMed

    Schwarz, Flavio; Springer, Stevan A; Altheide, Tasha K; Varki, Nissi M; Gagneux, Pascal; Varki, Ajit

    2016-01-01

    The individuals of most vertebrate species die when they can no longer reproduce. Humans are a rare exception, having evolved a prolonged postreproductive lifespan. Elders contribute to cooperative offspring care, assist in foraging, and communicate important ecological and cultural knowledge, increasing the survival of younger individuals. Age-related deterioration of cognitive capacity in humans compromises these benefits and also burdens the group with socially costly members. We investigated the contribution of the immunoregulatory receptor CD33 to a uniquely human postreproductive disease, Alzheimer's dementia. Surprisingly, even though selection at advanced age is expected to be weak, a CD33 allele protective against Alzheimer's disease is derived and unique to humans and favors a functional molecular state of CD33 resembling that of the chimpanzee. Thus, derived alleles may be compensatory and restore interactions altered as a consequence of human-specific brain evolution. We found several other examples of derived alleles at other human loci that protect against age-related cognitive deterioration arising from neurodegenerative disease or cerebrovascular insufficiency. Selection by inclusive fitness may be strong enough to favor alleles protecting specifically against cognitive decline in postreproductive humans. Such selection would operate by maximizing the contributions of postreproductive individuals to the fitness of younger kin. PMID:26621708

  11. Estimating copy numbers of alleles from population-scale high-throughput sequencing data

    PubMed Central

    2015-01-01

    Background With the recent development of microarray and high-throughput sequencing (HTS) technologies, a number of studies have revealed catalogs of copy number variants (CNVs) and their association with phenotypes and complex traits. In parallel, a number of approaches to predict CNV regions and genotypes are proposed for both microarray and HTS data. However, only a few approaches focus on haplotyping of CNV loci. Results We propose a novel approach to infer copy unit alleles and their numbers in each sample simultaneously from population-scale HTS data by variational Bayesian inference on a generative probabilistic model inspired by latent Dirichlet allocation, which is a well studied model for document classification problems. In simulation studies, we evaluated concordance between inferred and true copy unit alleles for lower-, middle-, and higher-copy number dataset, in which precision and recall were ? 0.9 for data with mean coverage ? 10× per copy unit. We also applied the approach to HTS data of 1123 samples at highly variable salivary amylase gene locus and a pseudogene locus, and confirmed consistency of the estimated alleles within samples belonging to a trio of CEPH/Utah pedigree 1463 with 11 offspring. Conclusions Our proposed approach enables detailed analysis of copy number variations, such as association study between copy unit alleles and phenotypes or biological features including human diseases. PMID:25707811

  12. A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations

    E-print Network

    A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations and Surgeons, New York, NY, March 18, 2008 (received for review November 8, 2007) DISC1 is a strong candidate an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal

  13. New Alleles of the Yeast MPS1 Gene Reveal Multiple Requirements in Spindle Pole Body Duplication

    PubMed Central

    Schutz, Amy R.; Winey, Mark

    1998-01-01

    In Saccharomyces cerevisiae, the Mps1p protein kinase is critical for both spindle pole body (SPB) duplication and the mitotic spindle assembly checkpoint. The mps1–1 mutation causes failure early in SPB duplication, and because the spindle assembly checkpoint is also compromised, mps1–1 cells proceed with a monopolar mitosis and rapidly lose viability. Here we report the genetic and molecular characterization of mps1–1 and five new temperature-sensitive alleles of MPS1. Each of the six alleles contains a single point mutation in the region of the gene encoding the protein kinase domain. The mutations affect several residues conserved among protein kinases, most notably the invariant glutamate in subdomain III. In vivo and in vitro kinase activity of the six epitope-tagged mutant proteins varies widely. Only two display appreciable in vitro activity, and interestingly, this activity is not thermolabile under the assay conditions used. While five of the six alleles cause SPB duplication to fail early, yielding cells with a single SPB, mps1–737 cells proceed into SPB duplication and assemble a second SPB that is structurally defective. This phenotype, together with the observation of intragenic complementation between this unique allele and two others, suggests that Mps1p is required for multiple events in SPB duplication. PMID:9529376

  14. Molecular mapping of the mutant fap4(A24) allele for elevated palmitate concentration in soybean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean [Glycine max L. Merr.] oil with an elevated palmitate concentration is useful for some food and industrial applications. The objective of this study was to map the genetic location of the fap4(A24) allele that controls an increase in palmitate concentration and to identify molecular marker...

  15. APOE 4 allele predicts faster cognitive decline in mild Alzheimer disease

    E-print Network

    APOE 4 allele predicts faster cognitive decline in mild Alzheimer disease S. Cosentino, PhD N and prev- alent Alzheimer disease (AD). Methods: Individuals were recruited from two longitudinal cohort stages of Alzheimer disease. Neurology® 2008;70:1842­1849 GLOSSARY AD Alzheimer disease; BDAE Boston

  16. Allelic Imbalance of mRNA Associated with ?2-HS Glycoprotein (Fetuin-A) Polymorphism

    PubMed Central

    Inaoka, Yoshihiko; Osawa, Motoki; Mukasa, Nahoko; Miyashita, Keiko; Satoh, Fumiko; Kakimoto, Yu

    2015-01-01

    Alpha 2-HS glycoprotein (AHSG), also designated as fetuin-A, exhibits polymorphism in population genetics consisting of two major alleles of AHSG?1 and AHSG?2. The serum level in the AHSG?1 homozygote is significantly higher than that of the AHSG?2 homozygote. This study examined the molecular mechanism for the cis-regulatory expression. To quantitate allele-specific mRNA in intra-assays of the heterozygote, RT-PCR method employing primers that were incorporated to the two closely located SNPs was developed. The respective magnitudes of AHSG?1 to AHSG?2 in the liver tissues and hepatic culture cells of PLC/PRF/5 were determined quantitatively as 2.5-fold and 6.2-fold. The mRNA expressional difference of two major alleles was observed, which is consistent with that in the serum level. The culture cells carried heterozygous genotypes in rs4917 and rs4918, but homozygous one in rs2248690. It was unlikely that the imbalance was derived from the SNP located in the promotor site. Furthermore, to investigate the effect of mRNA degradation, RNA synthesis in the cell culture was inhibited potently by the addition of actinomycin-D. No marked change was apparent between the two alleles. The results indicated that the cis-regulatory expressional difference is expected to occur at the level of transcription or splicing of mRNA. PMID:26549924

  17. Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck

    PubMed Central

    Balick, Daniel J.; Do, Ron; Cassa, Christopher A.; Reich, David; Sunyaev, Shamil R.

    2015-01-01

    Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that this response qualitatively depends on dominance. The number of dominant or additive deleterious alleles per haploid genome is expected to be slightly increased following the bottleneck and re-expansion. In contrast, the number of completely or partially recessive alleles should be sharply reduced. Changes of population size expose differences between recessive and additive selection, potentially providing insight into the prevalence of dominance in natural populations. Specifically, we use a simple statistic, BR??xipop1/?xjpop2, where xi represents the derived allele frequency, to compare the number of mutations in different populations, and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. We also provide empirical evidence showing that gene sets associated with autosomal recessive disease in humans may have a BR indicative of recessive selection. Together, these theoretical predictions and empirical observations show that complex demographic history may facilitate rather than impede inference of parameters of natural selection. PMID:26317225

  18. In vitro assessment of the allelic variants of cytochrome P450.

    PubMed

    Hiratsuka, Masahiro

    2012-01-01

    The cytochrome P450 (CYP) superfamily is one of the most important groups of enzymes involved in drug metabolism. It is responsible for the metabolism of a large number of drugs. Many CYP isoforms are expressed polymorphically, and catalytic alterations of allelic variant proteins can affect the metabolic activities of many drugs. The CYP2D6, CYP2C9, CYP2C19, and CYP2B6 genes are particularly polymorphic, whereas CYP1A1, CYP1A2, CYP2E1, and CYP3A4 are relatively well conserved without common functional polymorphisms. In vitro studies using cDNA expression systems are useful tools for evaluating functional alterations of the allelic variants of CYP, particularly for low-frequency alleles. Recombinant CYPs have been successfully expressed in bacteria, yeast, baculoviruses, and several mammalian cells. Determination of CYP variant-mediated kinetic parameters (Km and Vmax) in vitro can be useful for predicting drug dosing and clearance in humans. This review focuses on the advantages and disadvantages of the various cDNA-expression systems used to determine the kinetic parameters for CYP allelic variants, the methods for determining the kinetic parameters, and the findings of in vitro studies on highly polymorphic CYPs, including CYP2D6, CYP2C9, CYP2C19, and CYP2B6. PMID:22041138

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

    PubMed Central

    Eitan, Yuval; Kashi, Yechezkel

    2002-01-01

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

  20. Genetic Variation in the Strongly Canalized Sex Pheromone Communication System of the European Corn Borer, Ostrinia Nubilalis Hubner (Lepidoptera; Pyralidae)

    PubMed Central

    Zhu, J.; Lofstedt, C.; Bengtsson, B. O.

    1996-01-01

    The major difference in pheromone production between the so-called E and Z strains of the European corn borer Ostrinia nubilalis is controlled by two alleles at a single autosomal locus. E-strain females produce an (E)-11-tetradecenyl acetate pheromone with 1-3% of the Z isomer, whereas Z-strain females produce the opposite blend. In laboratory-reared insects we found that F(1) females produced, on average, a 71:29 E/Z ratio, but the distribution was clearly bimodal. The variability in pheromone blend produced by heterozygous females could be explained by the existence of two different alleles in the Z strain which in combination with the E-strain allele for the major production locus cause the production of a component mixture either high or low in the E isomer. In addition, evidence was found for an independently inherited factor, existing in the E strain, with a dominant effect on the amount of E isomer produced by females homozygous for Z-alleles at the major production locus. Thus, the low variability normally found in the pheromone mixture produced by O. nubilalis and other moth females may, by canalization, hide a considerable amount of underlying genetic variation. PMID:8889536

  1. Investigation of the Annexin A5 M2 haplotype in 500 white European couples who have experienced recurrent spontaneous abortion.

    PubMed

    Demetriou, Charalambos; Abu-Amero, Sayeda; White, Shawnelle; Peskett, Emma; Markoff, Arseni; Stanier, Philip; Moore, Gudrun E; Regan, Lesley

    2015-11-01

    Annexin A5 is a placental anti-coagulant protein that contains four nucleotide substitutions (M2 haplotype) in its promoter. This haplotype is a risk factor for recurrent spontaneous abortion (RSA). The influence of the M2 haplotype in the gestational timing of spontaneous abortions, paternal risk and relationships with known risk factors were investigated. European couples (n = 500) who had experienced three or more consecutive spontaneous abortions, and two fertile control groups, were selected for this study. The allele frequency of M2 was significantly higher among patients who had experienced early RSA than among controls (P = 0.002). No difference was found between controls and patients who had undergone late spontaneous abortions. No difference was found between patients who had experienced RSA who had a live birth or no live births, or between patients who were positive or negative for known risk factors. Male and female partners in each group had similar allele frequencies of M2. The M2 haplotype is a risk factor for early spontaneous abortions, before the 12th week of gestation, and confers about the same relative risk to carriers of both sexes. Having one or more M2 allele(s) in combination with other risk factors further increases the RSA risk. PMID:26371709

  2. Allele and Haplotype Diversity of 26 X-STR Loci in Four Nationality Populations from China

    PubMed Central

    Quan, Li; Zhao, Hu; Wu, Ye-Da; Huang, Xiao-Ling; Lu, De-Jian

    2013-01-01

    Background Haplotype analysis of closely associated markers has proven to be a powerful tool in kinship analysis, especially when short tandem repeats (STR) fail to resolve uncertainty in relationship analysis. STR located on the X chromosome show stronger linkage disequilibrium compared with autosomal STR. So, it is necessary to estimate the haplotype frequencies directly from population studies as linkage disequilibrium is population-specific. Methodology and Findings Twenty-six X-STR loci including six clusters of linked markers DXS6807-DXS8378-DXS9902(Xp22), DXS7132-DXS10079-DXS10074-DXS10075-DXS981 (Xq12), DXS6801-DXS6809-DXS6789-DXS6799(Xq21), DXS7424-DXS101-DXS7133(Xq22), DXS6804-GATA172D05(Xq23), DXS8377-DXS7423 (Xq28) and the loci DXS6800, DXS6803, DXS9898, GATA165B12, DXS6854, HPRTB and GATA31E08 were typed in four nationality (Han, Uigur, Kazakh and Mongol) samples from China (n?=?1522, 876 males and 646 females). Allele and haplotype frequency as well as linkage disequilibrium data for kinship calculation were observed. The allele frequency distribution among different populations was compared. A total of 5–20 alleles for each locus were observed and altogether 289 alleles for all the selected loci were found. Allele frequency distribution for most X-STR loci is different in different populations. A total of 876 male samples were investigated by haplotype analysis and for linkage disequilibrium. A total of 89, 703, 335, 147, 39 and 63 haplotypes were observed. Haplotype diversity was 0.9584, 0.9994, 0.9935, 0.9736, 0.9427 and 0.9571 for cluster I, II, III, IV, V and VI, respectively. Eighty-two percent of the haplotype of cluster IIwas found only once. And 94% of the haplotype of cluster III show a frequency of <1%. Conclusions These results indicate that allele frequency distribution for most X-STR loci is population-specific and haplotypes of six clusters provide a powerful tool for kinship testing and relationship investigation. So it is necessary to obtain allele frequency and haplotypes data of the linked loci for forensic application. PMID:23805185

  3. HLA Alleles Associated with the Adaptive Immune Response to Smallpox Vaccine: A Replication Study

    PubMed Central

    Ovsyannikova, Inna G.; Pankratz, V. Shane; Salk, Hannah M.; Kennedy, Richard B.; Poland, Gregory A.

    2014-01-01

    Background 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 and cytokine immune responses, including HLA-B (*13:02, *38:02, *44:03, *48:01), HLA-DQB1 (*03:02, *06:04) and HLA-DRB1 (*01:03, *03:01, *10:01, *13:01, *15:01), respectively. Methods 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 in order to evaluate previously discovered HLA allelic associations from the Dryvax study and determine if these associations are replicated with ACAM2000. Results 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). Conclusions 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

  4. Genetic Diversity and Population Structure Analysis of European Hexaploid Bread Wheat (Triticum aestivum L.) Varieties

    PubMed Central

    Nielsen, Nanna Hellum; Backes, Gunter; Stougaard, Jens; Andersen, Stig Uggerhøj; Jahoor, Ahmed

    2014-01-01

    Progress in plant breeding is facilitated by accurate information about genetic structure and diversity. Here, Diversity Array Technology (DArT) was used to characterize a population of 94 bread wheat (Triticum aestivum L.) varieties of mainly European origin. In total, 1,849 of 7,000 tested markers were polymorphic and could be used for population structure analysis. Two major subgroups of wheat varieties, GrI and GrII, were identified using the program STRUCTURE, and confirmed by principal component analysis (PCA). These subgroups were largely separated according to origin; GrI comprised varieties from Southern and Eastern Europe, whereas GrII contained mostly modern varieties from Western and Northern Europe. A large proportion of the markers contributing most to the genetic separation of the subgroups were located on chromosome 2D near the Reduced height 8 (Rht8) locus, and PCR-based genotyping suggested that breeding for the Rht8 allele had a major impact on subgroup separation. Consistently, analysis of linkage disequilibrium (LD) suggested that different selective pressures had acted on chromosome 2D in the two subgroups. Our data provides an overview of the allele composition of bread wheat varieties anchored to DArT markers, which will facilitate targeted combination of alleles following DArT-based QTL studies. In addition, the genetic diversity and distance data combined with specific Rht8 genotypes can now be used by breeders to guide selection of crossing parents. PMID:24718292

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

    PubMed Central

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

    1989-01-01

    DNA haplotype data from the phenylalanine hydroxylase (PAH) locus are available from a number of European populations as a result of RFLP testing for genetic counseling in families with phenylketonuria (PKU). We have analyzed data from Hungary and Czechoslovakia together with published data from five additional countries–Denmark, Switzerland, Scotland, Germany, and France–representing a broad geographic and ethnographic range. The data include 686 complete chromosomal haplotypes for eight RFLP sites assayed in 202 unrelated Caucasian families with PKU. Forty-six distinct RFLP haplotypes have been observed to date, 10 unique to PKU-bearing chromosomes, 12 unique to non-PKU chromosomes, and the remainder found in association with both types. Despite the large number of haplotypes observed (still much less than the theoretical maximum of 384), five haplotypes alone account for more than 76% of normal European chromosomes and four haplotypes alone account for more than 80% of PKU-bearing chromosomes. We evaluated the distribution of haplotypes and alleles within these populations and calculated pairwise disequilibrium values between RFLP sites and between these sites and a hypothetical PKU “locus.” There are statistically significant differences between European populations in the frequencies of non-PKU chromosomal haplotypes (P = .025) and PKU chromosomal haplotypes (P < < .001). Haplotype frequencies of the PKU and non-PKU chromosomes also differ significantly (P < < .001. Disequilibrium values are consistent with the PAH physical map and support the molecular evidence for multiple, independent PKU mutations in Caucasians. However, the data do not support a single geographic origin for these mutations. Within these European populations a parent carrying a PKU mutation has an average probability of greater than 86% of being heterozygous–and hence informative for linkage–at one or more PAH RFLP sites. Thus these RFLP alleles and haplotypes provide an effective tool for linkage diagnosis of disease and carrier status in PKU families. PMID:2569271

  6. Global phylogeography of the avian malaria pathogen Plasmodium relictum based on MSP1 allelic diversity

    USGS Publications Warehouse

    Hellgren, Olof; Atkinson, Carter T.; Bensch, Staffan; Albayrak, Tamer; Dimitrov, Dimitar; Ewen, John G.; Kim, Kyeong Soon; Lima, Marcos R.; Martin, Lynn; Palinauskas, Vaidas; Ricklefs, Robert; Sehgal, Ravinder N. M.; Gediminas, Valkiunas; Tsuda, Yoshio; Marzal, Alfonso

    2015-01-01

    Knowing the genetic variation that occurs in pathogen populations and how it is distributed across geographical areas is essential to understand parasite epidemiology, local patterns of virulence, and evolution of host-resistance. In addition, it is important to identify populations of pathogens that are evolutionarily independent and thus ‘free’ to adapt to hosts and environments. Here, we investigated genetic variation in the globally distributed, highly invasive avian malaria parasite Plasmodium relictum, which has several distinctive mitochondrial haplotyps (cyt b lineages, SGS1, GRW11 and GRW4). The phylogeography of P. relictum was accessed using the highly variable nuclear gene merozoite surface protein 1 (MSP1), a gene linked to the invasion biology of the parasite. We show that the lineage GRW4 is evolutionarily independent of GRW11 and SGS1 whereas GRW11 and SGS1 share MSP1 alleles and thus suggesting the presence of two distinct species (GRW4 versus SGS1 and GRW11). Further, there were significant differences in the global distribution of MSP1 alleles with differences between GRW4 alleles in the New and the Old World. For SGS1, a lineage formerly believed to have both tropical and temperate transmission, there were clear differences in MSP1 alleles transmitted in tropical Africa compared to the temperate regions of Europe and Asia. Further, we highlight the occurrence of multiple MSP1 alleles in GRW4 isolates from the Hawaiian Islands, where the parasite has contributed to declines and extinctions of endemic forest birds since it was introduced. This study stresses the importance of multiple independent loci for understanding patterns of transmission and evolutionary independence across avian malaria parasites.

  7. Detection of Ancestry Informative HLA Alleles Confirms the Admixed Origins of Japanese Population

    PubMed Central

    Nakaoka, Hirofumi; Mitsunaga, Shigeki; Hosomichi, Kazuyoshi; Shyh-Yuh, Liou; Sawamoto, Taiji; Fujiwara, Tsutomu; Tsutsui, Naohisa; Suematsu, Koji; Shinagawa, Akira; Inoko, Hidetoshi; Inoue, Ituro

    2013-01-01

    The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A, -B, -C, -DRB1, and -DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago. PMID:23577161

  8. Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.

    PubMed

    Balasubramanian, Ravikumar; Choi, Jin-Ho; Francescatto, Ludmila; Willer, Jason; Horton, Edward R; Asimacopoulos, Eleni P; Stankovic, Konstantina M; Plummer, Lacey; Buck, Cassandra L; Quinton, Richard; Nebesio, Todd D; Mericq, Veronica; Merino, Paulina M; Meyer, Brian F; Monies, Dorota; Gusella, James F; Al Tassan, Nada; Katsanis, Nicholas; Crowley, William F

    2014-12-16

    Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems. PMID:25472840

  9. pfmdr1 Amplification and Fixation of pfcrt Chloroquine Resistance Alleles in Plasmodium falciparum in Venezuela ? †

    PubMed Central

    Griffing, Sean; Syphard, Luke; Sridaran, Sankar; McCollum, Andrea M.; Mixson-Hayden, Tonya; Vinayak, Sumiti; Villegas, Leopoldo; Barnwell, John W.; Escalante, Ananias A.; Udhayakumar, Venkatachalam

    2010-01-01

    Molecular tools are valuable for determining evolutionary history and the prevalence of drug-resistant malaria parasites. These tools have helped to predict decreased sensitivity to antimalarials and fixation of multidrug resistance genotypes in some regions. In order to assess how historical drug policies impacted Plasmodium falciparum in Venezuela, we examined molecular changes in genes associated with drug resistance. We examined pfmdr1 and pfcrt in samples from Sifontes, Venezuela, and integrated our findings with earlier work describing dhfr and dhps in these samples. We characterized pfmdr1 genotypes and copy number variation, pfcrt genotypes, and proximal microsatellites in 93 samples originating from surveillance from 2003 to 2004. Multicopy pfmdr1 was found in 12% of the samples. Two pfmdr1 alleles, Y184F/N1042D/D1246Y (37%) and Y184F/S1034C/N1042D/D1246Y (63%), were found. These alleles share ancestry, and no evidence of strong selective pressure on mutations was found. pfcrt chloroquine resistance alleles are fixed with two alleles: StctVMNT (91%) and SagtVMNT (9%). These alleles are associated with strong selection. There was also an association between pfcrt, pfmdr1, dhfr, and dhps genotypes/haplotypes. Duplication of pfmdr1 suggests a potential shift in mefloquine sensitivity in this region, which warrants further study. A bottleneck occurred in P. falciparum in Sifontes, Venezuela, and multidrug resistance genotypes are present. This population could be targeted for malaria elimination programs to prevent the possible spread of multidrug-resistant parasites. PMID:20145087

  10. High-Resolution Analysis of Parent-of-Origin Allelic Expression in the Arabidopsis Endosperm

    PubMed Central

    Roszak, Pawel; Beisel, Christian; Donoghue, Mark T. A.; Spillane, Charles; Nordborg, Magnus; Rehmsmeier, Marc; Köhler, Claudia

    2011-01-01

    Genomic imprinting is an epigenetic phenomenon leading to parent-of-origin specific differential expression of maternally and paternally inherited alleles. In plants, genomic imprinting has mainly been observed in the endosperm, an ephemeral triploid tissue derived after fertilization of the diploid central cell with a haploid sperm cell. In an effort to identify novel imprinted genes in Arabidopsis thaliana, we generated deep sequencing RNA profiles of F1 hybrid seeds derived after reciprocal crosses of Arabidopsis Col-0 and Bur-0 accessions. Using polymorphic sites to quantify allele-specific expression levels, we could identify more than 60 genes with potential parent-of-origin specific expression. By analyzing the distribution of DNA methylation and epigenetic marks established by Polycomb group (PcG) proteins using publicly available datasets, we suggest that for maternally expressed genes (MEGs) repression of the paternally inherited alleles largely depends on DNA methylation or PcG-mediated repression, whereas repression of the maternal alleles of paternally expressed genes (PEGs) predominantly depends on PcG proteins. While maternal alleles of MEGs are also targeted by PcG proteins, such targeting does not cause complete repression. Candidate MEGs and PEGs are enriched for cis-proximal transposons, suggesting that transposons might be a driving force for the evolution of imprinted genes in Arabidopsis. In addition, we find that MEGs and PEGs are significantly faster evolving when compared to other genes in the genome. In contrast to the predominant location of mammalian imprinted genes in clusters, cluster formation was only detected for few MEGs and PEGs, suggesting that clustering is not a major requirement for imprinted gene regulation in Arabidopsis. PMID:21698132

  11. Novel natural allelic variations at the Rht-1 loci in wheat.

    PubMed

    Li, Aixia; Yang, Wenlong; Lou, Xueyuan; Liu, Dongcheng; Sun, Jiazhu; Guo, Xiaoli; Wang, Jing; Li, Yiwen; Zhan, Kehui; Ling, Hong-Qing; Zhang, Aimin

    2013-11-01

    Plant height is an important agronomic trait. Dramatic increase in wheat yield during the "green revolution" is mainly due to the widespread utilization of the Reduced height (Rht)-1 gene. We analyzed the natural allelic variations of three homoeologous loci Rht-A1, Rht-B1, and Rht-D1 in Chinese wheat (Triticum aestivum L.) micro-core collections and the Rht-B1/D1 genotypes in over 1,500 bred cultivars and germplasms using a modified EcoTILLING. We identified six new Rht-A1 allelic variations (Rht-A1b-g), eight new Rht-B1 allelic variations (Rht-B1h-o), and six new Rht-D1 allelic variations (Rht-D1e-j). These allelic variations contain single nucleotide polymorphisms (SNPs) or small insertions and deletions in the coding or uncoding regions, involving two frame-shift mutations and 15 missenses. Of which, Rht-D1e and Rht-D1h resulted in the loss of interactions of GID1-DELLA-GID2, Rht-B1i could increase plant height. We found that the Rht-B1h contains the same SNPs and 197 bp fragment insertion as reported in Rht-B1c. Further detection of Rht-B1h in Tibet wheat germplasms and wheat relatives indicated that Rht-B1c may originate from Rht-B1h. These results suggest rich genetic diversity at the Rht-1 loci and provide new resources for wheat breeding. PMID:23992198

  12. Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

    PubMed Central

    Balasubramanian, Ravikumar; Choi, Jin-Ho; Francescatto, Ludmila; Willer, Jason; Horton, Edward R.; Asimacopoulos, Eleni P.; Stankovic, Konstantina M.; Plummer, Lacey; Buck, Cassandra L.; Quinton, Richard; Nebesio, Todd D.; Mericq, Veronica; Meyer, Brian F.; Monies, Dorota; Gusella, James F.; Al Tassan, Nada; Katsanis, Nicholas; Crowley, William F.

    2014-01-01

    Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems. PMID:25472840

  13. Microsatellite variation and rare alleles in a bottlenecked Hawaiian Islands endemic: implications for reintroductions

    USGS Publications Warehouse

    Reynolds, Michelle H.; Pearce, John M.; Lavretsky, Philip; Seixas, Pedro P.; Courtot, Karen

    2015-01-01

    Conservation of genetic biodiversity in endangered wildlife populations is an important challenge to address since the loss of alleles and genetic drift may influence future adaptability. Reintroduction aims to re-establish species to restored or protected ecosystems; however, moving a subset of individuals may result in loss of gene variants during the management-induced bottleneck (i.e. translocation). The endangered Laysan teal Anas laysanensis was once widespread across the Hawaiian archipelago, but became isolated on Laysan Island (415 ha) from the mid-1800s until 2004 when a translocation to Midway Atoll (596 ha) was undertaken to reduce extinction risks. We compared genetic diversity and quantified variation at microsatellite loci sampled from 230 individuals from the wild populations at Laysan (1999 to 2009) and Midway (2007 to 2010; n = 133 Laysan, n = 96 Midway birds). We identified polymorphic markers by screening nuclear microsatellites (N = 83). Low nuclear variation was detected, consistent with the species’ insular isolation and historical bottleneck. Six of 83 microsatellites were polymorphic. We found limited but similar estimates of allelic richness (2.58 alleles per locus) and heterozygosity within populations. However, 2 rare alleles found in the Laysan source population were not present in Midway’s reintroduced population, and a unique allele was discovered in an individual on Midway. Differentiation between island populations was low (FST = 0.6%), but statistically significant. Our results indicate that genetic drift had little effect on offspring generations 3 to 6 yr post-release and demonstrate the utility of using known founder events to help quantify genetic capture during translocations and to inform management decisions.

  14. Characterization of 12 silent alleles of the human butyrylcholinesterase (BCHE) gene.

    PubMed Central

    Primo-Parmo, S. L.; Bartels, C. F.; Wiersema, B.; van der Spek, A. F.; Innis, J. W.; La Du, B. N.

    1996-01-01

    The silent phenotype of human butyrylcholinesterase (BChE), present in most human populations in frequencies of approximately 1/100,000, is characterized by the complete absence of BChE activity or by activity <10% of the average levels of the usual phenotype. Heterogeneity in this phenotype has been well established at the phenotypic level, but only a few silent BCHE alleles have been characterized at the DNA level. Twelve silent alleles of the human butyrylcholinesterase gene (BCHE) have been identified in 17 apparently unrelated patients who were selected by their increased sensitivity to the muscle relaxant succinylcholine. All of these alleles are characterized by single nucleotide substitutions or deletions leading to distinct changes in the structure of the BChE enzyme molecule. Nine of the nucleotide substitutions result in the replacement of single amino acid residues. Three of these variants, BCHE*33C, BCHE*198G, and BCHE*201T, produce normal amounts of immunoreactive but enzymatically inactive BChE protein in the plasma. The other six amino acid substitutions, encoded by BCHE*37S, BCHE*125F, BCHE*170E, BCHE*471R, and BCHE*518L, seem to cause reduced expression of BChE protein, and their role in determining the silent phenotype was confirmed by expression in cell culture. The other four silent alleles, BCHE*271STOP, BCHE*500STOP, BCHE*FS6, and BCHE*I2E3-8G, encode BChES truncated at their C-terminus because of premature stop codons caused by nucleotide substitutions, a frame shift, or altered splicing. The large number of different silent BCHE alleles found within a relatively small number of patients shows that the heterogeneity of the silent BChE phenotype is high. The characterization of silent BChE variants will be useful in the study of the structure/function relationship for this and other closely related enzymes. Images Figure 2 PMID:8554068

  15. Slight instability of a FMR-1 allele over three generations in a family from the general population

    SciTech Connect

    Abramowicz, M.J.; Parma, J.; Cochaux, P.

    1996-08-09

    We report on a family segregating a FMR-1 allele within the {open_quotes}grey zone{close_quotes} of triplet repeat length (n = 51). The allele showed a 1-unit increment when transmitted through a female meiosis and a 1-unit increment when transmitted through a male of the next generation. At the following generation, a pregnant woman had amniocentesis performed. The latter showed she transmitted the allele unchanged (n = 53) to her male fetus. This family was not ascertained through an affected subject, and there was no family history of mental retardation. Thus our observation reflects the natural history of an unstable allele in the general population. Systematic analysis of such alleles may help refine our understanding of the grey zone of triplet repeat length. 5 refs., 1 fig.

  16. Identification and distribution of three serologically undetected alleles of HLA-DR by oligonucleotide x DNA typing analysis

    SciTech Connect

    Tiercy, J.M.; Gorski, J.; Jeannet, M.; Mach, B.

    1988-01-01

    Recent progress in the molecular biology of human major histocompatibility complex class II genes (HLA-DP, -DQ, -DR) have shown that the genetic complexity and allelic polymorphism are greater than expected. In the case of HLA-DR, three DR ..beta..-chain loci have been identified and linked, two of which (DR ..beta..I and DR ..beta..III, now assigned names HLA-DR1B and HLA-DR3B) are functional. The authors have shown that the HLA micropolymorphism detected at the DNA sequence level can easily be analyzed by hybridization with allele-specific oligonucleotides (HLA oligotyping). In the case of the HLA DRw52 supertypic specificity, which includes the DR3, DR5, DRw6, and DRw8 haplotypes, three alleles, referred to as DRw52a, DRw52b, and DRw52c, have recently been identified at the HLA-DR3B locus by DNA sequencing. Hybridization with locus- and allele-specific oligonucleotide probes (designated 52a, 52b, and 52c) has been performed on DNA from normal individuals forming a panel of 82 haplotypes to establish the distribution of these three alleles. Individuals of the DR3 haplotype had either the DRw52a or DRw52b allele, and individuals of extended haplotype HLA-A1,B8,DR3 had only the DRw52a allele. DR5 individuals all had the DRw52b allele, while individuals of DRw6 haplotype had the DRw52a, -52b, or -52c allele. None of these three alleles are found in DRw8 individuals. Analysis of this micropolymorphism, undetectable by common typing procedures, is therefore now operational for more accurate HLA matching for transplantation and for improving correlations between HLA and disease susceptibility.

  17. Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector

    PubMed Central

    Ibrahim, Sulaiman S.; Riveron, Jacob M.; Bibby, Jaclyn; Irving, Helen; Yunta, Cristina; Paine, Mark J. I.; Wondji, Charles S.

    2015-01-01

    Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser) from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies. PMID:26517127

  18. Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector.

    PubMed

    Ibrahim, Sulaiman S; Riveron, Jacob M; Bibby, Jaclyn; Irving, Helen; Yunta, Cristina; Paine, Mark J I; Wondji, Charles S

    2015-10-01

    Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser) from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies. PMID:26517127

  19. Novel human CYP2A6 alleles confound gene deletion analysis.

    PubMed

    Nakajima, Miki; Yoshida, Ryoko; Fukami, Tatsuki; McLeod, Howard L; Yokoi, Tsuyoshi

    2004-07-01

    Cytochrome P450 (CYP) 2A6 metabolizes a number of drugs and a variety of procarcinogens. CYP2A6 also catalyzes nicotine C-oxidation leading to cotinine formation, a major metabolic pathway of nicotine in humans. There are genetic polymorphisms in the human CYP2A6 gene and a relationship between the CYP2A6 genotype and smoking habits as well as the incidence of lung cancer has been indicated. CYP2A6*4 alleles are the whole deleted type and are completely deficient in the enzymatic activity. An unequal crossover junction is located in the 3'-flanking region in the CYP2A6*4A allele, whereas the junction is located in either intron 8 or exon 9 in the CYP2A6*4D allele. In the present study, a novel genotyping method to distinguish between two different whole deleted alleles of CYP2A6*4A and CYP2A6*4D was established. In the process, two novel alleles, CYP2A6*1F and CYP2A6*1G, were found. The CYP2A6*1F has a single nucleotide polymorphism (SNP) of C5717T in exon 8, and the CYP2A6*1G has two SNPs, C5717T in exon 8 and A5825G in intron 8. The SNP of C5717T corresponds to C1224T on the cDNA sequence and is a synonymous mutation. Since the CYP2A6*1F produces a recognition site of the restriction enzymes that is the same as CYP2A6*4D, the presence of the CYP2A6*1F allele could cause a mistyping as the CYP2A6*4D allele. According to an improved genotyping method, the allele frequencies of CYP2A6*4A, CYP2A6*4D, CYP2A6*1F, and CYP2A6*1G in 165 Caucasians were 3.0%, 0%, 1.8%, and 1.2%, respectively. The allele frequencies of CYP2A6*4A, CYP2A6*4D, CYP2A6*1F, and CYP2A6*1G in 94 African-Americans were 0%, 0.5%, 0%, and 13.3%, respectively. This is the first report of a method that can distinguish between CYP2A6*4A, CYP2A6*4D, and CYP2A6*1F which could otherwise cause a mistyping as CYP2A6*4D. PMID:15225612

  20. Encon Motivation in European Refineries 

    E-print Network

    Gambera, S.; Lockett, W., Jr.

    1982-01-01

    One essential element in a successful energy conservation or Encon program is effective motivation of employees and organizations to conserve energy. Encon motivation in our European refineries is a continuing effort that requires utilization...

  1. European E-commerce Report

    E-print Network

    Kraemer, Kenneth L.; Dedrick, Jason

    2000-01-01

    countries might be future leaders in e-commerce based on theFuture reports will provide more detailed analyses as the research continues. European e-commercee-commerce will evolve in Europe. We will address these in future

  2. The host HLA-A*02 allele is associated with the response to pegylated interferon and ribavirin in patients with chronic hepatitis C virus infection.

    PubMed

    Wang, Meng; Li, Jian-Sheng; Ping, Yu; Li, Zhi-Qin; Wang, Li-Ping; Guo, Qian; Zhang, Zhen; Yue, Dong-Li; Wang, Fei; Zhang, Teng-Fei; Islam, Mohammad Serajul; Zhang, Yi

    2015-04-01

    Human leukocyte antigen (HLA) alleles are associated with both the progression of chronic hepatitis C (CHC) and the sustained virological response (SVR) to antiviral therapy. HLA-A*02 is the most common HLA allele in people of European/Caucasian descent and the Chinese and Japanese population. Therefore, we investigated whether HLA-A*02 expression is associated with disease outcome in Chinese CHC patients. Three hundred thirty-one treatment-naïve CHC patients were recruited in this study. The expression of HLA-A*02 was tested by FACS and LABType SSO assays. All patients were treated weekly with pegylated interferon plus ribavirin (PEG-IFN/RBV) according to a standard protocol. Virological response was assessed by TaqMan assay at the 4th, 12th, 24th, and 48th week of therapy, and again at the 24th week post-therapy. By the end of the study, 293 CHC patients, including 144 HLA-A*02-positive patients and 149 HLA-A*02-negative patients, were evaluable for analysis. There were no statistical differences in clinicopathological parameters between HLA-A*02-positive and negative patients before antiviral therapy (P > 0.05). The HLA-A*02-positive patients had a higher rapid virological response (RVR, 74.3 % versus 62.4 %, P = 0.03) and SVR (78.5 % versus 64.4 %, P = 0.01) and a lower relapse rate (4.2 % versus 11.9 %, P = 0.03) than HLA-A*02-negative patients. Multivariable logistic regression analysis showed that HLA-A*02 expression, liver fibrosis stages allele expression is associated with SVR, highlighting the importance of considering HLA-A*02 as a predictor of the response to PEG-IFN/RBV treatment in the Chinese population with CHC. PMID:25666200

  3. European Union enlargement A historic opportunity

    E-print Network

    Bilbao Arrese, Jesús Mario

    European Union enlargement A historic opportunity #12;"Enlargement is both a historical opportunity and an obligation for the European Union and therefore one of its highest priorities. My aim is to strike the right European Council 46 Table of contents European Union enlargement A historic opportunity TABLE OF CONTENTS

  4. Molecular validation of multiple allele inheritance for dominant genic male sterility gene in Brassica napus L.

    PubMed

    Song, Lai-Qiang; Fu, Ting-Dong; Tu, Jin-Xing; Ma, Cao-Zhi; Yang, Guang-Sheng

    2006-06-01

    Dominant genic male sterility (DGMS) has been playing an increasingly important role, not only as a tool for assisting in recurrent selection but also as an alternative approach for efficient production of hybrids. Previous studies indicate that fertility restoration of DGMS is the action of another unlinked dominant gene. Recently, through classical genetic analysis with various test populations we have verified that in a DGMS line 609AB the trait is inherited in a multiple allelic pattern. In this study, we applied molecular marker technology to provide further validation of the results. Eight amplified fragment length polymorphism (AFLP) markers tightly linked to the male sterility allele (Ms) were identified in a BC1 population from a cross between 609A (a sterile plant in 609AB) and a temporary maintainer GS2467 as recurrent parent. Four out of the eight markers reproduced the same polymorphism in a larger BC(1) population generated with microspore-derived doubled haploid (DH) parents (S148 and S467). The two nearest AFLP markers SA12MG14 and P05MG15, flanking the Ms locus at respective distances of 0.3 centiMorgan (cM) and 1.6 cM, were converted into sequence characterized amplified region (SCAR) markers designated SC6 and SC9. Based on the sequence difference of the marker P05MG15 between S148 and a DH restorer line S103, we further developed a SCAR marker SC9f that is specific to the restorer allele (Mf). The map distance between SC9f and Mf was consistent with that between SC9 and Ms allele. Therefore, successful conversion of the marker tightly linked to Ms into a marker tightly linked to Mf suggested that the restoration for DGMS in 609AB is controlled by an allele at the Ms locus or a tightly linked gene (regarded as an allele in practical application). The Ms and Mf-specific markers developed here will facilitate the breeding for new elite homozygous sterile lines and allow further research on map-based cloning of the Ms gene. PMID:16783591

  5. Disparities in allele frequencies and population differentiation for 101 disease-associated single nucleotide polymorphisms between Puerto Ricans and non-Hispanic whites

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Variations in gene allele frequencies can contribute to differences in the prevalence of some common complex diseases among populations. Natural selection modulates the balance in allele frequencies across populations. Population differentiation (FST) can evidence environmental selection...

  6. 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.

  7. Investigation of MGMT and DAPK1 methylation patterns in diffuse large B-cell lymphoma using allelic MSP-pyrosequencing

    PubMed Central

    Kristensen, Lasse Sommer; Treppendahl, Marianne Bach; Asmar, Fazila; Girkov, Mia Seremet; Nielsen, Helene Myrtue; Kjeldsen, Tina Ellegaard; Ralfkiaer, Elisabeth; Hansen, Lise Lotte; Grønbæk, Kirsten

    2013-01-01

    The tumor suppressor genes MGMT and DAPK1 become methylated in several cancers including diffuse large B-cell lymphoma (DLBCL). However, allelic methylation patterns have not been investigated in DLBCL. We developed a fast and cost-efficient method for the analysis of allelic methylation based on pyrosequencing of methylation specific PCR (MSP) products including a SNP. Allelic methylation patterns were reliably analyzed in standards of known allelic methylation status even when diluted in unmethylated DNA to below 1% methylation. When studying 148 DLBCL patients MGMT and DAPK1 methylation was observed in 19% and 89%, respectively, and among methylated and heterozygous patients 29% and 55%, respectively, were biallelically methylated. An association between the T-allele of the rs16906252 SNP and MGMT methylation was observed (p-value = 0.04), and DAPK1 methylation of the A-allele was associated with shorter overall survival (p-value = 0.006). In future cancer research allelic MSP-pyrosequencing may be used to study a wide range of other loci. PMID:24071855

  8. Short communication: the beta-casein (CSN2) silent allele C1 is highly spread in goat breeds.

    PubMed

    Chessa, S; Rignanese, D; Küpper, J; Pagnacco, G; Erhardt, G; Caroli, A

    2008-11-01

    Several single nucleotide polymorphisms have been identified in the goat milk casein genes, most of them modifying the amino acid sequence of the coded protein. At least 9 variants have been found in goat beta-CN (CSN2); 6 of them were characterized at the DNA level (A, A1, C, E, 0, and 0'), whereas the other 3 variants were described only at the protein level. The recently identified silent A1 allele is characterized by a C-->T transition at the 180th nucleotide of the ninth exon. In the present work, typing results from different breeds (3 Italian, 3 German, and a composite of African breeds for a total of 335 samples) demonstrated that the same mutation is carried by the CSN2*C allele. In addition, the T nucleotide at the 180th nucleotide of the ninth exon was always associated with CSN2*C in all the breeds analyzed. Thus, another silent allele occurs at goat CSN2 and can be named CSN2*C1. The much wider distribution of C1 with respect to the A1 allele indicates that the single nucleotide polymorphisms characterizing the silent mutation originated from CSN2*C. A method for the identification of this allele simultaneously with 5 of the 6 DNA-characterized alleles is also proposed. The mutation involved codifies for the same protein of the C allele; nevertheless, its location in the 3' untranslated region of the gene might affect the specific casein expression. PMID:18946150

  9. HLA-C locus allelic dropout in Sanger sequence-based typing due to intronic single nucleotide polymorphism.

    PubMed

    Cheng, Christopher; Kashi, Zahra Mehdizadeh; Martin, Russell; Woodruff, Gillian; Dinauer, David; Agostini, Tina

    2014-12-01

    We report a novel HLA-C allele that was identified during routine HLA typing using sequence-based methods. The patient was initially typed as a C*06:02, 06:04 with two nucleotide mismatches in exon 3, (C to T and T to G changes) which would have resulted in a non-synonymous mutation of a leucine residue being replaced with tryptophan. Further resolution of the patient's type by using sequence-specific primers (SSP) revealed that the companion allele to C*06:02 was a novel C*17:01. Confirmation of the existence of the new allele was performed across multiple platforms: Sanger sequencing, SSP, and Next Generation Sequencing (NGS) on the original sample and allele-specific clones for the entire HLA-C locus. The investigation revealed a single nucleotide mismatch within the Sanger sequencing primer binding site in intron 3. The mutation caused the initial C*17 dropout in exons 2 and 3. Further analysis of the Sanger and NGS data revealed that the C*17 had two additional unique positions in introns 2 and 7. The companion C*06:02 allele also possessed a novel position at intron 3. On August 31, 2013, the WHO nomenclature committee officially named the novel C*17:01 allele sequence as C*17:01:01:03 and the novel C*06:02 allele sequence as C*06:02:01:03. PMID:25315749

  10. Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus.

    PubMed

    Terao, Chikashi; Bayoumi, Nervana; McKenzie, Colin A; Zelenika, Diana; Muro, Shigeo; Mishima, Michiaki; Connell, John M C; Vickers, Mark A; Lathrop, G Mark; Farrall, Martin; Matsuda, Fumihiko; Keavney, Bernard D

    2013-11-01

    Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ?36% lower) and Type B alleles (in whom plasma ACE activity was ?36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects. PMID:23937567

  11. The Dynamics of Gynodioecy in Plantago Lanceolata L. II. Mode of Action and Frequencies of Restorer Alleles

    PubMed Central

    de-Haan, A. A.; Koelewijn, H. P.; Hundscheid, MPJ.; Van-Damme, JMM.

    1997-01-01

    Male fertility in Plantago lanceolata is controlled by the interaction of cytoplasmic and nuclear genes. Different cytoplasmic male sterility (CMS) types can be either male sterile or hermaphrodite, depending on the presence of nuclear restorer alleles. In three CMS types of P. lanceolata (CMSI, CMSIIa, and CMSIIb) the number of loci involved in male fertility restoration was determined. In each CMS type, male fertility was restored by multiple genes with either dominant or recessive action and capable either of restoring male fertility independently or in interaction with each other (epistasis). Restorer allele frequencies for CMSI, CMSIIa and CMSIIb were determined by crossing hermaphrodites with ``standard'' male steriles. Segregation of male steriles vs. non-male steriles was used to estimate overall restorer allele frequency. The frequency of restorer alleles was different for the CMS types: restorer alleles for CMSI were less frequent than for CMSIIa and CMSIIb. On the basis of the frequencies of male steriles and the CMS types an ``expected'' restorer allele frequency could be calculated. The correlation between estimated and expected restorer allele frequency was significant. PMID:9383073

  12. Prolonged P300 latency in children with the D[sub 2] dopamine receptor A1 allele

    SciTech Connect

    Noble, E.P.; Berman, S.M.; Ozkaragoz, T.Z.; Ritchie, T. )

    1994-04-01

    Previous studies have indicated the presence of a hereditary component in the generation of the P300, or P3, a late positive component of the event-related potential. Moreover, the dopaminergic system has been implicated in the P3. In the present study, 98 healthy Caucasian boys, mean age of 12.5 years and of above-average intelligence, were studied. The sample was composed of 32 sons of active alcoholic (SAA) fathers, 36 sons of recovering alcoholic (SRA) fathers, and 30 sons of social drinker (SSD) fathers, with none of them having yet begun to consume alcohol or other drugs. TaqI A D[sub 2] dopamine receptor alleles (A1 and A2) were determined. A significant difference in the frequency of the A1 allele was found among these three groups of boys, with the SAA group having the highest A1 allele frequency (.313), followed by the SRA (.139) and the SSD (.133) groups. The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between boys with the A1 and A2 allele. However, P3 latency was significantly longer in the total sample of boys with the A1 allele compared with those carrying the A2 allele. These findings suggest that polymorphism of the D[sub 2] dopamine receptor gene is an important determinant of P3 latency. 84 refs., 2 figs., 3 tabs.

  13. CYP2C9 allelic variants and frequencies in a pediatric sickle cell disease cohort: implications for NSAIDs pharmacotherapy.

    PubMed

    Jaja, Cheedy; Patel, Niren; Scott, Stuart A; Gibson, Robert; Kutlar, Abdullah

    2014-10-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat pain in patients with sickle cell disease (SCD) are metabolized by the CYP2C9 enzyme. Racial differences in CYP2C9 allele frequencies impact NSAIDs efficacy and safety. We determined the frequencies of CYP2C9 alleles in an African American pediatric SCD cohort. Genomic DNA was isolated from blood samples of 30 patients aged between 7 and 17 years. Genotyping of nine CYP2C9 alleles (*1,*2, *3, *4, *5, *6, *8, *11, and *13) was performed using restriction fragment length polymorphism-PCR assays and the Tag-It™ Mutation Detection System. The wild type *1 allele frequency was 0.850. The most common variant allele detected was CYP2C9*8 (0.067). The combined frequency of the *2, *5, *6, *8, and *11 variants was 0.151. Seventy percent of the study cohort were predicted extensive metabolizers (*1/*1) and 30% were intermediate metabolizers due mainly to the *1/*8 genotype. Analysis of CYP2C9 using an expanded assay panel facilitated improved classification of predicted drug metabolic phenotypes in our cohort. However, the pharmacokinetic effects of the CYP2C9*5,*6,*8, and *11 alleles on NSAIDs metabolism has not been evaluated and underscores the need for studies on substrate-specific effects of variant alleles common in populations with genetic susceptibility to SCD. PMID:24889181

  14. HLA alleles and haplotypes in Burmese (Myanmarese) and Karen in Thailand.

    PubMed

    Kongmaroeng, C; Romphruk, A; Puapairoj, C; Leelayuwat, C; Kulski, J K; Inoko, H; Dunn, D S; Romphruk, A V

    2015-09-01

    This is the first report on human leukocyte antigen (HLA) allele and haplotype frequencies at three class I loci and two class II loci in unrelated healthy individuals from two ethnic groups, 170 Burmese and 200 Karen, originally from Burma (Myanmar), but sampled while residing in Thailand. Overall, the HLA allele and haplotype frequencies detected by polymerase chain reaction sequence-specific primer (PCR-SSP) at five loci (A, B, C, DRB1 and DRQB1) at low resolution showed distinct differences between the Burmese and Karen. In Burmese, five HLA-B*15 haplotypes with different HLA-A and HLA-DR/DQ combinations were detected with three of these not previously reported in other Asian populations. The data are important in the fields of anthropology, transplantation and disease-association studies. PMID:26265055

  15. The effects of two alleles of IGF2 on fat content in pig carcasses and pork.

    PubMed

    Burgos, Carmen; Galve, Almudena; Moreno, Carlos; Altarriba, Juan; Reina, Raquel; García, Carmen; López-Buesa, Pascual

    2012-02-01

    The different fat infiltration capabilities of two alleles of IGF2 (G3072A) have been investigated in pigs of a Landrace-Large White×Duroc cross. Paternally inherited G allele carrier pigs show an increased content of adipose rich meat cuts such as the lard or the belly and 4mm larger backfat thickness values. Paternally inherited A carrier pigs on the other hand contain larger muscle tissue rich cuts such as the loin, the ham and the tenderloin and have 0.19 units lower feed conversion index. No substantial differences have been found neither in intramuscular fat content in several muscles nor in meat quality in both pig groups. Hams of paternally inherited G carrier pigs are richer in both subcutaneous adipose tissue (23.1 vs 19.1mm backfat thickness) and intermuscular fat content. The suitability and the economics of using any of the two of both genotypes for cured ham production are discussed. PMID:21907500

  16. A PCR-RFLP test to detect allelic variants of the bovine kappa-casein gene.

    PubMed

    Soria, L A; Iglesias, G M; Huguet, M J; Mirande, S L

    2003-05-01

    Point mutations in exon IV of bovine kappa-casein gene (kappaCn, CASK, CSN3) determine nine allelic variants (A, B, C, E, F, G, H, I, and A1) for the gene. These variants are associated with major differences in composition and manufacturing properties of milk (i.e., cheese yield). A PCR-RFLP test was developed in order to distinguish the different alleles. Polymorphisms are detected by digestion with the endonucleases HindIII, HaeIII, and MaeII followed by electrophoresis in agarose gels stained with ethidium bromide. Twenty eight DNA samples from different breeds of Argentina were analyzed for the A, B, and E variants. This simple PCR-RFLP test makes feasible the inclusion of kappa-casein genotypes in breeding plans. PMID:12887174

  17. Short alleles, bigger smiles? The effect of 5-HTTLPR on positive emotional expressions.

    PubMed

    Haase, Claudia M; Beermann, Ursula; Saslow, Laura R; Shiota, Michelle N; Saturn, Sarina R; Lwi, Sandy J; Casey, James J; Nguyen, Nguyen K; Whalen, Patrick K; Keltner, Dacher; Levenson, Robert W

    2015-08-01

    The present research examined the effect of the 5-HTTLPR polymorphism in the serotonin transporter gene on objectively coded positive emotional expressions (i.e., laughing and smiling behavior objectively coded using the Facial Action Coding System). Three studies with independent samples of participants were conducted. Study 1 examined young adults watching still cartoons. Study 2 examined young, middle-aged, and older adults watching a thematically ambiguous yet subtly amusing film clip. Study 3 examined middle-aged and older spouses discussing an area of marital conflict (that typically produces both positive and negative emotion). Aggregating data across studies, results showed that the short allele of 5-HTTLPR predicted heightened positive emotional expressions. Results remained stable when controlling for age, gender, ethnicity, and depressive symptoms. These findings are consistent with the notion that the short allele of 5-HTTLPR functions as an emotion amplifier, which may confer heightened susceptibility to environmental conditions. PMID:26029940

  18. Allelic association of human dopamine D sub 2 receptor gene in alcoholism

    SciTech Connect

    Blum, K.; Sheridan, P.J.; Montgomery, A.; Jagadeeswaran, P.; Nogami, H.; Briggs, A.H. ); Noble, E.P.; Ritchie, T.; Cohn, J.B. )

    1990-04-18

    In a blinded experiment, the authors report the first allelic association of the dopamine D{sub 2} receptor gene in alcoholism. From 70 brain samples of alcoholics and nonalcoholics, DNA was digested with restriction endonucleases and probed with a clone that contained the entire 3{prime} coding exon, the polyadenylation signal, and approximately 16.4 kilobases of noncoding 3{prime} sequence of the human dopamine D{sub 2} receptor gene ({lambda}hD2G1). In the present samples, the presence of A1 allele of the dopamine D{sub 2} receptor gene correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The polymorphic pattern of this receptor gene suggests that a gene that confers susceptibility to at least one form of alcoholism is located on the q22-q23 region of chromosome 11.

  19. An Allelic Series of Trp63 Mutations Defines TAp63 as a Modifier of EEC Syndrome

    PubMed Central

    Lindahl, Emma Vernersson; Garcia, Elvin L.; Mills, Alea A.

    2014-01-01

    Human Ectrodactyly, Ectodermal dysplasia, Clefting (EEC) syndrome is an autosomal dominant developmental disorder defined by limb deformities, skin defects, and craniofacial clefting. Although associated with heterozygous missense mutations in TP63, the genetic basis underlying the variable expressivity and incomplete penetrance of EEC is unknown. Here we show that mice heterozygous for an allele encoding the Trp63 p.Arg318His mutation, which corresponds to the human TP63 p.Arg279His mutation found in patients with EEC, have features of human EEC. Using an allelic series, we discovered that whereas clefting and skin defects are caused by loss of Trp63 function, limb anomalies are due to gain- and/or dominant-negative effects of Trp63. Furthermore, we identify TAp63 as a strong modifier of EEC-associated phenotypes with regard to both penetrance and expressivity. PMID:23775923

  20. An allelic series of Trp63 mutations defines TAp63 as a modifier of EEC syndrome.

    PubMed

    Vernersson Lindahl, Emma; Garcia, Elvin L; Mills, Alea A

    2013-08-01

    Human Ectrodactyly, Ectodermal dysplasia, Clefting (EEC) syndrome is an autosomal dominant developmental disorder defined by limb deformities, skin defects, and craniofacial clefting. Although associated with heterozygous missense mutations in TP63, the genetic basis underlying the variable expressivity and incomplete penetrance of EEC is unknown. Here, we show that mice heterozygous for an allele encoding the Trp63 p.Arg318His mutation, which corresponds to the human TP63 p.Arg279His mutation found in patients with EEC, have features of human EEC. Using an allelic series, we discovered that whereas clefting and skin defects are caused by loss of Trp63 function, limb anomalies are due to gain- and/or dominant-negative effects of Trp63. Furthermore, we identify TAp63 as a strong modifier of EEC-associated phenotypes with regard to both penetrance and expressivity. PMID:23775923

  1. Lactase polymorphism in adult British natives: estimating allele frequencies by enzyme assays in autopsy samples.

    PubMed Central

    Ho, M W; Povey, S; Swallow, D

    1982-01-01

    In an attempt to estimate allele frequencies of lactase persistence in adult British natives, sucrase was assayed simultaneously with lactase under conditions that gave optimal activities for both enzymes. A trimodal distribution in the ratios of enzyme activities was demonstrated. Circumstantial evidence and statistical analyses suggest that the trimodal distribution is due to the different levels of lactase activity in the three genotypes--homozygous persistent, heterozygous, and homozygous nonpersistent, and that it is possible to correct for "nongenetic" variation by using sucrase as an internal standard. The allele frequency for lactase persistence was estimated to be .747. The implications of our findings on the genetic mechanisms involved in lactase persistence are discussed. PMID:6808832

  2. Recombinase-based conditional and reversible gene regulation via XTR alleles

    PubMed Central

    Robles-Oteiza, Camila; Taylor, Sarah; Yates, Travis; Cicchini, Michelle; Lauderback, Brian; Cashman, Christopher R.; Burds, Aurora A.; Winslow, Monte M.; Jacks, Tyler; Feldser, David M.

    2015-01-01

    Synthetic biological tools that enable precise regulation of gene function within in vivo systems have enormous potential to discern gene function in diverse physiological settings. Here we report the development and characterization of a synthetic gene switch that, when targeted in the mouse germline, enables conditional inactivation, reports gene expression and allows inducible restoration of the targeted gene. Gene inactivation and reporter expression is achieved through Cre-mediated stable inversion of an integrated gene-trap reporter, whereas inducible gene restoration is afforded by Flp-dependent deletion of the inverted gene trap. We validate our approach by targeting the p53 and Rb genes and establishing cell line and in vivo cancer model systems, to study the impact of p53 or Rb inactivation and restoration. We term this allele system XTR, to denote each of the allelic states and the associated expression patterns of the targeted gene: eXpressed (XTR), Trapped (TR) and Restored (R). PMID:26537451

  3. Tri-allelic pattern of short tandem repeats identifies the murderer among identical twins and suggests an embryonic mutational origin.

    PubMed

    Wang, Li-Feng; Yang, Ying; Zhang, Xiao-Nan; Quan, Xiao-Liang; Wu, Yuan-Ming

    2015-05-01

    Monozygotic twins can be co-identified by genotyping of short tandem repeats (STRs); however, for distinguishing them, STR genotyping is ineffective, especially in the case of murder. Here, a rarely occurring tri-allelic pattern in the vWA locus (16, 18, 19) was identified only in the DNA of one identical twin, which could help to exonerate the innocent twin in a murder charge. This mutation was defined as primary through genotyping of the family and could be detected in blood, buccal and semen samples from the individual; however, two alternative allele-balanced di-allelic patterns (16, 18 or 16, 19) were detected in hair root sheath cells. Such a kind of segregation indicates a one-step mutation occurs in cell mitosis, which is after embryonic zygote formation and during the early development of the individual after the division of the blastocyte. Sequencing revealed the insertion between the allele 18 and 19 is a repeat unit of TAGA/TCTA (plus/minus strand), which belongs to "AGAT/ATCT"-based core repeats identified from all tri-allelic pattern reports recorded in the STR base and a detailed model was proposed for STR repeat length variation caused by false priming during DNA synthesis. Our model illustrates the possible origination of allele-balanced and unbalanced tri-allelic pattern, clarifies that the genotypes of parent-child mismatches, aberrant di-allelic patterns, and type 1 or 2 tri-allelic patterns should be considered as independent, but interconnected forms of STR mutation. PMID:25732248

  4. European Genetic Ancestry is Associated with a Decreased Risk of Lupus Nephritis

    PubMed Central

    Richman, Ilana B.; Taylor, Kimberly E.; Chung, Sharon A.; Trupin, Laura; Petri, Michelle; Yelin, Edward; Graham, Robert R.; Lee, Annette; Behrens, Timothy W.; Gregersen, Peter K.; Seldin, Michael F.; Criswell, Lindsey A.

    2013-01-01

    Objective African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than SLE patients of European descent. We investigated whether European genetic ancestry protects against the development of lupus nephritis and explored genetic and socioeconomic factors that might explain this effect. Methods This was a cross-sectional study of 1906 adults with SLE. Participants were genotyped for 126 single nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. We used logistic regression to test the association between European ancestry and renal disease. Analyses adjusted for continental ancestries, socioeconomic status, and candidate genes. Results Participants (n=1906) had on average 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among participants, 34% (n=656) had renal disease. A 10% increase in European ancestry was associated with a 15% reduction in the odds of having renal disease after adjustment for disease duration and sex (OR 0.85, 95% CI 0.82-0.87, p=1.9 × 10?30). Adjusting for other genetic ancestries, measures of socioeconomic status, or SNPs in genes most associated with renal disease (IRF5 (rs4728142), BLK (rs2736340), STAT4 (rs3024912), ITGAM (rs9937837) and HLA-DRB1*0301 and DRB1*1501, p<0.05) did not substantively alter this relationship. Conclusion European ancestry is protective against the development of renal disease in SLE, an effect independent of other genetic ancestries, common risk alleles, and socioeconomic status. PMID:23023776

  5. No Evidence for Enrichment in Schizophrenia for Common Allelic Associations at Imprinted Loci

    PubMed Central

    Escott-Price, Valentina; Kirov, George; Rees, Elliott; Isles, Anthony R.; Owen, Michael J.; O’Donovan, Michael C.

    2015-01-01

    Most genetic studies assume that the function of a genetic variant is independent of the parent from which it is inherited, but this is not always true. The best known example of parent-of-origin effects arises with respect to alleles at imprinted loci. In classical imprinting, characteristically, either the maternal or paternal copy is expressed, but not both. Only alleles present in one of the parental copies of the gene, the expressed copy, is likely to contribute to disease. It has been postulated that imprinting is important in central nervous system development, and that consequently, imprinted loci may be involved in schizophrenia. If this is true, allowing for parent-of-origin effects might be important in genetic studies of schizophrenia. Here, we use genome-wide association data from one of the world’s largest samples (N = 695) of parent schizophrenia-offspring trios to test for parent-of-origin effects. To maximise power, we restricted our analyses to test two main hypotheses. If imprinting plays a disproportionate role in schizophrenia susceptibility, we postulated a) that alleles showing robust evidence for association to schizophrenia from previous genome-wide association studies should be enriched for parent-of-origin effects and b) that genes at loci imprinted in humans or mice should be enriched both for genome-wide significant associations, and in our sample, for parent-of-origin effects. Neither prediction was supported in the present study. We have shown, that it is unlikely that parent-of-origin effects or imprinting play particularly important roles in schizophrenia, although our findings do not exclude such effects at specific loci nor do they exclude such effects among rare alleles. PMID:26633303

  6. Genetic influences on bone density: Physiological correlates of vitamin D receptor gene alleles in premonopausal women

    SciTech Connect

    Howard, G.; Nguyen, T.; Morrison, N.

    1995-09-01

    Common vitamin D receptor (VDR) gene alleles have recently been shown to contribute to the genetic variability in bone mass and bone turnover; however, the physiological mechanisms involved are unknown. To examine this, the response to 7 days of 2 {mu}g oral 1,25-dihydroxyvitamin D[1,25-(OH){sub 2}D] (calcitrol) stimulation was assessed in 21 premenopausal women, homozygous for one or other of the common VDR alleles (bb, N = 11; BB, n = 10). Indices of bone turnover and calcium homeostasis were measured during 2 weeks. Baseline osteocalcin, 1,25-(OH){sub 2}D, type I collagen carboxyterminal telopeptide, and inorganic phosphate levels were significantly higher and spinal bone mineral density was significantly lower in the BB allelic group. After calcitrol administration, similar levels of 1,25-(OH){sub 2}D were attained throughout the study in both genotypic groups. The increase in serum osteocalcin levels in the BB group was significantly less than that in the bb group (11% vs. 32%, P = 0.01). The genotype-related baseline difference in osteocalcin levels was not apparent at the similar serum 1,25-(OH){sub 2}D levels. By contrast, the baseline differences in phosphate and type I collagen carboxyterminal telopeptide persisted throughout the study. Serum ionized calcium levels did not differ between genotypes, nor did it move out of normal range values. However, parathyroid hormone was less suppressed in the low bone density group (38% vs. 11%, P = 0.01). These data indicate that the VDR alleles are associated with differences in the vitamin D endocrine system and may have important implications in relation to the pathophysiology of osteoporosis. 35 refs., 2 figs., 1 tab.

  7. High-resolution genetic mapping of allelic variants associated with cell wall chemistry in Populus

    SciTech Connect

    Muchero, Wellington; Guo, Jianjun; Difazio, Stephen P.; Chen, Jay; Ranjan, Priya; Slavov, Gancho; Gunter, Lee E; Jawdy, Sara; Bryan, Anthony C; Sykes, Robert; Ziebell, Angela L; Porth, Ilga; Skyba, Oleksandr; Unda, Faride; El-Kassaby, Yousry; Douglas, Carl; Mansfield, Shawn; Martin, Joel; Schackwitz, Wendy; Evans, Luke M; Tuskan, Gerald A

    2015-01-01

    We report the identification of six genetic loci and the allelic-variants associated with Populus cell wall phenotypes determined independently using pyrolysis Molecular Beam Mass Spectrometry (pyMBMS), saccharification assay and wet chemistry in two partially overlapping populations of P. trichocarpa genotypes sampled from multiple environments in the Pacific Northwest of North America. All 6 variants co-located with a quantitative trait locus (QTL) hotspot on chromosome XIV for lignin content, syringyl to guaiacyl (S/G) ratio, 5- and 6- carbon sugars identified in an interspecific P. trichocarpa x P. deltoides pseudo-backcross mapping pedigree. Genomic intervals containing an amino acid transporter, a MYB transcription factor, an angustifolia CtBP transcription factor, a copper transport protein ATOX1-related, a Ca2+ transporting ATPase and a protein kinase were identified within 5 QTL regions. Each interval contained single nucleotide polymorphisms (SNPs) that were significantly associated to cell-wall phenotypes, with associations exceeding the chromosome-wise Bonferroni-adjusted p-values in at least one environment. cDNA sequencing for allelic variants of 3 of the 6 genes identified polymorphisms leading to premature stop codons in the MYB transcription factor and protein kinase. On the other hand, variants of the Angustifolia CtBP transcription factor exhibited a polyglutamine (PolyQ) length polymorphism. Results from transient protoplast assays suggested that each of the polymorphisms conferred allelic differences in activation of cellulose, hemicelluloses and lignin pathway marker genes, with truncated and short PolyQ alleles exhibiting significantly reduced marker gene activation. Genes identified in this study represent novel targets for reducing cell wall recalcitrance for lignocellulosic biofuels production using plant biomass.

  8. Allelic polymorphism of GIGANTEA is responsible for naturally occurring variation in circadian period in Brassica rapa.

    PubMed

    Xie, Qiguang; Lou, Ping; Hermand, Victor; Aman, Rashid; Park, Hee Jin; Yun, Dae-Jin; Kim, Woe Yeon; Salmela, Matti Juhani; Ewers, Brent E; Weinig, Cynthia; Khan, Sarah L; Schaible, D Loring P; McClung, C Robertson

    2015-03-24

    GIGANTEA (GI) was originally identified by a late-flowering mutant in Arabidopsis, but subsequently has been shown to act in circadian period determination, light inhibition of hypocotyl elongation, and responses to multiple abiotic stresses, including tolerance to high salt and cold (freezing) temperature. Genetic mapping and analysis of families of heterogeneous inbred lines showed that natural variation in GI is responsible for a major quantitative trait locus in circadian period in Brassica rapa. We confirmed this conclusion by transgenic rescue of an Arabidopsis gi-201 loss of function mutant. The two B. rapa GI alleles each fully rescued the delayed flowering of Arabidopsis gi-201 but showed differential rescue of perturbations in red light inhibition of hypocotyl elongation and altered cold and salt tolerance. The B. rapa R500 GI allele, which failed to rescue the hypocotyl and abiotic stress phenotypes, disrupted circadian period determination in Arabidopsis. Analysis of chimeric B. rapa GI alleles identified the causal nucleotide polymorphism, which results in an amino acid substitution (S264A) between the two GI proteins. This polymorphism underlies variation in circadian period, cold and salt tolerance, and red light inhibition of hypocotyl elongation. Loss-of-function mutations of B. rapa GI confer delayed flowering, perturbed circadian rhythms in leaf movement, and increased freezing and increased salt tolerance, consistent with effects of similar mutations in Arabidopsis. Collectively, these data suggest that allelic variation of GI-and possibly of clock genes in general-offers an attractive target for molecular breeding for enhanced stress tolerance and potentially for improved crop yield. PMID:25775524

  9. Molecular characterization of both alleles in an unusual Tay-Sachs disease BI variant

    SciTech Connect

    Coulter-Mackie, M.B. Child Health Research Institute, Children's Hospital of Western Ontario, London Child Parent Resource Institute, London, Ontario )

    1994-06-01

    In a recent report, the authors described an exon 6 mutation in a Tay-Sachs B1 variant patient, first reported by Gordon et al. (1988), who displayed a typical B1 variant biochemical phenotype - i.e., (a) significant levels of hexosaminidase A (Hex A) activity in an assay with a neutral synthetic substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide, and (b) <2% of control Hex A in a test on the sulfated substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide-6-sulfate. The patient was found to carry a double mutation (G[sub 574][yields]C [val[sub 192][yields]leu] and G[sub 598][yields]A [val[sub 200][yields]met]) inherited from her mother. Only the 574 mutation produced a deleterious effect on Hex A activity in transfected COS0-1 cells, producing a B1 variant biochemical phenotype. The paternal allele apparently caused decreased abundance of mRNA, since no candidate paternal mutations were found in cloned reverse transcription-PCR (RT-PCR) products in the reported study. The biochemical phenotype of the original patient and the properties of the cDNA carrying the G[sub 574] [yields] C mutation in transient expression studies were compatible with a B1 variant mutation. The possibility remained that there might be some contribution from the paternal allele to the patient's phenotype. However, the paternal allele produces relatively low yields of a largely mis-spliced mRNA whose product would not be functional. Therefore, the G[sub 574] [yields] C (val[yields]leu) mutation in the maternal allele is clearly confirmed as a B1 variant mutation with all the ramifications for the substrate binding site and/or catalytic center that this implies.

  10. ORIGINAL ARTICLE Development of a molecular-beacon-based multi-allelic real-time

    E-print Network

    ORIGINAL ARTICLE Development of a molecular-beacon-based multi-allelic real-time RT-PCR assay-tol- erant molecular beacons designed to specifically detect the SARS-CoV S, E, M and N genes. These were-time RT-PCR assay using mismatch-tol- erant molecular beacons [6, 7, 24] to detect SARS-CoV A. V

  11. Better allele-level matching improves transplant-related mortality after double cord blood transplantation

    PubMed Central

    Oran, Betül; Cao, Kai; Saliba, Rima M.; Rezvani, Katayoun; de Lima, Marcos; Ahmed, Sairah; Hosing, Chitra M.; Popat, Uday R.; Carmazzi, Yudith; Kebriaei, Partow; Nieto, Yago; Rondon, Gabriela; Willis, Dana; Shah, Nina; Parmar, Simrit; Olson, Amanda; Moore, Brandt; Marin, David; Mehta, Rohtesh; Fernández-Viña, Marcelo; Champlin, Richard E.; Shpall, Elizabeth J.

    2015-01-01

    Cord blood transplant requires less stringent human leukocyte antigen matching than unrelated donors. In 133 patients with hematologic malignancies who engrafted after double cord blood transplantation with a dominant unit, we studied the effect of high resolution testing at 4 loci (-A, -B, -C, -DRB1) for its impact on 2-year transplant-related mortality. Ten percent of the dominant cord blood units were matched at 7–8/8 alleles using HLA-A, -B, -C, and -DRB1; 25% were matched at 6/8, 40% at 5/8, and 25% at 4/8 or less allele. High resolution typing at 4 loci showed that there was no 2-year transplant-related mortality in 7–8/8 matched patients. Patients with 5–6/8 matched dominant cord blood units had 2-year transplant-related mortality of 39% while patients with 4/8 or less matched units had 60%. Multivariate regression analyses confirmed the independent effect of high resolution typing on the outcome when adjusted for age, diagnosis, CD34+ cell dose infused, graft manipulation and cord to cord matching. The worst prognostic group included patients aged over 32 years with 4/8 or less matched cord blood units compared with patients who were either younger than 32 years old independent of allele-level matching, or aged over 32 years but with 5–6/8 matched cord blood units (Hazard Ratio 2.2; 95% confidence interval: 1.3–3.7; P<0.001). Patients with 7–8/8 matched units remained the group with the best prognosis. Our data suggest that high resolution typing at 4 loci and selecting cord blood units matched at at least 5/8 alleles may reduce transplant-related mortality after double cord blood transplantation. PMID:26250579

  12. Better allele-level matching improves transplant-related mortality after double cord blood transplantation.

    PubMed

    Oran, Betül; Cao, Kai; Saliba, Rima M; Rezvani, Katayoun; de Lima, Marcos; Ahmed, Sairah; Hosing, Chitra M; Popat, Uday R; Carmazzi, Yudith; Kebriaei, Partow; Nieto, Yago; Rondon, Gabriela; Willis, Dana; Shah, Nina; Parmar, Simrit; Olson, Amanda; Moore, Brandt; Marin, David; Mehta, Rohtesh; Fernández-Viña, Marcelo; Champlin, Richard E; Shpall, Elizabeth J

    2015-10-01

    Cord blood transplant requires less stringent human leukocyte antigen matching than unrelated donors. In 133 patients with hematologic malignancies who engrafted after double cord blood transplantation with a dominant unit, we studied the effect of high resolution testing at 4 loci (-A, -B, -C, -DRB1) for its impact on 2-year transplant-related mortality. Ten percent of the dominant cord blood units were matched at 7-8/8 alleles using HLA-A, -B, -C, and -DRB1; 25% were matched at 6/8, 40% at 5/8, and 25% at 4/8 or less allele. High resolution typing at 4 loci showed that there was no 2-year transplant-related mortality in 7-8/8 matched patients. Patients with 5-6/8 matched dominant cord blood units had 2-year transplant-related mortality of 39% while patients with 4/8 or less matched units had 60%. Multivariate regression analyses confirmed the independent effect of high resolution typing on the outcome when adjusted for age, diagnosis, CD34(+) cell dose infused, graft manipulation and cord to cord matching. The worst prognostic group included patients aged over 32 years with 4/8 or less matched cord blood units compared with patients who were either younger than 32 years old independent of allele-level matching, or aged over 32 years but with 5-6/8 matched cord blood units (Hazard Ratio 2.2; 95% confidence interval: 1.3-3.7; P<0.001). Patients with 7-8/8 matched units remained the group with the best prognosis. Our data suggest that high resolution typing at 4 loci and selecting cord blood units matched at at least 5/8 alleles may reduce transplant-related mortality after double cord blood transplantation. PMID:26250579

  13. Generation of New Hairless Alleles by Genomic Engineering at the Hairless Locus in Drosophila melanogaster

    PubMed Central

    Praxenthaler, Heiko; Smylla, Thomas K.; Nagel, Anja C.; Preiss, Anette; Maier, Dieter

    2015-01-01

    Hairless (H) is the major antagonist within the Notch signalling pathway of Drosophila melanogaster. By binding to Suppressor of Hairless [Su(H)] and two co-repressors, H induces silencing of Notch target genes in the absence of Notch signals. We have applied genomic engineering to create several new H alleles. To this end the endogenous H locus was replaced with an attP site by homologous recombination, serving as a landing platform for subsequent site directed integration of different H constructs. This way we generated a complete H knock out allele HattP, reintroduced a wild type H genomic and a cDNA-construct (Hgwt, Hcwt) as well as two constructs encoding H proteins defective of Su(H) binding (HLD, HiD). Phenotypes regarding viability, bristle and wing development were recorded, and the expression of Notch target genes wingless and cut was analysed in mutant wing discs or in mutant cell clones. Moreover, genetic interactions with Notch (N5419) and Delta (DlB2) mutants were addressed. Overall, phenotypes were largely as expected: both HLD and HiD were similar to the HattP null allele, indicating that most of H activity requires the binding of Su(H). Both rescue constructs Hgwt and Hcwt were homozygous viable without phenotype. Unexpectedly, the hemizygous condition uncovered that they were not identical to the wild type allele: notably Hcwt showed a markedly reduced activity, suggesting the presence of as yet unidentified regulatory or stabilizing elements in untranslated regions of the H gene. Interestingly, Hgwt homozygous cells expressed higher levels of H protein, perhaps unravelling gene-by-environment interactions. PMID:26448463

  14. Allele-specific gene silencing in two mouse models of autosomal dominant skeletal myopathy.

    PubMed

    Loy, Ryan E; Lueck, John D; Mostajo-Radji, Mohammed A; Carrell, Ellie M; Dirksen, Robert T

    2012-01-01

    We explored the potential of mutant allele-specific gene silencing (ASGS) in providing therapeutic benefit in two established mouse models of the autosomal dominantly-inherited muscle disorders, Malignant Hyperthermia (MH) and Central Core Disease (CCD). Candidate ASGS siRNAs were designed and validated for efficacy and specificity on ryanodine receptor (RyR1) cDNA mini-constructs expressed in HEK293 cells using RT-PCR- and confocal microscopy-based assays. In vivo delivery of the most efficacious identified siRNAs into flexor digitorum brevis (FDB) muscles was achieved by injection/electroporation of footpads of 4-6 month old heterozygous Ryr1(Y524S/+) (YS/+) and Ryr1(I4895T/+) (IT/+) knock-in mice, established mouse models of MH with cores and CCD, respectively. Treatment of IT/+ mice resulted in a modest rescue of deficits in the maximum rate (?38% rescue) and magnitude (?78%) of ligand-induced Ca(2+) release that occurred in the absence of a change in the magnitude of electrically-evoked Ca(2+) release. Compared to the difference between the caffeine sensitivity of Ca(2+) release in FDB fibers from YS/+ and WT mice treated with SCR siRNA (EC(50): 1.1 mM versus 4.4 mM, respectively), caffeine sensitivity was normalized in FDB fibers from YS/+ mice following 2 (EC(50): 2.8 mM) and 4 week (EC(50): 6.6 mM) treatment with YS allele-specific siRNA. Moreover, the temperature-dependent increase in resting Ca(2+) observed in FDB fibers from YS/+ mice was normalized to WT levels after 2 weeks of treatment with YS allele-specific siRNA. As determined by quantitative real time PCR, the degree of functional rescue in YS/+ and IT/+ mice correlated well with the relative increase in fractional WT allele expression. PMID:23152933

  15. Allele-Specific Gene Silencing in Two Mouse Models of Autosomal Dominant Skeletal Myopathy

    PubMed Central

    Loy, Ryan E.; Lueck, John D.; Mostajo-Radji, Mohammed A.; Carrell, Ellie M.; Dirksen, Robert T.

    2012-01-01

    We explored the potential of mutant allele-specific gene silencing (ASGS) in providing therapeutic benefit in two established mouse models of the autosomal dominantly-inherited muscle disorders, Malignant Hyperthermia (MH) and Central Core Disease (CCD). Candidate ASGS siRNAs were designed and validated for efficacy and specificity on ryanodine receptor (RyR1) cDNA mini-constructs expressed in HEK293 cells using RT-PCR- and confocal microscopy-based assays. In vivo delivery of the most efficacious identified siRNAs into flexor digitorum brevis (FDB) muscles was achieved by injection/electroporation of footpads of 4–6 month old heterozygous Ryr1Y524S/+ (YS/+) and Ryr1I4895T/+ (IT/+) knock-in mice, established mouse models of MH with cores and CCD, respectively. Treatment of IT/+ mice resulted in a modest rescue of deficits in the maximum rate (?38% rescue) and magnitude (?78%) of ligand-induced Ca2+ release that occurred in the absence of a change in the magnitude of electrically-evoked Ca2+ release. Compared to the difference between the caffeine sensitivity of Ca2+ release in FDB fibers from YS/+ and WT mice treated with SCR siRNA (EC50: 1.1 mM versus 4.4 mM, respectively), caffeine sensitivity was normalized in FDB fibers from YS/+ mice following 2 (EC50: 2.8 mM) and 4 week (EC50: 6.6 mM) treatment with YS allele-specific siRNA. Moreover, the temperature-dependent increase in resting Ca2+ observed in FDB fibers from YS/+ mice was normalized to WT levels after 2 weeks of treatment with YS allele-specific siRNA. As determined by quantitative real time PCR, the degree of functional rescue in YS/+ and IT/+ mice correlated well with the relative increase in fractional WT allele expression. PMID:23152933

  16. RHD alleles in Brazilian blood donors with weak D or D-negative phenotypes.

    PubMed

    Cruz, B R; Chiba, A K; Moritz, E; Bordin, J O

    2012-04-01

    The RHD gene is highly polymorphic and the existence of a large number of alleles results in RhD variant phenotypes. RHD genotyping has been used to distinguish normal D antigen from D variants due to limitations of serologic methods. The purpose of this study was to determine the phenotypic frequency of RhD and RhCE antigens and to investigate the RHD alleles present in samples with the weak D or D- phenotypes from Brazilian blood donors. A total of 2007 donors were phenotyped for D, C, c, E and e antigens. Samples phenotyped as D- were genotyped by polymerase chain reaction-sequence specific primers, and exon 10 and intron 4 of the RHD gene were analysed. D- samples containing the RHD gene or samples considered weak D were further characterised using genotyping platform or nucleotide sequencing. Using serologic methods we found that 87.3% of the donors were D+, 11.9% D- and 0.8% weak D. The frequency of RHD gene in D- individuals was 9.2%. Five RHD alleles from phenotypically D- donors were characterised in six molecular backgrounds: RHD?, RHD-CE-D(s), RHD-CE-(2-9)-D, RHD/RHD?, RHD?/RHD-CE-D(s) and RHD-CE(2)-D. The most common weak D antigens types found were 1, 3, 4.0/4.1 and 4.2, whereas the most prevalent weak D type was 4.2 (or DAR). The RHD genotyping proved to be a necessary tool to characterise RHD alleles in donors phenotyped as D- or weak D to increase the transfusion safety in highly racial mixed population. PMID:22211984

  17. Performance of Molecular Inversion Probes (MIP) in Allele CopyNumber Determination

    SciTech Connect

    Wang, Yuker; Moorhead, Martin; Karlin-Neumann, George; Wang,Nicolas J.; Ireland, James; Lin, Steven; Chen, Chunnuan; Heiser, LauraM.; Chin, Koei; Esserman, Laura; Gray, Joe W.; Spellman, Paul T.; Faham,Malek

    2007-05-14

    We have developed a new protocol for using MolecularInversion Probes (MIP) to accurately and specifically measure allele copynumber (ACN). The new protocol provides for significant improvementsincluding the reduction of input DNA (from 2?g) by more than 25 fold (to75ng total genomic DNA), higher overall precision resulting in one orderof magnitude lower false positive rate, and greater dynamic range withaccurate absolute copy number up to 60 copies.

  18. Allelic variation in Salmonella: an underappreciated driver of adaptation and virulence

    PubMed Central

    Yue, Min; Schifferli, Dieter M.

    2014-01-01

    Salmonella enterica causes substantial morbidity and mortality in humans and animals. Infection and intestinal colonization by S. enterica require virulence factors that mediate bacterial binding and invasion of enterocytes and innate immune cells. Some S. enterica colonization factors and their alleles are host restricted, suggesting a potential role in regulation of host specificity. Recent data also suggest that colonization factors promote horizontal gene transfer of antimicrobial resistance genes by increasing the local density of Salmonella in colonized intestines. Although a profusion of genes are involved in Salmonella pathogenesis, the relative importance of their allelic variation has only been studied intensely in the type 1 fimbrial adhesin FimH. Although other Salmonella virulence factors demonstrate allelic variation, their association with specific metadata (e.g., host species, disease or carrier state, time and geographic place of isolation, antibiotic resistance profile, etc.) remains to be interrogated. To date, genome-wide association studies (GWAS) in bacteriology have been limited by the paucity of relevant metadata. In addition, due to the many variables amid metadata categories, a very large number of strains must be assessed to attain statistically significant results. However, targeted approaches in which genes of interest (e.g., virulence factors) are specifically sequenced alleviates the time-consuming and costly statistical GWAS analysis and increases statistical power, as larger numbers of strains can be screened for non-synonymous single nucleotide polymorphisms (SNPs) that are associated with available metadata. Congruence of specific allelic variants with specific metadata from strains that have a relevant clinical and epidemiological history will help to prioritize functional wet-lab and animal studies aimed at determining cause-effect relationships. Such an approach should be applicable to other pathogens that are being collected in well-curated repositories. PMID:24454310

  19. Antagonistic effects of a Mhc class I allele on malaria-infected house sparrows

    E-print Network

    Federici, Pierre

    LETTER Antagonistic effects of a Mhc class I allele on malaria-infected house sparrows Claire, Ba^t. A, 7e`me e´tage, 7, quai St Bernard, Case 237, F-75252 Paris Cedex 05, France 2 Ge´ne´tique mole´culaire et inte´gration des fonctions cellulaires, CNRS FRE 2937, 7 rue Guy Mocquet, Bat. B, BP8

  20. DRD2 A1 allele and P300 abnormalities in obesity

    SciTech Connect

    Blum, K. |; Wood, R.; Sheridan, L.P.J.

    1994-09-01

    Obesity is a heterogeneous and prevalent disorder having both inheritable and environmental components. The role of the dopamine system in P300 has been implicated. We genotyped 193 neuropsychiatrically ill patients with and without comorbid drug and alcohol/abuse/dependence and obesity for the prevalence of the A1 allele of the DRD2 gene. We found a significant linear trend ({chi}{sup 2} = 40.4, df=1, p<0.00001) where the percent prevalence of the A1 increased with increasing polysubstance abuse. Where the A1 allele was found in 44% of 40 obese subjects, the A1 allele prevalence was found in as much as 91% of 11 obese subjects with comorbid polysubstance abuse. 53 obese subjects having a mean body weight (BMI) of 34.6{+-}8.2 were mapped for brain electrical activity and compared with 15 controls with a BMI of 22.3{+-}3.0 (P<.001). The P3 amplitude was significantly different (two tailed; t=3.24, df=16.2, P = 0.005), whereas P3 latency was not significant. Preliminarily, we found a significant decreased P3 amplitude correlated with parental polysubstance abuse (p=0.4) with prolongation of P3 latency correlated with the three risk factors of parental substance abuse, chemical dependency and carbohydrate bingeing (P<0.02). Finally, in a small sample, the A1 allele was present in 25% of probands having 0 risk compared to 66% in those obese subjects with any risk. This work represents the first electrophysiological data to implicate P3 abnormalities in a subset of obesity and further confirms an association of the DRD2 gene and a electrophysiological marker previously indicated to have predictive value in vulnerability to addictive behaviors.

  1. Presentation of Complex Homozygous Allele in ABCA4 Gene in a Patient with Retinitis Pigmentosa

    PubMed Central

    Audere, M?reta; Rutka, Katr?na; Šepetiene, Svetlana; L?ce, Baiba

    2015-01-01

    Retinitis pigmentosa is a degenerative retinal disease characterized by progressive photoreceptor damage, which causes loss of peripheral and night vision and the development of tunnel vision and may result in loss of central vision. This study describes a patient with retinitis pigmentosa caused by a mutation in the ABCA4 gene with complex allele c.1622T>C, p.L541P; c.3113C>T, p.A1038V in homozygous state. PMID:26229699

  2. Association of low-activity MAOA allelic variants with violent crime in incarcerated offenders

    PubMed Central

    Stetler, Dean A.; Davis, Chad; Leavitt, Kathryn; Schriger, Ilana; Benson, Katie; Bhakta, Samir; Wang, Lam Chee; Oben, Cynthia; Watters, Matthew; Haghnegahdar, Tara; Bortolato, Marco

    2015-01-01

    The main enzyme for serotonin degradation, monoamine oxidase (MAO) A, has recently emerged as a key biological factor in the predisposition to impulsive aggression. Male carriers of low-activity variants of the main functional polymorphism of the MAOA gene (MAOA-uVNTR) have been shown to exhibit a greater proclivity to engage in violent acts. Thus, we hypothesized that low-activity MAOA-uVNTR alleles may be associated with a higher risk for criminal violence among male offenders. To test this possibility, we analyzed the MAOA-uVNTR variants of violent (n=49) and non-violent (n=40) male Caucasian and African-American convicts in a correctional facility. All participants were also tested with the Childhood Trauma Questionnaire (CTQ), Barratt Impulsivity Scale (BIS-11) and Buss-Perry Aggression Questionnaire (BPAQ) to assess their levels of childhood trauma exposure, impulsivity and aggression, respectively. Our results revealed a robust (P<0.0001) association between low-activity MAOA-uVNTR alleles and violent crime. This association was replicated in the group of Caucasian violent offenders (P<0.01), but reached only a marginal trend (P=0.08) in their African American counterparts. While violent crime charges were not associated with CTQ, BIS-11 and BPAQ scores, carriers of low-activity alleles exhibited a mild, yet significant (P<0.05) increase in BIS-11 total and attentional-impulsiveness scores. In summary, these findings support the role of MAOA gene as a prominent genetic determinant for criminal violence. Further studies are required to confirm these results in larger samples of inmates and evaluate potential interactions between MAOA alleles and environmental vulnerability factors. PMID:25082653

  3. Effect of multiple allelic drop-outs in forensic RMNE calculations.

    PubMed

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

    2015-11-01

    Technological advances such as massively parallel sequencing enable increasing amounts of genetic information to be obtained from increasingly challenging samples. Certainly on low template, degraded and multi-contributor samples, drop-outs will increase in number for many profiles simply by analyzing more loci, making it difficult to probabilistically assess how many drop-outs have occurred and at which loci they might have occurred. Previously we developed a Random Man Not Excluded (RMNE) method that can take into account allelic drop-out while avoiding detailed estimations of the probability that drop-outs have occurred, nor making assumptions about at which loci these drop-outs might have occurred. The number of alleles that have dropped out, does not need to be exactly known. Here we report a generic Python algorithm to calculate the RMNE probabilities for any given number of loci. The number of allowed drop-outs can be set between 0 and twice the number of analyzed loci. The source code has been made available on https://github.com/fvnieuwe/rmne. An online web-based RMNE calculation tool has been made available on http://forensic.ugent.be/rmne. The tool can calculate these RMNE probabilities from a custom list of probabilities of the observed and non-observed alleles from any given number of loci. Using this tool, we explored the effect of allowing allelic drop-outs on the evidential value of random forensic profiles with a varying number of loci. Our results give insight into how the number of allowed drop-outs affects the evidential value of a profile and how drop-out can be managed in the RMNE approach. PMID:26280568

  4. Identification of Allelic Variants of Pendrin (SLC26A4) with Loss and Gain of Function

    PubMed Central

    Dossena, Silvia; Bizhanova, Aigerim; Nofziger, Charity; Bernardinelli, Emanuele; Ramsauer, Josef; Kopp, Peter; Paulmichl, Markus

    2011-01-01

    Background Pendrin is a multifunctional anion transporter that exchanges chloride and iodide in the thyroid, as well as chloride and bicarbonate in the inner ear, kidney and airways. Loss or reduction in the function of pendrin results in both syndromic (Pendred syndrome) and non-syndromic (non-syndromic enlarged vestibular aqueduct (ns-EVA)) hearing loss. Factors inducing an up-regulation of pendrin in the kidney and the lung may have an impact on the pathogenesis of hypertension, chronic obstructive pulmonary disease (COPD) and asthma. Here we characterize the ion transport activity of wild-type (WT) pendrin and seven of its allelic variants selected among those reported in the single nucleotide polymorphisms data base (dbSNPs), some of which were previously identified in a cohort of individuals with normal hearing or deaf patients belonging to the Spanish population. Methods WT and mutated pendrin allelic variants were functionally characterized in a heterologous over-expression system by means of fluorometric methods evaluating the I?/Cl? and Cl?/OH? exchange and an assay evaluating the efflux of radiolabeled iodide. Results The transport activity of pendrin P70L, P301L and F667C is completely abolished; pendrin V609G and D687Y allelic variants are functionally impaired but retain significant transport. Pendrin F354S activity is indistinguishable from WT, while pendrin V88I and G740S exhibit a gain of function. Conclusion Amino acid substitutions involving a proline always result in a severe loss of function of pendrin. Two hyperfunctional allelic variants (V88I, G740S) have been identified, and they may have a contributing role in the pathogenesis of hypertension, COPD and asthma. PMID:22116359

  5. Allele-specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci.

    PubMed

    Gerber, Madelyn M; Hampel, Heather; Zhou, Xiao-Ping; Schulz, Nathan P; Suhy, Adam; Deveci, Mehmet; Çatalyürek, Ümit V; Ewart Toland, Amanda

    2015-11-15

    Colorectal cancer (CRC) can be classified into different types. Chromosomal instable (CIN) colon cancers are thought to be the most common type of colon cancer. The risk of developing a CIN-related CRC is due in part to inherited risk factors. Genome-wide association studies have yielded over 40 single nucleotide polymorphisms (SNPs) associated with CRC risk, but these only account for a subset of risk alleles. Some of this missing heritability may be due to gene-gene interactions. We developed a strategy to identify interacting candidate genes/loci for CRC risk that utilizes both linkage and RNA-seq data from mouse models in combination with allele-specific imbalance (ASI) studies in human tumors. We applied our strategy to three previously identified CRC susceptibility loci in the mouse that show evidence of genetic interaction: Scc4, Scc5 and Scc13. 525 SNPs from genes showing differential expression in the mouse and/or a previous role in cancer from the literature were evaluated for allele-specific imbalance in 194 paired human normal/tumor DNAs from CIN-related CRCs. One hundred three SNPs showing suggestive evidence of ASI (31 variants with uncorrected p values?allelic selection after multiple comparisons testing. Future studies will evaluate the role of these variants in combination with interacting genetic partners in colon cancer risk in mouse and humans. PMID:25973956

  6. Prediction of peptides binding to MHC class I and II alleles by temporal motif mining

    PubMed Central

    2013-01-01

    Background MHC (Major Histocompatibility Complex) is a key player in the immune response of most vertebrates. The computational prediction of whether a given antigenic peptide will bind to a specific MHC allele is important in the development of vaccines for emerging pathogens, the creation of possibilities for controlling immune response, and for the applications of immunotherapy. One of the problems that make this computational prediction difficult is the detection of the binding core region in peptides, coupled with the presence of bulges and loops causing variations in the total sequence length. Most machine learning methods require the sequences to be of the same length to successfully discover the binding motifs, ignoring the length variance in both motif mining and prediction steps. In order to overcome this limitation, we propose the use of time-based motif mining methods that work position-independently. Results The prediction method was tested on a benchmark set of 28 different alleles for MHC class I and 27 different alleles for MHC class II. The obtained results are comparable to the state of the art methods for both MHC classes, surpassing the published results for some alleles. The average prediction AUC values are 0.897 for class I, and 0.858 for class II. Conclusions Temporal motif mining using partial periodic patterns can capture information about the sequences well enough to predict the binding of the peptides and is comparable to state of the art methods in the literature. Unlike neural networks or matrix based predictors, our proposed method does not depend on peptide length and can work with both short and long fragments. This advantage allows better use of the available training data and the prediction of peptides of uncommon lengths. PMID:23368521

  7. High-resolution genetic mapping of allelic variants associated with cell wall chemistry in Populus

    DOE PAGESBeta

    Muchero, Wellington; Guo, Jianjun; Difazio, Stephen P.; Chen, Jay; Ranjan, Priya; Slavov, Gancho; Gunter, Lee E; Jawdy, Sara; Bryan, Anthony C; Sykes, Robert; et al

    2015-01-01

    We report the identification of six genetic loci and the allelic-variants associated with Populus cell wall phenotypes determined independently using pyrolysis Molecular Beam Mass Spectrometry (pyMBMS), saccharification assay and wet chemistry in two partially overlapping populations of P. trichocarpa genotypes sampled from multiple environments in the Pacific Northwest of North America. All 6 variants co-located with a quantitative trait locus (QTL) hotspot on chromosome XIV for lignin content, syringyl to guaiacyl (S/G) ratio, 5- and 6- carbon sugars identified in an interspecific P. trichocarpa x P. deltoides pseudo-backcross mapping pedigree. Genomic intervals containing an amino acid transporter, a MYB transcriptionmore »factor, an angustifolia CtBP transcription factor, a copper transport protein ATOX1-related, a Ca2+ transporting ATPase and a protein kinase were identified within 5 QTL regions. Each interval contained single nucleotide polymorphisms (SNPs) that were significantly associated to cell-wall phenotypes, with associations exceeding the chromosome-wise Bonferroni-adjusted p-values in at least one environment. cDNA sequencing for allelic variants of 3 of the 6 genes identified polymorphisms leading to premature stop codons in the MYB transcription factor and protein kinase. On the other hand, variants of the Angustifolia CtBP transcription factor exhibited a polyglutamine (PolyQ) length polymorphism. Results from transient protoplast assays suggested that each of the polymorphisms conferred allelic differences in activation of cellulose, hemicelluloses and lignin pathway marker genes, with truncated and short PolyQ alleles exhibiting significantly reduced marker gene activation. Genes identified in this study represent novel targets for reducing cell wall recalcitrance for lignocellulosic biofuels production using plant biomass.« less

  8. Regulatory Divergence between Parental Alleles Determines Gene Expression Patterns in Hybrids

    PubMed Central

    Combes, Marie-Christine; Hueber, Yann; Dereeper, Alexis; Rialle, Stéphanie; Herrera, Juan-Carlos; Lashermes, Philippe

    2015-01-01

    Both hybridization and allopolyploidization generate novel phenotypes by conciliating divergent genomes and regulatory networks in the same cellular context. To understand the rewiring of gene expression in hybrids, the total expression of 21,025 genes and the allele-specific expression of over 11,000 genes were quantified in interspecific hybrids and their parental species, Coffea canephora and Coffea eugenioides using RNA-seq technology. Between parental species, cis- and trans-regulatory divergences affected around 32% and 35% of analyzed genes, respectively, with nearly 17% of them showing both. The relative importance of trans-regulatory divergences between both species could be related to their low genetic divergence and perennial habit. In hybrids, among divergently expressed genes between parental species and hybrids, 77% was expressed like one parent (expression level dominance), including 65% like C. eugenioides. Gene expression was shown to result from the expression of both alleles affected by intertwined parental trans-regulatory factors. A strong impact of C. eugenioides trans-regulatory factors on the upregulation of C. canephora alleles was revealed. The gene expression patterns appeared determined by complex combinations of cis- and trans-regulatory divergences. In particular, the observed biased expression level dominance seemed to be derived from the asymmetric effects of trans-regulatory parental factors on regulation of alleles. More generally, this study illustrates the effects of divergent trans-regulatory parental factors on the gene expression pattern in hybrids. The characteristics of the transcriptional response to hybridization appear to be determined by the compatibility of gene regulatory networks and therefore depend on genetic divergences between the parental species and their evolutionary history. PMID:25819221

  9. On coding genotypes for genetic markers with multiple alleles in genetic association study of quantitative traits

    PubMed Central

    2011-01-01

    Background In genetic association study of quantitative traits using F? models, how to code the marker genotypes and interpret the model parameters appropriately is important for constructing hypothesis tests and making statistical inferences. Currently, the coding of marker genotypes in building F? models has mainly focused on the biallelic case. A thorough work on the coding of marker genotypes and interpretation of model parameters for F? models is needed especially for genetic markers with multiple alleles. Results In this study, we will formulate F? genetic models under various regression model frameworks and introduce three genotype coding schemes for genetic markers with multiple alleles. Starting from an allele-based modeling strategy, we first describe a regression framework to model the expected genotypic values at given markers. Then, as extension from the biallelic case, we introduce three coding schemes for constructing fully parameterized one-locus F? models and discuss the relationships between the model parameters and the expected genotypic values. Next, under a simplified modeling framework for the expected genotypic values, we consider several reduced one-locus F? models from the three coding schemes on the estimability and interpretation of their model parameters. Finally, we explore some extensions of the one-locus F? models to two loci. Several fully parameterized as well as reduced two-locus F? models are addressed. Conclusions The genotype coding schemes provide different ways to construct F? models for association testing of multi-allele genetic markers with quantitative traits. Which coding scheme should be applied depends on how convenient it can provide the statistical inferences on the parameters of our research interests. Based on these F? models, the standard regression model fitting tools can be used to estimate and test for various genetic effects through statistical contrasts with the adjustment for environmental factors. PMID:21936918

  10. Apolipoprotein E epsilon4 allele increases risk for psychotic symptoms in Alzheimer's disease.

    PubMed

    Zdanys, Kristina F; Kleiman, Timothy G; MacAvoy, Martha G; Black, Benjamin T; Rightmer, Tracy E; Grey, Monique; Garman, Katherine S; Tampi, Rajesh R; Gelernter, Joel; van Dyck, Christopher H

    2007-01-01

    The apolipoprotein E (ApoE) epsilon4 allele is a well-documented genetic risk factor for sporadic Alzheimer's disease (AD). Its association with psychopathology among AD patients has been the subject of discrepant reports. We aimed to determine whether ApoE epsilon4+ and epsilon4- AD patients exhibit a different risk profile for psychotic symptoms and other behavioral disturbances. The Neuropsychiatric Inventory (NPI) was administered to determine the frequency and severity of psychotic and other behavioral symptoms in a sample of n=266 AD patients who had been genotyped for ApoE. Multiple logistic regression models were used to calculate the association between the ApoE epsilon4 allele and the presence of psychotic symptoms (delusions or hallucinations). Exploratory analyses were also conducted to determine the impact of disease severity on epsilon4 effects and to examine the association between epsilon4 and other behavioral symptoms. ApoE epsilon4 was significantly associated with psychotic symptoms (odds ratio (OR)=1.87, 95% CI=1.07-3.29, P=0.029), adjusting for age, sex, education, and MMSE score. More stringent definitions of clinically significant psychosis yielded similar results. Exploratory analyses suggested that this effect accrued specifically from patients with severe-stage AD and primarily from an association between epsilon4 and delusions. The epsilon4 allele did not appear to influence the development of most other behavioral symptoms in our sample. In conclusion, AD patients who carry the ApoE epsilon4 allele are at greater risk than noncarriers for developing psychotic symptoms, particularly as the severity of their dementia progresses. PMID:16841077

  11. Generation of mice encoding a conditional null allele of Gcm2

    PubMed Central

    Yuan, Ziqiang; Opas, Evan E.; Vrikshajanani, Chakravarthy; Libutti, Steven K.; Levine, Michael A.

    2014-01-01

    Glial cells missing homolog 2 (GCM2) is a transcription factor that is expressed predominately in the pharyngeal pouches and, at later stages, in the developing and mature parathyroid glands. In humans, loss of GCM2 function, either through recessive apomorphic mutations or dominant inhibitor mutations in the human GCM2 gene, leads to isolated hypoparathyroidism. In mice, homozygous disruption of Gcm2 by conventional gene targeting results in parathyroid aplasia and hypoparathyroidism. In this study, we report the generation and functional characterization of mice encoding a conditional null allele of Gcm2. We demonstrate the functional integrity of the conditional Gcm2 allele and report successful in vivo deletion of exon 2 using Cre recombinase. The mice with conditional deletion of Gcm2 displayed phenotypes similar to those previously described for a conventional Gcm2 knockout, including perinatal lethality, hypocalemia, low or undetectable serum levels of parathyroid hormone (PTH), and absent parathyroid glands. The production of a conditional mutant allele for Gcm2 represents a valuable resource for the study of the temporal- and spatial-specific roles for Gcm2, and for understanding the postnatal activities of GCM2 protein. PMID:24736975

  12. Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles

    PubMed Central

    de la Hera, Belén; Urcelay, Elena; Brassat, David; Chan, Andrew; Vidal-Jordana, Angela; Salmen, Anke; Villar, Luisa Maria; Álvarez-Cermeño, José Carlos; Izquierdo, Guillermo; Fernández, Oscar; Oliver, Begoña; Saiz, Albert; Ara, Jose Ramón; Vigo, Ana G.; Arroyo, Rafael; Meca, Virginia; Malhotra, Sunny; Fissolo, Nicolás; Horga, Alejandro; Montalban, Xavier

    2014-01-01

    Objectives: We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. Methods: HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. Results: A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (pM-H = 3 × 10?7; odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40–23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (pM-H = 6 × 10?4; ORM-H = 0.2, 95% CI = 0.08–0.50), with a PPV of 81%. Conclusions: HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration. PMID:25520955

  13. cDNA cloning and molecular analysis of two self-incompatibility alleles from apple.

    PubMed

    Broothaerts, W; Janssens, G A; Proost, P; Broekaert, W F

    1995-02-01

    Complementary DNA clones representing two alleles of the self-incompatibility (S) locus of apple (Malus x domestica Borkh.) have been isolated and characterised. One of the alleles corresponds to a 29 kDa ribonuclease (S-RNase) that was purified from pistil tissue. On northern blots, both cDNAs hybridized to a transcript that was only present in pistils and not in the other plant tissues analysed. Corresponding genomic sequences, amplified by PCR, were found to contain a single intron of 138 bp and 1100 bp respectively. Comparison of both sequences shows that the cDNAs encode mature proteins containing 65% of identical residues. Eight invariable cysteine residues, conserved regions around two histidines thought to play a role in RNA catalysis, and a number of other distinct residues are conserved between the apple S-RNases and similar proteins in the family Solanaceae. As this is the first report of sequences of S-alleles from a species belonging to a family that is not related with the Solanaceae, the structural features of S-RNases deduced from a comparison of their sequences are discussed. PMID:7894015

  14. Specific Silencing of L392V PSEN1 Mutant Allele by RNA Interference

    PubMed Central

    Sierant, Malgorzata; Paduszynska, Alina; Kazmierczak-Baranska, Julia; Nacmias, Benedetta; Sorbi, Sandro; Bagnoli, Silvia; Sochacka, Elzbieta; Nawrot, Barbara

    2011-01-01

    RNA interference (RNAi) technology provides a powerful molecular tool to reduce an expression of selected genes in eukaryotic cells. Short interfering RNAs (siRNAs) are the effector molecules that trigger RNAi. Here, we describe siRNAs that discriminate between the wild type and mutant (1174 C?G) alleles of human Presenilin1 gene (PSEN1). This mutation, resulting in L392V PSEN1 variant, contributes to early onset familial Alzheimer's disease. Using the dual fluorescence assay, flow cytometry and fluorescent microscopy we identified positions 8th–11th, within the central part of the antisense strand, as the most sensitive to mismatches. 2-Thiouridine chemical modification introduced at the 3?-end of the antisense strand improved the allele discrimination, but wobble base pairing adjacent to the mutation site abolished the siRNA activity. Our data indicate that siRNAs can be designed to discriminate between the wild type and mutant alleles of genes that differ by just a single nucleotide. PMID:21559198

  15. Germline allele-specific expression of DAPK1 in chronic lymphocytic leukemia.

    PubMed

    Wei, Quan-Xiang; Claus, Rainer; Hielscher, Thomas; Mertens, Daniel; Raval, Aparna; Oakes, Christopher C; Tanner, Stephan M; de la Chapelle, Albert; Byrd, John C; Stilgenbauer, Stephan; Plass, Christoph

    2013-01-01

    We previously reported a rare germline variant (c.1-6531) that resulted in allele-specific expression (ASE) of death-associated protein kinase 1 (DAPK1) and predisposition to chronic lymphocytic leukemia (CLL). We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE) with MALDI-TOF mass spectrometry, and detected germline DAPK1 ASE in 17 out of 120 (14.2%) CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the DAPK1 5' upstream regulatory region, within distinct exons or in the 3'-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL. PMID:23383130

  16. Gamma ray-induced loss of expression of HLA and glyoxalase I alleles in lymphoblastoid cells

    SciTech Connect

    Kavathas, P.; Bach, F.H.; DeMars, R.

    1980-07-01

    Gamma rays from a cesium source were used to generate human lymphoblastoid cell line variants that had lost expression of all major histocompatibility complex antigens coded for by a single haplotype. The cell line was heterozygous at the glyoxalase I locus and had the HLA haplotypes HLA-A1, B8, DRw3, and HLA-A2, B5, DRw1. We selected with anti-HLA-B8 antiserum in a population of cells that had been irradiated with 300R. The incidence of B8-loss variants was 4.1 X 10/sup -5/ on day 5 after irradiation. Analysis of variants showed that expressions of HLA and GLO alleles trans to B8 were retained. However, expression of additional cis-linked HLA and GLO gene products was lost in 12 of 17 variants. Variants that had lost expression of (i) HLA-B8, (ii) HLA-B8, A1, (iii) HLA-B8, A1, DRw3, or (iv) HLA-B8, A1, DRw3 and the cis-linked glyoxalase I allele were obtained. Karyotype analysis was performed on eight variants that had lost expression of two or more cis-linked alleles. Three variants had two normal appearing no. 6 chromosomes, four variants had a deletion that included the region coding for HLA genes on the short arm of one no. 6 chromosome, and one variant had an inversion or translocation involving the short arm of one no. 6.

  17. Structure and expression of wild-type and suppressible alleles of the Drosophila purple gene

    SciTech Connect

    Kim, Nacksung |; Park, Dongkook; Yim, John

    1996-04-01

    Viable mutant alleles of purple (pr), such as pr{sup bw}, exhibit mutant eye colors. This reflects low 6-pyruvoyl tetrahydropterin (PTP) synthase activity required for pigment synthesis. PTP synthase is also required for synthesis of the enzyme cofactor biopterin; presumably this is why some pr alleles are lethal. The pr{sup bw} eye color phenotype is suppressed by suppressor of sable [su(s)] mutations. The pr gene was cloned to explore the mechanism of this suppression. pr produces two PTP synthase mRNAs: one constitutively from a distal promoter and one in late pupae and young adult heads from a proximal promoter. The latter presumably supports eye pigment synthesis. The pr{sup bw} allele has a 412 retrotransposon in an intron spliced from both mRNAs. However, the head-specific mRNA is reduced > 10-fold in pr{sup bw} and is restored by a su(s) mutation, while the constitutive transcript is barely affected. The Su(s) protein probably alters processing of RNA containing 412. Because the intron containing 412 is the first in the head-specific mRNA and the second in the constitutive mRNA, binding of splicing machinery to nascent transcripts before the 412 insertion is transcribed may preclude the effects of Su(s) protein. 43 refs., 9 figs.

  18. Transcriptional and translational analyzes of recA mutant alleles in Pseudomonas aeruginosa

    SciTech Connect

    Horn, J.M.; Ohman, D.E.

    1988-04-01

    Recombinant plasmids containing the recA gene from Pseudomonas aeruginosa were used in complementation, transcriptional, and translational studies to examine the nature of rec-102 and rec-2, mutations which confer a recA-like mutant phenotype on P. aeruginosa PAO strains. For comparison, recA7::Tn501 mutants of strain PAO were constructed by gene replacement. The rec-2 and rec-102 alleles were shown to be recA alleles; plasmids containing the recA gene complemented the three rec mutants strains for defects associated with recA mutation. A minicell analysis showed that a plasmid expressing both of the recA gene transcripts or one that expressed only the smaller transcript both produced the same 42-kilodalton recA protein. A chloramphenicol acetyl-transferase gene fusion in the 3' end of the recA transcript showed that the recA gene of P. aeruginosa was induced following treatment with a DNA-damaging agent (methyl methanesulfonate). The rec-2 allele of recA was normal with respect to induction of mRNA, but these transcripts were defective in either translation or synthesis of a stable protein. The rec-102 mutant also produced a detectable transcript and no recA protein following induction. The recA defect in this mutant is apparently in the interaction between recA and a lexA-like repressor.

  19. Testing for High-Risk APOL1 Alleles in Potential Living Kidney Donors.

    PubMed

    Riella, Leonardo V; Sheridan, Alice M

    2015-09-01

    Accurate risk assessment is critical when evaluating potential living kidney donors. High-risk kidney APOL1 variants have been associated with end-stage renal disease of multiple causes among African Americans, though the predictive power of these variants in population-based studies is small. No studies have looked at the effect of high-risk APOL1 alleles on donor outcomes, though few transplantation centers in the United States offer screening for APOL1 among African American donors. Screening all African Americans for high-risk APOL1 alleles may result in the exclusion of many potential donors (?13% of African Americans). Such an exclusion may have a large effect on the availability of transplants for African Americans, who are already less likely to undergo transplantation. Nephrologists should be prepared to discuss with potential African American donors the relative increase in risk that is likely conferred by carrying 2 high-risk APOL1 alleles and how additional factors such as environmental exposures (eg, viral infections) and/or other genetic susceptibilities may be required for developing kidney disease. In this Perspective, we review the use of APOL1 testing for risk stratification of potential African American kidney donors. PMID:26049628

  20. Genetic polymorphisms, their allele combinations and IFN-? treatment response in Irish multiple sclerosis patients

    PubMed Central

    O’Doherty, Catherine; Favorov, Alexander; Heggarty, Shirley; Graham, Colin; Favorova, Olga; Ochs, Michael; Hawkins, Stanley; Hutchinson, Michael; O’Rourke, Killian; Vandenbroeck, Koen

    2009-01-01

    Introduction IFN-? is widely used as first-line immunomodulatory treatment for multiple sclerosis. Response to treatment is variable (30–50% of patients are nonresponders) and requires a long treatment duration for accurate assessment to be possible. Information about genetic variations that predict responsiveness would allow appropriate treatment selection early after diagnosis, improve patient care, with time saving consequences and more efficient use of resources. Materials & methods We analyzed 61 SNPs in 34 candidate genes as possible determinants of IFN-? response in Irish multiple sclerosis patients. Particular emphasis was placed on the exploration of combinations of allelic variants associated with response to therapy by means of a Markov chain Monte Carlo-based approach (APSampler). Results The most significant allelic combinations, which differed in frequency between responders and nonresponders, included JAK2–IL10RB–GBP1–PIAS1 (permutation p-value was pperm = 0.0008), followed by JAK2–IL10–CASP3 (pperm = 0.001). Discussion The genetic mechanism of response to IFN-? is complex and as yet poorly understood. Data mining algorithms may help in uncovering hidden allele combinations involved in drug response versus nonresponse. PMID:19604093

  1. A compound-heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype.

    PubMed Central

    Karttunen, L.; Raghunath, M.; Lönnqvist, L.; Peltonen, L.

    1994-01-01

    We describe here the identification of defined mutations in both alleles of the fibrillin gene (FBN1) in a compound-heterozygote Marfan syndrome (MFS) child who had a very severe form of MFS resulting in death from cardiac failure at the age of 4 mo. The nonconsanguineous parents were both affected with MFS. The father's heterozygous point mutation has earlier been reported to result in W217G substitution, the mother was here shown to carry a heterozygous point mutation resulting in G2627R substitution, and the child had inherited both these mutations. The mutant FBN1 alleles were demonstrated to be transcribed with equal efficiency compared with the normal alleles, but metabolic labeling of fibroblast cultures from the child and both parents showed reduced biosynthesis and secretion of profibrillin. Also, the respective amounts of fibrillin in cell-culture media and extracellular-matrix extracts were markedly diminished, particularly in the cell cultures from father and child. In addition, immunofluorescence analysis of the cell cultures of all three family members revealed a drastically reduced amount of microfibrils, and virtually no visible fibrils could be seen in the case of the compound-heterozygote child. These findings demonstrate incomplete dominance of fibrillin mutations and underline the fatal consequences of the complete absence of normal fibrillin molecules in the microfibrils. Images Figure 2 Figure 4 PMID:7977366

  2. Seed fates in crop–wild hybrid sunflower: crop allele and maternal effects

    PubMed Central

    Pace, Brian A; Alexander, Helen M; Emry, Jason D; Mercer, Kristin L

    2015-01-01

    Domestication has resulted in selection upon seed traits found in wild populations, yet crop-wild hybrids retain some aspects of both parental phenotypes. Seed fates of germination, dormancy, and mortality can influence the success of crop allele introgression in crop-wild hybrid zones, especially if crop alleles or crop-imparted seed coverings result in out-of-season germination. We performed a seed burial experiment using crop, wild, and diverse hybrid sunflower (Helianthus annuus) cross types to test how a cross type's maternal parent and nuclear genetic composition might affect its fate under field conditions. We observed higher maladaptive fall germination in the crop- and F1- produced seeds than wild-produced seeds and, due to an interaction with percent crop alleles, fall germination was higher for cross types with more crop-like nuclear genetics. By spring, crop-produced cross types had the highest overwintering mortality, primarily due to higher fall germination. Early spring germination was identical across maternal types, but germination continued for F1-produced seeds. In conclusion, the more wild-like the maternal parent or the less proportion of the cross type's genome contributed by the crop, the greater likelihood a seed will remain ungerminated than die. Wild-like dormancy may facilitate introgression through future recruitment from the soil seed bank. PMID:25685189

  3. Drosophila Cappuccino alleles provide insight into formin mechanism and role in oogenesis

    PubMed Central

    Yoo, Haneul; Roth-Johnson, Elizabeth A.; Bor, Batbileg; Quinlan, Margot E.

    2015-01-01

    During Drosophila development, the formin actin nucleator Cappuccino (Capu) helps build a cytoplasmic actin mesh throughout the oocyte. Loss of Capu leads to female sterility, presumably because polarity determinants fail to localize properly in the absence of the mesh. To gain deeper insight into how Capu builds this actin mesh, we systematically characterized seven capu alleles, which have missense mutations in Capu's formin homology 2 (FH2) domain. We report that all seven alleles have deleterious effects on fly fertility and the actin mesh in vivo but have strikingly different effects on Capu's biochemical activity in vitro. Using a combination of bulk and single- filament actin-assembly assays, we find that the alleles differentially affect Capu's ability to nucleate and processively elongate actin filaments. We also identify a unique “loop” in the lasso region of Capu's FH2 domain. Removing this loop enhances Capu's nucleation, elongation, and F-actin–bundling activities in vitro. Together our results on the loop and the seven missense mutations provides mechanistic insight into formin function in general and Capu's role in the Drosophila oocyte in particular. PMID:25788286

  4. HLA-DRB1 alleles in four Amerindian populations from Argentina and Paraguay

    PubMed Central

    2009-01-01

    The major histocompatibility complex (MHC) is one of the biological systems of major polymorphisms. The study of HLA class II variability has allowed the identification of several alleles that are characteristic to Amerindian populations, and it is an excellent tool to define the relations and biological affinities among them. In this work, we analyzed the allelic distribution of the HLA-DRB1 class II locus in four Amerindian populations: Mapuche (n = 34) and Tehuelche (n = 23) from the Patagonian region of Argentina, and Wichi SV (n = 24) and Lengua (n = 17) from the Argentinean and Paraguayan Chaco regions, respectively. In all of these groups, relatively high frequencies of Amerindian HLA-DRB1 alleles were observed (DRB1*0403, DRB1*0407, DRB1*0411, DRB1*0417, DRB1*0802, DRB1*0901, DRB1*1402, DRB1*1406 and DRB1*1602). However, we also detected the presence of non-Amerindian variants in Mapuche (35%) and Tehuelche (22%). We compared our data with those obtained in six indigenous groups of the Argentinean Chaco region and in a sample from Buenos Aires City. The genetic distance dendrogram showed a clear-cut division between the Patagonian and Chaco populations, which formed two different clusters. In spite of their linguistic differences, it can be inferred that the biological affinities observed are in concordance with the geographic distributions and interethnic relations established among the groups studied. PMID:21637670

  5. HLA-DRB1 alleles in four Amerindian populations from Argentina and Paraguay.

    PubMed

    Parolín, Maria L; Carnese, Francisco R

    2009-04-01

    The major histocompatibility complex (MHC) is one of the biological systems of major polymorphisms. The study of HLA class II variability has allowed the identification of several alleles that are characteristic to Amerindian populations, and it is an excellent tool to define the relations and biological affinities among them. In this work, we analyzed the allelic distribution of the HLA-DRB1 class II locus in four Amerindian populations: Mapuche (n = 34) and Tehuelche (n = 23) from the Patagonian region of Argentina, and Wichi SV (n = 24) and Lengua (n = 17) from the Argentinean and Paraguayan Chaco regions, respectively. In all of these groups, relatively high frequencies of Amerindian HLA-DRB1 alleles were observed (DRB1*0403, DRB1*0407, DRB1*0411, DRB1*0417, DRB1*0802, DRB1*0901, DRB1*1402, DRB1*1406 and DRB1*1602). However, we also detected the presence of non-Amerindian variants in Mapuche (35%) and Tehuelche (22%). We compared our data with those obtained in six indigenous groups of the Argentinean Chaco region and in a sample from Buenos Aires City. The genetic distance dendrogram showed a clear-cut division between the Patagonian and Chaco populations, which formed two different clusters. In spite of their linguistic differences, it can be inferred that the biological affinities observed are in concordance with the geographic distributions and interethnic relations established among the groups studied. PMID:21637670

  6. Intraclass and Interclass Correlations of Allele Sizes within and between Loci in DNA Typing Data

    PubMed Central

    Chakraborty, R.; Srinivasan, M. R.; Andrade, M. D.

    1993-01-01

    Nonparametric measures of correlations of DNA fragment lengths within and between variable number of tandem repeat (VNTR) loci are proposed to test the hypothesis of random association of allele sizes at VNTR loci. Transformations of these nonparametric correlation measures are suggested to detect deviations of their null expectations caused by population subdivision and errors of measurement of VNTR fragment lengths. Analytic and permutation-based computer simulation studies are performed to show that under the hypothesis of independence of allele sizes the transformed correlation measures are normally distributed, irrespective of the VNTR fragment size distribution in the population even when the number of individuals samples is as low as 100. Power calculations are performed to establish that the current population data on six VNTR loci in the US Hispanic sample are in accordance with the hypothesis of random association of allele sizes within and between loci. Implications of these results in the context of forensic use of DNA typing are also discussed. PMID:8094698

  7. High levels of MHC class II allelic diversity in lake trout from Lake Superior

    USGS Publications Warehouse

    Dorschner, M.O.; Duris, T.; Bronte, C.R.; Burnham-Curtis, M. K.; Phillips, R.B.

    2000-01-01

    Sequence variation in a 216 bp portion of the major histocompatibility complex (MHC) II B1 domain was examined in 74 individual lake trout (Salvelinus namaycush) from different locations in Lake Superior. Forty-three alleles were obtained which encoded 71-72 amino acids of the mature protein. These sequences were compared with previous data obtained from five Pacific salmon species and Atlantic salmon using the same primers. Although all of the lake trout alleles clustered together in the neighbor-joining analysis of amino acid sequences, one amino acid allelic lineage was shared with Atlantic salmon (Salmo salar), a species in another genus which probably diverged from Salvelinus more than 10-20 million years ago. As shown previously in other salmonids, the level of nonsynonymous nucleotide substitution (d(N)) exceeded the level of synonymous substitution (d(S)). The level of nucleotide diversity at the MHC class II B1 locus was considerably higher in lake trout than in the Pacific salmon (genus Oncorhynchus). These results are consistent with the hypothesis that lake trout colonized Lake Superior from more than one refuge following the Wisconsin glaciation. Recent population bottlenecks may have reduced nucleotide diversity in Pacific salmon populations.

  8. Marker assisted accelerated introgression of null allele of kunitz trypsin inhibitor in soybean

    PubMed Central

    Kumar, Vineet; Rani, Anita; Rawal, Reena; Mourya, Vaishali

    2015-01-01

    Development of kunitz trypsin inhibitor (KTI)-free soybean is crucial for soy-food industry as the heat inactivation employed to inactivate the anti-nutritional factor in regular soybean incurs extra cost and affects protein solubility. In the presented work, a null allele of KTI from PI542044 was introgressed into cultivar ‘JS97-52’ (recurrent parent) through marker assisted backcrossing. Foreground selection in BC1F2, BC2F2 and BC3F2 was carried out using the null allele-specific marker in tandem with SSR marker Satt228, tightly linked with a trypsin inhibitor Ti locus. Background selection in null allele-carrying plants through 106 polymorphic SSR markers across the genome led to the identification of 9 KTI-free lines exhibiting 98.6% average recurrent parent genome content (RPGC) after three backcrosses, which otherwise had required 5–6 backcrosses through conventional method. Introgressed lines (ILs) were free from KTI and yielded at par with recurrent parent. Reduction of 68.8–83.5% in trypsin inhibitor content (TIC) in ILs compared to the recurrent parent (‘JS97-52’) was attributed to the elimination of KTI. PMID:26719748

  9. Intraclass and interclass correlations of allele sizes within and between loci in DNA typing data

    SciTech Connect

    Chakraborty, R.; Srinivasan, M.R.; Andrade, M. de )

    1993-02-01

    Nonparametric measures of correlations of DNA fragment lengths within and between variable number of tandem repeat (VNTR) loci are proposed to test the hypothesis of random association of allele sizes at VNTR loci. Transformations of these nonparametric correlation measures are suggested to detect deviations of their null expectations caused by population subdivision and errors of measurement of VNTR fragment lengths. Analytic and permutation-based computer simulation studies are performed to show that under the hypothesis of independence of allele sizes the transformed correlation measures are normally distributed, irrespective of the VNTR fragment size distribution in the population even when the number of individuals samples is as low as 100. Power calculations are performed to establish that the current population data on six VNTR loci in the US Hispanic sample are in accordance with the hypothesis of random association of allele sizes within and between loci. Implications of these results in the context of forensic use of DNA typing are also discussed. 29 refs., 1 fig., 4 tabs.

  10. A novel HBA2 gene conversion in cis or trans: "?12 allele" in a Saudi population.

    PubMed

    Borgio, J Francis; AbdulAzeez, S; Al-Nafie, Awatif N; Naserullah, Zaki A; Al-Jarrash, Sana; Al-Madan, Mohammed S; Al-Muhanna, Fahad; Steinberg, Martin H; Al-Ali, Amein K

    2014-12-01

    Thalassemia and sickle cell disease are the most prevalent hemoglobin disorders in the populations of Dammam, Al-Qatif and Al-Ahsa regions in the Eastern Province of Saudi Arabia where our study cases originated. Increased HbF can modify these disorders. Direct sequencing of the HBA2 and HBA1 genes from 157 Saudi subjects revealed a new HBA2 gene conversion in cis or trans in 5.7% of the total. We refer to this new HBA2 gene convert as an ?12 (HBA12) allele due to its combination of ?1 (HBA1) and ?2 (HBA2) sequences. Three genotypes, homozygous (-?12(3.7)/?1?12), heterozygous (?1?2/?1?12) and hemizygous (?1- (4.2)/?1?12) for the ?12 allele were observed. The majority of individuals who were positive for the ?12 allele had a reduction in the percentage of HbA2. Further studies are necessary to evaluate the possible effect of these changes on globin gene expression. PMID:25065854

  11. Generation of a conditional allele of the mouse prostaglandin EP4 receptor.

    PubMed

    Schneider, André; Guan, YouFei; Zhang, Yahua; Magnuson, Mark A; Pettepher, Cathy; Loftin, Charles D; Langenbach, Robert; Breyer, Richard M; Breyer, Matthew D

    2004-09-01

    Genetic disruption of the mouse EP4 receptor results in perinatal lethality associated with persistent patent ductus areteriosus (PDA). To circumvent this, an EP4 allele amenable to conditional deletion using the Cre/loxP system was generated. The targeting construct was comprised of a floxed exon2 in tandem with the neomycin-resistance gene in intron 2, flanked by third 3' LoxP site. Mice homozygous for the targeted allele (EP4(lox+neo/lox+neo)), or following its Cre-mediated deletion (EP4(del/del)), also die within hours of birth with PDA. In contrast, mice homozygous for a partially recombined allele, retaining exon2 but lacking neo (EP4(flox/flox)), are viable and show no overt phenotype. Postnatal deletion of the floxed EP4 gene is efficiently achieved in the liver and kidney in a transgenic mouse expressing the inducible Mx1Cre recombinase. The EP4(flox) mouse should provide a useful reagent with which to examine the physiologic roles of the EP4 receptor. PMID:15354288

  12. Lack of association between human leukocyte antigen-E alleles and nasopharyngeal carcinoma in Tunisians.

    PubMed

    Hassen, Elham; Ghedira, Randa; Ghandri, Nahla; Farhat, Karim; Gabbouj, Sallouha; Bouaouina, Noureddine; Abdelaziz, Hamdi; Nouri, Abdelatif; Chouchane, Lotfi

    2011-08-01

    Nasopharyngeal carcinoma (NPC), a cancer with a remarkable geographical and worldwide ethnic distribution, has been strongly associated with human leukocyte antigen (HLA) class I genes. The presence of additional HLA risk factors has been suggested by several reports. In the present study, we analyzed the implication of HLA-E gene polymorphisms in NPC susceptibility in Tunisians, a population characterized by an intermediate incidence of NPC with specific clinical features. Peripheral blood DNA was obtained from 185 patients with NPC and 177 matched controls. Genotyping for three single-nucleotide polymorphisms, codon 83Gly/Arg, codon 157Arg/Gly, and codon 107Arg/Gly, was performed using the polymerase chain reaction method. The HLA-E*01:01 and HLA-E*01:03 were the only alleles found among Tunisians. The HLA-E*01:03 allele had a slight increase in patients with NPC (43%) compared with controls (37%), but the difference did not reach a statistical significance. Our results show the lack of association between HLA-E alleles and NPC in the Tunisian population. This is not in agreement with the previous studies, suggesting a potential implication of HLA-E gene polymorphisms in the susceptibility to NPC among populations with high-risk incidence. Our study further supports the dissimilarity of NPC between populations with different NPC incidence. PMID:21332388

  13. Genetic polymorphisms in Japanese fragrant landraces and novel fragrant allele domesticated in northern Japan.

    PubMed

    Ootsuka, Kenta; Takahashi, Ikuya; Tanaka, Katsunori; Itani, Tomio; Tabuchi, Hiroaki; Yoshihashi, Tadashi; Tonouchi, Akio; Ishikawa, Ryuji

    2014-06-01

    Rice fragrance is an important characteristic for Southeast Asian consumers, and fragrant landraces from Japan were first recorded in the 17th century. Principal component analysis clearly showed that Japanese fragrant landraces were genetically different from non-Japanese fragrant landraces. Japanese fragrant landraces were composed of six clades, none of which carried the most common fragrance mutation, an 8-bp deletion in exon 7 of Badh2. Fragrant landraces comprised two major groups carrying different Badh2 mutations. One group carried a known SNP at exon13 and the other a SNP at the exon1-intron1 junction as splicing donor site. The latter was considered to be a potential splicing mutant group as a novel allele at Badh2. Heterozygosity (He) scores in the two fragrant groups were not significantly different from non-fragrant landraces and modern cultivars. However, lower He scores were found around the Badh2 locus in the two groups. The potential splicing mutant group showed a more extended haplotype than the E13 SNP group. A likely causal factor responsible for loss of function is a novel splicing mutation allele that may have been generated quite recently. The fragrance allele has dispersed as a result of out-crossing under local environmental conditions. PMID:24987297

  14. Association of ABO Blood Group Phenotype and Allele Frequency with Chikungunya Fever

    PubMed Central

    Rujirojindakul, Pairaya; Chongsuvivatwong, Virasakdi; Limprasert, Pornprot

    2015-01-01

    Background. The objective of this study was to investigate the association of the ABO blood group phenotype and allele frequency with CHIK fever. Methods. A rural community survey in Southern Thailand was conducted in August and September 2010. A total of 506 villagers were enrolled. Cases were defined as individuals having anti-CHIK IgG by hemagglutination ?1?:?10. Results. There were 314 cases (62.1%) with CHIK seropositivity. Females were less likely to have positive anti-CHIK IgG with odds ratio (OR) (95% CI) of 0.63 (0.43, 0.93). All samples tested were Rh positive. Distribution of CHIK seropositivity versus seronegativity (P value) in A, B, AB, and O blood groups was 80 versus 46 (0.003), 80 versus 48 (0.005), 24 versus 20 (0.55), and 130 versus 78 (<0.001), respectively. However, chi-square test between ABO and CHIK infection showed no statistical significance (P = 0.76). Comparison of the ABO blood group allele frequency between CHIK seropositivity and seronegativity was not statistically significant. Conclusion. This finding demonstrated no association of the ABO blood group phenotypes and allele frequencies with CHIK infection. PMID:25977691

  15. Seed fates in crop-wild hybrid sunflower: crop allele and maternal effects.

    PubMed

    Pace, Brian A; Alexander, Helen M; Emry, Jason D; Mercer, Kristin L

    2015-02-01

    Domestication has resulted in selection upon seed traits found in wild populations, yet crop-wild hybrids retain some aspects of both parental phenotypes. Seed fates of germination, dormancy, and mortality can influence the success of crop allele introgression in crop-wild hybrid zones, especially if crop alleles or crop-imparted seed coverings result in out-of-season germination. We performed a seed burial experiment using crop, wild, and diverse hybrid sunflower (Helianthus annuus) cross types to test how a cross type's maternal parent and nuclear genetic composition might affect its fate under field conditions. We observed higher maladaptive fall germination in the crop- and F1- produced seeds than wild-produced seeds and, due to an interaction with percent crop alleles, fall germination was higher for cross types with more crop-like nuclear genetics. By spring, crop-produced cross types had the highest overwintering mortality, primarily due to higher fall germination. Early spring germination was identical across maternal types, but germination continued for F1-produced seeds. In conclusion, the more wild-like the maternal parent or the less proportion of the cross type's genome contributed by the crop, the greater likelihood a seed will remain ungerminated than die. Wild-like dormancy may facilitate introgression through future recruitment from the soil seed bank. PMID:25685189

  16. Ancient allelism at the cytosolic chaperonin-alpha-encoding gene of the zebrafish.

    PubMed Central

    Takami, K; Figueroa, F; Mayer, W E; Klein, J

    2000-01-01

    The T-complex protein 1, TCP1, gene codes for the CCT-alpha subunit of the group II chaperonins. The gene was first described in the house mouse, in which it is closely linked to the T locus at a distance of approximately 11 cM from the Mhc. In the zebrafish, Danio rerio, in which the T homolog is linked to the class I Mhc loci, the TCP1 locus segregates independently of both the T and the Mhc loci. Despite its conservation between species, the zebrafish TCP1 locus is highly polymorphic. In a sample of 15 individuals and the screening of a cDNA library, 12 different alleles were found, and some of the allelic pairs were found to differ by up to nine nucleotides in a 275-bp-long stretch of sequence. The substitutions occur in both translated and untranslated regions, but in the former they occur predominantly at synonymous codon sites. Phylogenetically, the alleles fall into two groups distinguished also by the presence or absence of a 10-bp insertion/deletion in the 3' untranslated region. The two groups may have diverged as long as 3.5 mya, and the polymorphic differences may have accumulated by genetic drift in geographically isolated populations. PMID:10628990

  17. Allele frequency data for 15 autosomal STR loci in eight Indonesian subpopulations.

    PubMed

    Venables, Samantha J; Daniel, Runa; Sarre, Stephen D; Soedarsono, Nurtami; Sudoyo, Herawati; Suryadi, Helena; van Oorschot, Roland A H; Walsh, Simon J; Widodo, Putut T; McNevin, Dennis

    2016-01-01

    Evolutionary and cultural history can affect the genetic characteristics of a population and influences the frequency of different variants at a particular genetic marker (allele frequency). These characteristics directly influence the strength of forensic DNA evidence and make the availability of suitable allele frequency information for every discrete country or jurisdiction highly relevant. Population sub-structure within Indonesia has not been well characterised but should be expected given the complex geographical, linguistic and cultural architecture of the Indonesian population. Here we use forensic short tandem repeat (STR) markers to identify a number of distinct genetic subpopulations within Indonesia and calculate appropriate population sub-structure correction factors. This data represents the most comprehensive investigation of population sub-structure within Indonesia to date using these markers. The results demonstrate that significant sub-structure is present within the Indonesian population and must be accounted for using island specific allele frequencies and corresponding sub-structure correction factors in the calculation of forensic DNA match statistics. PMID:26517173

  18. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype

    PubMed Central

    Rutherford, Nicola J.; Heckman, Michael G.; DeJesus-Hernandez, Mariely; Baker, Matt C.; Soto-Ortolaza, Alexandra I.; Rayaprolu, Sruti; Stewart, Heather; Finger, Elizabeth; Volkening, Kathryn; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol; Knopman, David S.; Kretzschmar, Hans A.; Neumann, Manuela; Caselli, Richard J.; White, Charles L.; Mackenzie, Ian R.; Petersen, Ronald C.; Strong, Michael J.; Miller, Bruce L.; Boeve, Bradley F.; Uitti, Ryan J.; Boylan, Kevin; Wszolek, Zbigniew K.; Graff-Radford, Neill R.; Dickson, Dennis W.; Ross, Owen A.; Rademakers, Rosa

    2012-01-01

    Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers. PMID:22840558

  19. Beaded of Goldschmidt, an Antimorphic Allele of Serrate, Encodes a Protein Lacking Transmembrane and Intracellular Domains

    PubMed Central

    Hukriede, N. A.; Fleming, R. J.

    1997-01-01

    Serrate (Ser) is an essential gene in Drosophila melanogaster best known for the Ser dominant (Ser(D)) allele and its effects on wing development. Animals heterozygous or homozygous for Ser(D) are viable and exhibit loss of wing margin tissue and associated bristles and hairs. The Beaded of Goldschmidt (Bd(G)) allele of Ser, when heterozygous to wild type, will also produce animals exhibiting loss of wing margin material. However, animals homozygous for Bd(G) exhibit a larval lethal phenotype comparable to animals homozygous for loss-of-function Ser alleles. Bd(G) is a partial duplication of the Ser locus with a single 5' Ser-homologous region and two distinct 3' regions. Meiotic recombination between Bd(G) and a wild-type Ser chromosome demonstrated that only one DNA lesion, caused by the insertion of a transposable roo element into the coding regions of the Ser transcript, appears capable of generating Bd(G) phenotypes. Due to the roo insertion, the protein product is predicted to be prematurely truncated and lack an extracellular cysteine-rich region along with the transmembrane and intracellular domains found within the normal SERRATE (SER) protein. The loss of these protein domains apparently contributes to the antimorphic nature of this mutation. PMID:9071590

  20. Allele-specific deposition of macroH2A1 in Imprinting Control Regions

    SciTech Connect

    Choo, J H; Kim, J D; Chung, J H; Stubbs, L; Kim, J

    2006-01-13

    In the current study, we analyzed the deposition patterns of macroH2A1 at a number of different genomic loci located in X chromosome and autosomes. MacroH2A1 is preferentially deposited at methylated CpG CpG-rich regions located close to promoters. The macroH2A1 deposition patterns at the methylated CpG islands of several imprinted domains, including the Imprinting Control Regions (ICRs) of Xist, Peg3, H19/Igf2 Igf2, Gtl2/Dlk1, and Gnas domains, show consistent allele-specificity towards inactive, methylated alleles. The macroH2A1 deposition levels at the ICRs and other Differentially Methylated Regions (DMRs) of these domains are also either higher or comparable to those observed at the inactive X chromosome of female mammals. Overall, our results indicate that besides DNA methylation macroH2A1 is another epigenetic component in the chromatin of ICRs displaying differential association with two parental alleles.

  1. Description and Power Analysis of Two Tests for Detecting Recent Population Bottlenecks from Allele Frequency Data

    PubMed Central

    Cornuet, J. M.; Luikart, G.

    1996-01-01

    When a population experiences a reduction of its effective size, it generally develops a heterozygosity excess at selectively neutral loci, i.e., the heterozygosity computed from a sample of genes is larger than the heterozygosity expected from the number of alleles found in the sample if the population were at mutation drift equilibrium. The heterozygosity excess persists only a certain number of generations until a new equilibrium is established. Two statistical tests for detecting a heterozygosity excess are described. They require measurements of the number of alleles and heterozygosity at each of several loci from a population sample. The first test determines if the proportion of loci with heterozygosity excess is significantly larger than expected at equilibrium. The second test establishes if the average of standardized differences between observed and expected heterozygosities is significantly different from zero. Type I and II errors have been evaluated by computer simulations, varying sample size, number of loci, bottleneck size, time elapsed since the beginning of the bottleneck and level of variability of loci. These analyses show that the most useful markers for bottleneck detection are those evolving under the infinite allele model (IAM) and they provide guidelines for selecting sample sizes of individuals and loci. The usefulness of these tests for conservation biology is discussed. PMID:8978083

  2. Hitchhiking of Deleterious Alleles and the Cost of Adaptation in Partially Selfing Species

    PubMed Central

    Hartfield, Matthew; Glémin, Sylvain

    2014-01-01

    Self-fertilization is generally seen to be disadvantageous in the long term. It increases genetic drift, which subsequently reduces polymorphism and the efficiency of selection, which also challenges adaptation. However, high selfing rates can increase the fixation probability of recessive beneficial mutations, but existing theory has generally not accounted for the effect of linked sites. Here, we analyze a model for the fixation probability of deleterious mutants that hitchhike with selective sweeps in diploid, partially selfing populations. Approximate analytical solutions show that, conditional on the sweep not being lost by drift, higher inbreeding rates increase the fixation probability of the deleterious allele, due to the resulting reduction in polymorphism and effective recombination. When extending the analysis to consider a distribution of deleterious alleles, as well as the average fitness increase after a sweep, we find that beneficial alleles generally need to be more recessive than the previously assumed dominance threshold (h < 1/2) for selfing to be beneficial from one-locus theory. Our results highlight that recombination aiding the efficiency of selection on multiple loci amplifies the fitness benefits of outcrossing over selfing, compared to results obtained from one-locus theory. This effect additionally increases the parameter range under which obligate outcrossing is beneficial over partial selfing. PMID:24240529

  3. Prevalence of Incompletely Penetrant Huntington’s Disease Alleles Among Individuals With Major Depressive Disorder

    PubMed Central

    Perlis, Roy H.; Smoller, Jordan W.; Mysore, Jayalakshmi; Sun, Mei; Gillis, Tammy; Purcell, Shaun; Rietschel, Marcella; Nöthen, Markus M.; Witt, Stephanie; Maier, Wolfgang; Iosifescu, Dan V.; Sullivan, Patrick; Rush, A. John; Fava, Maurizio; Breiter, Hans; Macdonald, Marcy; Gusella, James

    2011-01-01

    Objective Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington’s disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established. Method This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression. Results CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats. Conclusions In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles. PMID:20360314

  4. Human leukocyte antigen haplotype phasing by allele-specific enrichment with peptide nucleic acid probes

    PubMed Central

    Murphy, Nicholas M; Pouton, Colin W; Irving, Helen R

    2014-01-01

    Targeted capture of large fragments of genomic DNA that enrich for human leukocyte antigen (HLA) system haplotypes has utility in haematopoietic stem cell transplantation. Current methods of HLA matching are based on inference or familial studies of inheritance; and each approach has its own inherent limitations. We have designed and tested a probe–target-extraction method for capturing specific HLA haplotypes by hybridization of peptide nucleic acid (PNA) probes to alleles of the HLA-DRB1 gene. Short target fragments contained in plasmids were initially used to optimize the method followed by testing samples of genomic DNA from human subjects with preselected HLA haplotypes and obtained approximately 10% enrichment for the specific haplotype. When performed with high-molecular-weight genomic DNA, 99.0% versus 84.0% alignment match was obtained for the specific haplotype probed. The allele-specific target enrichment that we obtained can facilitate the elucidation of haplotypes between the 65 kb separating the HLA-DRB1 and the HLA-DQA1 genes, potentially spanning a total distance of at least 130 kb. Allele-specific target enrichment with PNA probes is a straightforward technique that has the capability to improve the resolution of DNA and whole genome sequencing technologies by allowing haplotyping of enriched DNA and crucially, retaining the DNA methylation profile. PMID:24936514

  5. Genetic variability and distribution of mating type alleles in field populations of Leptosphaeria maculans from France.

    PubMed

    Gout, Lilian; Eckert, Maria; Rouxel, Thierry; Balesdent, Marie-Hélène

    2006-01-01

    Leptosphaeria maculans is the most ubiquitous fungal pathogen of Brassica crops and causes the devastating stem canker disease of oilseed rape worldwide. We used minisatellite markers to determine the genetic structure of L. maculans in four field populations from France. Isolates were collected at three different spatial scales (leaf, 2-m2 field plot, and field) enabling the evaluation of spatial distribution of the mating type alleles and of genetic variability within and among field populations. Within each field population, no gametic disequilibrium between the minisatellite loci was detected and the mating type alleles were present at equal frequencies. Both sexual and asexual reproduction occur in the field, but the genetic structure of these populations is consistent with annual cycles of randomly mating sexual reproduction. All L. maculans field populations had a high level of gene diversity (H = 0.68 to 0.75) and genotypic diversity. Within each field population, the number of genotypes often was very close to the number of isolates. Analysis of molecular variance indicated that >99.5% of the total genetic variability was distributed at a small spatial scale, i.e., within 2-m2 field plots. Population differentiation among the four field populations was low (GST < 0.02), suggesting a high degree of gene exchange between these populations. The high gene flow evidenced here in French populations of L. maculans suggests a rapid countrywide diffusion of novel virulence alleles whenever novel resistance sources are used. PMID:16391041

  6. Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models

    PubMed Central

    Osborne, Melissa; Gomez, Daniel; Feng, Zhihua; McEwen, Corissa; Beltran, Jose; Cirillo, Kim; El-Khodor, Bassem; Lin, Ming-Yi; Li, Yun; Knowlton, Wendy M.; McKemy, David D.; Bogdanik, Laurent; Butts-Dehm, Katherine; Martens, Kimberly; Davis, Crystal; Doty, Rosalinda; Wardwell, Keegan; Ghavami, Afshin; Kobayashi, Dione; Ko, Chien-Ping; Ramboz, Sylvie; Lutz, Cathleen

    2012-01-01

    A number of mouse models for spinal muscular atrophy (SMA) have been genetically engineered to recapitulate the severity of human SMA by using a targeted null mutation at the mouse Smn1 locus coupled with the transgenic addition of varying copy numbers of human SMN2 genes. Although this approach has been useful in modeling severe SMA and very mild SMA, a mouse model of the intermediate form of the disease would provide an additional research tool amenable for drug discovery. In addition, many of the previously engineered SMA strains are multi-allelic by design, containing a combination of transgenes and targeted mutations in the homozygous state, making further genetic manipulation difficult. A new genetic engineering approach was developed whereby variable numbers of SMN2 sequences were incorporated directly into the murine Smn1 locus. Using combinations of these alleles, we generated an allelic series of SMA mouse strains harboring no, one, two, three, four, five, six or eight copies of SMN2. We report here the characterization of SMA mutants in this series that displayed a range in disease severity from embryonic lethal to viable with mild neuromuscular deficits. PMID:22802075

  7. German and British labour law in a European context following European Union enlargement 

    E-print Network

    Zahn, Rebecca Lisa

    2011-07-01

    This thesis examines and compares German and British trade union responses in a European context following the recent European enlargements which are unprecedented in the history of the European Union. In terms of labour ...

  8. Homozygosity, inbreeding and health in European populations 

    E-print Network

    McQuillan, Ruth

    2009-10-14

    Inbreeding results in increased levels of homozygosity for deleterious recessive alleles, leading to increased incidence of monogenic disease in inbred families. It has also been suggested that inbreeding increases the ...

  9. Comprehensive Genotyping in Two Homogeneous Graves' Disease Samples Reveals Major and Novel HLA Association Alleles

    PubMed Central

    Chen, Pei-Lung; Chang, Chien-Ching; Chang, Su-Wei; Hsieh, Hsin-Yi; Lin, Marie; Yang, Wei-Shiung; Chang, Tien-Chun

    2011-01-01

    Background Graves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians. Methodology/Principal Findings We conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR] ?=?1.33, Bonferroni corrected combined P [PBc] ?=?1.17×10?2), DPB1*05:01 (OR ?=?2.34, PBc?=?2.58×10?10), DQB1*03:02 (OR ?=?0.62, PBc ?=?1.97×10?2), DRB1*15:01 (OR ?=?1.68, PBc?=?1.22×10?2) and DRB1*16:02 (OR ?=?2.63, PBc ?=?1.46×10?5) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk. Conclusions/Significance These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation. PMID:21307958

  10. Correlation analysis of severe aplastic anemia immunosuppressive therapy and human leukocyte antigen alleles in pediatric patients

    PubMed Central

    FU, RU-TING; XUE, HONG-MAN; ZHANG, BI-HONG; WANG, JIAN; LIN, SHAO-FEN; CHEN, CHUN

    2015-01-01

    The aim of the present study was to investigate the correlation between the efficacy of immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA) and human leukocyte antigen (HLA) alleles. The polymerase chain reaction-sequence based typing high-resolution genotyping method was used to profile the HLA alleles of 115 SAA cases that were treated with rabbit-antithymocyte globulin (r-ATG) + cyclosporine (CsA) immunosuppressive therapy and 222 normal control subjects. The aim was to compare the frequency distribution of HLA alleles among the IST-effective group, the IST-ineffective group and the healthy control group. The results showed that the gene frequencies (GFs) of HLA-B*15:02, B*40:02, B*48:01, DRB1*09:01, C*01:02, C*03:04, DQB1*03:03 and DQB1*06:02 in the IST-effective group were significantly higher compared with those in the healthy control group, with a statistically significant difference. The GFs of HLA-B*15:11, B*38:01, B*39:05, DRB1*15:01, C*01:02 and C*08:22 in the IST-ineffective group were significantly increased compared with those in the healthy control group, with a statistically significant difference. The gene frequency of HLA-A*29:01 in the IST-effective group was significantly reduced compared with that in the IST-ineffective group, and the difference was statistically significant. In summary, IST efficacy in children with SAA that express the HLA-B*15:02, B*40:02, B*48:01, DRB1*09:01, C*01:02, C*03:04, DQB1*03:03 and DQB1*06:02 alleles may be superior, while the efficacy may be mitigated in children with SAA who express HLA-A*29:01, B*15:11, B*38:01, B*39:05, DRB1*15:01, C*01:02, C*08:22 alleles. PMID:26668647

  11. Molecular and biochemical characterization of puroindoline a and b alleles in Chinese landraces and historical cultivars.

    PubMed

    Chen, F; He, Z H; Xia, X C; Xia, L Q; Zhang, X Y; Lillemo, M; Morris, C F

    2006-02-01

    Kernel hardness that is conditioned by puroindoline genes has a profound effect on milling, baking and end-use quality of bread wheat. In this study, 219 landraces and 166 historical cultivars from China and 12 introduced wheats were investigated for their kernel hardness and puroindoline alleles, using molecular and biochemical markers. The results indicated that frequencies of soft, mixed and hard genotypes were 42.7, 24.3, and 33.0%, respectively, in Chinese landraces and 45.2, 13.9, and 40.9% in historical cultivars. The frequencies of PINA null, Pinb-D1b and Pinb-D1p genotypes were 43.8, 12.3, and 39.7%, respectively, in hard wheat of landraces, while 48.5, 36.8, and 14.7%, respectively, in historical hard wheats. A new Pinb-D1 allele, designated Pinb-D1t, was identified in two landraces, Guangtouxianmai and Hongmai from the Guizhou province, with the characterization of a glycine to arginine substitution at position 47 in the coding region of Pinb gene. Surprisingly, a new Pina-D1 allele, designated Pina-D1m, was detected in the landrace Hongheshang, from the Jiangsu province, with the characterization of a proline to serine substitution at position 35 in the coding region of Pina gene; it was the first novel mutation found in bread wheat, resulting in a hard endosperm with PINA expression. Among the PINA null genotypes, an allele designed as Pina-D1l, was detected in five landraces with a cytosine deletion at position 265 in Pina locus; while another novel Pina-D1 allele, designed as Pina-D1n, was identified in six landraces, with the characterization of an amino acid change from tryptophan-43 to a 'stop' codon in the coding region of Pina gene. The study of puroindoline polymorphism in Chinese wheat germplasm could provide useful information for the further understanding of the molecular basis of kernel hardness in bread wheat. PMID:16344983

  12. Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

    PubMed Central

    Wu, Ying; Waite, Lindsay L.; Jackson, Anne U.; Sheu, Wayne H-H.; Buyske, Steven; Absher, Devin; Arnett, Donna K.; Boerwinkle, Eric; Bonnycastle, Lori L.; Carty, Cara L.; Cheng, Iona; Cochran, Barbara; Croteau-Chonka, Damien C.; Dumitrescu, Logan; Eaton, Charles B.; Franceschini, Nora; Guo, Xiuqing; Henderson, Brian E.; Hindorff, Lucia A.; Kim, Eric; Kinnunen, Leena; Komulainen, Pirjo; Lee, Wen-Jane; Le Marchand, Loic; Lin, Yi; Lindström, Jaana; Lingaas-Holmen, Oddgeir; Mitchell, Sabrina L.; Narisu, Narisu; Robinson, Jennifer G.; Schumacher, Fred; Stan?áková, Alena; Sundvall, Jouko; Sung, Yun-Ju; Swift, Amy J.; Wang, Wen-Chang; Wilkens, Lynne; Wilsgaard, Tom; Young, Alicia M.; Adair, Linda S.; Ballantyne, Christie M.; B?žková, Petra; Chakravarti, Aravinda; Collins, Francis S.; Duggan, David; Feranil, Alan B.; Ho, Low-Tone; Hung, Yi-Jen; Hunt, Steven C.; Hveem, Kristian; Juang, Jyh-Ming J.; Kesäniemi, Antero Y.; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A.; Lee, I-Te; Leppert, Mark F.; Matise, Tara C.; Moilanen, Leena; Njølstad, Inger; Peters, Ulrike; Quertermous, Thomas; Rauramaa, Rainer; Rotter, Jerome I.; Saramies, Jouko; Tuomilehto, Jaakko; Uusitupa, Matti; Wang, Tzung-Dau; Mohlke, Karen L.

    2013-01-01

    Genome-wide association studies (GWAS) have identified ?100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n?=?6,832), East Asian (n?=?9,449), and European (n?=?10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10?4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies. PMID:23555291

  13. Genetic differentiation among natural European populations of Atlantic salmon, Salmo salar L., from drainages of the Atlantic Ocean.

    PubMed

    Blanco, G; Sanchez, J A; Vazquez, E; Rubio, J; Utter, F M

    1992-01-01

    Previously published allelic frequencies at four polymorphic protein coding loci were used as a basis for examining genetic relationships among 19 European populations of Atlantic salmon, Salmo salar L.--exclusive of Baltic drainages--from the Barents Sea to Spain. The data did not support a model of distinct ancestral (e.g. Boreal and Celtic) origins, but were consistent with all populations descending from a single ancestral group within this region with genetically diverged populations drawn together through limited local migrations. PMID:1570892

  14. The dynamic influence of the DRB1*1101 allele on the resistance of sheep to experimental Teladorsagia circumcincta infection

    E-print Network

    Hassan, Musa A.

    Suffolk sheep carrying the DRB1*1101 (previously referred to as-DRB1*0203 or G2) allele have been reported to show increased resistance to natural Teladorsagia circumcincta infection compared to non-carriers. The objective ...

  15. Comprehensive analysis of imprinted genes in maize reveals allelic variation for imprinting and limited conservation with other species

    E-print Network

    Waters, Amanda J.

    In plants, a subset of genes exhibit imprinting in endosperm tissue such that expression is primarily from the maternal or paternal allele. Imprinting may arise as a consequence of mechanisms for silencing of transposons ...

  16. Better memory functioning associated with higher total and LDL cholesterol levels in very elderly subjects without the APOE4 allele

    PubMed Central

    West, Rebecca; Beeri, Michal Schnaider; Schmeidler, James; Hannigan, Christine M.; Angelo, Gary; Grossman, Hillel T.; Rosendorff, Clive; Silverman, Jeremy M.

    2008-01-01

    Objective To examine the association of cholesterol with cognitive functioning in oldest old community dwelling individuals with and without the APOE4 allele. Method 185 non-demented community dwelling individuals (? 85) were assessed with a broad neuropsychological battery. Bloods were drawn to assess total, LDL, and HDL cholesterol, as well as for APOE genotyping. Results In contrast to our expectations, high total cholesterol and high LDL cholesterol were associated with higher memory scores for non-carriers of the APOE4 allele. No significant associations between cognitive performance and lipid profile were found for carriers of the APOE4 allele. Conclusions In oldest old non-demented non-carriers of the APOE4 allele, high cholesterol is associated with better memory function. Further examination of the role of APOE genotype on the association between cholesterol and cognitive performance, especially in the oldest old, is warranted. PMID:18757771

  17. nature biotechnology volume 30 number 4 april 2012 333 converted into homozygous parental breeding lines, as desirable allele

    E-print Network

    Walsworth, Ronald L.

    lines, as desirable allele combinations are lost through recombination during meiosis. That obstacle has. The pol- len was used to generate reverse-breeding haploids from which fertile double haploids were grown

  18. alpha 1-Antichymotrypsin as a risk modifier for late-onset Alzheimer's disease in Japanese apolipoprotein E epsilon 4 allele carriers.

    PubMed

    Yoshiiwa, A; Kamino, K; Yamamoto, H; Kobayashi, T; Imagawa, M; Nonomura, Y; Yoneda, H; Sakai, T; Nishiwaki, Y; Sato, N; Rakugi, H; Miki, T; Ogihara, T

    1997-07-01

    In the Japanese population, sporadic late-onset Alzheimer's disease (LOAD) cases had significantly higher frequencies of the A allele of alpha 1-antichymotrypsin (ACT) gene as well as the epsilon 4 allele of apolipoprotein E (APOE) gene than controls. The odds ratio for LOAD in APOE4 carriers with the ACT-A allele was more than six times that in APOE4 carriers without the ACT-A allele (21.1 vs 3.2). These results indicate that the ACT-A allele is a risk modifier for LOAD in APOE4 carriers. PMID:9225693

  19. Association of the apolipoprotein E {epsilon}4 allele with clinical subtypes of autopsy-confirmed Alzheimer`s Disease

    SciTech Connect

    Zubenko, G.S.; Stiffler, S.; Kopp, U.

    1994-09-15

    Consistent with previous reports, we observed a significant association of the APOE {epsilon}4 allele with Alzheimer`s Disease (AD) in a series of 91 autopsy-confirmed cases. The {epsilon}4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 {+-} 0.07), although the {epsilon}4 allele frequency in the AD cases with a negative family history (0.38 {+-} 0.05) remained significantly greater than that for the non-AD control group (0.13 {+-} 0.03). A similar increase in {epsilon}4 allele frequency (0.54 {+-} 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.35 {+-} 0.04). Contrary to previous reports, no effect of the dosage of the {epsilon}4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of {epsilon}4 and atherosclerosis, the {epsilon}4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of {epsilon}4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the {epsilon}4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an {epsilon}4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the {epsilon}4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE {epsilon}4 allele. 22 refs., 2 figs., 5 tabs.

  20. European Union a New Babylon?

    NASA Astrophysics Data System (ADS)

    Mesch, F.

    2010-07-01

    The growing European Union faces growing problems in personal communication. These problems cannot be overcome only by more language courses in school. As important is a better mutual knowledge of the culture of other countries, a knowledge that can be gained only by a personal, professional stay in foreign countries. On university level, such stays are best organized by networks connecting European universities. In the broad field of measurement, this IMEKO symposium might offer a unique forum to thoroughly discuss structure and realization of such a network with all interested colleagues.