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Sample records for ala12 allele carriers

  1. Is the Ala12 variant of the PPARG gene an "unthrifty allele"?

    PubMed Central

    Ruiz-Narvaez, E

    2005-01-01

    Background: The thrifty genotype hypothesis proposes that genetic susceptibility to type 2 diabetes results from the positive selection of "thrifty" alleles in the past. A corollary of this hypothesis is that genetic variants protecting against the development of diabetes are "unthrifty" and thus subject to negative selection during human evolution. Methods: It was assessed whether age estimates of the diabetes protective PPARG Ala12 allele indicate effects of natural selection. Based on published data from four populations, the date of origin of the diabetes protective PPARG Ala12 variant was estimated using both allele frequency and linkage disequilibrium (LD) with the C1431T single nucleotide polymorphism in exon 6 of the PPARG gene. Results: The best LD based estimate of the age of the Ala12 allele gave an average of ∼32 000 years with a maximum upper bound of ∼58 000 years. Assuming a population with a growth rate of r = 0.01 per generation, the frequency based estimate of the age of the Ala12 variant gave an average of ∼27 000 years with a maximum upper bound of ∼42 000 years. Discussion: The similarity of both time estimates is consistent with selective equivalence of the diabetes protective PPARG Ala12 allele and the diabetes susceptible PPARG Pro12 allele. PMID:15994875

  2. 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.

  3. 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.

  4. Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles.

    PubMed

    Boone, Philip M; Campbell, Ian M; Baggett, Brett C; Soens, Zachry T; Rao, Mitchell M; Hixson, Patricia M; Patel, Ankita; Bi, Weimin; Cheung, Sau Wai; Lalani, Seema R; Beaudet, Arthur L; Stankiewicz, Pawel; Shaw, Chad A; Lupski, James R

    2013-09-01

    Over 1200 recessive disease genes have been described in humans. The prevalence, allelic architecture, and per-genome load of pathogenic alleles in these genes remain to be fully elucidated, as does the contribution of DNA copy-number variants (CNVs) to carrier status and recessive disease. We mined CNV data from 21,470 individuals obtained by array-comparative genomic hybridization in a clinical diagnostic setting to identify deletions encompassing or disrupting recessive disease genes. We identified 3212 heterozygous potential carrier deletions affecting 419 unique recessive disease genes. Deletion frequency of these genes ranged from one occurrence to 1.5%. When compared with recessive disease genes never deleted in our cohort, the 419 recessive disease genes affected by at least one carrier deletion were longer and located farther from known dominant disease genes, suggesting that the formation and/or prevalence of carrier CNVs may be affected by both local and adjacent genomic features and by selection. Some subjects had multiple carrier CNVs (307 subjects) and/or carrier deletions encompassing more than one recessive disease gene (206 deletions). Heterozygous deletions spanning multiple recessive disease genes may confer carrier status for multiple single-gene disorders, for complex syndromes resulting from the combination of two or more recessive conditions, or may potentially cause clinical phenotypes due to a multiply heterozygous state. In addition to carrier mutations, we identified homozygous and hemizygous deletions potentially causative for recessive disease. We provide further evidence that CNVs contribute to the allelic architecture of both carrier and recessive disease-causing mutations. Thus, a complete recessive carrier screening method or diagnostic test should detect CNV alleles.

  5. Immune-mediated disorders among women carriers of fragile X premutation alleles.

    PubMed

    Winarni, Tri Indah; Chonchaiya, Weerasak; Sumekar, Tanjung Ayu; Ashwood, Paul; Morales, Guadalupe Mendoza; Tassone, Flora; Nguyen, Danh V; Faradz, Sultana M H; Van de Water, Judy; Cook, Kylee; Hamlin, Alyssa; Mu, Yi; Hagerman, Paul J; Hagerman, Randi J

    2012-10-01

    The relative risk of immune-mediated disorders (IMDs) among women carriers of premutation alleles is estimated by a survey for IMDs among 344 carrier women (age 19-81 years; mean 46.35 and SD 12.60) and 72 controls (age 18-87 years; mean 52.40 and SD 15.40). One hundred fifty four (44.77%) women carrier had at least one IMD, as did 20 controls (27.78%). Among women carriers, autoimmune thyroid disorder was the most common (24.4%), then fibromyalgia (10.2%), irritable bowel syndrome (IBS; 9.9%), Raynaud's phenomenon (7.6%), rheumatoid arthritis (RA; 3.8%), Sjögren syndrome (2.6%), systemic lupus erythematosus (SLE; 2.03%), multiple sclerosis (1.74%). Of 55 carriers age 40 or older with FXTAS, 72.73% had at least one IMD, compared to 46.54% of those without FXTAS (n = 159), and 31.58% of controls (n = 57). The estimated odds ratio (OR) for IMD is 2.6 (95% CI 1.2-5.6, P = 0.015) for women with FXTAS relative to those without FXTAS; the likelihood of IMD in carriers without or with FXTAS was also significantly higher than for controls (OR 2.1, 95% CI 1.1-4.2, P = 0.034; OR 5.5, 95% CI 2.4-12.5, P < 0.001, respectively). Similarly, the odds of having an IMD among carriers with FXPOI is about 2.4 times higher when compared to carriers without FXPOI (95% CI 1.1-5.0; P = 0.021). The likelihood of IMD in carriers with or without FXPOI is greater (OR 2.4, 95% CI 1.1-5.0; P = 0.021) compared to that of controls.

  6. A FDG-PET Study of Metabolic Networks in Apolipoprotein E ε4 Allele Carriers.

    PubMed

    Yao, Zhijun; Hu, Bin; Zheng, Jiaxiang; Zheng, Weihao; Chen, Xuejiao; Gao, Xiang; Xie, Yuanwei; Fang, Lei

    2015-01-01

    Recently, some studies have applied the graph theory in brain network analysis in Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). However, relatively little research has specifically explored the properties of the metabolic network in apolipoprotein E (APOE) ε4 allele carriers. In our study, all the subjects, including ADs, MCIs and NCs (normal controls) were divided into 165 APOE ε4 carriers and 165 APOE ε4 noncarriers. To establish the metabolic network for all brain regions except the cerebellum, cerebral glucose metabolism data obtained from FDG-PET (18F-fluorodeoxyglucose positron emission tomography) were segmented into 90 areas with automated anatomical labeling (AAL) template. Then, the properties of the networks were computed to explore the between-group differences. Our results suggested that both APOE ε4 carriers and noncarriers showed the small-world properties. Besides, compared with APOE ε4 noncarriers, the carriers showed a lower clustering coefficient. In addition, significant changes in 6 hub brain regions were found in between-group nodal centrality. Namely, compared with APOE ε4 noncarriers, significant decreases of the nodal centrality were found in left insula, right insula, right anterior cingulate, right paracingulate gyri, left cuneus, as well as significant increases in left paracentral lobule and left heschl gyrus in APOE ε4 carriers. Increased local short distance interregional correlations and disrupted long distance interregional correlations were found, which may support the point that the APOE ε4 carriers were more similar with AD or MCI in FDG uptake. In summary, the organization of metabolic network in APOE ε4 carriers indicated a less optimal pattern and APOE ε4 might be a risk factor for AD.

  7. Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

    PubMed Central

    Bowman, Caitlyn E.; Hartung, Thomas

    2016-01-01

    Glucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. PMID:27215380

  8. Frequencies of HKαα and anti-HKαα Alleles in Chinese Carriers of Silent Deletional α-Thalassemia.

    PubMed

    Wu, Man-Yu; Li, Jian; Li, Shu-Chen; Li, Yan; Li, Dong-Zhi

    2015-01-01

    The HKαα (HongKongαα) allele is an unusual rearrangement of the α-globin gene cluster containing both the -α(3.7) (rightward) and ααα(anti 4.2) crossover deletion/duplication. The anti-HKαα (anti-HongKongαα) allele is the reciprocal product containing both the -α(4.2) (leftward) and ααα(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 -α(3.7) and -α(4.2) deletions of α-thalassemia (α-thal). Because the HKαα and anti-HKαα alleles also contain the single α-globin gene deletion, individuals with these alleles would be misdiagnosed as -α(3.7) or -α(4.2) carriers. This would likely produce misleading or incorrect information in genetic counseling. In this study, we investigated the HKαα and anti-HKαα alleles in Chinese carriers of silent deletional α-thal, and reported their frequencies to be 2.27 and 0.35% in -α(3.7) and -α(4.2) carriers, respectively. Given the rarity of the HKαα and anti-HKαα alleles, a routine screening for these two rearrangements are unlikely to be necessary on most occasions.

  9. Rare alleles of the HRAS polymorphism do not modify the risk of breast or ovarian cancer in BRCA1 carriers

    SciTech Connect

    Phelan, C.; Tonin, P.; Lynch, H.T.

    1994-09-01

    The presence of one of the rare alleles of a minisatellite polymorphism at the HRAS locus on chromosome 11p15 has been associated with a roughly two-fold increase in the risk of breast cancer. The BRCA1 gene on chromosome 17q12-21 is responsible for the majority of the families with the breast-ovarian cancer syndrome. It is estimated that 87% of BRCA1 carriers will be affected with breast cancer by age 70. The relative risk for premenopausal breast cancer in carriers, compared to non-carriers, is roughly 100. Because of the wide range in ages of onset of cancer among BRCA1 carriers, it is likely that additional factors modify the risk of cancer. The role of other modifying genetic loci has not been studied. Through haplotype analysis we have identified 199 female BRCA1 carriers above the age of 20 years in 25 linked families. 127 of these women have been diagnosed with cancer and 72 are currently healthy. DNA was available on 59 carriers. Each sample was typed for the HRAS polymorphism by PCR, using primers flanking the minisatellite. Rare alleles were identified in 18 carriers. The penetrance of the BRCA1 gene was not higher among those women who carried a rare HRAS allele (mean age of onset 49 years) than among those who carried two common alleles (mean age of onset 43 years) (p= 0.59; log rank test). Similar results were obtained for ovarian cancer. These data do not support the hypothesis that the HRAS locus modified the risk of cancer among carriers of mutations in BRCA1.

  10. Neuronal fiber bundle lengths in healthy adult carriers of the ApoE4 allele: A quantitative tractography DTI study

    PubMed Central

    Schofield, Peter R.; Lane, Elizabeth M.; Heaps, Jodi M.; Pierce, Kerrie D.; Cabeen, Ryan; Laidlaw, David H.; Akbudak, Erbil; Conturo, Thomas E.; Correia, Stephen; Paul, Robert H.

    2013-01-01

    The epsilon 4 (e4) isoform of apolipoprotein E (ApoE) is a known genetic risk factor for suboptimal brain health. Morphometry studies of brains with Alzheimer’s disease have reported significant alterations in temporal lobe brain structure of e4 carriers, yet it remains unclear if the presence of an e4 allele is associated with alterations in the microstructure of white matter fiber bundles in healthy populations. The present study used quantitative tractography based on diffusion tensor imaging (qtDTI) to examine the influence of the e4 allele on temporal lobe fiber bundle lengths (FBLs) in 64 healthy older adults with at least one e4 allele (carriers, N=23) versus no e4 allele (non-carriers, N=41). Subtests from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were also analyzed to examine memory performance between groups. Analyses revealed shorter FBLs in the left uncinate fasciculus (UF) (p=.038) of e4 carriers compared to non-carriers. By contrast, neither FBLs specific to the temporal lobe nor memory performances differed significantly between groups. Increased age correlated significantly with shorter FBL in the temporal lobe and UF, and with decreased performance on tests of memory. This is the first study to utilize qtDTI to examine relationships between FBL and ApoE genotype. Results suggest that FBL in the UF is influenced by the presence of an ApoE e4 allele (ApoE4) in healthy older adults. Temporal lobe FBLs, however, are more vulnerable to aging than the presence of an e4 allele. PMID:23475756

  11. Allele frequencies of three factor VIII gene polymorphisms in Iranian populations and their application in hemophilia A carrier detection.

    PubMed

    Azimifar, S Babak; Seyedna, S Yoosef; Zeinali, Sirous

    2006-05-01

    Hemophilia A is an X-linked recessive bleeding disorder caused by a quantitative or qualitative deficiency of blood coagulation factor VIII (FVIII). ARMS (amplification refractory mutation system) primers were designed to determine allele frequencies of three FVIII gene linked markers, IVS7 nt 27 G/A SNP, BclI/intron 18, and HindIII/intron 19 among 85 normal Iranian women from unrelated families. Then same method was applied to perform carrier detection for hemophilia A families. The allele frequencies of IVS7 nt 27 "G"/"A" allele, BclI "T"/"A" allele, and HindIII "C"/"T" allele among normal women were 0.88/0.12, 0.52/0.48, and 0.48/0.52, respectively. The three polymorphisms were found to be in strong linkage disequilibrium, which decreased the overall heterozygosity to 51%. Twenty-one women from 15 unrelated hemophilia A families were referred to us for hemophilia A carrier detection. Taking advantage of these three biallelic polymorphisms in conjunction with multiallelic St14 VNTR (locus DXS52), IVS13 (CA)n STR, and IVS22 (CA)n STR, carrier status was determined in 16 women (16/21 or 76% of the at-risk women) from 11 families (11/15 or 73% of the families). The used ARMS methods are rapid and can easily be applied in conjunction with other FVIII gene linked polymorphisms for indirect mutation detection of hemophilia A where they are informative.

  12. [VARIOUS ALLELES OF HSF HEAT-SHOCK TRANSCRIPTION FACTOR OF DROSOPHILA MELANOGASTER INCREASE VIABILITY OF ITS CARRIERS IN UNFAVORABLE ENVIRONMENTS].

    PubMed

    Weisman, N Ya; Evgen'ev, M B; Golubovsky, M D

    2015-01-01

    We found increased viability in heterozygous carriers of hsf heat shock transcription factor n comparison with wild type. The effect depends on temperature, sex and direction of crosses. Viability effect is more evident in conditions of soft temperature stress. The males are more sensitive. The maternal effect is observed: if hsf*allele came from mother, the viability effect is stronger. The survival curves of heterozygotes on hsf-1 and hsf-4 alleles are similar in spite of HSF-4 protein is slightly active on normal temperature.

  13. Comparison between subjects with long- and short-allele carriers in the BOLD signal within amygdala during emotional tasks

    NASA Astrophysics Data System (ADS)

    Hadi, Shamil; Siadat, Mohamad R.; Babajani-Feremi, Abbas

    2012-03-01

    Emotional tasks may result in a strong blood oxygen level-dependent (BOLD) signal in the amygdala in 5- HTTLRP short-allele. Reduced anterior cingulate cortex (ACC)-amygdala connectivity in short-allele provides a potential mechanistic account for the observed increase in amygdala activity. In our study, fearful and threatening facial expressions were presented to two groups of 12 subjects with long- and short-allele carriers. The BOLD signals of the left amygdala of each group were averaged to increase the signal-to-noise ratio. A Bayesian approach was used to estimate the model parameters to elucidate the underlying hemodynamic mechanism. Our results showed a positive BOLD signal in the left amygdala for short-allele individuals, and a negative BOLD signal in the same region for long-allele individuals. This is due to the fact that short-allele is associated with lower availability of serotonin transporter (5-HTT) and this leads to an increase of serotonin (5-HT) concentration in the cACC-amygdala synapse.

  14. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E; Aalfs, Cora M; Meijers-Heijboer, Hanne E J; van Asperen, Christi J; van Roozendaal, K E P; Hoogerbrugge, Nicoline; Collée, J Margriet; Kriege, Mieke; van der Luijt, Rob B; Peock, Susan; Frost, Debra; Ellis, Steve D; Platte, Radka; Fineberg, Elena; Evans, D Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J; Walker, Lisa; Porteous, Mary E; Kennedy, M John; Pathak, Harsh; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v O; Ejlertsen, Bent; Johannsson, Oskar Th; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Issacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Iganacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B; Karlan, Beth Y; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A; Beattie, Mary S; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B; Neuhausen, Susan L; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H; Mai, Phuong L; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D P; Gayther, Simon A; Simard, Jacques; Easton, Douglas F; Couch, Fergus J; Chenevix-Trench, Georgia

    2012-04-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

  15. Increased risk of the abdominal aortic aneurysm in carriers of the MTHFR 677T allele.

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Gabriel, Marcin; Zapalski, Stanisław; Pawlak, Andrzej L

    2003-01-01

    Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Several genetic, biochemical and environmental factors are recognized as relevant for the pathogenesis of AAA. We determined the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (C677T) in 63 patients with AAA and compared it to that in 75 subjects of the population sample. The frequencies of the C/C, C/T and T/T genotypes were 65%, 27%, and 8% in the population sample and 33%, 60%, and 6% in the patients. This corresponds to a 4.4-fold greater risk of AAA in subjects who have the 677C/T variant of MTHFR, as compared with those who are 677C/C (p < 0.0001; 95% CI=2.11-9.34). The frequency of allele MTHFR 677T in patients (0.37) was higher than in the population sample (0.21; p < 0.007). This association between the common allele of the MTHFR gene--MTHFR 677T--and the development of AAA suggests that elevated homocysteine (Hcy) may disturb the function of the aortic wall. The disturbance may involve enhancement of elastin degradation, the process enhanced by mild hyperhomocysteinemia in minipigs. The magnitude of this effect, which refers to the AAA patients unselected for familial occurrence, indicates that the disturbance of aortic wall physiology caused by the presence of the MTHFR 677T allele is greater than the effect of the earlier described allele disequilibrium at the polymorphic alleles of the PAI1 (plasminogen activator inhibitor 1) gene seen only in familial cases of AAA.

  16. Higher Brain Perfusion May Not Support Memory Functions in Cognitively Normal Carriers of the ApoE ε4 Allele Compared to Non-Carriers

    PubMed Central

    Zlatar, Zvinka Z.; Bischoff-Grethe, Amanda; Hays, Chelsea C.; Liu, Thomas T.; Meloy, M. J.; Rissman, Robert A.; Bondi, Mark W.; Wierenga, Christina E.

    2016-01-01

    Age-related changes in cerebral blood flow (CBF), which carries necessary nutrients to the brain, are associated with increased risk for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Whether the association between CBF and cognition is moderated by apolipoprotein E (ApoE) ε4 genotype, a known risk factor for AD, remains understudied, with most research focusing on exploring brain regions in which there are diagnostic group differences in CBF (i.e., cognitively normal vs. MCI vs. AD). This study measured resting CBF via arterial spin labeling (ASL) magnetic resonance imaging (MRI) and verbal memory functions using a composite score in 59 older adults with normal cognition (38 ε3; 21 ε4). Linear mixed effect models were employed to investigate if the voxel-wise relationship between verbal memory performance and resting CBF was modified by ApoE genotype. Results indicated that carriers of the ApoE ε4 allele display negative associations between verbal memory functions and CBF in medial frontal cortex, medial and lateral temporal cortex, parietal regions, insula, and the basal ganglia. Contrarily, ε3 carriers exhibited positive associations between verbal memory functions and CBF in medial frontal cortex, thalamus, insula, and basal ganglia. Findings suggest that higher CBF was associated with worse verbal memory functions in cognitively normal ε4 carriers, perhaps reflecting dysregulation within the neurovascular unit, which is no longer supportive of cognition. Results are discussed within the context of the vascular theory of AD risk. PMID:27445794

  17. Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele.

    PubMed

    Anders, Silke; Sack, Benjamin; Pohl, Anna; Münte, Thomas; Pramstaller, Peter; Klein, Christine; Binkofski, Ferdinand

    2012-04-01

    Patients with Parkinson's disease suffer from significant motor impairments and accompanying cognitive and affective dysfunction due to progressive disturbances of basal ganglia-cortical gating loops. Parkinson's disease has a long presymptomatic stage, which indicates a substantial capacity of the human brain to compensate for dopaminergic nerve degeneration before clinical manifestation of the disease. Neuroimaging studies provide evidence that increased motor-related cortical activity can compensate for progressive dopaminergic nerve degeneration in carriers of a single mutant Parkin or PINK1 gene, who show a mild but significant reduction of dopamine metabolism in the basal ganglia in the complete absence of clinical motor signs. However, it is currently unknown whether similar compensatory mechanisms are effective in non-motor basal ganglia-cortical gating loops. Here, we ask whether asymptomatic Parkin mutation carriers show altered patterns of brain activity during processing of facial gestures, and whether this might compensate for latent facial emotion recognition deficits. Current theories in social neuroscience assume that execution and perception of facial gestures are linked by a special class of visuomotor neurons ('mirror neurons') in the ventrolateral premotor cortex/pars opercularis of the inferior frontal gyrus (Brodmann area 44/6). We hypothesized that asymptomatic Parkin mutation carriers would show increased activity in this area during processing of affective facial gestures, replicating the compensatory motor effects that have previously been observed in these individuals. Additionally, Parkin mutation carriers might show altered activity in other basal ganglia-cortical gating loops. Eight asymptomatic heterozygous Parkin mutation carriers and eight matched controls underwent functional magnetic resonance imaging and a subsequent facial emotion recognition task. As predicted, Parkin mutation carriers showed significantly stronger activity in

  18. Ovarian Cancer Susceptibility Alleles and Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Ramus, Susan J.; Antoniou, Antonis C; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E.J.; van Asperen, Christi J.; van Roozendaal, K.E.P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D.P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P-trend = 1.8 × 10−4, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.6 × 10−4, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81–0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.1 × 10−4. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID:22253144

  19. Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype

    PubMed Central

    2012-01-01

    Background Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial. Methods Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females. Results The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers. Conclusions This is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the

  20. Identification of a novel pseudodeficiency allele in the GLB1 gene in a carrier of GM1 gangliosidosis.

    PubMed

    Gort, L; Santamaria, R; Grinberg, D; Vilageliu, L; Chabás, A

    2007-08-01

    The term 'pseudodeficiency' is used in lysosomal storage diseases to denote the situation in which individuals show greatly reduced enzyme activity but remain clinically healthy. Pseudodeficiencies have been reported for several lysosomal hydrolases. GM1 gangliosidosis is a rare autosomal recessive lysosomal storage disorder caused by beta-galactosidase hydrolase deficiency as a result of mutations in the GLB1 gene. Until now, two variants altering the beta-galactosidase activity have been described, p.Arg521Cys and p.Ser532Gly. Here we report the new variant p.Arg595Trp in the GLB1 gene, which markedly reduces beta-galactosidase activity when expressed in COS-1 cells. The variant was identified in the healthy father of a girl with GM1 gangliosidosis. He was a heterozygous compound with p.Arg595Trp in trans with one of the disease-causing mutations identified in his daughter; in leukocytes and plasma he showed lower beta-galactosidase activity than that observed in GM1 gangliosidosis carriers. As this family originated from the Basque Country in the north of Spain, we decided to analyse individuals of Basque and non-Basque origin, finding the p.Arg595Trp allele in 3.2% of Basque and in 0.8% of non-Basque alleles. The detection of the presence of alterations resulting in pseudodeficient activity in leukocytes and plasma is important for the correct diagnosis of GM1 gangliosidosis.

  1. Prevalence of carriers of premutation-size alleles of the FMR1 gene-and implications for the population genetics of the fragile X syndrome

    SciTech Connect

    Rousseau, F.; Rouillard, P.; Morel, M.L.

    1995-11-01

    The fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Fragile X premutations are not associated with any clinical phenotype but are at high risk of expanding to full mutations causing the disease when they are transmitted by a carrier woman. There is no reliable estimate of the prevalence of women who are carriers of fragile X premutations. We have screened 10,624 unselected women by Southern blot for the presence of FMR1 premutation alleles and have confirmed their size by PCR analysis. We found 41 carriers of alleles with 55-101 CGG repeats, a prevalence of 1/259 women (95% confidence interval 1/373-1/198). Thirty percent of these alleles carry an inferred haplotype that corresponds to the most frequent haplotype found in fragile X males and may indeed constitute premutations associated with a significant risk of expansion on transmission by carrier women. We identified another inferred haplotype that is rare in both normal and fragile X chromosomes but that is present on 13 (57%) of 23 chromosomes carrying FMR1 alleles with 53-64 CGG repeats. This suggests either (1) that this haplotype may be stable or (2) that the associated premutation-size alleles have not yet reached equilibrium in this population and that the incidence of fragile X syndrome may increase in the future. 42 refs., 3 figs., 4 tabs.

  2. DRD4 long allele carriers show heightened attention to high-priority items relative to low-priority items.

    PubMed

    Gorlick, Marissa A; Worthy, Darrell A; Knopik, Valerie S; McGeary, John E; Beevers, Christopher G; Maddox, W Todd

    2015-03-01

    Humans with seven or more repeats in exon III of the DRD4 gene (long DRD4 carriers) sometimes demonstrate impaired attention, as seen in attention-deficit hyperactivity disorder, and at other times demonstrate heightened attention, as seen in addictive behavior. Although the clinical effects of DRD4 are the focus of much work, this gene may not necessarily serve as a "risk" gene for attentional deficits, but as a plasticity gene where attention is heightened for priority items in the environment and impaired for minor items. Here we examine the role of DRD4 in two tasks that benefit from selective attention to high-priority information. We examine a category learning task where performance is supported by focusing on features and updating verbal rules. Here, selective attention to the most salient features is associated with good performance. In addition, we examine the Operation Span (OSPAN) task, a working memory capacity task that relies on selective attention to update and maintain items in memory while also performing a secondary task. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. These results suggest that DRD4 may serve as a "plasticity" gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context.

  3. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.

    PubMed

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Neuhausen, Susan L; Ding, Yuan Chun; Rebbeck, Timothy R; Weitzel, Jeffrey N; Lynch, Henry T; Isaacs, Claudine; Ganz, Patricia A; Tomlinson, Gail; Olopade, Olufunmilayo I; Couch, Fergus J; Wang, Xianshu; Lindor, Noralane M; Pankratz, Vernon S; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L; Greene, Mark H; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Birk Jensen, Uffe; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E J; Blok, Marinus J; Aalfs, Cora M; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J; Porteous, Mary E; Walker, Lisa; Kennedy, M John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L; Daly, Mary B; Terry, Mary B; John, Esther M; Buys, Saundra S; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V O; Jønson, Lars; Agnarsson, Bjarni A; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C; Wakeley, Katie; Boggess, John F; Basil, Jack; Schwartz, Peter E; Blank, Stephanie V; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F

    2010-12-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  4. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    PubMed Central

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall’Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E.J.; Blok, Marinus J; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alex; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jønson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers. PMID:21118973

  5. Temporal dynamics of attentional selection in adult male carriers of the fragile X premutation allele and adult controls

    PubMed Central

    Wong, Ling M.; Tassone, Flora; Rivera, Susan M.; Simon, Tony J.

    2015-01-01

    Carriers of the fragile X premutation allele (fXPCs) have an expanded CGG trinucleotide repeat size within the FMR1 gene and are at increased risk of developing fragile x-associated tremor/ataxia syndrome (FXTAS). Previous research has shown that male fXPCs with FXTAS exhibit cognitive decline, predominantly in executive functions such as inhibitory control and working memory. Recent evidence suggests fXPCs may also exhibit impairments in processing temporal information. The attentional blink (AB) task is often used to examine the dynamics of attentional selection, but disagreements exist as to whether the AB is due to excessive or insufficient attentional control. In this study, we used a variant of the AB task and neuropsychological testing to explore the dynamics of attentional selection, relate AB performance to attentional control, and determine whether fXPCs exhibited temporal and/or attentional control impairments. Participants were adult male fXPCs, aged 18–48 years and asymptomatic for FXTAS (n = 19) and age-matched male controls (n = 20). We found that fXPCs did not differ from controls in the AB task, indicating that the temporal dynamics of attentional selection were intact. However, they were impaired in the letter-number sequencing task, a test of executive working memory. In the combined fXPC and control group, letter-number sequencing performance correlated positively with AB magnitude. This finding supports models that posit the AB is due to excess attentional control. In our two-pronged analysis approach, in control participants we replicated a previously observed effect and demonstrated that it persists under more stringent theoretical constraints, and we enhance our understanding of fXPCs by demonstrating that at least some aspects of temporal processing may be spared. PMID:25698960

  6. Negative BOLD response and serotonin concentration within rostral subgenual portion of the anterior cingulate cortex for long-allele carriers during perceptual processing of emotional tasks

    NASA Astrophysics Data System (ADS)

    Hadi, Shamil M.; Siadat, Mohamad R.; Babajani-Feremi, Abbas

    2012-03-01

    We investigated the effect of synaptic serotonin concentration on hemodynamic responses. The stimuli paradigm involved the presentation of fearful and threatening facial expressions to a set of 24 subjects who were either5HTTLPR long- or short-allele carriers (12 of each type in each group). The BOLD signals of the rACC from subjects of each group were averaged to increase the signal-to-noise ratio. We used a Bayesian approach to estimate the parameters of the underlying hemodynamic model. Our results, during this perceptual processing of emotional task, showed a negative BOLD signal in the rACC in the subjects with long-alleles. In contrast, the subjects with short-alleles showed positive BOLD signals in the rACC. These results suggest that high synaptic serotonin concentration in the rACC inhibits neuronal activity in a fashion similar to GABA, and a consequent negative BOLD signal ensues.

  7. Carnitine Palmitoyltransferase 1B 531K Allele Carriers Sustain a Higher Respiratory Quotient after Aerobic Exercise, but β3-Adrenoceptor 64R Allele Does Not Affect Lipolysis: A Human Model

    PubMed Central

    Gómez-Gómez, Eduardo; Ríos-Martínez, Martín Efrén; Castro-Rodríguez, Elena Margarita; Del-Toro-Equíhua, Mario; Ramírez-Flores, Mario; Delgado-Enciso, Ivan; Pérez-Huitimea, Ana Lilia; Baltazar-Rodríguez, Luz Margarita; Velasco-Pineda, Gilberto; Muñiz-Murguía, Jesús

    2014-01-01

    Carnitine palmitoyltransferase IB (CPT1B) and adrenoceptor beta-3 (ADRB3) are critical regulators of fat metabolism. CPT1B transports free acyl groups into mitochondria for oxidation, and ADRB3 triggers lipolysis in adipocytes, and their respective polymorphisms E531K and W64R have been identified as indicators of obesity in population studies. It is therefore important to understand the effects of these mutations on ADRB3 and CPT1B function in adipose and skeletal muscle tissue, respectively. This study aimed to analyze the rate of lipolysis of plasma indicators (glycerol, free fatty acids, and beta hydroxybutyrate) and fat oxidation (through the non-protein respiratory quotient). These parameters were measured in 37 participants during 30 min of aerobic exercise at approximately 62% of maximal oxygen uptake, followed by 30 min of recovery. During recovery, mean respiratory quotient values were higher in K allele carriers than in non-carriers, indicating low post-exercise fatty acid oxidation rates. No significant differences in lipolysis or lipid oxidation were observed between R and W allele carriers of ADRB3 at any time during the aerobic load. The substitution of glutamic acid at position 531 by lysine in the CPT1B protein decreases the mitochondrial beta-oxidation pathway, which increases the non-protein respiratory quotient value during recovery from exercise. This may contribute to weight gain or reduced weight-loss following exercise. PMID:24905907

  8. Carnitine palmitoyltransferase 1B 531K allele carriers sustain a higher respiratory quotient after aerobic exercise, but β3-adrenoceptor 64R allele does not affect lipolysis: a human model.

    PubMed

    Gómez-Gómez, Eduardo; Ríos-Martínez, Martín Efrén; Castro-Rodríguez, Elena Margarita; Del-Toro-Equíhua, Mario; Ramírez-Flores, Mario; Delgado-Enciso, Ivan; Pérez-Huitimea, Ana Lilia; Baltazar-Rodríguez, Luz Margarita; Velasco-Pineda, Gilberto; Muñiz-Murguía, Jesús

    2014-01-01

    Carnitine palmitoyltransferase IB (CPT1B) and adrenoceptor beta-3 (ADRB3) are critical regulators of fat metabolism. CPT1B transports free acyl groups into mitochondria for oxidation, and ADRB3 triggers lipolysis in adipocytes, and their respective polymorphisms E531K and W64R have been identified as indicators of obesity in population studies. It is therefore important to understand the effects of these mutations on ADRB3 and CPT1B function in adipose and skeletal muscle tissue, respectively. This study aimed to analyze the rate of lipolysis of plasma indicators (glycerol, free fatty acids, and beta hydroxybutyrate) and fat oxidation (through the non-protein respiratory quotient). These parameters were measured in 37 participants during 30 min of aerobic exercise at approximately 62% of maximal oxygen uptake, followed by 30 min of recovery. During recovery, mean respiratory quotient values were higher in K allele carriers than in non-carriers, indicating low post-exercise fatty acid oxidation rates. No significant differences in lipolysis or lipid oxidation were observed between R and W allele carriers of ADRB3 at any time during the aerobic load. The substitution of glutamic acid at position 531 by lysine in the CPT1B protein decreases the mitochondrial beta-oxidation pathway, which increases the non-protein respiratory quotient value during recovery from exercise. This may contribute to weight gain or reduced weight-loss following exercise.

  9. Tract Based Spatial Statistic Reveals No Differences in White Matter Microstructural Organization between Carriers and Non-Carriers of the APOE ɛ4 and ɛ2 Alleles in Young Healthy Adolescents.

    PubMed

    Dell'Acqua, Flavio; Khan, Wasim; Gottlieb, Natalie; Giampietro, Vincent; Ginestet, Cedric; Bouls, David; Newhouse, Steven; Dobson, Richard; Banaschewski, Tobias; Barker, Gareth J; Bokde, Arun L W; Büchel, Christian; Conrod, Patricia; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Heinz, Anreas; Lemaítre, Hervé; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Smolka, Michael N; Ströhle, Andreas; Gallinat, Jean; Westman, Eric; Schumann, Gunther; Lovestone, Simon; Simmons, Andrew

    2015-01-01

    The apolipoprotein E (APOE) ɛ4 allele is the best established genetic risk factor for Alzheimer's disease (AD) and has been previously associated with alterations in structural gray matter and changes in functional brain activity in healthy middle-aged individuals and older non-demented subjects. In order to determine the neural mechanism by which APOE polymorphisms affect white matter (WM) structure, we investigated the diffusion characteristics of WM tracts in carriers and non-carriers of the APOE ɛ4 and ɛ2 alleles using an unbiased whole brain analysis technique (Tract Based Spatial Statistics) in a healthy young adolescent (14 years) cohort. A large sample of healthy young adolescents (n = 575) were selected from the European neuroimaging-genetics IMAGEN study with available APOE status and accompanying diffusion imaging data. MR Diffusion data was acquired on 3T systems using 32 diffusion-weighted (DW) directions and 4 non-DW volumes (b-value = 1,300 s/mm² and isotropic resolution of 2.4×2.4×2.4  mm). No significant differences in WM structure were found in diffusion indices between carriers and non-carriers of the APOE ɛ4 and ɛ2 alleles, and dose-dependent effects of these variants were not established, suggesting that differences in WM structure are not modulated by the APOE polymorphism. In conclusion, our results suggest that microstructural properties of WM structure are not associated with the APOE ɛ4 and ɛ2 alleles in young adolescence, suggesting that the neural effects of these variants are not evident in 14-year-olds and may only develop later in life.

  10. Homozygous carriers of the TCF7L2 rs7903146 T-allele show altered postprandial response in triglycerides and triglyceride-rich lipoproteins

    PubMed Central

    Engelbrechtsen, L.; Hansen, T. H.; Mahendran, Y.; Pyl, P.; Andersson, E.; Jonsson, A.; Gjesing, A.; Linneberg, A.; Jørgensen, T.; Hansen, T.; Vestergaard, H.

    2017-01-01

    The TCF7L2 rs7903146 T-allele shows the strongest association with type 2 diabetes (T2D) among common gene variants. The aim of this study was to assess circulating levels of metabolites following a meal test in individuals carrying the high risk rs790346 TT genotype (cases) and low-risk CC genotype (controls). Sixty-two men were recruited based on TCF7L2 genotype, 31 were TT carriers and 31 were age- and BMI-matched CC carriers. All participants consumed a test meal after 12 hours of fasting. Metabolites were measured using proton nuclear magnetic resonance (NMR) spectroscopy. Metabolomic profiling of TCF7L2 carriers were performed for 141 lipid estimates. TT carriers had lower fasting levels of L-VLDL-L (total lipids in large very low density lipoproteins, p = 0.045), L-VLDL-CE (cholesterol esters in large VLDL, p = 0.03), and L-VLDL-C (total cholesterol in large VLDL, p = 0.045) compared to CC carriers. Additionally, TT carriers had lower postprandial levels of total triglycerides (TG) (q = 0.03), VLDL-TG (q = 0.05, including medium, small and extra small, q = 0.048, q = 0.0009, q = 0.04, respectively), HDL-TG (triglycerides in high density lipoproteins q = 0.037) and S-HDL-TG (q = 0.00003). In conclusion, TT carriers show altered postprandial triglyceride response, mainly influencing VLDL and HDL subclasses suggesting a genotype-mediated effect on hepatic lipid regulation. PMID:28220878

  11. Stressful life events increase aggression and alcohol use in young carriers of the GABRA2 rs279826/rs279858 A-allele.

    PubMed

    Kiive, Evelyn; Laas, Kariina; Vaht, Mariliis; Veidebaum, Toomas; Harro, Jaanus

    2017-02-23

    Research of GABRA2 gene in alcohol use and impulse control suggests its role in aggressive behaviour. The purpose of the present study was to examine the effects of GABRA2 genotype and stressful life events on aggressive behaviour, alcohol use frequency and occurrence of alcohol use disorder in a population representative sample of adolescents followed up from third grade to 25 years of age. The sample consisted of the younger cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study. Aggressive behaviour was rated with the activity scale of af Klinteberg, Illinois Bully Scale and Buss-Perry Aggression Questionnaire. Stressful life events and alcohol use were self-reported. Life history of aggression and lifetime occurrence of psychiatric disorders were estimated in a structured interview. The sample was genotyped for GABRA2 rs279826 and rs279858 polymorphisms that are in strong linkage disequilibrium and yielded very similar findings: Higher number of stressful life events reported at age 15 was associated with increased fighting in A-allele carriers, but not in GG homozygotes. At age 25, A-allele carriers with more stressful life events scored higher on physical aggression than those with less stress, and this was also observed regarding life history of aggression. A-allele carriers exposed to higher stress had consumed alcoholic beverages more frequently at age 15, and by age 25, they had alcohol use disorder with higher prevalence. The results of the present study suggest that the GABRA2 genotype interacts with stress in young people with impact on the development of alcohol use and aggressive behaviour.

  12. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

    PubMed

    Cox, David G; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H; Mai, Phuong L; Andrulis, Irene L; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S; Borg, Åke; Karlsson, Per; Askmalm, Marie Stenmark; Bustinza, Gisela Barbany; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Benítez, Javier; Hamann, Ute; Rookus, Matti A; van den Ouweland, Ans M W; Ausems, Margreet G E M; Aalfs, Cora M; van Asperen, Christi J; Devilee, Peter; Gille, Hans J J P; Peock, Susan; Frost, Debra; Evans, D Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Eisinger, François; Bressac de Paillerets, Brigitte; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C; Terry, Mary Beth; Singer, Christian F; Dressler, Anne-Catharina; Tea, Muy-Kheng; Hansen, Thomas V O; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C; Basil, Jack B; Blank, Stephanie; Toland, Amanda E; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A; Moysich, Kirsten B; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B; Neuhausen, Susan L; Ding, Yuan C; Couch, Fergus J; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M

    2011-12-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

  13. Allelic Variation in CXCL16 Determines CD3+ T Lymphocyte Susceptibility to Equine Arteritis Virus Infection and Establishment of Long-Term Carrier State in the Stallion

    PubMed Central

    Cook, R. Frank; Eberth, John; Chelvarajan, R. Lakshman; Artiushin, Sergey; Timoney, Peter J.

    2016-01-01

    Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a respiratory, systemic, and reproductive disease of horses and other equid species. Following natural infection, 10–70% of the infected stallions can become persistently infected and continue to shed EAV in their semen for periods ranging from several months to life. Recently, we reported that some stallions possess a subpopulation(s) of CD3+ T lymphocytes that are susceptible to in vitro EAV infection and that this phenotypic trait is associated with long-term carrier status following exposure to the virus. In contrast, stallions not possessing the CD3+ T lymphocyte susceptible phenotype are at less risk of becoming long-term virus carriers. A genome wide association study (GWAS) using the Illumina Equine SNP50 chip revealed that the ability of EAV to infect CD3+ T lymphocytes and establish long-term carrier status in stallions correlated with a region within equine chromosome 11. Here we identified the gene and mutations responsible for these phenotypes. Specifically, the work implicated three allelic variants of the equine orthologue of CXCL16 (EqCXCL16) that differ by four non-synonymous nucleotide substitutions (XM_00154756; c.715 A → T, c.801 G → C, c.804 T → A/G, c.810 G → A) within exon 1. This resulted in four amino acid changes with EqCXCL16S (XP_001504806.1) having Phe, His, Ile and Lys as compared to EqCXL16R having Tyr, Asp, Phe, and Glu at 40, 49, 50, and 52, respectively. Two alleles (EqCXCL16Sa, EqCXCL16Sb) encoded identical protein products that correlated strongly with long-term EAV persistence in stallions (P<0.000001) and are required for in vitro CD3+ T lymphocyte susceptibility to EAV infection. The third (EqCXCL16R) was associated with in vitro CD3+ T lymphocyte resistance to EAV infection and a significantly lower probability for establishment of the long-term carrier state (viral persistence) in the male reproductive tract. EqCXCL16Sa and Eq

  14. Meta-analysis of Methylenetetrahydrofolate reductase maternal gene in Down syndrome: increased susceptibility in women carriers of the MTHFR 677T allele.

    PubMed

    Victorino, D B; Godoy, M F; Goloni-Bertollo, E M; Pavarino, E C

    2014-08-01

    Because a number of data studies include some controversial results about Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Down syndrome (DS), we performed a meta-analysis to determine a more precise estimation of this association. Studies were searched on PubMed, EMBASE and Lilacs-Scielo, up to April 2013, and they were eligible if they included case mothers (DSM) that have gave birth to children with DS, and controls mothers (CM) that have gave birth to healthy children without chromosomal abnormality, syndrome or malformation. The combined odds ratio with 95% confidence intervals was calculated by fixed or random effects models to assess the strength of associations. Potential sources of heterogeneity between studies were evaluated using Q test and the I(2). Publication bias was estimated using Begg's test and Egger's linear regression test. Sensitivity analyses were performed by using allelic, dominant, recessive and codominant genetic models, Hardy-Weinberg equilibrium (HWE) and ethnicity. Twenty-two studies with 2,223 DSM and 2,807 CM were included for MTHFR C677T and 15 studies with 1,601 DSM and 1,849 CM were included for MTHFR A1298C. Overall analysis suggests an association of the MTHFR C677T polymorphism with maternal risk for DS. Moreover, no association between the MTHFR A1298C polymorphism and maternal risk for DS was found. There is also evidence of higher heterogeneity, with I(2) test values ranging from 8 to 89%. No evidence of publication bias was found. Taken together, our meta-analysis implied that the T allele carriers might carry an increased maternal risk for DS.

  15. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    PubMed Central

    2011-01-01

    Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models

  16. Association of the C47T Polymorphism in SOD2 with Amnestic Mild Cognitive Impairment and Alzheimer's Disease in Carriers of the APOEε4 Allele

    PubMed Central

    Gamarra, David; Elcoroaristizabal, Xabier; Fernández-Martínez, Manuel; de Pancorbo, Marian M.

    2015-01-01

    Oxidative stress plays an important part in amnestic mild cognitive impairment (aMCI), the prodromal phase of Alzheimer's disease (AD). Recent evidence shows that polymorphisms in the SOD2 gene affect the elimination of the reactive oxygen species (ROS) generated in mitochondria. The aim of this study was to determine whether the functional rs4880 SNP in the SOD2 gene is a risk factor associated with aMCI and sporadic AD. 216 subjects with aMCI, 355 with AD, and 245 controls have been studied. The SNP rs4880 of the SOD2 gene was genotyped by RT-PCR and the APOE genotype was determined by PCR and RFLPs. Different multinomial logistic regression models were used to determine the risk levels for aMCI and AD. Although the T allele of the SOD2 rs4880 SNP gene (rs4880-T) is not an independent risk for aMCI or AD, this allele increases the risk to aMCI patients carrying at least one APOEε4 allele. Moreover, rs4880-T allele and APOEε4 allele combination has been found to produce an increased risk for AD compared to aMCI reference patients. These results suggest that APOEε4 and rs4880-T genotype may be a risk for aMCI and a predictor of progression from aMCI to AD. PMID:26696693

  17. Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)

    PubMed Central

    Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G.; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

    2015-01-01

    Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations– c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family’s HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40−2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins—the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C

  18. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M.; Soucy, Penny; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Barile, Monica; Pensotti, Valeria; Pasini, Barbara; Dolcetti, Riccardo; Giannini, Giuseppe; Laura Putignano, Anna; Varesco, Liliana; Radice, Paolo; Mai, Phuong L.; Greene, Mark H.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Birk Jensen, Uffe; Crüger, Dorthe G.; Caligo, Maria A.; Laitman, Yael; Milgrom, Roni; Kaufman, Bella; Paluch-Shimon, Shani; Friedman, Eitan; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Ehrencrona, Hans; Melin, Beatrice; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy; Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Osorio, Ana; Ramón y Cajal, Teresa; Fostira, Florentia; Andrés, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; Rookus, Matti A.; Hooning, Maartje J.; Nelen, Marcel R.; van der Luijt, Rob B.; van Os, Theo A.M.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, Hanne E.J.; Gómez Garcia, Encarna B.; Peock, Susan; Cook, Margaret; Frost, Debra; Platte, Radka; Leyland, Jean; Gareth Evans, D.; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Ong, Kai-ren; Cook, Jackie; Douglas, Fiona; Paterson, Joan; John Kennedy, M.; Miedzybrodzka, Zosia; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Belotti, Muriel; Tirapo, Carole; Mazoyer, Sylvie; Barjhoux, Laure; Lasset, Christine; Leroux, Dominique; Faivre, Laurence; Bronner, Myriam; Prieur, Fabienne; Nogues, Catherine; Rouleau, Etienne; Pujol, Pascal; Coupier, Isabelle; Frénay, Marc; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Tea, Muy-Kheng; Pfeiler, Georg; Catharina Dressler, Anne; Hansen, Thomas v.O.; Jønson, Lars; Ejlertsen, Bent; Bjork Barkardottir, Rosa; Kirchhoff, Tomas; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo; Small, Laurie; Boggess, John; Blank, Stephanie; Basil, Jack; Azodi, Masoud; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Agata, Simona; Imyanitov, Evgeny; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Pharoah, Paul D.P.; Sucheston, Lara; Karlan, Beth Y.; Walsh, Christine S.; Olah, Edith; Bozsik, Aniko; Teo, Soo-Hwang; Seldon, Joyce L.; Beattie, Mary S.; van Rensburg, Elizabeth J.; Sluiter, Michelle D.; Diez, Orland; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Varon-Mateeva, Raymonda; Kast, Karin; Deissler, Helmut; Niederacher, Dieter; Arnold, Norbert; Gadzicki, Dorothea; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Dumont, Martine; Chiquette, Jocelyne; Tischkowitz, Marc; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Chun Ding, Yuan; Fredericksen, Zachary; Wang, Xianshu; Pankratz, Vernon S.; Couch, Fergus; Simard, Jacques; Easton, Douglas F.; Chenevix-Trench, Georgia

    2011-01-01

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2 = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11–1.23, P-trend = 4.5 × 10−9 for rs2046210; HR = 1.28, 95% CI: 1.18–1.40, P-trend = 1.3 × 10−8 for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01–1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02–1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92–1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women. PMID:21593217

  19. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

    PubMed

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M; Soucy, Penny; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Barile, Monica; Pensotti, Valeria; Pasini, Barbara; Dolcetti, Riccardo; Giannini, Giuseppe; Putignano, Anna Laura; Varesco, Liliana; Radice, Paolo; Mai, Phuong L; Greene, Mark H; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A; Birk Jensen, Uffe; Crüger, Dorthe G; Caligo, Maria A; Laitman, Yael; Milgrom, Roni; Kaufman, Bella; Paluch-Shimon, Shani; Friedman, Eitan; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Ehrencrona, Hans; Melin, Beatrice; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy; Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Osorio, Ana; Ramón y Cajal, Teresa; Fostira, Florentia; Andrés, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B; Rookus, Matti A; Hooning, Maartje J; Nelen, Marcel R; van der Luijt, Rob B; van Os, Theo A M; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, Hanne E J; Gómez Garcia, Encarna B; Peock, Susan; Cook, Margaret; Frost, Debra; Platte, Radka; Leyland, Jean; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Ong, Kai-ren; Cook, Jackie; Douglas, Fiona; Paterson, Joan; Kennedy, M John; Miedzybrodzka, Zosia; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Belotti, Muriel; Tirapo, Carole; Mazoyer, Sylvie; Barjhoux, Laure; Lasset, Christine; Leroux, Dominique; Faivre, Laurence; Bronner, Myriam; Prieur, Fabienne; Nogues, Catherine; Rouleau, Etienne; Pujol, Pascal; Coupier, Isabelle; Frénay, Marc; Hopper, John L; Daly, Mary B; Terry, Mary B; John, Esther M; Buys, Saundra S; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Dressler, Anne Catharina; Hansen, Thomas v O; Jønson, Lars; Ejlertsen, Bent; Barkardottir, Rosa Bjork; Kirchhoff, Tomas; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo; Small, Laurie; Boggess, John; Blank, Stephanie; Basil, Jack; Azodi, Masoud; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Agata, Simona; Imyanitov, Evgeny; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Pharoah, Paul D P; Sucheston, Lara; Karlan, Beth Y; Walsh, Christine S; Olah, Edith; Bozsik, Aniko; Teo, Soo-Hwang; Seldon, Joyce L; Beattie, Mary S; van Rensburg, Elizabeth J; Sluiter, Michelle D; Diez, Orland; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Varon-Mateeva, Raymonda; Kast, Karin; Deissler, Helmut; Niederacher, Dieter; Arnold, Norbert; Gadzicki, Dorothea; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Dumont, Martine; Chiquette, Jocelyne; Tischkowitz, Marc; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B; Neuhausen, Susan L; Chun Ding, Yuan; Fredericksen, Zachary; Wang, Xianshu; Pankratz, Vernon S; Couch, Fergus; Simard, Jacques; Easton, Douglas F; Chenevix-Trench, Georgia

    2011-08-15

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

  20. Phenotypic differences of human neutrophils of carriers of the PSGL-1 A and B-allele in binding to immobilised P-selectin under flow conditions.

    PubMed

    Meyer dos Santos, Sascha; Klinkhardt, Ute; Lang, Katharina; Parisius, Jeannine; Kuczka, Karina; Harder, Sebastian

    2011-02-01

    P-selectin glycoprotein ligand-1 (PSGL-1) interacts with P-selectin expressed on endothelial cells and platelets. PSGL-1 extracellular mucin-like domain displays a variable number of tandem repeats (VNTRs) polymorphism. The wildtype consists of 16 decameric repeats (designated A isoforms) and variants with 15 (B allele) and 14 (C allele) repeats that are assumed to be associated with reduced risk of vascular disease. We investigated the adhesion of these natural variants to P-selectin in native human neutrophils. Healthy volunteers were genotyped and the adhesion of neutrophils expressing the PSGL-1 isoforms A/A, A/B and B/B were studied under static and physiologic flow conditions. Homozygous B/B neutrophils attached significantly weaker to P-selectin at elevated shear rates from 24 up to 64 dyn/cm(2) than A/A and A/B neutrophils. No difference in adhesion rate was found under static conditions and shear stress below 24 dyn/cm(2), but B/B neutrophils rolled significantly faster than A/A neutrophils at shear stress ≥ 12 dyn/cm(2). There was no difference in the adhesive capacity between A/A an A/B neutrophils. These data support the view that the role of the decamers is to extend the ligand binding domain far above the cell surface to support stable leukocyte adhesion and rolling.

  1. Non-Carriers of Reduced-Function CYP2C19 Alleles are Most Susceptible to Impairment of the Anti-Platelet Effect of Clopidogrel by Proton-Pump Inhibitors: A Pilot Study

    PubMed Central

    Lee, Jen-Kuang; Wu, Cho-Kai; Juang, Jyh-Ming; Tsai, Chia-Ti; Hwang, Juey-Jen; Lin, Jiuun-Lee; Chiang, Fu-Tien

    2016-01-01

    Background The phenomenon of CYP2C19 polymorphism affects the metabolism of both clopidogrel and proton-pump inhibitors (PPI). However, concomitant use of both drugs may reduce the desired therapeutic effects. In this study, we evaluated whether individuals with different numbers of reduced-function CYP2C19 alleles were equally affected and whether PPIs with different dependencies on CYP2C19 metabolism were equally involved. Methods Thirty healthy volunteers were recruited to a six-week regimen of clopidogrel. Three PPIs with different metabolic dependencies on CYP2C19 were included and separately administered in this order. Each PPI was given for a week, followed by a one-week washout period before the intervention of the next PPI. The anti-platelet effect was examined by Thromboelastography Platelet MappingTM (TEG®) and vasodilator-stimulated phosphoprotein (VASP) assays. Results Both TEG® and VASP tests showed the same general qualitative trend, but TEG® detected a statistically significant fluctuation of platelet aggregation in response to different drug interventions. The TEG® results also demonstrated that non-carriers experienced the most significant impairment of anti-platelet effect of clopidogrel after concomitant use of PPIs. This impairment was closely related to the metabolic dependence on CYP2C19 of PPI. Conclusions Our study indicated that non-carriers of reduced-function CYP2C19 alleles are most susceptible to impairment of the anti-platelet effect of clopidogrel after concomitant PPI use. Individual subjects are not equally affected, and PPIs are not equally involved. However, large-scale randomized clinical trials are needed to evaluate the clinical outcome. PMID:27122952

  2. Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry

    PubMed Central

    Nikolic, Ana; Ricci, Giulia; Sera, Francesco; Bucci, Elisabetta; Govi, Monica; Mele, Fabiano; Rossi, Marta; Ruggiero, Lucia; Vercelli, Liliana; Ravaglia, Sabrina; Brisca, Giacomo; Fiorillo, Chiara; Villa, Luisa; Maggi, Lorenzo; Cao, Michelangelo; D'Amico, Maria Chiara; Siciliano, Gabriele; Antonini, Giovanni; Santoro, Lucio; Mongini, Tiziana; Moggio, Maurizio; Morandi, Lucia; Pegoraro, Elena; Angelini, Corrado; Di Muzio, Antonio; Rodolico, Carmelo; Tomelleri, Giuliano; Grazia D'Angelo, Maria; Bruno, Claudio; Berardinelli, Angela; Tupler, Rossella

    2016-01-01

    Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA. Setting Italy. Participants 66 index cases and 33 relatives carrying 1–3 DRA. Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high

  3. [The normotensive carriers of the MTHFR 677T allele, displaying the increased risk of development of the abdominal aortic aneurysm (AAA), occur at the highest frequency among the smoking patients].

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Pawlak, Andrzej L

    2004-01-01

    Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Smoking, hypertension and several genetic factors are recognized as relevant for the pathogenesis of AAA. We studied association between the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (677C>T) and the occurrence of hypertension and smoking status in the group of 74 male patients with AAA. In the patients group, the smoking hypertensive persons represented the largest subgroup (43%). We determined the the MTHFR 677C>T polymorphism in AAA patients and compared it to that in 71 healthy normotensive males. The frequencies of the 677T allele and MTHFR 677C>T genotypes were similar in both groups, but the subgroup of normotensive AAA patients (n=29) displayed significantly increased frequencies of 677T allele (0.4) and of 677CT and TT genotypes (69%), as compared to those in the control group (0.28 and 46%, respectively). This corresponds to the 3.3-fold greater risk of AAA in normotensive subjects with the 677T allele of MTHFR, as compared to the homo-zygotes 677CC (p<0.03; 95% CI=1.2-9.2). The highest frequencies of MTHFR 677T allele (0.43) and 677CT and TT genotypes (73%) were found in the subgroup of normotensive smoking patients (n=22).

  4. Carrier Diagnosis

    MedlinePlus

    ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ...

  5. Lack of association between the pancreatitis risk allele CEL-HYB and pancreatic cancer.

    PubMed

    Shindo, Koji; Yu, Jun; Suenaga, Masaya; Fesharakizadeh, Shahriar; Tamura, Koji; Almario, Jose Alejandro Navarro; Brant, Aaron; Borges, Michael; Siddiqui, Abdulrehman; Datta, Lisa; Wolfgang, Christopher L; Hruban, Ralph H; Klein, Alison Patricia; Goggins, Michael

    2017-02-07

    CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (CEL) gene and the nearby CEL pseudogene (CELP) and was recently identified as a risk factor for chronic pancreatitis. Since chronic pancreatitis is a risk factor for the development of pancreatic cancer, we compared the prevalence of the CEL-HYB allele in patients with pancreatic ductal adenocarcinoma to spousal controls and disease controls. The CEL-HYB allele was detected using Sanger and next generation sequencing. There was no significant difference in the prevalence of the CEL-HYB allele between cases with pancreatic ductal adenocarcinoma compared to controls; 2.6% (22/850) vs. 1.8% (18/976) (p=0.35). CEL-HYB carriers were not more likely to report a history of pancreatitis. Patients with pancreatic cancer are not more likely than controls to be carriers of the CEL-HYB allele.

  6. Identification of 2127 new HLA class I alleles in potential stem cell donors from Germany, the United States and Poland.

    PubMed

    Hernández-Frederick, C J; Giani, A S; Cereb, N; Sauter, J; Silva-González, R; Pingel, J; Schmidt, A H; Ehninger, G; Yang, S Y

    2014-03-01

    We describe 2127 new human leukocyte antigen (HLA) class I alleles found in registered stem cell donors. These alleles represent 28.9% of the currently known class I alleles. Comparing new allele sequences to homologous sequences, we found 68.1% nonsynonymous nucleotide substitutions, 28.9% silent mutations and 3.0% nonsense mutations. Many substitutions occurred at positions that have not been known to be polymorphic before. A large number of HLA alleles and nucleotide variations underline the extreme diversity of the HLA system. Strikingly, 156 new alleles were found not only multiple times, but also in carriers of various parentage, suggesting that some new alleles are not necessarily rare. Moreover, new alleles were found especially often in minority donors. This emphasizes the benefits of specifically recruiting such groups of individuals.

  7. Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk allele

    PubMed Central

    Chen, Helen; Gregersen, Peter K.; Diamond, Betty

    2017-01-01

    A SNP identified as rs548234, which is found in PRDM1, the gene that encodes BLIMP1, is a risk allele associated with systemic lupus erythematosus (SLE). BLIMP1 expression was reported to be decreased in women with the PRDM1 rs548234 risk allele compared with women with the nonrisk allele in monocyte-derived DCs (MO-DCs). In this study, we demonstrate that BLIMP1 expression is regulated by the binding of Kruppel-like factor 4 (KLF4) to the risk SNP. KLF4 is highly expressed in MO-DCs but undetectable in B cells, consistent with the lack of altered expression of BLIMP1 in B cells from risk SNP carriers. Female rs548234 risk allele carriers, but not nonrisk allele carriers, exhibited decreased levels of BLIMP1 in MO-DCs, showing that the regulatory function of KLF4 is influenced by the risk allele. In addition, KLF4 directly recruits histone deacetylases (HDAC4, HDAC6, and HDAC7), established negative regulators of gene expression. Finally, the knock down of KLF4 expression reversed the inhibitory effects of the risk SNP on promoter activity and BLIMP1 expression. Therefore, the binding of KLF4 and the subsequent recruitment of HDACs represent a mechanism for reduced BLIMP1 expression in MO-DCs bearing the SLE risk allele rs548234. PMID:28097234

  8. Hydrogen carriers

    NASA Astrophysics Data System (ADS)

    He, Teng; Pachfule, Pradip; Wu, Hui; Xu, Qiang; Chen, Ping

    2016-12-01

    Hydrogen has the potential to be a major energy vector in a renewable and sustainable future energy mix. The efficient production, storage and delivery of hydrogen are key technical issues that require improvement before its potential can be realized. In this Review, we focus on recent advances in materials development for on-board hydrogen storage. We highlight the strategic design and optimization of hydrides of light-weight elements (for example, boron, nitrogen and carbon) and physisorbents (for example, metal-organic and covalent organic frameworks). Furthermore, hydrogen carriers (for example, NH3, CH3OH-H2O and cycloalkanes) for large-scale distribution and for on-site hydrogen generation are discussed with an emphasis on dehydrogenation catalysts.

  9. 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)

  10. Choreography of Ig allelic exclusion.

    PubMed

    Cedar, Howard; Bergman, Yehudit

    2008-06-01

    Allelic exclusion guarantees that each B or T cell only produces a single antigen receptor, and in this way contributes to immune diversity. This process is actually initiated in the early embryo when the immune receptor loci become asynchronously replicating in a stochastic manner with one early and one late allele in each cell. This distinct differential replication timing feature then serves an instructive mark that directs a series of allele-specific epigenetic events in the immune system, including programmed histone modification, nuclear localization and DNA demethylation that ultimately bring about preferred rearrangement on a single allele, and this decision is temporally stabilized by feedback mechanisms that inhibit recombination on the second allele. In principle, these same molecular components are also used for controlling monoallelic expression at other genomic loci, such as those carrying interleukins and olfactory receptor genes that require the choice of one gene out of a large array. Thus, allelic exclusion appears to represent a general epigenetic phenomenon that is modeled on the same basis as X chromosome inactivation.

  11. Carriage of One or Two FMR1 Premutation Alleles Seems to Have No Effect on Illness Severity in a FXTAS Female with an Autozygous FMR1 Premutation Allele.

    PubMed

    Rodriguez-Revenga, Laia; Pagonabarraga, Javier; Gómez-Anson, Beatriz; López-Mourelo, Olga; Izquierdo, Silvia; Alvarez-Mora, Maria Isabel; Granell, Esther; Madrigal, Irene; Milà, Montserrat

    2016-10-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity.

  12. Molecular characterization and clinical presentation of HKαα and anti-HKαα alleles in southern Chinese subjects.

    PubMed

    Shang, X; Li, Q; Cai, R; Huang, J; Wei, X; Xu, X

    2013-05-01

    The HKαα allele is a rearrangement occurring in the α-globin gene cluster containing both the -α(3.7) and ααα(anti4.2) unequal crossover junctions. The anti-HKαα allele is the reciprocal product containing both the -α(4.2) and ααα(anti3.7) unequal crossover junctions, which had been predicted but had not been detected previously. The phenotypic feature and population frequency of these two unusual alleles were not described. We report the identification of nine individuals carrying the HKαα allele and two individuals carrying the anti-HKαα allele in southern China and describe their phenotype and haplotype data. The molecular structures of HKαα allele and anti-HKαα allele were confirmed by two-round nested polymerase chain reaction assay. The mechanism of origin of both alleles is related to probably simultaneous double crossover. Heterozygotes of HKαα or anti-HKαα allele show a normal hematological phenotype. Finally, we report the carrier rates of these both alleles in the Guangxi Zhuang Autonomous Region of southern China, namely, ∼0.07% for the HKαα allele and ∼0.02% for the anti-HKαα allele.

  13. 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.

  14. No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations.

    PubMed

    Zou, Wen-Bin; Boulling, Arnaud; Masamune, Atsushi; Issarapu, Prachand; Masson, Emmanuelle; Wu, Hao; Sun, Xiao-Tian; Hu, Liang-Hao; Zhou, Dai-Zhan; He, Lin; Fichou, Yann; Nakano, Eriko; Hamada, Shin; Kakuta, Yoichi; Kume, Kiyoshi; Isayama, Hiroyuki; Paliwal, Sumit; Mani, K Radha; Bhaskar, Seema; Cooper, David N; Férec, Claude; Shimosegawa, Tooru; Chandak, Giriraj R; Chen, Jian-Min; Li, Zhao-Shen; Liao, Zhuan

    2016-06-01

    A hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL-HYB), generated by nonallelic homologous recombination between CEL intron 10 and CELP intron 10', was found to increase susceptibility to chronic pancreatitis in a case-control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL-HYB allele in any of these populations. The CEL-HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL-HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis.

  15. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers.

    PubMed

    Cohn, Jonathan A; Neoptolemos, John P; Feng, Jinong; Yan, Jin; Jiang, Zefei; Greenhalf, William; McFaul, Christopher; Mountford, Roger; Sommer, Steve S

    2005-10-01

    Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.

  16. The CASP8 rs3834129 polymorphism and breast cancer risk in BRCA1 mutation carriers.

    PubMed

    Catucci, Irene; Verderio, Paolo; Pizzamiglio, Sara; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Roversi, Gaia; Ripamonti, Carla B; Pasini, Barbara; Barile, Monica; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Varesco, Liliana; Martayan, Aline; Riboni, Mirko; Volorio, Sara; Radice, Paolo; Peterlongo, Paolo

    2011-02-01

    The rs3834129 polymorphism, in the promoter of CASP8 gene, has been recently reported as associated with breast cancer risk in the general population, with the minor allele del having a protective effect. Some of the genetic variants found associated with breast cancer risk were reported as risk modifiers in individuals with mutations in BRCA1 and BRCA2 genes. Here, we tested the effect of the rs3834129 del allele on breast cancer risk in BRCA mutation carriers. The rs3834129 was genotyped in a total of 1,207 Italian female BRCA mutation carriers. Of these, 740 carried a BRCA1 mutation and 467 a BRCA2 mutation. Overall, 699 were affected with breast cancer and 508 were unaffected. When considering class 1 (loss-of-function) BRCA mutations, hazard ratios estimated by weighted multivariable Cox regression model, for individuals with at least one copy of the del allele, were 1.46 (95% confidence interval (CI): 1.08-1.99) for BRCA1 and BRCA2 mutation carriers combined, 1.74 (95% CI: 1.24-2.46) for BRCA1 mutation carriers, and 1.09 (95% CI: 0.66-1.80) for BRCA2 mutation carriers. These results suggest that the minor allele del of rs3834129 is associated under a dominant model with increased breast cancer risk in carriers of BRCA1 mutations but not in carriers of BRCA2 mutations.

  17. Altered White Matter Architecture in BDNF Met Carriers

    PubMed Central

    Ziegler, Erik; Foret, Ariane; Mascetti, Laura; Muto, Vincenzo; Le Bourdiec-Shaffii, Anahita; Stender, Johan; Balteau, Evelyne; Dideberg, Vinciane; Bours, Vincent; Maquet, Pierre; Phillips, Christophe

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture. PMID:23935975

  18. A novel measurement of allele discrimination for assessment of allele-specific silencing by RNA interference.

    PubMed

    Takahashi, Masaki; Hohjoh, Hirohiko

    2014-11-01

    Allele-specific silencing by RNA interference (ASP-RNAi) is an atypical RNAi that is capable of discriminating target alleles from non-target alleles, and may be therapeutically useful for specific inhibition of disease-causing alleles without affecting their corresponding normal alleles. However, it is difficult to design and select small interfering RNA (siRNAs) that confer ASP-RNAi. A major problem is that there are few appropriate measures in determining optimal allele-specific siRNAs. Here we show two novel formulas for calculating a new measure of allele-discrimination, named "ASP-score". The formulas and ASP-score allow for an unbiased determination of optimal siRNAs, and may contribute to characterizing such allele-specific siRNAs.

  19. Allelic selection of human IL-2 gene.

    PubMed

    Matesanz, F; Delgado, C; Fresno, M; Alcina, A

    2000-12-01

    The allelic expression of mouse IL-2 cannot be definitely extrapolated to what might happen in humans. Therefore, we investigated the regulation of allelic expression of the IL-2 gene in non-genetically manipulated human T lymphocytes by following natural allelic polymorphisms. We found a phenotypically silent punctual change in the human IL-2 at position 114 after the first nucleotide of the initiation codon, which represents a dimorphic polymorphism at the first exon of the IL-2 gene. This allowed the study by single-cell PCR of the regulation of the human IL-2 allelic expression in heterozygous CD4(+) T cells, which was found to be tightly controlled monoallelically. These findings may be used as a suitable marker for monitoring the IL-2 allelic contribution to effector activities and in immune responses against different infections or in pathological situations.

  20. Common Carrier Services.

    ERIC Educational Resources Information Center

    Federal Communications Commission, Washington, DC.

    After outlining the Federal Communications Commission's (FCC) responsibility for regulating interstate common carrier communication (non-broadcast communication whose carriers are required by law to furnish service at reasonable charges upon request), this information bulletin reviews the history, technological development, and current…

  1. [Prognostic implications of GP3a glucoprotein gene PLA1/PLA2 allele in prostatic cancer: pilot results of the study].

    PubMed

    Loran, O B; Itkes, A V; Seregin, A A; Miandina, G I

    2005-01-01

    We studied the role of integrins, primarily, the role of allele distribution of GP3a gene in development of prostatic cancer (PC) and assessment of its prognostic significance. From November 2003 to May 2004 we examined 32 patients with PC: 11 patients with local PC T1-2N0M0; 14 patients with locally advanced cancer T3N0M0 and 7 patients with invasive and/or metastatic cancer T3-4N10-1 or T3-4N0-1M1. The blood from all the patients we studied with PCR for alleles of GP3a gene, PSA. Seventeen patients were found to have alleles PLA1A1, 14(44%)--alleles PLA1A2, 1(3%)--alleles PLA2A2. Alleles PLA1A2 occurred significantly more often than in the population (p < 0.005). The group analysis has found that 8 patients with local PC had alleles PLA1A1, 3 patients--alleles PLA1A2 (27%). We discovered alleles PLA2A2, PLA1A1 and PLA1A2 in 1(7%), 5(36%) and 8(57%) patients with locally advanced PC, respectively. Among patients with metastatic and/or invasive prostatic cancer, there were 4 (57%) and 3 (43%) cases of alleles PLA1A1 and PLA1A2, respectively. Our study demonstrated influence of carriage of PLA2 allele on occurrence of PC risk (5-fold higher) and its invasive forms (10-fold higher and more). Probability to develop local invasion among patients with prostatic cancer--carriers allele PLA1A2 is 6 times higher than among carriers of alleles PLA1A1. A PC course in carriers of alleles PLA1A2 may be characterized by faster development of local invasion and metastasizing vs carriers of alleles PLA1A1. These findings can be used in design of nomograms for prognostication of invasion of clinically small tumors in verification of significance on greater number of the patients.

  2. Estimation of the frequency of hexosaminidase a variant alleles in the American Jewish population.

    PubMed

    Greenberg, D A; Kaback, M M

    1982-05-01

    There appear to be several alleles of the hexosaminidase A (HEX A) gene that lead to different clinical syndromes. In addition to the infantile-onset Tay-Sachs disease (TSD), there is a juvenile-onset and an adult-onset form, which are also characterized by low HEX A levels. There are also apparently healthy adults with low HEX A activity. Based primarily on data from population screening for TSD carrier status, we estimate the allele frequency of the combined variant alleles for which data are available to be about 4.5 x 10(-4) and the frequency of adults showing zero HEX A levels (when tested using artificial substrate) to be about 1:67,000. The implications for population screening and prenatal diagnosis are discussed.

  3. 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

  4. Reduced Physiological Complexity in Robust Elderly Adults with the APOE ε4 Allele

    PubMed Central

    Hong, Chen-Jee; Yang, Albert C.

    2009-01-01

    Background It is unclear whether the loss of physiological complexity during the aging process is due to genetic variations. The APOE gene has been studied extensively in regard to its relationship with aging-associated medical illness. We hypothesize that diminished physiological complexity, as measured by heart rate variability, is influenced by polymorphisms in the APOE allele among elderly individuals. Methodology/Principal Findings A total of 102 robust, non-demented, elderly subjects with normal functions of daily activities participated in this study (97 males and 5 females, aged 79.2±4.4 years, range 72–92 years). Among these individuals, the following two APOE genotypes were represented: ε4 non-carriers (n = 87, 85.3%) and ε4 carriers (n = 15, 14.7%). Multi-scale entropy (MSE), an analysis used in quantifying complexity for nonlinear time series, was employed to analyze heart-rate dynamics. Reduced physiological complexity, as measured by MSE, was significantly associated with the presence of the APOE ε4 allele in healthy elderly subjects, as compared to APOE ε4 allele non-carriers (24.6±5.5 versus 28.9±5.2, F = 9.429, p = 0.003, respectively). Conclusions/Significance This finding suggests a role for the APOE gene in the diminished physiological complexity seen in elderly populations. PMID:19890394

  5. 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.

  6. 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.

  7. CYP2C9*2 allele increases risk for hypoglycemia in POR*1/*1 type 2 diabetic patients treated with sulfonylureas.

    PubMed

    Ragia, G; Tavridou, A; Elens, L; Van Schaik, R H N; Manolopoulos, V G

    2014-01-01

    It is previously shown that carriers of the defective allele CYP2C9*3 that leads to impaired sulfonylurea metabolism are at increased sulfonylurea-induced hypoglycemia risk due to diminished drug metabolism, whereas no effect of CYP2C9*2 allele was found. Recently, a polymorphism in P450 oxidoreductase (POR) gene, assigned as POR*28 allele, was associated with increased CYP2C9 activity. The aim of this study was to assess i) the effect of POR*28 allele on sulfonylurea-induced hypoglycemia risk and ii) the association of CYP2C9*2 allele with hypoglycemia risk in non-carriers of POR*28 allele. The study group consisted of 176 patients with diagnosed type 2 diabetes mellitus (T2DM) treated with sulfonylureas, of whom 92 patients had experienced at least one drug-associated hypoglycemic event (cases), while 84 had never experienced a hypoglycemic event (controls). POR*28 allele was detected by use of real-time TaqMan PCR. POR*28 allele was not associated with sulfonyl-urea-induced hypoglycemia. In POR*1/*1 patients, CYP2C9*1/*2 genotype was more common in cases than in controls (32.7 vs. 14.3%, p=0.041). In a model adjusted for age, BMI, duration of T2DM and renal function, and POR*1/*1 entered as a selection variable, CYP2C9*2 allele increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 3.218, p=0.031). In conclusion, our results suggest that POR*28 allele is masking the association of CYP2C9*2 allele with sulfonyl-urea-induced hypoglycemia. Therefore, POR*28 allele is an important source of CYP2C9 activity variability and combined with CYP2C9 gene poly-morphisms may explain individual variability in the effect of sulfonylureas.

  8. Cytochrome P450 2D6 variants in a Caucasian population: Allele frequencies and phenotypic consequences

    SciTech Connect

    Sachse, C.; Brockmoeller, J.; Bauer, S.; Roots, I.

    1997-02-01

    Cytochrome P450 2D6 (CYP2D6) metabolizes many important drugs. CYP2D6 activity ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different known alleles. Their frequencies were determined in 589 unrelated German volunteers and correlated with enzyme activity measured by phenotyping with dextromethorphan or debrisoquine. For genotyping, nested PCR-RFLP tests from a PCR amplificate of the entire CYP2D6 gene were developed. The frequency of the CYP2D6*1 allele coding for extensive metabolizer (EM) phenotype was .364. The alleles coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity (intermediate metabolizer phenotype [IM]) showed frequencies of .324, .018, and .015, respectively. By use of novel PCR tests for discrimination, CYP2D6 gene duplication alleles were found with frequencies of.005 (*1 x 2), .013 (* 2 x 2), and .001 (*4 x 2). Frequencies of alleles with complete deficiency (poor metabolizer phenotype [PM]) were .207 (*4), .020 (*3 and *5), .009 (*6), and .001 (*7, *15, and *16). The defective CYP2D6 alleles *8, *11, *12, *13, and *14 were not found. All 41 PMs (7.0%) in this sample were explained by five mutations detected by four PCR-RFLP tests, which may suffice, together with the gene duplication test, for clinical prediction of CYP2D6 capacity. Three novel variants of known CYP2D6 alleles were discovered: *1C (T{sub 1957}C), *2B (additional C{sub 2558}T), and *4E (additional C{sub 2938}T). Analysis of variance showed significant differences in enzymatic activity measured by the dextromethorphan metabolic ratio (MR) between carriers of EN/PM (mean MR = .006) and IM/PM (mean MR = .014) alleles and between carriers of one (mean MR = .009) and two (mean MR = .003) functional alleles. The results of this study provide a solid basis for prediction of CYP2D6 capacity, as required in drug research and routine drug treatment. 35 refs., 4 figs., 5 tabs.

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

    PubMed

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

    2015-04-01

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

  10. Comparison of HLA allelic imputation programs.

    PubMed

    Karnes, Jason H; Shaffer, Christian M; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M; Steiner, Heidi E; Mosley, Jonathan D; Mallal, Simon; Denny, Joshua C; Phillips, Elizabeth J; Roden, Dan M

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.

  11. Comparison of HLA allelic imputation programs

    PubMed Central

    Shaffer, Christian M.; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M.; Steiner, Heidi E.; Mosley, Jonathan D.; Mallal, Simon; Denny, Joshua C.; Phillips, Elizabeth J.; Roden, Dan M.

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations. PMID:28207879

  12. X chromosome inactivation in carriers of Barth syndrome.

    PubMed Central

    Orstavik, K H; Orstavik, R E; Naumova, A K; D'Adamo, P; Gedeon, A; Bolhuis, P A; Barth, P G; Toniolo, D

    1998-01-01

    Barth syndrome (BTHS) is a rare X-linked recessive disorder characterized by cardiac and skeletal myopathy, neutropenia, and short stature. A gene for BTHS, G4.5, was recently cloned and encodes several novel proteins, named "tafazzins." Unique mutations have been found. No correlation between the location or type of mutation and the phenotype of BTHS has been found. Female carriers of BTHS seem to be healthy. This could be due to a selection against cells that have the mutant allele on the active X chromosome. We therefore analyzed X chromosome inactivation in 16 obligate carriers of BTHS, from six families, using PCR in the androgen-receptor locus. An extremely skewed X-inactivation pattern (>=95:5), not found in 148 female controls, was found in six carriers. The skewed pattern in two carriers from one family was confirmed in DNA from cultured fibroblasts. Five carriers from two families had a skewed pattern (80:20-<95:5), a pattern that was found in only 11 of 148 female controls. Of the 11 carriers with a skewed pattern, the parental origin of the inactive X chromosome was maternal in all seven cases for which this could be determined. In two families, carriers with an extremely skewed pattern and carriers with a random pattern were found. The skewed X inactivation in 11 of 16 carriers is probably the result of a selection against cells with the mutated gene on the active X chromosome. Since BTHS also shows great clinical variation within families, additional factors are likely to influence the expression of the phenotype. Such factors may also influence the selection mechanism in carriers. PMID:9792874

  13. A pseudodeficiency allele (D152N) of the human beta-glucuronidase gene.

    PubMed

    Vervoort, R; Islam, M R; Sly, W; Chabas, A; Wevers, R; de Jong, J; Liebaers, I; Lissens, W

    1995-10-01

    We present evidence that a 480G-->A transition in the coding region of the beta-glucuronidase gene, which results in an aspartic-acid-to-asparagine substitution at amino acid position 152 (D152N), produces a pseudodeficiency allele (GUSBp) that leads to greatly reduced levels of beta-glucuronidase activity without apparent deleterious consequences. The 480G-->A mutation was found initially in the pseudodeficient mother of a child with mucopolysaccharidosis VII (MPSVII), but it was not on her disease-causing allele, which carried the L176F mutation. The 480G-->A change was also present in an unrelated individual with another MPSVII allele who had unusually low beta-glucuronidase activity, but whose clinical symptoms were probably unrelated to beta-glucuronidase deficiency. This individual also had an R357X mutation, probably on his second allele. We screened 100 unrelated normal individuals for the 480G-->A mutation with a PCR method and detected one carrier. Reduced beta-glucuronidase activity following transfection of COS cells with the D152N cDNA supported the causal relationship between the D152N allele and pseudodeficiency. The mutation reduced the fraction of expressed enzyme that was secreted. Pulse-chase experiments indicated that the reduced activity in COS cells was due to accelerated intracellular turnover of the D152N enzyme. They also suggested that a potential glycosylation site created by the mutation is utilized in approximately 50% of the enzyme expressed.

  14. 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

  15. Ten novel HLA-DRB1 alleles and one novel DRB3 allele.

    PubMed

    Lazaro, A M; Steiner, N K; Moraes, M E; Moraes, J R; Ng, J; Hartzman, R J; Hurley, C K

    2005-10-01

    Ten novel HLA-DRB1 and one DRB3 alleles are described. Eight of the variants are single-nucleotide substitutions, four resulting in an amino acid change (DRB1*1145, *1148, *0828 and *1514) and four with silent substitutions (DRB1*040504, *130103, *160502 and DRB3*020204). Two alleles differ by two nucleotide changes altering one (DRB1*1447 and *1361) amino acid and one allele alters three nucleotides and two amino acids.

  16. Abnormal segregation of alleles in CEPH pedigree DNAs arising from allele loss in lymphoblastoid DNA

    SciTech Connect

    Royle, N.J.; Armour, J.A.L.; Crosier, M.; Jeffreys, A.J. )

    1993-01-01

    Somatic events that result in the reduction to hemior homozygosity at all loci affected by the event have been identified in lymphoblastoid DNA from mothers of two CEPH families. Using suitably informative probes, the allele deficiencies were detected by the abnormal transmission of alleles from grandparents to grandchildren, with the apparent absence of the alleles from the parent. Undetected somatic deficiencies in family DNAs could result in misscoring of recombination events and consequently introduce errors into linkage analysis. 15 refs., 2 figs.

  17. The Pro12Ala variant at the peroxisome proliferator-activated receptor γ gene and change in obesity-related traits in the Diabetes Prevention Program

    PubMed Central

    Franks, P. W.; Jablonski, K. A.; Delahanty, L.; Hanson, R. L.; Kahn, S. E.; Altshuler, D.; Knowler, W. C.; Florez, J. C.

    2008-01-01

    Aims/hypothesis Peroxisome proliferator-activated receptor γ (PPARγ), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA. Methods We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomized clinical trial of treatment with metformin (n=989), troglita-zone (n=363) or lifestyle modification (n=1,004) vs placebo (n=1,000) for diabetes prevention in high-risk individuals. Results At baseline, Ala12 carriers had larger waists (p<0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/3; p=0.04) than Pro12 homozygotes. There was a genotype-by-intervention interaction on 1-year weight change (p=0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p=0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p<0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p=0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p≤0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/3) reductions occurred across genotypes, but were greater in Ala12 carriers (p=0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/5; p=0.04) was also observed, which was most evident with metformin treatment (p<0.001). Conclusions /interpretation Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992). PMID:17898990

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

    DTIC Science & Technology

    2006-05-31

    BRIEF COMMUNICATION Ten novel HLA-DRB1 alleles and one novel DRB3 allele A. M. Lazaro1, N. K. Steiner1, M. E. Moraes2, J. R. Moraes2, J. Ng1, R. J...accepted for publication 31 May 2005 doi: 10.1111/j.1399-0039.2005.00459.x Abstract Ten novel HLA-DRB1 and one DRB3 alleles are described. Eight of the...substitutions (DRB1*040504, *130103, *160502 and DRB3 *020204). Two alleles differ by two nucleotide changes altering one (DRB1*1447 and *1361) amino acid and

  19. Identification of β-globin haplotypes linked to sickle hemoglobin (Hb S) alleles in Mazandaran province, Iran.

    PubMed

    Aghajani, Faeghe; Mahdavi, Mohammad Reza; Kosaryan, Mehrnoush; Mahdavi, Mehrad; Hamidi, Mohaddese; Jalali, Hossein

    2016-12-21

    Carrier frequency of the β(S) allele has been reported to be 0.19% in Mazandaran province, northern Iran. Haplotype analysis of the β(S) allele helps trace the origin of its encoded hemoglobin (Hb) variant, Hb S, in a region. The aim of this study was to investigate the haplotypes associated with β(S) alleles in Mazandaran province. Capillary electrophoresis was carried out to detect individuals suspected to have a βS allele(s). DNA analysis (PCR-RFLP) was used for final confirmation. To identify 5\\' to 3\\' β-globin gene cluster haplotypes associated with β(S) alleles, family linkage analysis was applied. Six polymorphic sites (HincII 5' to ε, XmnI 5' to (G)γ, HindIII in (G)γ, HindIII in (A)γ, HincII 3' to ψβ and AvaII in β) were investigated using the PCR-RFLP method. Five different haplotypes were linked to β(S) alleles, while β(A) alleles were associated with nine haplotypes. Among the β(S) alleles, 53.9% were associated with the Benin (----++) haplotype, and the Arab-Indian (+++-++) haplotype had the second-highest frequency (23%). Unlike southern provinces, where the Arab-Indian haplotype is prominent, the Benin haplotype is the most frequent haplotype in northern Iran, and this may represent a founder effect. Since the Benin haplotype does not carry the XmnI polymorphism 5' to the (G)γ gene, which is responsible for high expression of Hb F, a severe form of sickle cell disease can be anticipated in patients that are homozygous for the β(S) allele in the northern region.

  20. Evidence of the phenotypic expression of a lethal recessive allele under inbreeding in a wild population of conservation concern.

    PubMed

    Trask, Amanda E; Bignal, Eric M; McCracken, Davy I; Monaghan, Pat; Piertney, Stuart B; Reid, Jane M

    2016-07-01

    Deleterious recessive alleles that are masked in outbred populations are predicted to be expressed in small, inbred populations, reducing both individual fitness and population viability. However, there are few definitive examples of phenotypic expression of lethal recessive alleles under inbreeding conditions in wild populations. Studies that demonstrate the action of such alleles, and infer their distribution and dynamics, are required to understand their potential impact on population viability and inform management responses. The Scottish population of red-billed choughs (Pyrrhocorax pyrrhocorax), which currently totals <60 breeding pairs and is of major conservation concern, has recently been affected by lethal blindness in nestlings. We used family data to show that the pattern of occurrence of blindness within and across affected families that produced blind nestlings was exactly 0·25, matching that expected given a single-locus autosomal lethal recessive allele. Furthermore, the observed distribution of blind nestlings within affected families did not differ from that expected given Mendelian inheritance of such an allele. Relatedness estimates showed that individuals from affected families were not more closely related to each other than they were to individuals from unaffected families that did not produce blind nestlings. Blind individuals tended to be less heterozygous than non-blind individuals, as expected if blindness was caused by the expression of a recessive allele under inbreeding. However, there was no difference in the variance in heterozygosity estimates, suggesting that some blind individuals were relatively outbred. These results suggest carriers of the blindness allele may be widely distributed across contemporary families rather than restricted to a single family lineage, implying that the allele has persisted across multiple generations. Blindness occurred at low frequency (affecting 1·6% of observed nestlings since 1981). However

  1. Allele-specific DNA methylation: beyond imprinting.

    PubMed

    Tycko, Benjamin

    2010-10-15

    Allele-specific DNA methylation (ASM) and allele-specific gene expression (ASE) have long been studied in genomic imprinting and X chromosome inactivation. But these types of allelic asymmetries, along with allele-specific transcription factor binding (ASTF), have turned out to be far more pervasive-affecting many non-imprinted autosomal genes in normal human tissues. ASM, ASE and ASTF have now been mapped genome-wide by microarray-based methods and NextGen sequencing. Multiple studies agree that all three types of allelic asymmetries, as well as the related phenomena of expression and methylation quantitative trait loci, are mostly accounted for by cis-acting regulatory polymorphisms. The precise mechanisms by which this occurs are not yet understood, but there are some testable hypotheses and already a few direct clues. Future challenges include achieving higher resolution maps to locate the epicenters of cis-regulated ASM, using this information to test mechanistic models, and applying genome-wide maps of ASE/ASM/ASTF to pinpoint functional regulatory polymorphisms influencing disease susceptibility.

  2. Automatic carrier acquisition system

    NASA Technical Reports Server (NTRS)

    Bunce, R. C. (Inventor)

    1973-01-01

    An automatic carrier acquisition system for a phase locked loop (PLL) receiver is disclosed. It includes a local oscillator, which sweeps the receiver to tune across the carrier frequency uncertainty range until the carrier crosses the receiver IF reference. Such crossing is detected by an automatic acquisition detector. It receives the IF signal from the receiver as well as the IF reference. It includes a pair of multipliers which multiply the IF signal with the IF reference in phase and in quadrature. The outputs of the multipliers are filtered through bandpass filters and power detected. The output of the power detector has a signal dc component which is optimized with respect to the noise dc level by the selection of the time constants of the filters as a function of the sweep rate of the local oscillator.

  3. AlleleSeq: analysis of allele-specific expression and binding in a network framework.

    PubMed

    Rozowsky, Joel; Abyzov, Alexej; Wang, Jing; Alves, Pedro; Raha, Debasish; Harmanci, Arif; Leng, Jing; Bjornson, Robert; Kong, Yong; Kitabayashi, Naoki; Bhardwaj, Nitin; Rubin, Mark; Snyder, Michael; Gerstein, Mark

    2011-08-02

    To study allele-specific expression (ASE) and binding (ASB), that is, differences between the maternally and paternally derived alleles, we have developed a computational pipeline (AlleleSeq). Our pipeline initially constructs a diploid personal genome sequence (and corresponding personalized gene annotation) using genomic sequence variants (SNPs, indels, and structural variants), and then identifies allele-specific events with significant differences in the number of mapped reads between maternal and paternal alleles. There are many technical challenges in the construction and alignment of reads to a personal diploid genome sequence that we address, for example, bias of reads mapping to the reference allele. We have applied AlleleSeq to variation data for NA12878 from the 1000 Genomes Project as well as matched, deeply sequenced RNA-Seq and ChIP-Seq data sets generated for this purpose. In addition to observing fairly widespread allele-specific behavior within individual functional genomic data sets (including results consistent with X-chromosome inactivation), we can study the interaction between ASE and ASB. Furthermore, we investigate the coordination between ASE and ASB from multiple transcription factors events using a regulatory network framework. Correlation analyses and network motifs show mostly coordinated ASB and ASE.

  4. 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).

  5. Transformation of QTL genotypic effects to allelic effects

    PubMed Central

    Nagamine, Yoshitaka

    2005-01-01

    The genotypic and allelic effect models are equivalent in terms of QTL detection in a simple additive model, but the QTL allelic model has the advantage of providing direct information for marker-assisted selection. However, the allelic matrix is four times as large as the genotypic IBD matrix, causing computational problems, especially in genome scans examining multiple positions. Transformation from genotypic to allelic effects, after estimating the genotypic effects with a smaller IBD matrix, can solve this problem. Although the validity of transformation from genotypic to allelic effects has been disputed, this work proves that transformation can successfully yield unique allelic effects when genotypic and allelic IBD matrixes exist. PMID:16093016

  6. Preconception Carrier Screening

    MedlinePlus

    ... What can the results of a carrier screening test tell me? A genetic counselor or your health care provider will use the results to calculate the ... the publisher. Related FAQs Genetic Disorders (FAQ094) Screening Tests for Birth Defects ... Education & Events Annual Meeting CME Overview CREOG ...

  7. Common Carrier Services.

    ERIC Educational Resources Information Center

    Federal Communications Commission, Washington, DC.

    This bulletin outlines the Federal Communications Commission's (FCC) responsibilities in regulating the interstate and foreign common carrier communication via electrical means. Also summarized are the history, technological development, and current capabilities and prospects of telegraph, wire telephone, radiotelephone, satellite communications,…

  8. Synthetic carriers of oxygen.

    PubMed

    Dellacherie, E; Labrude, P; Vigneron, C; Riess, J G

    1987-01-01

    During the last decade, construction of artificial carriers of oxygen for transfusion purposes has evolved in three main directions, which can be reviewed as follows. The first approach consists of modifying hemoglobin (Hb), the natural oxygen carrier, in order to lower its oxygen affinity and increase its intravascular persistence. To achieve this aim, two basic procedures have been used: molecular and environmental modification. In the first case, Hb is modified with chemical reagents; the second requires encapsulation of Hb to obtain artificial erythrocytes. The second approach is based on the use of synthetic oxygen-carrying chelates that mimic the oxygenation function of Hb. The main products in this class are metalloporphyrins, whose chemical environment is designed to render them efficient as reversible carriers of oxygen in vivo. Finally, the third approach deals with the perfluorochemicals used in emulsified form. Perfluorochemical liquids are excellent gas solvents, but some problems remain unsolved with regard to their development as oxygen carriers in vivo: low O2 dissolving capacity, toxicity, and excretion.

  9. [Association of allelic polymorphisms of genes matrix Gla-protein system with ischemic atherothrombotic stroke].

    PubMed

    Garbuzova, V Yu; Stroy, D A; Dosenko, V E; Dubovyk, Ye I; Borodenko, A O; Shimko, K A; Obukhova, O A; Ataman, O V

    2015-01-01

    There are results of the determination of 10 polymorphisms of matrix Gla-protein system (gene MGP-T(-138)-->C (rs1800802), G(-7)-->A (rs1800801), Thr83-->Ala (rs4236), gene VDR-FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236), gene GGCX-Arg325-->Gln (rs699664), gene VKORS1-T(2255)-->C (rs2359612), gene BMP-2-Ser37-->Ala (rs2273073)) into 170 patients with ischemic atherothrombotic stroke (IATS) and 124 healthy individual is (control group). It is established that there is a connection between the IATS and polymorphic variants of genes MGP (G(-7)-->A) and VKORC1 (T(2255)-->C). The risk of IATS in carriers of minor allele A/A (G(-7)-->A polymorphism) in 2.6 times higher than in carriers of the major allele (G/A + G/G), and C/C genotype (T(2255)-->C polymorphism) in 2.2 times higher than the homozygotes of major allele. The coincidence of patients T/C and G/G, C/C and G/A genotypes, and A/A genotype (G(-7)-->A polymorphism) with any genotype T(2255)-->C polymorphism are increases the risk of IATS.

  10. Sealed substrate carrier for electroplating

    DOEpatents

    Ganti, Kalyana Bhargava [Fremont, CA

    2012-07-17

    One embodiment relates to a substrate carrier for use in electroplating a plurality of substrates. The substrate carrier includes a non-conductive carrier body on which the substrates are held, and conductive lines are embedded within the carrier body. A conductive bus bar is embedded into a top side of the carrier body and is conductively coupled to the conductive lines. A thermoplastic overmold covers a portion of the bus bar, and there is a plastic-to-plastic bond between the thermoplastic overmold and the non-conductive carrier body. Other embodiments, aspects and features are also disclosed.

  11. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease.

    PubMed Central

    Poirier, J; Delisle, M C; Quirion, R; Aubert, I; Farlow, M; Lahiri, D; Hui, S; Bertrand, P; Nalbantoglu, J; Gilfix, B M

    1995-01-01

    Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APO epsilon 2, APO epsilon 3, and APO epsilon 4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (ChAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that > 80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients. Images Fig. 2 PMID:8618881

  12. Intragenic allele pyramiding combines different specificities of wheat Pm3 resistance alleles.

    PubMed

    Brunner, Susanne; Hurni, Severine; Streckeisen, Philipp; Mayr, Gabriele; Albrecht, Mario; Yahiaoui, Nabila; Keller, Beat

    2010-11-01

    Some plant resistance genes occur as allelic series, with each member conferring specific resistance against a subset of pathogen races. In wheat, there are 17 alleles of the Pm3 gene. They encode nucleotide-binding (NB-ARC) and leucine-rich-repeat (LRR) domain proteins, which mediate resistance to distinct race spectra of powdery mildew. It is not known if specificities from different alleles can be combined to create resistance genes with broader specificity. Here, we used an approach based on avirulence analysis of pathogen populations to characterize the molecular basis of Pm3 recognition spectra. A large survey of mildew races for avirulence on the Pm3 alleles revealed that Pm3a has a resistance spectrum that completely contains that of Pm3f, but also extends towards additional races. The same is true for the Pm3b and Pm3c gene pair. The molecular analysis of these allelic pairs revealed a role of the NB-ARC protein domain in the efficiency of effector-dependent resistance. Analysis of the wild-type and chimeric Pm3 alleles identified single residues in the C-terminal LRR motifs as the main determinant of allele specificity. Variable residues of the N-terminal LRRs are necessary, but not sufficient, to confer resistance specificity. Based on these data, we constructed a chimeric Pm3 gene by intragenic allele pyramiding of Pm3d and Pm3e that showed the combined resistance specificity and, thus, a broader recognition spectrum compared with the parental alleles. Our findings support a model of stepwise evolution of Pm3 recognition specificities.

  13. Lack of neural compensatory mechanisms of BDNF val66met met carriers and APOE E4 carriers in healthy aging, mild cognitive impairment, and Alzheimer's disease.

    PubMed

    Gomar, Jesus J; Conejero-Goldberg, Concepcion; Huey, Edward D; Davies, Peter; Goldberg, Terry E

    2016-03-01

    Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging.

  14. Estimating the probability of allelic drop-out of STR alleles in forensic genetics.

    PubMed

    Tvedebrink, Torben; Eriksen, Poul Svante; Mogensen, Helle Smidt; Morling, Niels

    2009-09-01

    In crime cases with available DNA evidence, the amount of DNA is often sparse due to the setting of the crime. In such cases, allelic drop-out of one or more true alleles in STR typing is possible. We present a statistical model for estimating the per locus and overall probability of allelic drop-out using the results of all STR loci in the case sample as reference. The methodology of logistic regression is appropriate for this analysis, and we demonstrate how to incorporate this in a forensic genetic framework.

  15. Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene

    PubMed Central

    Szekely, Anna; Bircher, Julianna; Vereczkei, Andrea; Balota, David A.; Sasvari-Szekely, Maria; Ronai, Zsolt

    2016-01-01

    Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90–109 years old Californian centenarians, as compared to an ancestry-matched young population. In the present study we demonstrate the same association using continuous age groups in an 18–97 years old Caucasian sample (N = 1801, p = 0.007). We found a continuous pattern of increase from 18–75, however frequency of allele 7 carriers decreased in our oldest age groups. Possible role of gene-environment interaction effects driven by historical events are discussed. In accordance with previous findings, we observed association preferentially in females (p = 0.003). Our results underlie the importance of investigating non-disease related genetic variants as inherited components of longevity, and confirm, that the 7-repeat allele of the dopamine D4 receptor gene is a longevity enabling genetic factor, accumulating in the elderly female population. PMID:27992450

  16. Yarn carrier with clutch

    NASA Technical Reports Server (NTRS)

    Doyne, Richard A. (Inventor); Benson, Rio H. (Inventor); El-Shiekh, Aly (Inventor)

    1994-01-01

    A yarn carrier apparatus particularly suited for use in braiding machinery or the like due to its capability of continuous yarn feeding and retraction of long lengths of yarn. The yarn carrier apparatus comprises a yarn supply spool which is rotatably mounted within the housing, a spring motor also mounted within the housing and operatively connected to the yarn supply spool through a mechanical transmission assembly which is adapted to multiply rotational movement between the first element of the gear assembly operatively connected to the spring motor and the final element of the gear assembly operatively connected to the yarn supply spool. The spring motor is adapted to tension the yarn during both feeding and retraction thereof, and it is further adapted to periodically rotatably slip within the housing and partially unwind so as to allow for continuous withdrawal of a long length of yarn without the spring motor becoming fully wound and preventing further yarn retraction.

  17. The dynamic influence of the DRB1*1101 allele on the resistance of sheep to experimental Teladorsagia circumcincta infection.

    PubMed

    Hassan, Musa; Good, Barbara; Hanrahan, James P; Campion, Deirdre; Sayers, Gearoid; Mulcahy, Grace; Sweeney, Torres

    2011-03-08

    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 of this study was to compare the biochemical and physiological responses of DRB1*1101 carrier and non-carrier twin lambs to an experimental infection with 3 × 10(4) L3 Teladorsagia circumcincta. The variables studied included worm burden, faecal egg count, abomasal mast cells, IgA, IgE, IgG1 plus IgG2 and haematological parameters at 0, 3, 7, 21 and 35 days post infection (dpi), and duodenal smooth muscle contractility at 0 and 35 dpi. DRB1*1101 carrier lambs had significantly lower worm burden, higher mast cell and plasma platelet counts than the DRB1*1101 non-carriers (P < 0.05). Before infection, the non-carrier lambs exhibited significantly higher mucosal levels of all antibody isotypes measured compared to the carriers; these levels remained relatively stable over the course of infection in the non-carriers while there was a slow build up of these antibodies in the carriers up to day 21 post infection (pi). The DRB1*1101 non-carrier lambs had a significantly higher plasma lymphocyte count, and produced greater duodenal contractile force relative to the carrier lambs (P < 0.05). There was no significant difference between genotypes in the level of plasma eosinophils, monocytes, neutrophils or FEC. This evidence suggests that resistance conferred by DRB1*1101 is acquired rather than innate, depends on worm expulsion rather than fecundity and is dependent on mucosal mast cell proliferation, platelet activation, and IgA and IgE antibody responses.

  18. The dynamic influence of the DRB1*1101 allele on the resistance of sheep to experimental Teladorsagia circumcincta infection

    PubMed Central

    2011-01-01

    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 of this study was to compare the biochemical and physiological responses of DRB1*1101 carrier and non-carrier twin lambs to an experimental infection with 3 × 104 L3 Teladorsagia circumcincta. The variables studied included worm burden, faecal egg count, abomasal mast cells, IgA, IgE, IgG1 plus IgG2 and haematological parameters at 0, 3, 7, 21 and 35 days post infection (dpi), and duodenal smooth muscle contractility at 0 and 35 dpi. DRB1*1101 carrier lambs had significantly lower worm burden, higher mast cell and plasma platelet counts than the DRB1*1101 non-carriers (P < 0.05). Before infection, the non-carrier lambs exhibited significantly higher mucosal levels of all antibody isotypes measured compared to the carriers; these levels remained relatively stable over the course of infection in the non-carriers while there was a slow build up of these antibodies in the carriers up to day 21 post infection (pi). The DRB1*1101 non-carrier lambs had a significantly higher plasma lymphocyte count, and produced greater duodenal contractile force relative to the carrier lambs (P < 0.05). There was no significant difference between genotypes in the level of plasma eosinophils, monocytes, neutrophils or FEC. This evidence suggests that resistance conferred by DRB1*1101 is acquired rather than innate, depends on worm expulsion rather than fecundity and is dependent on mucosal mast cell proliferation, platelet activation, and IgA and IgE antibody responses. PMID:21385412

  19. High-Throughput Genotyping with TaqMan Allelic Discrimination and Allele-Specific Genotyping Assays.

    PubMed

    Heissl, Angelika; Arbeithuber, Barbara; Tiemann-Boege, Irene

    2017-01-01

    Real-time PCR-based genotyping methods, such as TaqMan allelic discrimination assays and allele-specific genotyping, are particularly useful when screening a handful of single nucleotide polymorphisms in hundreds of samples; either derived from different individuals, tissues, or pre-amplified DNA. Although real-time PCR-based methods such as TaqMan are well-established, alternative methods, like allele-specific genotyping, are powerful alternatives, especially for genotyping short tandem repeat (STR) length polymorphisms. Here, we describe all relevant aspects when developing an assay for a new SNP or STR using either TaqMan or allele-specific genotyping, respectively, such as primer and probe design, optimization of reaction conditions, the experimental procedure for typing hundreds of samples, and finally the data evaluation. Our goal is to provide a guideline for developing genotyping assays using these two approaches that render reliable and reproducible genotype calls involving minimal optimization.

  20. HLA-B alleles of the Cayapa of Ecuador: new B39 and B15 alleles.

    PubMed

    Garber, T L; Butler, L M; Trachtenberg, E A; Erlich, H A; Rickards, O; De Stefano, G; Watkins, D I

    1995-01-01

    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.

  1. 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

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

    PubMed

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

    2014-11-01

    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.

  3. Symptomatic lipid storage in carriers for the PNPLA2 gene

    PubMed Central

    Janssen, Mirian C H; van Engelen, Baziel; Kapusta, Livia; Lammens, Martin; van Dijk, Martin; Fischer, Judith; van der Graaf, Marinette; Wevers, Ron A; Fahrleitner, Manuela; Zimmermann, Robert; Morava, Eva

    2013-01-01

    Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with associated cardiac disease, myopathy and frequent infections, but without ichthyosis. Here we describe the clinical and biochemical characteristics of a long surviving patient and report on four carrier family members with diverse clinical involvement. Interestingly, heterozygous patients show neutral lipid storage in muscle and in the keratocytes of the skin, Jordans' bodies, mild myopathy and frequent infections. Biochemical analysis of fibroblasts obtained from patients revealed increased triglyceride storage and reduced lipid droplet-associated triglyceride hydrolase activity. Together, our data implicate that the wild-type allele cannot fully compensate for the mutated dysfunctional allele of PNPLA2 leading to triglyceride accumulation in muscle and mild myopathy in PNPLA2 mutation carriers. The presence of neutral lipid droplets in the skin in PNPLA2 mutation carriers strengthens the link between NLSD and other neutral lipid storage diseases with ichthyosis. PMID:23232698

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

    PubMed

    Sakai, Satoki; Wakoh, Haluka

    2014-08-01

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

  5. Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Kartsonaki, Christiana; Gayther, Simon A.; Pharoah, Paul D. P.; Sinilnikova, Olga M.; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Healey, Sue; Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Roversi, Gaia; Barile, Monica; Viel, Alessandra; Allavena, Anna; Ottini, Laura; Papi, Laura; Gismondi, Viviana; Capra, Fabio; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria Adelaide; Olsson, Håkan; Kristoffersson, Ulf; Lindblom, Annika; Arver, Brita; Karlsson, Per; Stenmark Askmalm, Marie; Borg, Ake; Neuhausen, Susan L.; Ding, Yuan Chun; Nathanson, Katherine L.; Domchek, Susan M.; Jakubowska, Anna; Lubiński, Jan; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Górski, Bohdan; Cybulski, Cezary; Dębniak, Tadeusz; Osorio, Ana; Durán, Mercedes; Tejada, Maria-Isabel; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; Verhoef, Senno; Tilanus-Linthorst, Madeleine A.; Vreeswijk, Maaike P.; Bodmer, Danielle; Ausems, Margreet G. E. M.; van Os, Theo A.; Asperen, Christi J.; Blok, Marinus J.; Meijers-Heijboer, Hanne E. J.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Dunning, Alison M.; Evans, D. Gareth; Eeles, Ros; Pichert, Gabriella; Cole, Trevor; Hodgson, Shirley; Brewer, Carole; Morrison, Patrick J.; Porteous, Mary; Kennedy, M. John; Rogers, Mark T.; Side, Lucy E.; Donaldson, Alan; Gregory, Helen; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Moncoutier, Virginie; Castera, Laurent; Mazoyer, Sylvie; Barjhoux, Laure; Bonadona, Valérie; Leroux, Dominique; Faivre, Laurence; Lidereau, Rosette; Nogues, Catherine; Bignon, Yves-Jean; Prieur, Fabienne; Collonge-Rame, Marie-Agnès; Venat-Bouvet, Laurence; Fert-Ferrer, Sandra; Miron, Alex; Buys, Saundra S.; Hopper, John L.; Daly, Mary B.; John, Esther M.; Terry, Mary Beth; Goldgar, David; Hansen, Thomas v. O.; Jønson, Lars; Ejlertsen, Bent; Agnarsson, Bjarni A.; Offit, Kenneth; Kirchhoff, Tomas; Vijai, Joseph; Dutra-Clarke, Ana V. C.; Przybylo, Jennifer A.; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N.; Janavicius, Ramunas; Blanco, Ignacio; Lázaro, Conxi; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Beattie, Mary S.; Schmutzler, Rita; Wappenschmidt, Barbara; Meindl, Alfons; Ruehl, Ina; Fiebig, Britta; Sutter, Christian; Arnold, Norbert; Deissler, Helmut; Varon-Mateeva, Raymonda; Kast, Karin; Niederacher, Dieter; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Soucy, Penny; Spurdle, Amanda B.; Holland, Helene; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

    2011-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. Methods We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation. PMID:21169536

  6. Maintainable substrate carrier for electroplating

    DOEpatents

    Chen, Chen-An; Abas, Emmanuel Chua; Divino, Edmundo Anida; Ermita, Jake Randal G.; Capulong, Jose Francisco S.; Castillo, Arnold Villamor; Ma, Diana Xiaobing

    2016-08-02

    One embodiment relates to a substrate carrier for use in electroplating a plurality of substrates. The carrier includes a non-conductive carrier body on which the substrates are placed and conductive lines embedded within the carrier body. A plurality of conductive clip attachment parts are attached in a permanent manner to the conductive lines embedded within the carrier body. A plurality of contact clips are attached in a removable manner to the clip attachment parts. The contact clips hold the substrates in place and conductively connecting the substrates with the conductive lines. Other embodiments, aspects and features are also disclosed.

  7. Maintainable substrate carrier for electroplating

    DOEpatents

    Chen, Chen-An [Milpitas, CA; Abas, Emmanuel Chua [Laguna, PH; Divino, Edmundo Anida [Cavite, PH; Ermita, Jake Randal G [Laguna, PH; Capulong, Jose Francisco S [Laguna, PH; Castillo, Arnold Villamor [Batangas, PH; Ma,; Xiaobing, Diana [Saratoga, CA

    2012-07-17

    One embodiment relates to a substrate carrier for use in electroplating a plurality of substrates. The carrier includes a non-conductive carrier body on which the substrates are placed and conductive lines embedded within the carrier body. A plurality of conductive clip attachment parts are attached in a permanent manner to the conductive lines embedded within the carrier body. A plurality of contact clips are attached in a removable manner to the clip attachment parts. The contact clips hold the substrates in place and conductively connecting the substrates with the conductive lines. Other embodiments, aspects and features are also disclosed.

  8. 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

  9. Allelic polymorphism in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease.

    PubMed Central

    Bioque, G; Crusius, J B; Koutroubakis, I; Bouma, G; Kostense, P J; Meuwissen, S G; Peña, A S

    1995-01-01

    Recent reports have shown that allele 2 of the IL-1 receptor antagonist (IL-1Ra) gene is over-represented in ulcerative colitis (UC). Healthy individuals carrying allele 2 of this gene have increased production of IL-1Ra protein. Since the final outcome of the biological effects of IL-1 beta may depend on the relative proportion of these two cytokines, we have studied if a TaqI polymorphism in the IL-1 beta gene, which is relevant to IL-1 beta protein production, may be involved in the genetic susceptibility to UC and Crohn's disease (CD), in association with the established IL-1Ra gene polymorphism. Polymorphisms in the closely linked genes for IL-1 beta and IL-1Ra were typed in 100 unrelated Dutch patients with UC, 79 with CD, and 71 healthy controls. The polymorphic regions in exon 5 of the IL-1 beta gene and in intron 2 of the IL-1Ra gene, were studied by polymerase chain reaction (PCR)-based methods. The IL-1 beta allele frequencies in UC and CD patients did not differ from those in healthy controls. In order to study if the IL-1 beta gene polymorphism might participate synergistically with the IL-1Ra gene polymorphism in susceptibility to UC and CD, individuals were distributed into carriers and non-carriers of allele 2 of the genes encoding IL-1 beta and IL-1Ra, in each of the patient groups and controls. Results indicated a significant association of this pair of genes, estimated by the odds ratio (OR) after performing Fisher's exact test, in the UC group (P = 0.023, OR = 2.81), as well as in the CD group (P = 0.01, OR = 3.79). Thus, non-carriers of IL-1 beta allele 2 were more often present in the subgroup of patients carrying the IL-1Ra allele 2. By contrast, no association of these alleles was detected in the group of healthy controls (P = 1.00, OR = 0.92). These results suggest that the IL-1 beta/IL-1Ra allelic cluster may participate in defining the biological basis of predisposition to chronic inflammatory bowel diseases. PMID:7586694

  10. Allelic variation contributes to bacterial host specificity

    SciTech Connect

    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.

    2015-10-30

    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. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.

  11. Allelic variation contributes to bacterial host specificity

    DOE PAGES

    Yue, Min; Han, Xiangan; Masi, Leon De; ...

    2015-10-30

    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 andmore » 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. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.« less

  12. HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

    PubMed Central

    Stephens, Camilla; López-Nevot, Miguel-Ángel; Ruiz-Cabello, Francisco; Ulzurrun, Eugenia; Soriano, Germán; Romero-Gómez, Manuel; Moreno-Casares, Antonia; Lucena, M. Isabel; Andrade, Raúl J.

    2013-01-01

    Background and Aim The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. Methods High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. Results The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). Conclusions HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients. PMID:23874514

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  14. 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.

  15. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, Oliver E.; Pan, David

    1994-01-01

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

  16. Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening.

    PubMed

    Hoffman, Jodi D; Greger, Valerie; Strovel, Erin T; Blitzer, Miriam G; Umbarger, Mark A; Kennedy, Caleb; Bishop, Brian; Saunders, Patrick; Porreca, Gregory J; Schienda, Jaclyn; Davie, Jocelyn; Hallam, Stephanie; Towne, Charles

    2013-11-01

    Tay-Sachs disease (TSD) is the prototype for ethnic-based carrier screening, with a carrier rate of ∼1/27 in Ashkenazi Jews and French Canadians. HexA enzyme analysis is the current gold standard for TSD carrier screening (detection rate ∼98%), but has technical limitations. We compared DNA analysis by next-generation DNA sequencing (NGS) plus an assay for the 7.6 kb deletion to enzyme analysis for TSD carrier screening using 74 samples collected from participants at a TSD family conference. Fifty-one of 74 participants had positive enzyme results (46 carriers, five late-onset Tay-Sachs [LOTS]), 16 had negative, and seven had inconclusive results. NGS + 7.6 kb del screening of HEXA found a pathogenic mutation, pseudoallele, or variant of unknown significance (VUS) in 100% of the enzyme-positive or obligate carrier/enzyme-inconclusive samples. NGS detected the B1 allele in two enzyme-negative obligate carriers. Our data indicate that NGS can be used as a TSD clinical carrier screening tool. We demonstrate that NGS can be superior in detecting TSD carriers compared to traditional enzyme and genotyping methodologies, which are limited by false-positive and false-negative results and ethnically focused, limited mutation panels, respectively, but is not ready for sole use due to lack of information regarding some VUS.

  17. Alleles versus mutations: Understanding the evolution of genetic architecture requires a molecular perspective on allelic origins.

    PubMed

    Remington, David L

    2015-12-01

    Perspectives on the role of large-effect quantitative trait loci (QTL) in the evolution of complex traits have shifted back and forth over the past few decades. Different sets of studies have produced contradictory insights on the evolution of genetic architecture. I argue that much of the confusion results from a failure to distinguish mutational and allelic effects, a limitation of using the Fisherian model of adaptive evolution as the lens through which the evolution of adaptive variation is examined. A molecular-based perspective reveals that allelic differences can involve the cumulative effects of many mutations plus intragenic recombination, a model that is supported by extensive empirical evidence. I discuss how different selection regimes could produce very different architectures of allelic effects under a molecular-based model, which may explain conflicting insights on genetic architecture from studies of variation within populations versus between divergently selected populations. I address shortcomings of genome-wide association study (GWAS) practices in light of more suitable models of allelic evolution, and suggest alternate GWAS strategies to generate more valid inferences about genetic architecture. Finally, I discuss how adopting more suitable models of allelic evolution could help redirect research on complex trait evolution toward addressing more meaningful questions in evolutionary biology.

  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.

  19. 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.

  20. Breast cancer in BRCA mutation carriers: medical treatment.

    PubMed

    Milani, Andrea; Geuna, Elena; Zucchini, Giorgia; Aversa, Caterina; Martinello, Rossella; Montemurro, Filippo

    2016-10-01

    About 10% of breast cancers are associated with the inheritance of autosomal dominant breast cancer susceptibility alleles BRCA1 and BRCA2. Until recently, the medical management of BRCA mutation-associated breast cancer has not differed from that of the sporadic breast cancer counterpart. However, there is mounting evidence that this molecular alteration confers sensitivity or resistance to systemic therapies that can be exploited in terms of medical management. For example, studies support the use of platinum salts chemotherapy in BRCA mutated cancers. Moreover, a number of targeted therapies are showing activity in BRCA mutation carriers. Above all, BRCA defective tumor cells are particularly sensitive to Poly(ADP-ribose) polymerase (PARP) inhibitors. This review will summarize the state of the art of the medical treatment of breast cancer in BRCA mutation carriers, with a particular focus on chemotherapies and targeted therapies.

  1. Telemetry carrier ring and support

    NASA Technical Reports Server (NTRS)

    Wakeman, Thomas G. (Inventor)

    1992-01-01

    A telemetry carrier ring for use in a gas turbine engine includes an annular support ring connected to the engine and an annular carrier ring coupled to the support ring, each ring exhibiting different growth characteristics in response to thermal and mechanical loading. The carrier ring is coupled to the support ring by a plurality of circumferentially spaced web members which are relatively thin in an engine radial direction to provide a predetermined degree of radial flexibility. the web members have a circumferential width and straight axial line of action selected to transfer torque and thrust between the support ring and the carrier ring without substantial deflection. The use of the web members with radial flexibility provides compensation between the support ring and the carrier ring since the carrier ring grows at a different rate than the supporting ring.

  2. Borrowed alleles and convergence in serpentine adaptation

    PubMed Central

    Arnold, Brian J.; Lahner, Brett; DaCosta, Jeffrey M.; Weisman, Caroline M.; Hollister, Jesse D.; Salt, David E.; Bomblies, Kirsten; Yant, Levi

    2016-01-01

    Serpentine barrens represent extreme hazards for plant colonists. These sites are characterized by high porosity leading to drought, lack of essential mineral nutrients, and phytotoxic levels of metals. Nevertheless, nature forged populations adapted to these challenges. Here, we use a population-based evolutionary genomic approach coupled with elemental profiling to assess how autotetraploid Arabidopsis arenosa adapted to a multichallenge serpentine habitat in the Austrian Alps. We first demonstrate that serpentine-adapted plants exhibit dramatically altered elemental accumulation levels in common conditions, and then resequence 24 autotetraploid individuals from three populations to perform a genome scan. We find evidence for highly localized selective sweeps that point to a polygenic, multitrait basis for serpentine adaptation. Comparing our results to a previous study of independent serpentine colonizations in the closely related diploid Arabidopsis lyrata in the United Kingdom and United States, we find the highest levels of differentiation in 11 of the same loci, providing candidate alleles for mediating convergent evolution. This overlap between independent colonizations in different species suggests that a limited number of evolutionary strategies are suited to overcome the multiple challenges of serpentine adaptation. Interestingly, we detect footprints of selection in A. arenosa in the context of substantial gene flow from nearby off-serpentine populations of A. arenosa, as well as from A. lyrata. In several cases, quantitative tests of introgression indicate that some alleles exhibiting strong selective sweep signatures appear to have been introgressed from A. lyrata. This finding suggests that migrant alleles may have facilitated adaptation of A. arenosa to this multihazard environment. PMID:27357660

  3. An allele-specific PCR system for rapid detection and discrimination of the CYP2C19∗4A, ∗4B, and ∗17 alleles: implications for clopidogrel response testing.

    PubMed

    Scott, Stuart A; Tan, Qian; Baber, Usman; Yang, Yao; Martis, Suparna; Bander, Jeffrey; Kornreich, Ruth; Hulot, Jean-Sébastien; Desnick, Robert J

    2013-11-01

    CYP2C19 is involved in the metabolism of clinically relevant drugs, including the antiplatelet prodrug clopidogrel, which has prompted interest in clinical CYP2C19 genotyping. The CYP2C19∗4B allele is defined by both gain-of-function [c.-806C>T (∗17)] and loss-of-function [c.1A>G (∗4)] variants on the same haplotype; however, current genotyping and sequencing assays are unable to determine the phase of these variants. Thus, the aim of this study was to develop an assay that could rapidly detect and discriminate the related ∗4A, ∗4B, and ∗17 alleles. An allele-specific PCR assay, composed of four unique primer mixes that specifically interrogate the defining ∗17 and ∗4 variants, was developed by using samples (n = 20) with known genotypes, including the ∗4A, ∗4B, and/or ∗17 alleles. The assay was validated by testing 135 blinded samples, and the results were correlated with CYP2C19 genotyping and allele-specific cloning/sequencing. Importantly, among the six ∗4 carriers in the validation cohort, after allele-specific PCR testing both samples with a ∗1/∗4 genotype were reclassified to ∗1/∗4A, all three samples with a ∗4/∗17 genotype were reclassified to ∗1/∗4B, and a sample with a ∗4/∗17/∗17 genotype was reclassified to ∗4B/∗17. In conclusion, this rapid and robust allele-specific PCR assay can refine CYP2C19 genotyping and metabolizer phenotype classification by determining the phase of the defining ∗17 and ∗4 variants, which may have utility when testing CYP2C19 for clopidogrel response.

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

    PubMed

    Lachance, Joseph; Tishkoff, Sarah A

    2014-10-02

    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.

  5. Prolactin rs1341239 T allele may have protective role against the brick tea type skeletal fluorosis

    PubMed Central

    Li, Bing-Yun; Yang, Yan-Mei; Liu, Yang; Sun, Jing; Ye, Yan; Liu, Xiao-Na; Liu, Hong-Xu; Sun, Zhen-Qi; Li, Mang; Cui, Jing; Sun, Dian-Jun; Gao, Yan-Hui

    2017-01-01

    Objective Prolactin (PRL) has been reported to be associated with increased bone turnover, and increased bone turnover is also a feature of skeletal fluorosis (SF). Autocrine/paracrine production of PRL is regulated by the extrapituitary promoter and a polymorphism in the extrapituitary PRL promoter at -1149 (rs1341239) is associated with disturbances of bone metabolism in other diseases. Here, we have investigated the possibility that the rs1341239 polymorphism is associated with SF, which results from the consumption of brick tea. Design We conducted a cross-sectional study in Sinkiang, Qinghai, Inner Mongolia in China. Demography survey questionnaires were completed and physical examination and X-ray diagnoses were used to diagnose SF. Brick tea water fluoride intake (IF) and urinary fluoride (UF) were tested by an F-ion selective electrode method. A Sequenom MassARRAY system was used to determine PRL gene polymorphisms. Results Subjects who were younger than 45 years of age and carried the T allele had a significantly decreased risk of SF [OR = 0.279 (95%CI, 0.094–0.824)] compared to those carrying the homozygous G allele. This phenomenon was only observed in Kazakh subjects [OR = 0.127 (95%CI, 0.025–0.646)]. Kazakh females who carried T alleles has a decreased risk of SF [OR = 0.410 (95%CI, 0.199–0.847)]. For Kazakh subjects which IF is less than 3.5 mg/d, a decreased risk of SF was observed among the participants who carried T alleles [OR = 0.118 (95%CI, 0.029–0.472)]. Overall, subjects with 1.6–3.2 mg/L UF and carried T alleles had a significantly decreased risk of SF [OR = 0.476 (95%CI, 0.237–0.955)] compared to homozygous G allele carriers. This phenomenon was only observed in Kazakh subjects [OR = 0.324 (95%CI, 0.114–0.923)]. Conclusions Our results suggested that the PRL rs1341239 T allele decreases the risk of brick tea SF. PMID:28152004

  6. Personnel emergency carrier vehicle

    NASA Technical Reports Server (NTRS)

    Owens, Lester J. (Inventor); Fedor, Otto H. (Inventor)

    1987-01-01

    A personnel emergency carrier vehicle is disclosed which includes a vehicle frame supported on steerable front wheels and driven rear wheels. A supply of breathing air is connected to quick connect face mask coupling and umbilical cord couplings for supplying breathing air to an injured worker or attendant either with or without a self-contained atmospheric protection suit for protection against hazardous gases at an accident site. A non-sparking hydraulic motion is utilized to drive the vehicle and suitable direction and throttling controls are provided for controlling the delivery of a hydraulic driving fluid from a pressurized hydraulic fluid accumulator. A steering axis is steerable through a handle to steer the front wheels through a linkage assembly.

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

    PubMed Central

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

    1998-01-01

    Expectations for the time scale and structure of allelic genealogies in finite populations are formed under three models of sporophytic self-incompatibility. The models differ in the dominance interactions among the alleles that determine the self-incompatibility phenotype: In the SSIcod model, alleles act codominantly in both pollen and style, in the SSIdom model, alleles form a dominance hierarchy, and in SSIdomcod, alleles are codominant in the style and show a dominance hierarchy in the pollen. Coalescence times of alleles rarely differ more than threefold from those under gametophytic self-incompatibility, and transspecific polymorphism is therefore expected to be equally common. The previously reported directional turnover process of alleles in the SSIdomcod model results in coalescence times lower and substitution rates higher than those in the other models. The SSIdom model assumes strong asymmetries in allelic action, and the most recessive extant allele is likely to be the most recent common ancestor. Despite these asymmetries, the expected shape of the allele genealogies does not deviate markedly from the shape of a neutral gene genealogy. The application of the results to sequence surveys of alleles, including interspecific comparisons, is discussed. PMID:9799270

  8. Positive Selection of Deleterious Alleles through Interaction with a Sex-Ratio Suppressor Gene in African Buffalo: A Plausible New Mechanism for a High Frequency Anomaly

    PubMed Central

    van Hooft, Pim; Greyling, Ben J.; Getz, Wayne M.; van Helden, Paul D.; Zwaan, Bas J.; Bastos, Armanda D. S.

    2014-01-01

    Although generally rare, deleterious alleles can become common through genetic drift, hitchhiking or reductions in selective constraints. Here we present a possible new mechanism that explains the attainment of high frequencies of deleterious alleles in the African buffalo (Syncerus caffer) population of Kruger National Park, through positive selection of these alleles that is ultimately driven by a sex-ratio suppressor. We have previously shown that one in four Kruger buffalo has a Y-chromosome profile that, despite being associated with low body condition, appears to impart a relative reproductive advantage, and which is stably maintained through a sex-ratio suppressor. Apparently, this sex-ratio suppressor prevents fertility reduction that generally accompanies sex-ratio distortion. We hypothesize that this body-condition-associated reproductive advantage increases the fitness of alleles that negatively affect male body condition, causing genome-wide positive selection of these alleles. To investigate this we genotyped 459 buffalo using 17 autosomal microsatellites. By correlating heterozygosity with body condition (heterozygosity-fitness correlations), we found that most microsatellites were associated with one of two gene types: one with elevated frequencies of deleterious alleles that have a negative effect on body condition, irrespective of sex; the other with elevated frequencies of sexually antagonistic alleles that are negative for male body condition but positive for female body condition. Positive selection and a direct association with a Y-chromosomal sex-ratio suppressor are indicated, respectively, by allele clines and by relatively high numbers of homozygous deleterious alleles among sex-ratio suppressor carriers. This study, which employs novel statistical techniques to analyse heterozygosity-fitness correlations, is the first to demonstrate the abundance of sexually-antagonistic genes in a natural mammal population. It also has important

  9. Sequence analysis of the fragile X trinucleotide repeat: Correlations with stability and haplotype and implications for the origin of fragile X alleles

    SciTech Connect

    Snow, K.; Tester, D.J.; Kruckeberg, K.E.; Thibodeau, S.N.

    1994-09-01

    Fragile X (FX) syndrome is associated with amplification of a CGG trinucleotide repeat in the 5{prime} untranslated region of the gene FMR-1. To address mechanism of instability and concern related to overlap between sizes of normal stable alleles and FX unstable alleles, we have sequenced 165 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines instability. For 17 stably transmitted alleles with total repeat lengths between 33 and 51, the longest stretch of uninterrupted CGGs was 41. In contrast, for 13 premutation alleles, the shortest stretch of uninterrupted CGGs was 48, suggesting a threshold for expansion between 41 and 48 pure CGGs. For expansion from a premutation to a full mutation, the threshold appears to be {ge}70 uninterrupted repeats. Interestingly, an AGG was detected in some carriers of a full mutation. Comparison of the number of {open_quote}shadow bands{close_quote} in PCR products from similar size alleles with different AGG interruption patterns supports replication slippage as a potential mechanism, i.e. replication slippage occurs more readily as the length of pure repeat increases. Alleles with high total repeat lengths but up to 3 AGGs may be relatively protected against expansion, whereas smaller alleles with pure CGG sequence could be at higher risk for instability. Comparison of sequence data and DXS548 (CA)n data revealed specific sequence trends for each of the DXS548 alleles, explaining the previously reported haplotype association with FX. Incorporating these observations into models for the origin of FX alleles, we consider replication slippage, unequal crossover within the CGG repeat region, recombination between FMR-1 and DXS548, and loss of AGGs by A to C transversion.

  10. Positive selection of deleterious alleles through interaction with a sex-ratio suppressor gene in African Buffalo: a plausible new mechanism for a high frequency anomaly.

    PubMed

    van Hooft, Pim; Greyling, Ben J; Getz, Wayne M; van Helden, Paul D; Zwaan, Bas J; Bastos, Armanda D S

    2014-01-01

    Although generally rare, deleterious alleles can become common through genetic drift, hitchhiking or reductions in selective constraints. Here we present a possible new mechanism that explains the attainment of high frequencies of deleterious alleles in the African buffalo (Syncerus caffer) population of Kruger National Park, through positive selection of these alleles that is ultimately driven by a sex-ratio suppressor. We have previously shown that one in four Kruger buffalo has a Y-chromosome profile that, despite being associated with low body condition, appears to impart a relative reproductive advantage, and which is stably maintained through a sex-ratio suppressor. Apparently, this sex-ratio suppressor prevents fertility reduction that generally accompanies sex-ratio distortion. We hypothesize that this body-condition-associated reproductive advantage increases the fitness of alleles that negatively affect male body condition, causing genome-wide positive selection of these alleles. To investigate this we genotyped 459 buffalo using 17 autosomal microsatellites. By correlating heterozygosity with body condition (heterozygosity-fitness correlations), we found that most microsatellites were associated with one of two gene types: one with elevated frequencies of deleterious alleles that have a negative effect on body condition, irrespective of sex; the other with elevated frequencies of sexually antagonistic alleles that are negative for male body condition but positive for female body condition. Positive selection and a direct association with a Y-chromosomal sex-ratio suppressor are indicated, respectively, by allele clines and by relatively high numbers of homozygous deleterious alleles among sex-ratio suppressor carriers. This study, which employs novel statistical techniques to analyse heterozygosity-fitness correlations, is the first to demonstrate the abundance of sexually-antagonistic genes in a natural mammal population. It also has important

  11. Exquisite allele discrimination by toehold hairpin primers

    PubMed Central

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

    2014-01-01

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

  12. Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency.

    PubMed

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

    2013-01-01

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

  13. Apolipoprotein E epsilon4 allele differentiates the clinical response to donepezil in Alzheimer's disease.

    PubMed

    Bizzarro, A; Marra, C; Acciarri, A; Valenza, A; Tiziano, F D; Brahe, C; Masullo, C

    2005-01-01

    The existence of an association between apolipoprotein E (APOE) and Alzheimer's disease (AD) has been reported in several studies. The possession of an ApoE epsilon4 allele is now considered a genetic risk factor for sporadic AD. There has been a growing agreement about the role exerted by the ApoE epsilon4 allele on the neuropsychological profile and the rate of cognitive decline in AD patients. However, a more controversial issue remains about a possible influence of the APOE genotype on acetylcholinesterase inhibitor therapy response in AD patients. In order to address this issue, 81 patients diagnosed as having probable AD were evaluated by a complete neuropsychological test battery at the time of diagnosis (baseline) and after 12-16 months (retest). Patients were divided into two subgroups: (1) treated with donepezil at a dose of 5 mg once a day (n = 41) and (2) untreated (n = 40). Donepezil therapy was started after baseline evaluation. The APOE genotype was determined according to standardized procedures. We evaluated the possible effect of the APOE genotype on the neuropsychological tasks in relation to donepezil therapy. The statistical analysis of the results showed a global worsening of cognitive performances for all AD patients at the retest. Differences in the clinical outcome were analysed in the four subgroups of AD patients for each neuropsychological task. ApoE epsilon4 carriers/treated patients had improved or unchanged scores at retest evaluation for the following tasks: visual and verbal memory, visual attention and inductive reasoning and Mini Mental State Examination. These results indicate an effect of donepezil on specific cognitive domains (attention and memory) in the ApoE epsilon4 carriers with AD. This might suggest an early identification of AD patients carrying at least one epsilon4 allele as responders to donepezil therapy.

  14. Microarrays for high-throughput genotyping of MICA alleles using allele-specific primer extension.

    PubMed

    Baek, I C; Jang, J-P; Choi, H-B; Choi, E-J; Ko, W-Y; Kim, T-G

    2013-10-01

    The role of major histocompatibility complex (MHC) class I chain-related gene A (MICA), a ligand of NKG2D, has been defined in human diseases by its allele associations with various autoimmune diseases, hematopoietic stem cell transplantation (HSCT) and cancer. This study describes a practical system to develop MICA genotyping by allele-specific primer extension (ASPE) on microarrays. From the results of 20 control primers, strict and reliable cut-off values of more than 30,000 mean fluorescence intensity (MFI) as positive and less than 3000 MFI as negative, were applied to select high-quality specific extension primers. Among 55 allele-specific primers, 44 primers could be initially selected as optimal primer. Through adjusting the length, six primers were improved. The other failed five primers were corrected by refractory modification. MICA genotypes by ASPE on microarrays showed the same results as those by nucleotide sequencing. On the basis of these results, ASPE on microarrays may provide high-throughput genotyping for MICA alleles for population studies, disease-gene associations and HSCT.

  15. Infrared hot carrier diode mixer.

    PubMed

    Aukerman, L W; Erler, J W

    1977-11-01

    Detection of a 54.3-GHz beatnote at 10.6 microm has been observed with a hot carrier diode mixer. The diode consists of a "cat whisker" antenna, which forms an ohmic point contact to n-InAs. The mechanism of this room-temperature detector is described as the "thermoelectric effect" of hot carriers.

  16. Apolipoprotein E4 allele is associated with substantial changes in the plasma lipids and hyaluronic acid content in patients with nonalcoholic fatty liver disease.

    PubMed

    Stachowska, E; Maciejewska, D; Ossowski, P; Drozd, A; Ryterska, K; Banaszczak, M; Milkiewicz, M; Raszeja-Wyszomirska, J; Slebioda, M; Milkiewicz, P; Jelen, H

    2013-12-01

    Fat may affect progression of liver damage in patients with non-alcoholic fatty liver disease (NAFLD). In this study we characterize the state of lipid metabolism in 22 patients with NAFLD and different Apo-E variants. Total concentration of plasma total fatty acids was quantified by gas chromatography, while their derivatives by liquid chromatography/tandem mass spectrometry (LC ESI MS/MS). The ratio of plasma saturated fatty acid to monounsaturated fatty acid increased, whereas the ratio of polyunsaturated fatty acids to saturated fatty acids was reduced in Apo-E4 carriers. Simultaneously, the levels of individual plasma linoleic, arachidonic, and alpha linolenic acids significantly increased in subjects with the Apo-E4 allele. The 15-lipoxygenase metabolite, 13-hydroxyoctadecadienoic acid, was significantly higher in Apo-E3 carriers (p<0.006). 5-oxo-6,8,11,14-eicosatetraenoic acid was significantly elevated in Apo-E4 carriers (p<0.009). A significant difference in hyaluronic acid concentration (p<0.0016) as well as predicted advanced fibrosis (using the BARD scoring system) was found in Apo-E4 carriers (p<0.01). We suggest that a distinct mechanism of fibrosis between Apo E alleles. In Apo-E4 carriers, an elevation in 5-oxo-6,8,11,14-eicosatetraenoic acid synthesis and fatty acid dysfunction may induce fibrosis, while an inflammatory process may be the main cause of fibrosis in Apo-E3 carriers.

  17. Use of allele scores as instrumental variables for Mendelian randomization

    PubMed Central

    Burgess, Stephen; Thompson, Simon G

    2013-01-01

    Background An allele score is a single variable summarizing multiple genetic variants associated with a risk factor. It is calculated as the total number of risk factor-increasing alleles for an individual (unweighted score), or the sum of weights for each allele corresponding to estimated genetic effect sizes (weighted score). An allele score can be used in a Mendelian randomization analysis to estimate the causal effect of the risk factor on an outcome. Methods Data were simulated to investigate the use of allele scores in Mendelian randomization where conventional instrumental variable techniques using multiple genetic variants demonstrate ‘weak instrument’ bias. The robustness of estimates using the allele score to misspecification (for example non-linearity, effect modification) and to violations of the instrumental variable assumptions was assessed. Results Causal estimates using a correctly specified allele score were unbiased with appropriate coverage levels. The estimates were generally robust to misspecification of the allele score, but not to instrumental variable violations, even if the majority of variants in the allele score were valid instruments. Using a weighted rather than an unweighted allele score increased power, but the increase was small when genetic variants had similar effect sizes. Naive use of the data under analysis to choose which variants to include in an allele score, or for deriving weights, resulted in substantial biases. Conclusions Allele scores enable valid causal estimates with large numbers of genetic variants. The stringency of criteria for genetic variants in Mendelian randomization should be maintained for all variants in an allele score. PMID:24062299

  18. Allele-specific disparity in breast cancer

    PubMed Central

    2011-01-01

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

  19. CYP3A7*1C allele is associated with reduced levels of 2-hydroxylation pathway oestrogen metabolites

    PubMed Central

    Sood, Deepti; Johnson, Nichola; Jain, Pooja; Siskos, Alexandros P; Bennett, Mark; Gilham, Clare; Busana, Marta Cecilia; Peto, Julian; dos-Santos-Silva, Isabel; Keun, Hector C; Fletcher, Olivia

    2017-01-01

    Background: Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear. We have previously identified a CYP3A7*1C allele that is associated with lower urinary oestrone (E1) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs. Methods: We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS. Results: In addition to having lower urinary E1 levels, CYP3A7*1C carriers had significantly lower levels of four of the 2-hydroxylation pathway EMs that we measured (2-hydroxyestrone, P=1.1 × 10−12; 2-hydroxyestradiol, P=2.7 × 10−7; 2-methoxyestrone, P=1.9 × 10−12; and 2-methoxyestradiol, P=0.0009). By contrast, 16α-hydroxylation pathway EMs were slightly higher in carriers and significantly so for 17-epiestriol (P=0.002). Conclusions: The CYP3A7*1C allele is associated with a lower urinary E1 levels, a more pronounced reduction in 2-hydroxylation pathway EMs and a lower ratio of 2-hydroxylation:16α-hydroxylation EMs in premenopausal women. To further characterise the association between parent oestrogens, EMs and subsequent risk of breast cancer, characterisation of additional genetic variants that influence oestrogen metabolism and large prospective studies of a broad spectrum of EMs will be required. PMID:28072767

  20. Protective Effect of R Allele of PON1 Gene on the Coronary Artery Disease in the Presence of Specific Genetic Background

    PubMed Central

    Balcerzyk, Anna; Zak, Iwona; Krauze, Jolanta

    2008-01-01

    Background: Genetic susceptibility to CAD may be determined by polymorphic variants of genes encoding isoforms involved in the processes important in the pathogenesis of atherosclerosis, including lipids disorders. Participation of single polymorphic variants is relatively small, however its significance may increase in the presence of specific genetic or environmental background. Aim: The aim of the study was an evaluation a possible association between single polymorphic variants of PON1, APOE, ABCA1 and PPARA genes and CAD and looking for specific multigene genotype patterns which differentiate study groups. Materials and methods: We studied 358 subjects:178 patients with angiographically confirmed CAD and 180 blood donors without history of CAD. Polymorphisms were genotyped using PCR-RFLP method. Results: We observed statistically significant differences in the frequencies of R allele and R allele carriers of PON1 gene between CAD and controls. The distribution of genotypes and alleles of other analyzed genes did not differentiate the study groups, however the presence of specific genotypes (APOE– ɛ3ɛ3, ɛ3ɛ2, ABCA1 – AG, PPARA – GG) increased the protective effect of R allele. Conclusion: The present study revealed an independent protective association between carrier-state of PON1 R allele and CAD. This protective effect was especially strong in the presence of specific genotype arrangements of other analyzed genes. PMID:18219093

  1. 14 CFR Section 04 - Air Carrier Groupings

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Air Carrier Groupings Section 04 Section 04... REGULATIONS UNIFORM SYSTEM OF ACCOUNTS AND REPORTS FOR LARGE CERTIFICATED AIR CARRIERS Section 04 Air Carrier Groupings (a) All large certificated air carriers are placed into three basic air carrier groupings...

  2. 14 CFR Section 04 - Air Carrier Groupings

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Air Carrier Groupings Section 04 Section 04... REGULATIONS UNIFORM SYSTEM OF ACCOUNTS AND REPORTS FOR LARGE CERTIFICATED AIR CARRIERS Section 04 Air Carrier Groupings (a) All large certificated air carriers are placed into three basic air carrier groupings...

  3. Optically induced free carrier light modulator

    NASA Technical Reports Server (NTRS)

    Gruber, C. L.; Richards, W. E.

    1969-01-01

    Signal carrier laser beam is optically modulated by a second laser beam of different frequency acting on a free carrier source to which the signal carrier laser is directed. The second laser beam affects the transmission characteristics of the free carrier source to light from the signal carrier laser, thus modulating it.

  4. 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

  5. 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

    2010-05-04

    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.

  6. Allele-specific expression at the RET locus in blood and gut tissue of individuals carrying risk alleles for Hirschsprung disease.

    PubMed

    Matera, Ivana; Musso, Marco; Griseri, Paola; Rusmini, Marta; Di Duca, Marco; So, Man-Ting; Mavilio, Domenico; Miao, Xiaoping; Tam, Paul Hk; Ravazzolo, Roberto; Ceccherini, Isabella; Garcia-Barcelo, Merce

    2013-05-01

    RET common variants are associated with Hirschsprung disease (HSCR; colon aganglionosis), a congenital defect of the enteric nervous system. We analyzed a well-known HSCR-associated RET haplotype that encompasses linked alleles in coding and noncoding/regulatory sequences. This risk haplotype correlates with reduced level of RET expression when compared with the wild-type counterpart. As allele-specific expression (ASE) contributes to phenotypic variability in health and disease, we investigated whether RET ASE could contribute to the overall reduction of RET mRNA detected in carriers. We tested heterozygous neuroblastoma cell lines, ganglionic gut tissues (18 HSCR and 14 non-HSCR individuals) and peripheral blood mononuclear cells (PBMCs; 16 HSCR and 14 non-HSCR individuals). Analysis of the data generated by SNaPshot and Pyrosequencing revealed that the RET risk haplotype is significantly more expressed in gut than in PBMCs (P = 0.0045). No ASE difference was detected between patients and controls, irrespective of the sample type. Comparison of total RET expression levels between gut samples with and without ASE, correlated reduced RET expression with preferential transcription from the RET risk haplotype. Nonrandom RET ASE occurs in ganglionic gut regardless of the disease status. RET ASE should not be excluded as a disease mechanism acting during development.

  7. Methylization analysis of the FMR1 gene in carrier females

    SciTech Connect

    Meyers, S.; Cappon, S.; Khalifa, M.M.

    1994-09-01

    The fragile X syndrome mutation is associated with an expansion of a CGG repeat sequence and methylation of the CpG island in the promoter of the FMR1 gene. Methylation of the CpG island silences the FMR1 gene, thereby generating the disease phenotypes. Previous studies suggest that the normal FMR1 gene has the properties of an X-linked housekeeping gene that is subject to X inactivation, i.e., its CpG island is unmethylated on the active X chromosome and methylated on the inactive X. Because methylation of the mutant FMR1 gene occurs in both males and females with the full mutation, inactivating the FMR1 gene in these females might be a localized event independent from X inactivation. To test this hypothesis we compared the methylation pattern of two housekeeping genes, PGK1 and androgen receptor (AR) with that of the FMR1 in 46 female carriers of the fragile X syndrome. Twenty eight females were in the premutation range (63-193 repeats) and 16 were carriers of the full mutation (263-996 repeats). The data revealed complete correlation between the methylation pattern of PGK1 and AR. There was also a close correlation between X inactivation pattern detected by PGK1 and/or AR and that detected by FMR1 in female carriers of the premutation. In all female carriers of the full mutation there was complete methylation of the BssHII site in the expanded FMR1 allele. The X chromosome inactivation pattern in these females as detected by PGK1 and/or AR was as follows: in 10 cases the X inactivation was skewed in favor of the mutant FMR1, i.e. the mutant allele was on the inactive X chromosome, in 3 the inactivation was random and in 3 the inactivation was skewed in favor of the normal allele. These data suggest that the methylation of the FMR1 gene in females with the full mutation is a localized event and methylation of the FMR1 gene in these females cannot be used as a predictor of X inactivation.

  8. Identification of a novel HLA-A allele, A*3120.

    PubMed

    Chang, Y; Pascual, C J; Alonzo, P; Chamizo, A

    2009-03-01

    A novel human leukocyte antigen (HLA)-A allele, HLA-A*3120, was first identified in a National Marrow Donor Program (NMDP) donor. The A*3120 allele resulted from a single nucleotide substitution (T to G) at codon 92 of exon 3 of A*310102. The substitution caused an amino acid change (serine to alanine). This novel allele was also seen in two other unrelated NMDP donors.

  9. Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.

    PubMed

    Alcántara-Ortigoza, M A; García-de Teresa, B; González-Del Angel, A; Berumen, J; Guardado-Estrada, M; Fernández-Hernández, L; Navarrete-Martínez, J I; Maza-Morales, M; Rius-Domínguez, R

    2016-05-01

    Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.

  10. Frequency Specific Effects of ApoE ε4 Allele on Resting-State Networks in Nondemented Elders

    PubMed Central

    Liang, Ying; Li, Zhenzhen; Neuroimaging Initiative, Alzheimer's Disease

    2017-01-01

    We applied resting-state functional magnetic resonance imaging (fMRI) to examine the Apolipoprotein E (ApoE) ε4 allele effects on functional connectivity of the default mode network (DMN) and the salience network (SN). Considering the frequency specific effects of functional connectivity, we decomposed the brain network time courses into two bands: 0.01–0.027 Hz and 0.027–0.08 Hz. All scans were acquired by the Alzheimer's Disease Neuroscience Initiative (ADNI). Thirty-two nondemented subjects were divided into two groups based on the presence (n = 16) or absence (n = 16) of the ApoE ε4 allele. We explored the frequency specific effects of ApoE ε4 allele on the default mode network (DMN) and the salience network (SN) functional connectivity. Compared to ε4 noncarriers, the DMN functional connectivity of ε4 carriers was significantly decreased while the SN functional connectivity of ε4 carriers was significantly increased. Many functional connectivities showed significant differences at the lower frequency band of 0.01–0.027 Hz or the higher frequency band of 0.027–0.08 Hz instead of the typical range of 0.01–0.08 Hz. The results indicated a frequency dependent effect of resting-state signals when investigating RSNs functional connectivity.

  11. Peroxisome proliferator-activated receptor-gamma2 polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes: The Berlin Diabetes Mellitus (BeDiaM) Study.

    PubMed

    Herrmann, Stefan-Martin; Ringel, Jens; Wang, Ji-Guang; Staessen, Jan A; Brand, Eva

    2002-08-01

    The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor (PPAR)-gamma2 has recently been shown to be associated with type 2 diabetes. In the present analysis, we investigated whether PPAR-gamma2 Pro12Ala was associated with microvascular complications of type 2 diabetes, such as albuminuria, end-stage renal failure (ESRF), or retinopathy. A total of 445 patients with type 2 diabetes who were enrolled in the Berlin Diabetes Mellitus Study and in whom we determined albuminuria and the presence of ESRF and retinopathy were genotyped for the PPAR-gamma2 Pro12Ala polymorphism. We also measured potentially important covariables, such as blood pressure, BMI, duration of diabetes, glycosylated hemoglobin, serum creatinine, and serum lipids. Among 445 patients with type 2 diabetes (mean age 59.3 years), the Pro12Ala genotype distribution was in Hardy-Weinberg equilibrium (P = 0.42). The Ala12 allele frequency was 0.14. With adjustment for covariables, the 118 Ala12 allele carriers had significantly lower urinary albumin excretion (UAE) than the 327 noncarriers (17.1 vs. 25.8 mg/d; P = 0.01). The percentage decrease in UAE observed in PPAR-gamma Ala12 allele carriers relative to noncarriers (P = 0.003) rose from 0.2% (P = 0.99) to 54% (P = 0.008) and to 70% (P = 0.01) when the duration of diabetes increased from <10 years to 10-19 years and to >or=20 years, respectively. Similarly, the odds ratios of having albuminuria decreased from 1.22 (P = 0.54) to 0.61 (P = 0.23) and to 0.11 (P = 0.007), respectively. Among patients with type 2 diabetes, PPAR-gamma2 Ala12 allele carriers had significantly lower UAE and tended to develop overt proteinuria less frequently. These observations suggest a protective effect of the Ala12 allele in relation to diabetic nephropathy.

  12. Novel HLA-A and HLA-B alleles.

    PubMed

    Hurley, C K; Steiner, N; Kosman, C; Mitton, W; Koester, R; Bei, M; Bush, J; McCormack, J; Hahn, A; Henson, V; Hoyer, R; Wade, J A; Hartzman, R J; Ng, J

    1998-07-01

    Nine novel HLA-A and HLA-B alleles are described: A*2609, A*6803, A*6806, B*1539, B*1540, B*2712, B*4103, B*5109, and B*5603. Most appear to have arisen by gene conversion events. B*5603 appears to have arisen by a reciprocal recombination event joining exon 2 of a B*55/ *56 allele with exon 3 of a B*15 allele. Serologically, the antigen encoded by this allele types with broad B22- and Bw6-specific alloantisera. Also unique, the antigen encoded by B*2712 does not react with B27-specific alloantisera but does react with Bw6-specific alloantisera.

  13. Mutated tumor alleles are expressed according to their DNA frequency.

    PubMed

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

    2014-04-22

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

  14. ω-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression.

    PubMed

    Samieri, Cécilia; Féart, Catherine; Proust-Lima, Cécile; Peuchant, Evelyne; Dartigues, Jean-François; Amieva, Hélène; Barberger-Gateau, Pascale

    2011-12-01

    Long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may slow cognitive decline. The ε4 allele of the ApolipoproteinE (ApoE), the main genetic risk factor for Alzheimer's disease, and depressive symptoms, which are frequently associated with cognitive impairment in older persons, may modify this relationship. We estimated the associations between EPA and DHA plasma levels and subsequent cognitive decline over 7 years, taking into account ApoE-ε4 status and depressive symptoms, in a prospective population-based cohort. Participants (≥ 65 years, n = 1,228 nondemented at baseline) were evaluated at least once over three follow-up visits using four cognitive tests. Plasma EPA was associated with slower decline on Benton Visual Retention Test (BVRT) performances in ApoE-ε4 carriers, or in subjects with high depressive symptoms at baseline. Plasma DHA was associated with slower decline on BVRT performances in ApoE-ε4 carriers only. EPA and DHA may contribute to delaying decline in visual working memory in ApoE-ε4 carriers. In older depressed subjects, EPA, but not DHA, may slow cognitive decline.

  15. 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

  16. The GLO1 C332 (Ala111) allele confers autism vulnerability: family-based genetic association and functional correlates.

    PubMed

    Gabriele, Stefano; Lombardi, Federica; Sacco, Roberto; Napolioni, Valerio; Altieri, Laura; Tirindelli, Maria Cristina; Gregorj, Chiara; Bravaccio, Carmela; Rousseau, Francis; Persico, Antonio M

    2014-12-01

    Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.

  17. 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

  18. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots.

    PubMed

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

    2015-09-01

    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.

  19. Stable wafer-carrier system

    DOEpatents

    Rozenzon, Yan; Trujillo, Robert T; Beese, Steven C

    2013-10-22

    One embodiment of the present invention provides a wafer-carrier system used in a deposition chamber for carrying wafers. The wafer-carrier system includes a base susceptor and a top susceptor nested inside the base susceptor with its wafer-mounting side facing the base susceptor's wafer-mounting side, thereby forming a substantially enclosed narrow channel. The base susceptor provides an upward support to the top susceptor.

  20. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients.

    PubMed

    Paradowska-Gorycka, A; Stypińska, B; Olesińska, M; Felis-Giemza, A; Mańczak, M; Czuszynska, Z; Zdrojewski, Z; Wojciechowicz, J; Jurkowska, M

    2015-11-09

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD.

  1. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients.

    PubMed

    Paradowska-Gorycka, A; Stypińska, B; Olesińska, M; Felis-Giemza, A; Mańczak, M; Czuszynska, Z; Zdrojewski, Z; Wojciechowicz, J; Jurkowska, M

    2016-01-01

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD.

  2. Who is a carrier? Detection of unsuspected mutations in 21-hydroxylase deficiency

    SciTech Connect

    Witchel, S.S.; Lee, P.A.; Trucco, M.

    1996-01-02

    Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common autosomal-recessive disorder. During our routine genotyping of affected individuals and their relatives using allele-specific oligonucleotide hybridization and single-strand conformational polymorphism analysis, we identified two families each segregating three mutations. In both families, a mutation known to be associated with 21-hydroxylase deficiency was identified in healthy individuals but was not detected in the propositus. The propositus in family 1 was shown to be a homozygous carrier for G at nucleotide 655, which alters the splice acceptor site at exon 3. The propositus in family 2 carried the same splicing mutation on the maternal allele and a gene deletion/conversion on the paternal allele. In both families, other clinically unaffected relatives carried the Q318X mutation in exon 8. If molecular diagnostic studies had been limited to the mutation carried by the propositi, relatives would have been misinformed regarding their status as carriers or mildly affected individuals. The findings in these two families emphasize the high frequency of alleles causing 21-hydroxylase deficiency in the population. 29 refs., 3 figs., 2 tabs.

  3. Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

    PubMed Central

    2012-01-01

    Background Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. Methods We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. Results Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. Conclusions Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene. PMID:23092449

  4. Observations Suggesting Allelism of the Achondroplasia and Hypochondroplasia Genes

    PubMed Central

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

    1973-01-01

    It is argued that there are at least two alleles at the achondroplasia locus: one responsible for classic achondroplasia and one responsible for hypochondroplasia. Homozygosity for the achondroplasia gene produces a lethal skeletal dysplasia; homozygosity for hypochondroplasia has not been described. We report here a child considered to be a genetic compound for the achondroplasia and hypochondroplasia alleles. Images PMID:4697848

  5. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia

    PubMed Central

    van Blitterswijk, Marka; Mullen, Bianca; Nicholson, Alexandra M.; Bieniek, Kevin F.; Heckman, Michael G.; Baker, Matthew C.; DeJesus-Hernandez, Mariely; Finch, NiCole A.; Brown, Patricia H.; Murray, Melissa E.; Hsiung, Ging-Yuek R.; Stewart, Heather; Karydas, Anna M.; Finger, Elizabeth; Kertesz, Andrew; Bigio, Eileen H.; Weintraub, Sandra; Mesulam, Marsel; Hatanpaa, Kimmo J.; White, Charles L.; Strong, Michael J.; Beach, Thomas G.; Wszolek, Zbigniew K.; Lippa, Carol; Caselli, Richard; Petrucelli, Leonard; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Mackenzie, Ian R.; Seeley, William W.; Grinberg, Lea T.; Miller, Bruce L.; Boylan, Kevin B.; Graff-Radford, Neill R.; Boeve, Bradley F.; Dickson, Dennis W.; Rademakers, Rosa

    2014-01-01

    Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions (with or without motor neuron disease [MND]; cohort 2), and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls (11.9% versus 19.1%, odds ratio (OR): 0.57, p=0.014; same direction as carriers of GRN mutations). The strongest evidence was provided by FTD patients (OR: 0.33, p=0.009) followed by FTD/MND patients (OR: 0.38, p=0.017), whereas no significant difference was observed in MND patients (OR: 0.85, p=0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR: 0.77, p=0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR: 0.26, p<0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations, and might be relevant for prognostic testing, and as a promising

  6. [R74W;R1070W;D1270N]: a new complex allele responsible for cystic fibrosis.

    PubMed

    de Prada Merino, Ana; Bütschi, Florence Niel; Bouchardy, Isabelle; Beckmann, Jacques S; Morris, Michael A; Hafen, Gaudenz M; Fellmann, Florence

    2010-12-01

    Since the beginning of population screening for CF carriers, it has become apparent that complex CFTR alleles are not uncommon. Deciphering their impact in disease pathogenesis remains a challenge for both clinicians and researchers. We report the observation of a new complex allele p.[R74W+R1070W+D1270N] found in trans with a type 1 mutation and associated with clinical diagnosis of cystic fibrosis in a one year-old Moroccan patient. This case underlines the difficulties in counseling patients with uncommon mutations and the necessity of functional studies to evaluate the structure-function relationships, since the association of several variations in cis can dramatically alter CFTR function.

  7. Assortative mating can impede or facilitate fixation of underdominant alleles.

    PubMed

    Newberry, Mitchell G; McCandlish, David M; Plotkin, Joshua B

    2016-12-01

    Underdominant mutations have fixed between divergent species, yet classical models suggest that rare underdominant alleles are purged quickly except in small or subdivided populations. We predict that underdominant alleles that also influence mate choice, such as those affecting coloration patterns visible to mates and predators alike, can fix more readily. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans random mating (n=1) and complete assortment (n→∞), yet it produces sexual selection whose strength depends non-monotonically on n. This sexual selection interacts with viability selection to either inhibit or facilitate fixation. As mating opportunities increase, underdominant alleles fix as frequently as neutral mutations, even though sexual selection and underdominance independently each suppress rare alleles. This mechanism allows underdominant alleles to fix in large populations and illustrates how life history can affect evolutionary change.

  8. Estimating Relatedness in the Presence of Null Alleles.

    PubMed

    Huang, Kang; Ritland, Kermit; Dunn, Derek W; Qi, Xiaoguang; Guo, Songtao; Li, Baoguo

    2016-01-01

    Studies of genetics and ecology often require estimates of relatedness coefficients based on genetic marker data. However, with the presence of null alleles, an observed genotype can represent one of several possible true genotypes. This results in biased estimates of relatedness. As the numbers of marker loci are often limited, loci with null alleles cannot be abandoned without substantial loss of statistical power. Here, we show how loci with null alleles can be incorporated into six estimators of relatedness (two novel). We evaluate the performance of various estimators before and after correction for null alleles. If the frequency of a null allele is <0.1, some estimators can be used directly without adjustment; if it is >0.5, the potency of estimation is too low and such a locus should be excluded. We make available a software package entitled PolyRelatedness v1.6, which enables researchers to optimize these estimators to best fit a particular data set.

  9. 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.

  10. Frequency of FCGR3B Alleles in Thai Blood Donors

    PubMed Central

    Kaset, Chollanot; Leetrakool, Nipapan; Intharanut, Kamphon

    2013-01-01

    Background Human neutrophil antigens (HNAs) are involved in autoimmune and alloimmune neutropenia and transfusion-related acute lung injury. The HNA-1 system is important in immunogenetics, and allele frequencies have been described in different populations. This study investigated the frequency of FCGR3B alleles encoding HNA-1a, HNA-1b, and HNA-1c among Thai blood donors and compared these frequencies with those previously reported for other populations. Methods Eight hundred DNA samples obtained from unrelated healthy blood donors at the National Blood Centre, Thai Red Cross Society, Bangkok, and the Blood Bank, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, were included. Samples were simultaneously typed for each FCGR3B allele using an in-house polymerase chain reaction with sequence-specific primer (PCR-SSP) technique. Results The frequencies of FCGR3B*1, FCGR3B*2, and FCGR3B*3 alleles in central Thai blood donors were 0.548, 0.452, and 0.004, respectively; only FCGR3B*1 and FCGR3B*2 alleles were found in northern Thai blood donors (0.68 and 0.32, respectively). Compared with other Asian populations, central Thais had higher frequencies of the FCGR3B*2 allele (P<0.001), while the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in northern Thais were similar to those previously reported in Taiwanese and Japanese populations. In contrast, the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in the northern Thai population were statistically different from those observed in central Thai, Korean, German, and Turkish populations. Conclusions FCGR3B allele frequencies were significantly different between central and northern Thai blood donors. Our in-house PCR-SSP method is a simple, cost-effective, and convenient method for FCGR3B allele detection. PMID:24205492

  11. Microsatellite null alleles and estimation of population differentiation.

    PubMed

    Chapuis, Marie-Pierre; Estoup, Arnaud

    2007-03-01

    Microsatellite null alleles are commonly encountered in population genetics studies, yet little is known about their impact on the estimation of population differentiation. Computer simulations based on the coalescent were used to investigate the evolutionary dynamics of null alleles, their impact on F(ST) and genetic distances, and the efficiency of estimators of null allele frequency. Further, we explored how the existing method for correcting genotype data for null alleles performed in estimating F(ST) and genetic distances, and we compared this method with a new method proposed here (for F(ST) only). Null alleles were likely to be encountered in populations with a large effective size, with an unusually high mutation rate in the flanking regions, and that have diverged from the population from which the cloned allele state was drawn and the primers designed. When populations were significantly differentiated, F(ST) and genetic distances were overestimated in the presence of null alleles. Frequency of null alleles was estimated precisely with the algorithm presented in Dempster et al. (1977). The conventional method for correcting genotype data for null alleles did not provide an accurate estimate of F(ST) and genetic distances. However, the use of the genetic distance of Cavalli-Sforza and Edwards (1967) corrected by the conventional method gave better estimates than those obtained without correction. F(ST) estimation from corrected genotype frequencies performed well when restricted to visible allele sizes. Both the proposed method and the traditional correction method have been implemented in a program that is available free of charge at http://www.montpellier.inra.fr/URLB/. We used 2 published microsatellite data sets based on original and redesigned pairs of primers to empirically confirm our simulation results.

  12. Allele-Specific Reduction of the Mutant Huntingtin Allele Using Transcription Activator-Like Effectors in Human Huntington's Disease Fibroblasts.

    PubMed

    Fink, Kyle D; Deng, Peter; Gutierrez, Josh; Anderson, Joseph S; Torrest, Audrey; Komarla, Anvita; Kalomoiris, Stefanos; Cary, Whitney; Anderson, Johnathon D; Gruenloh, William; Duffy, Alexandra; Tempkin, Teresa; Annett, Geralyn; Wheelock, Vicki; Segal, David J; Nolta, Jan A

    2016-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG repeats. Although pathogenesis has been attributed to this polyglutamine expansion, the underlying mechanisms through which the huntingtin protein functions have yet to be elucidated. It has been suggested that postnatal reduction of mutant huntingtin through protein interference or conditional gene knockout could prove to be an effective therapy for patients suffering from HD. For allele-specific targeting, transcription activator-like effectors (TALE) were designed to target single-nucleotide polymorphisms (SNP) in the mutant allele and packaged into a vector backbone containing KRAB to promote transcriptional repression of the disease-associated allele. Additional TALEs were packaged into a vector backbone containing heterodimeric FokI and were designed to be used as nucleases (TALEN) to cause a CAG-collapse in the mutant allele. Human HD fibroblasts were treated with each TALE-SNP or TALEN. Allele-expression was measured using a SNP-genotyping assay and mutant protein aggregation was quantified with Western blots for anti-ubiquitin. The TALE-SNP and TALEN significantly reduced mutant allele expression (p < 0.05) when compared to control transfections while not affecting expression of the nondisease allele. This study demonstrates the potential of allele-specific gene modification using TALE proteins, and provides a foundation for targeted treatment for individuals suffering from Huntington's or other genetically linked diseases.

  13. Allele-specific H3K79 Di- versus trimethylation distinguishes opposite parental alleles at imprinted regions.

    PubMed

    Singh, Purnima; Han, Li; Rivas, Guillermo E; Lee, Dong-Hoon; Nicholson, Thomas B; Larson, Garrett P; Chen, Taiping; Szabó, Piroska E

    2010-06-01

    Imprinted gene expression corresponds to parental allele-specific DNA CpG methylation and chromatin composition. Histone tail covalent modifications have been extensively studied, but it is not known whether modifications in the histone globular domains can also discriminate between the parental alleles. Using multiplex chromatin immunoprecipitation-single nucleotide primer extension (ChIP-SNuPE) assays, we measured the allele-specific enrichment of H3K79 methylation and H4K91 acetylation along the H19/Igf2 imprinted domain. Whereas H3K79me1, H3K79me2, and H4K91ac displayed a paternal-specific enrichment at the paternally expressed Igf2 locus, H3K79me3 was paternally biased at the maternally expressed H19 locus, including the paternally methylated imprinting control region (ICR). We found that these allele-specific differences depended on CTCF binding in the maternal ICR allele. We analyzed an additional 11 differentially methylated regions (DMRs) and found that, in general, H3K79me3 was associated with the CpG-methylated alleles, whereas H3K79me1, H3K79me2, and H4K91ac enrichment was specific to the unmethylated alleles. Our data suggest that allele-specific differences in the globular histone domains may constitute a layer of the "histone code" at imprinted genes.

  14. 29 CFR 1201.1 - Carrier.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 4 2011-07-01 2011-07-01 false Carrier. 1201.1 Section 1201.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD DEFINITIONS § 1201.1 Carrier. The term carrier includes any express company, sleeping car company, carrier by railroad, subject to the Interstate Commerce...

  15. 29 CFR 1201.1 - Carrier.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Carrier. 1201.1 Section 1201.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD DEFINITIONS § 1201.1 Carrier. The term carrier includes any express company, sleeping car company, carrier by railroad, subject to the Interstate Commerce...

  16. 7 CFR 35.4 - Carrier.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Carrier. 35.4 Section 35.4 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... AND PLUMS Definitions § 35.4 Carrier. Carrier means any common or private carrier, including, but...

  17. 29 CFR 1201.1 - Carrier.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 4 2014-07-01 2014-07-01 false Carrier. 1201.1 Section 1201.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD DEFINITIONS § 1201.1 Carrier. The term carrier includes any express company, sleeping car company, carrier by railroad, subject to the Interstate Commerce...

  18. 29 CFR 1201.1 - Carrier.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 4 2012-07-01 2012-07-01 false Carrier. 1201.1 Section 1201.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD DEFINITIONS § 1201.1 Carrier. The term carrier includes any express company, sleeping car company, carrier by railroad, subject to the Interstate Commerce...

  19. Cooperation of Adhesin Alleles in Salmonella-Host Tropism

    PubMed Central

    De Masi, Leon; Yue, Min; Hu, Changmin; Rakov, Alexey V.; Rankin, Shelley C.

    2017-01-01

    ABSTRACT Allelic combinations and host specificities for three fimbrial adhesins, FimH, BcfD, and StfH, were compared for 262 strains of Salmonella enterica serovar Newport, a frequent human and livestock pathogen. Like FimH, BcfD had two major alleles (designated A and B), whereas StfH had two allelic groups, each with two alleles (subgroup A1 and A2 and subgroup B1 and B2). The most prevalent combinations of FimH/BcfD/StfH alleles in S. Newport were A/A/A1 and B/B/B1. The former set was most frequently found in bovine and porcine strains, whereas the latter combination was most frequently found in environmental and human isolates. Bacteria genetically engineered to express Fim, Bcf, or Stf fimbriae on their surface were tested with the different alleles for binding to human, porcine, and bovine intestinal epithelial cells. The major allelic combinations with bovine and porcine strains (A/A/A1) or with human isolates (B/B/B1) provided at least two alleles capable of binding significantly better than the other alleles to an intestinal epithelial cell line from the respective host(s). However, each combination of alleles kept at least one allele mediating binding to an intestinal epithelial cell from another host. These findings indicated that allelic variation in multiple adhesins of S. Newport contributes to bacterial adaptation to certain preferential hosts without losing the capacity to maintain a broad host range. IMPORTANCE Salmonella enterica remains a leading foodborne bacterial pathogen in the United States; infected livestock serve often as the source of contaminated food products. A study estimated that over a billion Salmonella gastroenteritis cases and up to 33 million typhoid cases occur annually worldwide, with 3.5 million deaths. Although many Salmonella strains with a broad host range present preferential associations with certain host species, it is not clear what determines the various levels of host adaptation. Here, causal properties of host

  20. HLA-B*57 Allele Is Associated with Concomitant Anti-tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians

    PubMed Central

    Petros, Zelalem; Kishikawa, Junko; Makonnen, Eyasu; Yimer, Getnet; Habtewold, Abiy; Aklillu, Eleni

    2017-01-01

    Drug-induced liver injury (DILI) is a known adverse effect of both anti-tuberculosis (anti-TB) and antiretroviral (ARV) drugs. Recent studies highlight the implications of genetic predispositions to DILI. We performed a case-control study to identify Human Leukocyte Antigen-B (HLA-B) variant alleles associated with anti-TB and ARV co-treatment induced liver toxicity in Ethiopian TB and HIV co-infected patients. A total of 495 newly diagnosed TB and HIV co-infected patients were enrolled and received rifampicin based anti-TB and efavirenz based ARV therapy. Change in liver enzyme level from baseline was monitored 1st, 2nd, 4th, 8th, 12th, and 24th weeks after treatment initiation to identify patients who developed DILI (cases) and those who did not (treatment tolerants). Genomic DNA from 46 cases and 46 sex and age matched treatment tolerants were genotyped for HLA-B variant alleles using Olerup SSP®HLA-B DNA Typing Kits. The proportion of HLA-B*57 allele carriers in DILI cases (37.0%), particularly in those who developed cholestatic type of DILI (44.8%) was significantly higher compared with those who tolerated the treatment (2.2%). The HLA-B*57 allele frequency was significantly higher in cases (25%) than treatment tolerants (1.1%). In a multivariate logistic analysis, the proportion of patients carrying HLA-B*57 (P = 0.002) and HLA-B*14 (P = 0.014) alleles were significantly higher in DILI cases compared with treatment tolerants. HLA-B*57 was significantly associated with cholestatic (P = 0.001) and mixed (P = 0.017) types of liver toxicity, and mild-to-moderate severity (P = 0.001). Of all HLA-B*57 alleles detected, HLA-B*57:03 accounted 58.3% and HLA-B*57:02 accounted 41.7%. HLA-B*57:01 was not detected. The variant allele frequencies of HLA-B*57:03 (15.2 vs. 0%) and HLA-B*57:02 (9.8 vs. 1.1%) were significantly higher in the DILI cases than treatment tolerants (P < 0.03). We conclude that HLA-B*57 alleles (B*57:03 and B*57:02) confer susceptibility to the

  1. Beta-thalassemia mutations in Rome. A high frequency of the IVSII-745 allele in subjects of latium origin.

    PubMed

    Massa, A; Cianciulli, P; Cianetti, L; Iazzone, R; Cenci, A; Sorrentino, F; Franco, G; Pecci, G; Papa, G; Peschle, C

    1994-01-01

    We studied the molecular bases of beta-thalassemia in Rome, a city centrally located in Latium, which is a region with a low incidence of beta-carriers. People also come to Rome from other regions for specific or prenatal diagnostic assessment. Only 11 patients (20%) out of 62 characterized beta-thalassemia subjects were of Latium family origin. They presented five mutations with an uncommonly high frequency of the IVSII-745 allele, that was found in homozygosis in 4 unrelated patients from a southeastern area in the province of Frosinone. These data may indicate a founder effect.

  2. Influence of the APOE ε4 allele and mild cognitive impairment diagnosis in the disruption of the MEG resting state functional connectivity in sources space.

    PubMed

    Cuesta, Pablo; Garcés, Pilar; Castellanos, Nazareth P; López, Maria Eugenia; Aurtenetxe, Sara; Bajo, Ricardo; Pineda-Pardo, José Angel; Bruña, Ricardo; Marín, Antonio García; Delgado, Marisa; Barabash, Ana; Ancín, Inés; Cabranes, Jose Antonio; Fernandez, Alberto; Del Pozo, Francisco; Sancho, Miguel; Marcos, Alberto; Nakamura, Akinori; Maestú, Fernando

    2015-01-01

    The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.

  3. 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 [θ 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

  4. Multiple rare alleles at LDLR and APOA5 confer risk for early-onset myocardial infarction

    PubMed Central

    Do, Ron; Stitziel, Nathan O.; Won, Hong-Hee; Jørgensen, Anders Berg; Duga, Stefano; Merlini, Pier Angelica; Kiezun, Adam; Farrall, Martin; Goel, Anuj; Zuk, Or; Guella, Illaria; Asselta, Rosanna; Lange, Leslie A.; Peloso, Gina M.; Auer, Paul L.; Girelli, Domenico; Martinelli, Nicola; Farlow, Deborah N.; DePristo, Mark A.; Roberts, Robert; Stewart, Alexander F.R.; Saleheen, Danish; Danesh, John; Epstein, Stephen E.; Sivapalaratnam, Suthesh; Hovingh, G. Kees; Kastelein, John J.; Samani, Nilesh J.; Schunkert, Heribert; Erdmann, Jeanette; Shah, Svati H.; Kraus, William E.; Davies, Robert; Nikpay, Majid; Johansen, Christopher T.; Wang, Jian; Hegele, Robert A.; Hechter, Eliana; Marz, Winfried; Kleber, Marcus E.; Huang, Jie; Johnson, Andrew D.; Li, Mingyao; Burke, Greg L.; Gross, Myron; Liu, Yongmei; Assimes, Themistocles L.; Heiss, Gerardo; Lange, Ethan M.; Folsom, Aaron R.; Taylor, Herman A.; Olivieri, Oliviero; Hamsten, Anders; Clarke, Robert; Reilly, Dermot F.; Yin, Wu; Rivas, Manuel A.; Donnelly, Peter; Rossouw, Jacques E.; Psaty, Bruce M.; Herrington, David M.; Wilson, James G.; Rich, Stephen S.; Bamshad, Michael J.; Tracy, Russell P.; Cupples, L. Adrienne; Rader, Daniel J.; Reilly, Muredach P.; Spertus, John A.; Cresci, Sharon; Hartiala, Jaana; Tang, W.H. Wilson; Hazen, Stanley L.; Allayee, Hooman; Reiner, Alex P.; Carlson, Christopher S.; Kooperberg, Charles; Jackson, Rebecca D.; Boerwinkle, Eric; Lander, Eric S.; Schwartz, Stephen M.; Siscovick, David S.; McPherson, Ruth; Tybjaerg-Hansen, Anne; Abecasis, Goncalo R.; Watkins, Hugh; Nickerson, Deborah A.; Ardissino, Diego; Sunyaev, Shamil R.; O’Donnell, Christopher J.; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar

    2014-01-01

    Summary Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. PMID:25487149

  5. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

    PubMed

    Do, Ron; Stitziel, Nathan O; Won, Hong-Hee; Jørgensen, Anders Berg; Duga, Stefano; Angelica Merlini, Pier; Kiezun, Adam; Farrall, Martin; Goel, Anuj; Zuk, Or; Guella, Illaria; Asselta, Rosanna; Lange, Leslie A; Peloso, Gina M; Auer, Paul L; Girelli, Domenico; Martinelli, Nicola; Farlow, Deborah N; DePristo, Mark A; Roberts, Robert; Stewart, Alexander F R; Saleheen, Danish; Danesh, John; Epstein, Stephen E; Sivapalaratnam, Suthesh; Hovingh, G Kees; Kastelein, John J; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; Shah, Svati H; Kraus, William E; Davies, Robert; Nikpay, Majid; Johansen, Christopher T; Wang, Jian; Hegele, Robert A; Hechter, Eliana; Marz, Winfried; Kleber, Marcus E; Huang, Jie; Johnson, Andrew D; Li, Mingyao; Burke, Greg L; Gross, Myron; Liu, Yongmei; Assimes, Themistocles L; Heiss, Gerardo; Lange, Ethan M; Folsom, Aaron R; Taylor, Herman A; Olivieri, Oliviero; Hamsten, Anders; Clarke, Robert; Reilly, Dermot F; Yin, Wu; Rivas, Manuel A; Donnelly, Peter; Rossouw, Jacques E; Psaty, Bruce M; Herrington, David M; Wilson, James G; Rich, Stephen S; Bamshad, Michael J; Tracy, Russell P; Cupples, L Adrienne; Rader, Daniel J; Reilly, Muredach P; Spertus, John A; Cresci, Sharon; Hartiala, Jaana; Tang, W H Wilson; Hazen, Stanley L; Allayee, Hooman; Reiner, Alex P; Carlson, Christopher S; Kooperberg, Charles; Jackson, Rebecca D; Boerwinkle, Eric; Lander, Eric S; Schwartz, Stephen M; Siscovick, David S; McPherson, Ruth; Tybjaerg-Hansen, Anne; Abecasis, Goncalo R; Watkins, Hugh; Nickerson, Deborah A; Ardissino, Diego; Sunyaev, Shamil R; O'Donnell, Christopher J; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar

    2015-02-05

    Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

  6. Hypersensitivity to chemoradiation in FANCA carrier with cervical carcinoma—A case report and review of the literature

    PubMed Central

    Sirák, Igor; Šinkorová, Zuzana; Šenkeříková, Mária; Špaček, Jiří; Laco, Jan; Vošmiková, Hana; John, Stanislav; Petera, Jiří

    2015-01-01

    Objective Compared to Fanconi anemia (FA) patients with homozygous defective two-alleles inheritance, there is a scarce or no evidence on one defective allele FANCA carriers, with respect to their cancer incidence, clinical and in vitro radiosensitivity and chemosensitivity. On that account, we report a case of a 30-year old FANCA mutation carrier woman with uterine cervix adenocarcinoma who was treated with chemoradiotherapy, in which unexpected acute toxicity and fatal late morbidity occured. Methods We also report the results of an in vitro test for radiosensitivity, immunohistochemical examination with FANCA staining and human papillomavirus genotypization, and a review of the literature for FA carrier patients with respect to cancer incidence, clinical and in vitro response to chemo/radiotherapy, options of early heterozygosity detection, and methods of in vitro prediction of hypersensitivity to oncologic treatment. Conclusion Although there are no standard guidelines for management of FA carriers with malignancies and reports about chemo- or radiosensitivity in this population are scarce; patients with FA-A heterozygosity may have a high rate of complications from chemo/radiotherapy. Up to now, an optimum method for the prediction of radiosensitivity and the best parameter has not been found. Clinical radioresponsiveness is unpredictable in FA carriers and there is a pressing need of new rapid and predictive in vitro assays of radiation responses. Until then, the treatment of FA carriers with malignancies should be individualized, with respect to potential hypersensitivity to ionizing radiation or cross-linking agents. PMID:26109920

  7. Sex and APOE: A memory advantage in male APOE ε4 carriers in midlife.

    PubMed

    Zokaei, Nahid; Giehl, Kathrin; Sillence, Annie; Neville, Matt J; Karpe, Fredrik; Nobre, Anna C; Husain, Masud

    2017-03-01

    Short-term memory in middle-aged individuals with different APOE alleles was examined using a recently developed task which is sensitive to medial temporal lobe (MTL) damage. Individuals (age-range: 40-51 years) with ε3/ε3, ε3/ε4 and ε4/ε4 APOE genotypes (N = 60) performed a delayed estimation task with a sensitive continuous measure of report. The paradigm allowed us to measure memory for items and their locations, as well as maintenance of identity-location feature binding in memory. There was a significant gene-dosage dependent effect of the ε4 allele on performance: memory decay or forgetting was slower in ε4 carriers, as measured by localization error and after controlling for misbinding errors. Furthermore ε4 carriers made less misbinding errors. These findings were specific to male carriers only. Thus, male ε4 carriers are at a behavioral advantage in midlife on a sensitive task of short-term memory. The results would be consistent with an antagonistic pleiotropy hypothesis and hightight the interaction of gender on the influence of APOE in cognition.

  8. Generation of a Conditional Null Allele of Jumonji

    PubMed Central

    Mysliwiec, Matthew R.; Chen, Junqin; Powers, Patricia A.; Bartley, Christopher R.; Schneider, Michael D.; Lee, Youngsook

    2007-01-01

    Summary: The jumonji (jmj) gene plays important roles in multiple organ development in mouse, including cardiovascular development. Since JMJ is expressed widely during mouse development, it is essential that conditional knockout approaches be employed to ablate JMJ in a tissue-specific manner to identify the cell lineage specific roles of JMJ. In this report, we describe the establishment of a jmj conditional null allele in mice by generating a loxP-flanked (floxed) jmj allele, which allows the in vivo ablation of jmj via Cre recombinase-mediated deletion. Gene targeting was used to introduce loxP sites flanking exon 3 of the jmj allele to mouse embryonic stem cells. Our results indicate that the jmj floxed allele converts to a null allele in a heart-specific manner when embryos homozygous for the floxed jmj allele and carrying the α-myosin heavy chain promoter-Cre transgene were analyzed by Southern and Northern blot analyses. Therefore, this mouse line harboring the conditional jmj null allele will provide a valuable tool for deciphering the tissue and cell lineage specific roles of JMJ. PMID:16900512

  9. Allele Frequencies at Microsatellite Loci: The Stepwise Mutation Model Revisited

    PubMed Central

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

    1993-01-01

    We summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. We show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. We show that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size. PMID:8454213

  10. Estimating relatedness and relationships using microsatellite loci with null alleles.

    PubMed

    Wagner, A P; Creel, S; Kalinowski, S T

    2006-11-01

    Relatedness is often estimated from microsatellite genotypes that include null alleles. When null alleles are present, observed genotypes represent one of several possible true genotypes. If null alleles are detected, but analyses do not adjust for their presence (ie, observed genotypes are treated as true genotypes), then estimates of relatedness and relationship can be incorrect. The number of loci available in many wildlife studies is limited, and loci with null alleles are commonly a large proportion of data that cannot be discarded without substantial loss of power. To resolve this problem, we present a new approach for estimating relatedness and relationships from data sets that include null alleles. Once it is recognized that the probability of the observed genotypes is dependent on the probabilities of a limited number of possible true genotypes, the required adjustments are straightforward. The concept can be applied to any existing estimators of relatedness and relationships. We review established maximum likelihood estimators and apply the correction in that setting. In an application of the corrected method to data from striped hyenas, we demonstrate that correcting for the presence of null alleles affect results substantially. Finally, we use simulated data to confirm that this method works better than two common approaches, namely ignoring the presence of null alleles or discarding affected loci.

  11. Hydrogen as an energy carrier

    SciTech Connect

    Winter, C.J.; Nitsch, J

    1988-01-01

    The book deals with the possibilities of an energetic utilization of hydrogen. This energy carrier can be produced from the unlimited energy sources solar energy, wind energy and hydropower, and from nuclear energy. It is also in a position to one day supplement or supersede the fossil energy carriers oil, coal and gas. Contents: Significance and Use of Hydrogen: Energy Supply Structures and the Importance of Gaseous Energy Carriers. Technologies for the Energetic Use of Hydrogen. Hydrogen as Raw Material. Safety Aspects of Hydrogen Energy. Production of Hydrogen from Nonfossil Primary Energy: Photovoltaic Electricity Generation. Thermo-mechanical Electricity Generation. Water Splitting Methods. Selected Hydrogen Production Systems. Storage, Transport and Distribution of Hydrogen. Design of a Future Hydrogen Energy Economy: Potential and Chances of Hydrogen. Hydrogen in a Future Energy Economy. Concepts for the Introduction of Nonfossil Hydrogen. Energy-economic Conditions and the Cooperation with Hydrogen Producing Countries. Index.

  12. Charge carrier transport in polyvinylcarbazole

    NASA Astrophysics Data System (ADS)

    Tyutnev, Andrey P.; Saenko, Vladimir S.; Pozhidaev, Evgenii D.; Kolesnikov, Vladislav A.

    2006-07-01

    A critical analysis of the existing time-of-flight (TOF) data in poly(N-vinylcarbazole) (PVK) proves that these are highly controversial with claims and counterclaims about charge carrier transport (dispersive versus Gaussian). It is felt that the TOF method taken alone is incapable of resolving the standing dilemma. As a final means to resolve it, we propose a combination of two varieties of the TOF technique using both sheet-like and uniform carrier generation modes in conjunction with radiation-induced conductivity measurements. All three techniques are realized using the ELA-50 electron gun facility. To demonstrate the effectiveness of our approach we report experimental data for PVK, which show that carrier transport in this polymer is indeed dispersive. Evidence is presented substantiating the gross interference the surface traps could exert on the shape of a TOF transient. As a result, a preflight part of the TOF signal should not be used for parameter evaluation.

  13. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus.

    PubMed

    Lechner, Judith; Porter, Louise F; Rice, Aine; Vitart, Veronique; Armstrong, David J; Schorderet, Daniel F; Munier, Francis L; Wright, Alan F; Inglehearn, Chris F; Black, Graeme C; Simpson, David A; Manson, Forbes; Willoughby, Colin E

    2014-10-15

    Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.

  14. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

    PubMed Central

    Lechner, Judith; Porter, Louise F.; Rice, Aine; Vitart, Veronique; Armstrong, David J.; Schorderet, Daniel F.; Munier, Francis L.; Wright, Alan F.; Inglehearn, Chris F.; Black, Graeme C.; Simpson, David A.; Manson, Forbes; Willoughby, Colin E.

    2014-01-01

    Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date. PMID:24895405

  15. DNA Methylation Analysis of BRD1 Promoter Regions and the Schizophrenia rs138880 Risk Allele

    PubMed Central

    Dyrvig, Mads; Qvist, Per; Lichota, Jacek; Larsen, Knud; Nyegaard, Mette; Børglum, Anders D.

    2017-01-01

    The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced BRD1 expression. Insights into the transcriptional regulation of BRD1 and the pathogenic mechanisms associated with BRD1 risk variants, however, remain sparse. By studying transcripts in human HeLa and SH-SY5Y cells we provide evidence for differences in relative expression of BRD1 transcripts with three alternative 5’ UTRs (exon 1C, 1B, and 1A). We further show that expression of these transcript variants covaries negatively with DNA methylation proportions in their upstream promoter regions suggesting that promoter usage might be regulated by DNA methylation. In line with findings that the risk allele of the rs138880 SNP in the BRD1 promoter region correlates with reduced BRD1 expression, we find that it is also associated with moderate regional BRD1 promoter hypermethylation in both adipose tissue and blood. Importantly, we demonstrate by inspecting available DNA methylation and expression data that these regions undergo changes in methylation during fetal brain development and that differences in their methylation proportions in fetal compared to postnatal frontal cortex correlate significantly with BRD1 expression. These findings suggest that BRD1 may be dysregulated in both the developing and mature brain of risk allele carriers. Finally, we demonstrate that commonly used mood stabilizers Lithium, Valproate, and Carbamazepine affect the expression of BRD1 in SH-SY5Y cells. Altogether this study indicates a link between genetic risk and epigenetic dysregulation of BRD1 which raises interesting perspectives for targeting the mechanisms pharmacologically. PMID:28095495

  16. The apolipoprotein epsilon4 allele confers additional risk in children with familial hypercholesterolemia.

    PubMed

    Wiegman, Albert; Sijbrands, Eric J G; Rodenburg, Jessica; Defesche, Joep C; de Jongh, Saskia; Bakker, Henk D; Kastelein, John J P

    2003-06-01

    Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 +/- 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 +/- 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one epsilon4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the epsilon4 allele explained 72.4% of the variance of HDL cholesterol levels (-0.15 mmol/L, 95% confidence interval -0.24 to -0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the epsilon4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children.

  17. Comparison of acetaminophen toxicity in primary hepatocytes isolated from transgenic mice with different appolipoprotein E alleles.

    PubMed

    Mezera, V; Kucera, O; Moravcova, A; Peterova, E; Rousar, T; Rychtrmoc, D; Sobotka, O; Cervinkova, Z

    2015-12-01

    The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, important for combating electrophilic and oxidative stress in the liver and other organs. This encompasses detoxification of hepatotoxic drugs, including acetaminophen (APAP). Recently, an association between apolipoprotein E (ApoE) genotype and Nrf2 expression was described. We compared the toxicity of APAP on primary culture hepatocytes isolated from transgenic mice carrying two different human ApoE alleles and wild-type controls. The cells were exposed to APAP in concentrations from 0.5 to 4 mM for up to 24 hours. APAP led to a dose-dependent hepatotoxicity from 1 mM after 16 h exposure in all mice tested. The toxicity was higher in hepatocytes isolated from both transgenic strains than in wild-type controls and most pronounced in ApoE3 mice. Concurrently, there was a decline in mitochondrial membrane potential, especially in ApoE3 hepatocytes. The formation of reactive oxygen species was increased after 24 hours with 2.5 mM APAP in hepatocytes of all strains tested, with the highest increase being in the ApoE3 genotype. The activity of caspases 3 and 7 did not differ among groups and was minimal after 24 hour incubation with 4 mM APAP. We observed higher lipid accumulation in hepatocytes isolated from both transgenic strains than in wild-type controls. The expression of Nrf2-dependent genes was higher in ApoE3 than in ApoE4 hepatocytes and some of these genes were induced by APAP treatment. In conclusion, transgenic mice with ApoE4 and ApoE3 alleles displayed higher susceptibility to acute APAP toxicity in vitro than wild-type mice. Of the two transgenic genotypes tested, ApoE3 allele carriers were more prone to injury.

  18. Carrier sense data highway system

    DOEpatents

    Frankel, Robert

    1984-02-14

    A data transmission system includes a transmission medium which has a certain propagation delay time over its length. A number of data stations are successively coupled to the transmission medium for communicating with one another. Each of the data stations includes a transmitter for originating signals, each signal beginning with a carrier of a duration which is at least the propagation delay time of the transmission medium. Each data station also includes a receiver which receives other signals from other data stations and inhibits operation of the transmitter at the same data station when a carrier of another signal is received.

  19. Carrier-Mediated Antiviral Therapy

    DTIC Science & Technology

    1988-01-01

    encapsulat- ed nbavirin (3 mg per mouse) on days 0 and 2. " %.. - V % % CARRIER- MEDIATED ANTIVIRAL THERAPY 245 Table 2. Effect or MTP-PE Treatment on the...illustrates the effect of IV MTP-PE on the survival of mice injected int’a- .. - ,.,.,.. nasally with HSV- 1 . A small but significant enhancement of...dosage of interferon was marginally effective when given in %%’. CARRIER- MEDIATED ANTIVIRAL THERAPY 251 only two or three injections (on days I and 6 or

  20. Quantifying RNA allelic ratios by microfluidic multiplex PCR and sequencing.

    PubMed

    Zhang, Rui; Li, Xin; Ramaswami, Gokul; Smith, Kevin S; Turecki, Gustavo; Montgomery, Stephen B; Li, Jin Billy

    2014-01-01

    We developed a targeted RNA sequencing method that couples microfluidics-based multiplex PCR and deep sequencing (mmPCR-seq) to uniformly and simultaneously amplify up to 960 loci in 48 samples independently of their gene expression levels and to accurately and cost-effectively measure allelic ratios even for low-quantity or low-quality RNA samples. We applied mmPCR-seq to RNA editing and allele-specific expression studies. mmPCR-seq complements RNA-seq for studying allelic variations in the transcriptome.

  1. 14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where...

  2. 14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where...

  3. 14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where...

  4. 14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where...

  5. 75 FR 72863 - Motor Carrier Safety Advisory Committee Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-26

    ... Federal Motor Carrier Safety Administration Motor Carrier Safety Advisory Committee Public Meeting AGENCY: Federal Motor Carrier Safety Administration, DOT. ACTION: Notice of Motor Carrier Safety Advisory Committee Meeting. SUMMARY: FMCSA announces that the Agency's Motor Carrier Safety Advisory Committee...

  6. 76 FR 12214 - Motor Carrier Safety Advisory Committee Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-04

    ... Federal Motor Carrier Safety Administration Motor Carrier Safety Advisory Committee Public Meeting AGENCY: Federal Motor Carrier Safety Administration, DOT. ACTION: Notice: Announcement of Motor Carrier Safety Advisory Committee meeting; request for comment. SUMMARY: The Federal Motor Carrier Safety...

  7. 75 FR 50797 - Motor Carrier Safety Advisory Committee Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-17

    ... Federal Motor Carrier Safety Administration Motor Carrier Safety Advisory Committee Public Meeting AGENCY: Federal Motor Carrier Safety Administration (FMCSA), DOT. ACTION: Notice of Motor Carrier Safety Advisory Committee Meeting. SUMMARY: FMCSA announces that its Motor Carrier Safety Advisory Committee (MCSAC)...

  8. 75 FR 29384 - Motor Carrier Safety Advisory Committee Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-25

    ... Federal Motor Carrier Safety Administration Motor Carrier Safety Advisory Committee Public Meeting AGENCY: Federal Motor Carrier Safety Administration (FMCSA), DOT. ACTION: Notice of Motor Carrier Safety Advisory Committee meeting. SUMMARY: FMCSA announces that its Motor Carrier Safety Advisory Committee (MCSAC)...

  9. Carrier lifetimes in silicon carbide

    NASA Astrophysics Data System (ADS)

    Nigam, Saurav

    Carrier lifetimes are one of the most crucial parameters that govern the performance of high voltage/high power devices. The lack of understanding of the factors that determine the carrier lifetimes in silicon carbide is currently a major impediment in the development of high voltage/high power technology based on this material. The objective of this dissertation was to identify and subsequently, characterize various recombination channels present in silicon carbide. Of special importance was identification of lifetime limiting defects in the high quality epitaxial layers grown by state-of-the-art chemical vapor deposition technique for high voltage application. The effect of growth conditions (C/Si ratio, growth temperature, seed polarity, epilayer thickness, and background doping) on the concentrations of various defects were investigated with the aim of manipulating carrier lifetimes by controlling different growth parameters. Based on the qualitative correlations between various point defects and carrier lifetimes in more than thirty epitaxial layers, three defects (Z-defect, EH6/7 center, and P1 center) were identified as potential lifetime limiting defects. The P1 center was shown to act as efficient recombination channel whenever present in concentrations greater than 1013 cm-3. Such concentrations were observed in layers grown on the C-face and at low C/Si ratio (less than 1.5). The measurement of recombination rates of electrons and holes via the Z-defect and the EH6/7 center (as a function of temperature) were performed by analyzing the carrier dynamics in specially designed p-n diodes. At 300 K, the capture cross section of the two states of the Z-defect were sigman1˜6x10-15 cm2 (electron capture at the donor state), sigmap1˜2x1014 cm2 (hole capture at the donor state), sigman2˜1x10 16 cm2 (electron capture at the acceptor state), and sigma p2˜1e-13 cm2 (hole capture at the acceptor state). The electron capture cross section for the EH6/7 centers was

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

    PubMed

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

    1999-01-01

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

  11. ISS qualified thermal carrier equipment

    NASA Astrophysics Data System (ADS)

    Deuser, Mark S.; Vellinger, John C.; Jennings, Wm. M.

    2000-01-01

    Biotechnology is undergoing a period of rapid and sustained growth, a trend which is expected to continue as the general population ages and as new medical treatments and products are conceived. As pharmaceutical and biomedical companies continue to search for improved methods of production and, for answers to basic research questions, they will seek out new avenues of research. Space processing on the International Space Station (ISS) offers such an opportunity! Space is rapidly becoming an industrial laboratory for biotechnology research and processing. Space bioprocessing offers exciting possibilities for developing new pharmaceuticals and medical treatments, which can be used to benefit mankind on Earth. It also represents a new economic frontier for the private sector. For over eight years, the thermal carrier development team at SHOT has been working with government and commercial sector scientists who are conducting microgravity experiments that require thermal control. SHOT realized several years ago that the hardware currently being used for microgravity thermal control was becoming obsolete. It is likely that the government, academic, and industrial bioscience community members could utilize SHOT's hardware as a replacement to their current microgravity thermal carrier equipment. Moreover, SHOT is aware of several international scientists interested in utilizing our space qualified thermal carrier. SHOT's economic financing concept could be extremely beneficial to the international participant, while providing a source of geographic return for their particular region. Beginning in 2000, flight qualified thermal carriers are expected to be available to both the private and government sectors. .

  12. Whey drying on porous carriers

    SciTech Connect

    Mitura, E.; Kaminski, W.

    1996-05-01

    Whey is treated very often as a waste which pollutes the natural environment. Whey which is a valuable source of protein, lacrose, vitamins and mineral salts should be utilized completely. The present paper is a proposal of whey drying on porous carriers. It is proved experimentally that the proposed drying method guarantees good product quality.

  13. 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...

  14. Altered Episodic Memory in Introverted Young Adults Carrying the BDNFMet Allele

    PubMed Central

    Bombardier, Andreanne; Beauchemin, Maude; Gosselin, Nadia; Poirier, Judes; De Beaumont, Louis

    2016-01-01

    While most studies have been interested in the distinct, predisposing roles of the common BDNF Val66Met variant and extraversion personality traits on episodic memory, very few studies have looked at the synergistic effects of genetic and personality factors to account for cognitive variance. This is surprising considering recent reports challenging the long-held belief that the BDNFMet variant negatively impacts cognitive function. A total of 75 young healthy adults (26 of them carried at least one copy of the BDNFMet allele) took part in this study consisting of genetic profiling from saliva, personality assessment using the Revised NEO Personality Inventory (NEO PI-R) and a short battery of neuropsychological tests. An ANOVA revealed that BDNFMet carriers were significantly less extraverted than BDNFVal carriers (F1,73 = 9.54; p < 0.01; ηp2 = 0.126). Moreover, extraversion was found to significantly moderate the relationship between the BDNF genotype and episodic memory performance (p = 0.03). Subsequent correlational analyses yielded a strong and significant correlation (r = 0.542; p < 0.005) between introversion and delayed episodic memory specific to BDNFMet individuals. The present study suggests that introversion and the BDNFMet variant synergistically interact to reduce episodic memory performance in healthy, young adults. These findings reaffirm that a more accurate explanation of cognitive variance can be achieved by looking at the synergistic effects of genotype and phenotype factors. PMID:27845759

  15. Robust identification of local adaptation from allele frequencies.

    PubMed

    Günther, Torsten; Coop, Graham

    2013-09-01

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

  16. Sequencing of 15 new BoLA-DRB3 alleles.

    PubMed

    Wang, K; Sun, D; Zhang, Y

    2008-08-01

    The class II DR of bovine major histocompatibility complex of cattle (BoLA) plays a central role in the regulation of the immune response through their ability to present those peptides to T-cell receptors. In this work, we sequenced the exon2 of DRB3 to identify new alleles in Chinese yellow cattle, a total of 15 new BoLA-DRB3 alleles were found.

  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. Serum Levels of MicroRNA-206 and Novel Mini-STR Assays for Carrier Detection in Duchenne Muscular Dystrophy.

    PubMed

    Anaya-Segura, Mónica Alejandra; Rangel-Villalobos, Héctor; Martínez-Cortés, Gabriela; Gómez-Díaz, Benjamín; Coral-Vázquez, Ramón Mauricio; Zamora-González, Edgar Oswaldo; García, Silvia; López-Hernández, Luz Berenice

    2016-08-13

    Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a "liquid biopsy" for carrier detection and genetic counseling in DMD.

  19. Serum Levels of MicroRNA-206 and Novel Mini-STR Assays for Carrier Detection in Duchenne Muscular Dystrophy

    PubMed Central

    Anaya-Segura, Mónica Alejandra; Rangel-Villalobos, Héctor; Martínez-Cortés, Gabriela; Gómez-Díaz, Benjamín; Coral-Vázquez, Ramón Mauricio; Zamora-González, Edgar Oswaldo; García, Silvia; López-Hernández, Luz Berenice

    2016-01-01

    Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a “liquid biopsy” for carrier detection and genetic counseling in DMD. PMID:27529242

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

    PubMed

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

    2006-01-01

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

  1. Mutable R-Navajo Alleles of Cyclic Origin in Maize

    PubMed Central

    Brink, R. Alexander; Williams, Elizabeth

    1973-01-01

    The generation in cyclic fashion of 26 mutable R-Navajo (mRnj) alleles in maize involved transposition of a non-specific repressor of gene action, Modulator (Mp), first away from, and then back to, the R locus represented by the R-Navajo (Rnj) allele on chromosome 10. The mRnj alleles reconstituted in this way varied widely, and continuously, in mutability to Rnj—that is, in transposition of Mp away from the R locus, thus derepressing the Rnj gene. They were alike, or nearly so, however, in activating Ds chromosome breakage and in increasing the stability of variegated pericarp, another unstable compound allele comprising Mp conjoined with Prr on chromosomal 1. These latter two phenomena are based primarily on loci elsewhere in the genome. It is postulated that the 26 reconstituted mRnj alleles carry a common Mp which, however, is intercalated at a different site within each allele. Nucleotide sequence in the regions adjacent to Mp is assumed to determine the frequency with which a form of micro-nondisjunction occurs whereby Mp is released from a donor site. Transposition to a new site is interpreted in terms of a chromosome model that gives effect to nicking, or single strand breaks, occurring throughout the genome as a prerequisite to unwinding, strand separation, and replication, of the DNA double helix. PMID:17248592

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

    SciTech Connect

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

    2006-09-29

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

  3. Overdominant alleles in a population of variable size.

    PubMed Central

    Slatkin, M; Muirhead, C A

    1999-01-01

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

  4. Association between the aldehyde dehydrogenase 2*2 allele and smoking-related chronic airway obstruction in a Japanese general population: a pilot study.

    PubMed

    Morita, Kazunori; Masuda, Natsuki; Oniki, Kentaro; Saruwatari, Junji; Kajiwara, Ayami; Otake, Koji; Ogata, Yasuhiro; Nakagawa, Kazuko

    2015-07-16

    Aldehyde dehydrogenase 2 (ALDH2) detoxifies exogenous and endogenous toxic aldehydes; however, its protective effect against cigarette smoke in airways is unknown. We therefore examined whether the inactive ALDH2*2 allele is associated with smoking-related chronic airway obstruction. We conducted a cross-sectional study including 684 Japanese participants in a health screening program, and a retrospective longitudinal study in the elderly subgroup. The risks of airway obstruction in the ever-smokers with the ALDH2*1/*2 and *2/*2 genotypes were two and three times higher, respectively, than in the never-smokers with the ALDH2*1/*1 genotype. Moreover, the combined effect of smoking and the ALDH2*2 allele was prominent in the asthmatic subjects. In a longitudinal association analysis, the combination of the ALDH2 genotype and pack-years of smoking synergistically increased the risk of airway obstruction. The number of pack-years of smoking at baseline was identified to be a significant predictor of airway obstruction only in the ALDH2*2 allele carriers. In addition, the ALDH2*2 allele was also associated with the incidence of smoking-related airway obstruction, in the Cox proportional hazards model. This pilot study demonstrated for the first time a significant gene-environment interaction between the ALDH2*2 allele and cumulative exposure to cigarette smoke on the risk of airway obstruction.

  5. Human Leukocyte Antigens and Systemic Lupus Erythematosus: A Protective Role for the HLA-DR6 Alleles DRB1*13:02 and *14:03

    PubMed Central

    Furukawa, Hiroshi; Kawasaki, Aya; Oka, Shomi; Ito, Ikue; Shimada, Kota; Sugii, Shoji; Hashimoto, Atsushi; Komiya, Akiko; Fukui, Naoshi; Kondo, Yuya; Ito, Satoshi; Hayashi, Taichi; Matsumoto, Isao; Kusaoi, Makio; Amano, Hirofumi; Nagai, Tatsuo; Hirohata, Shunsei; Setoguchi, Keigo; Kono, Hajime; Okamoto, Akira; Chiba, Noriyuki; Suematsu, Eiichi; Katayama, Masao; Migita, Kiyoshi; Suda, Akiko; Ohno, Shigeru; Hashimoto, Hiroshi; Takasaki, Yoshinari; Sumida, Takayuki; Nagaoka, Shouhei

    2014-01-01

    Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10−10, corrected P (Pc) = 1.59×10−8, odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69–2.79), decreased DRB1*13:02 (P = 7.17×10−5, Pc = 0.0020, OR 0.46, 95% CI 0.34–0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18–0.63). Additionally, the “*15:01/*13:02 or *14:03” genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10−11, OR 2.39, 95% CI 1.84–3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population. PMID:24498373

  6. Screening for the presence of FMR1 premutation alleles in a Spanish population with fibromyalgia.

    PubMed

    Martorell, Loreto; Tondo, Mireia; Garcia-Fructuoso, Ferrán; Naudo, Montserrat; Alegre, Cayetano; Gamez, Josep; Genovés, Jordi; Poo, Pilar

    2012-11-01

    Fragile X mental retardation 1 (FMR1) premutation carriers, who are at risk of having children with fragile X Syndrome, were initially considered as clinically unaffected. However, recent clinical and molecular studies have shifted this point of view. The incidence of premutation in the general population is substantial. Apart from the well-documented fragile X-associated tremor-ataxia and fragile X premature ovarian insufficiency, there is a broad constellation of symptoms including depression, anxiety, muscle pain, autoimmune and thyroid disease, chronic fatigue, and fibromyalgia that has been described, particularly in females with the premutation (55-200 repeats). Fibromyalgia (FM) is the most common cause of widespread pain and comprises a heterogeneous group of patients, affecting 2-3 % of the general population. We analyzed the FMR1 gene in a cohort of females diagnosed with fibromyalgia in order to assess the incidence of premutated alleles. CGG repeat size was determined in 353 females suffering from FM and results were compared with a control group. Four premutated carriers in the FM group were detected. The observed incidence is higher than that described for a normal female population (1/88 vs 1/250). The early detection of premutation carriers for the FMR1 gene among individuals diagnosed with fibromyalgia is important and would be helpful in correct genetic counseling of patients and their families, who may be at risk of having children with fragile X syndrome, the most common known cause of inherited intellectual disability and autism. Our data should be cautiously interpreted based on just this study; nevertheless, screening for the FMR1 gene in FM patients at least with presentations suggestive of FMR1 gene-related disease seems recommendable.

  7. Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers.

    PubMed

    Aradottir, Margret; Reynisdottir, Sigridur T; Stefansson, Olafur A; Jonasson, Jon G; Sverrisdottir, Asgerdur; Tryggvadottir, Laufey; Eyfjord, Jorunn E; Bodvarsdottir, Sigridur K

    2015-01-01

    Overexpression of the Aurora A kinase has been shown to have prognostic value in breast cancer. Previously, we showed a significant association between AURKA gene amplification and BRCA2 mutation in breast cancer. The aim of this study was to assess the prognostic impact of Aurora A overexpression on breast cancer arising in BRCA2 mutation carriers. Aurora A expression was evaluated by immunohistochemistry on breast tumour tissue microarrays from 107 BRCA2 999del5 mutation carriers and 284 of sporadic origin. Prognostic value of Aurora A nuclear staining was estimated in relation to clinical markers and adjuvant treatment, using multivariate Cox's proportional hazards ratio regression model. BRCA2 wild-type allele loss was measured by TaqMan in BRCA2 mutated tumour samples. All statistical tests were two sided. Multivariate analysis of breast cancer-specific survival, including proliferative markers and treatment, indicated independent prognostic value of Aurora A nuclear staining for BRCA2 mutation carriers (hazards ratio = 7.06; 95% confidence interval = 1.23-40.6; p = 0.028). Poor breast cancer-specific survival of BRCA2 mutation carriers was found to be significantly associated with combined Aurora A nuclear expression and BRCA2 wild type allele loss in tumours (p < 0.001). Multivariate analysis indicated independent prognostic value of both positive Aurora A nuclear staining (hazards ratio = 10.09; 95% confidence interval = 1.19-85.4, p = 0.034) and BRCA2 wild type allele loss (hazards ratio = 9.63; 95% confidence interval = 1.81-51.0, p = 0.008) for BRCA2 mutation carriers. Aurora A nuclear expression was found to be a significant prognostic marker for BRCA2 mutation carriers, independent of clinical parameters and adjuvant treatment. Our conclusion is that treatment benefits for BRCA2 mutation carriers and sporadic breast cancer patients with Aurora A positive tumours may be enhanced by giving attention to Aurora A

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

    SciTech Connect

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

    1993-07-01

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

  9. Development of tropical spastic paraparesis in human T-lymphotropic virus type 1 carriers is influenced by interleukin 28B gene polymorphisms.

    PubMed

    Treviño, Ana; Lopez, Mariola; Vispo, Eugenia; Aguilera, Antonio; Ramos, Jose M; Benito, Rafael; Roc, Lourdes; Eiros, Jose M; de Mendoza, Carmen; Soriano, Vincent

    2012-07-01

    Interleukin 28B (IL28B) rs12979860 polymorphisms were examined in 41 individuals with human T-lymphotrophic virus type 1 (HTLV-1). The alleles CT/TT were more frequent in 12 individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis than in 29 asymptomatic carriers (80% vs 20%; P = .03), and median HTLV-1 proviral load was greater in CT/TT than CC carriers (P = .01). Thus, IL28B testing and closer follow-up of HTLV-1 asymptomatic CT/TT carriers is warranted.

  10. Distribution of BoLA-DRB3 allelic frequencies and identification of two new alleles in Iranian buffalo breed.

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2012-01-01

    The role of the major histocompatibility complex (MHC) in the immune response makes it an attractive candidate gene for associations with disease resistance and susceptibility. This study describes genetic variability in the BoLA-DRB3 in Iranian buffaloes. Heminested PCR-RFLP method was used to identify the frequency of BoLA-DRB3 alleles. The BoLA-DRB3 locus is highly polymorphic in the study herd (12 alleles). Almost 63.50% of the alleles were accounted for by four alleles (BoLA-DRB3.2 ∗48, ∗20, ∗21, and obe) in Iranian buffalo. The DRB3.2 ∗48 allele frequency (24.20%) was higher than the others. The frequencies of the DRB3.2 ∗20 and DRB3.2 ∗21 are 14.52 and 14.00, respectively, and obe and gbb have a new pattern. Significant distinctions have been found between Iranian buffalo and other cattle breed studied. In the Iranian buffaloes studied alleles associated with resistance to various diseases are found. PMID:22454612

  12. A limit to the divergent allele advantage model supported by variable pathogen recognition across HLA-DRB1 allele lineages.

    PubMed

    Lau, Q; Yasukochi, Y; Satta, Y

    2015-11-01

    Genetic diversity in human leukocyte antigen (HLA) molecules is thought to have arisen from the co-evolution between host and pathogen and maintained by balancing selection. Heterozygote advantage is a common proposed scenario for maintaining high levels of diversity in HLA genes, and extending from this, the divergent allele advantage (DAA) model suggests that individuals with more divergent HLA alleles bind and recognize a wider array of antigens. While the DAA model seems biologically suitable for driving HLA diversity, there is likely an upper threshold to the amount of sequence divergence. We used peptide-binding and pathogen-recognition capacity of DRB1 alleles as a model to further explore the DAA model; within the DRB1 locus, we examined binding predictions based on two distinct phylogenetic groups (denoted group A and B) previously identified based on non-peptide-binding region (PBR) nucleotide sequences. Predictions in this study support that group A allele and group B allele lineages have contrasting binding/recognition capacity, with only the latter supporting the DAA model. Furthermore, computer simulations revealed an inconsistency in the DAA model alone with observed extent of polymorphisms, supporting that the DAA model could only work effectively in combination with other mechanisms. Overall, we support that the mechanisms driving HLA diversity are non-exclusive. By investigating the relationships among HLA alleles, and pathogens recognized, we can provide further insights into the mechanisms on how humans have adapted to infectious diseases over time.

  13. Clinical manifestations in female carriers of mucopolysaccharidosis type II: a spanish cross-sectional study

    PubMed Central

    2013-01-01

    , most likely affecting the normal allele. Further comparative studies with systematized clinical examinations in larger age-stratified populations of MPS II female carriers are required. PMID:23800320

  14. Albinism and disease causing pathogens in Tanzania: are alleles that are associated with OCA2 being maintained by balancing selection?

    PubMed

    Tuli, Abbas M; Valenzuela, Robert K; Kamugisha, Erasmus; Brilliant, Murray H

    2012-12-01

    Oculocutaneous albinism type 2 (OCA2) is present at significantly higher frequencies in sub-Saharan African populations compared to populations in other regions of the world. In Tanzania and other sub-Saharan countries, most OCA2 is associated with a common 2.7kb deletion allele. Leprosy is also in high prevalence in sub-Saharan African populations. The infectious agent of leprosy, Mycobacterium leprae, contains a gene, 38L, that is similar to OCA2. Hypopigmented patches of skin are early symptoms that present with infection of leprosy. In consideration of both the genetic similarity of OCA2 and the 38L gene of M. leprae and the involvement of pigmentation in both disorders, we hypothesized that the high rates of OCA2 may be due to heterozygote advantage. Hence, we hypothesized that carriers of the 2.7kb deletion allele of OCA2 may provide a protective advantage from infection with leprosy. We tested this hypothesis by determining the carrier frequency of the 2.7kb deletion allele from a sample of 240 individuals with leprosy from Tanzania. The results were inconclusive due to the small sample size; however, they enabled us to rule out a large protective effect, but perhaps not a small advantage. Mycobacterium tuberculosis is another infectious organism prevalent in sub-Saharan Africa that contains a gene, arsenic-transport integral membrane protein that is also similar to OCA2. Interestingly, chromosomal region 15q11-13, which also contains OCA2, was reported to be linked to tuberculosis susceptibility. Although variants within OCA2 were tested for association, the 2.7kb deletion allele of OCA2 was not tested. This led us to hypothesize that the deletion allele may confer resistance to susceptibility. Confirmation of our hypothesis would enable development of novel pharmocogenetic therapies for the treatment of tuberculosis, which in turn, may enable development of drugs that target other pathogens that utilize a similar infection mechanism as M. tuberculosis

  15. How the Number of Alleles Influences Gene Expression

    NASA Astrophysics Data System (ADS)

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

    2007-07-01

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

  16. Association between ACE D allele and elite short distance swimming.

    PubMed

    Costa, Aldo Matos; Silva, António José; Garrido, Nuno Domingos; Louro, Hugo; de Oliveira, Ricardo Jacó; Breitenfeld, Luiza

    2009-08-01

    The influence of ACE gene on athletic performance has been widely explored, and most of the published data refers to an I/D polymorphism leading to the presence (I allele) or absence (D allele) of a 287-bp sequence in intron 16, determining ACE activity in serum and tissues. A higher I allele frequency has been reported among elite endurance athletes, while the D allele was more frequent among those engaged in more power-orientated sports. However, on competitive swimming, the reproducibility of such associations is controversial. We thus compared the ACE genotype of elite swimmers with that of non-elite swimming cohort and of healthy control subjects. We thus sought an association of the ACE genotype of elite swimmers with their competitive distance. 39 Portuguese Olympic swimming candidates were classified as: short (<200 m) and middle (400-1,500 m) distance swimmers, respectively. A group of 32 non-elite swimmers were studied and classified as well, and a control group (n = 100) was selected from the Portuguese population. Chelex 100 was used for DNA extraction and genotype was determined by PCR-RFLP methods. We found that ACE genotype distribution and allelic frequency differs significantly by event distance only among elite swimmers (P < or = 0.05). Moreover, the allelic frequency of the elite short distance swimmers differed significantly from that of the controls (P = 0.021). No associations were found between middle distance swimmers and controls. Our results seem to support an association between the D allele and elite short distance swimming.

  17. The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Laitman, Yael; Kuchenbaecker, Karoline B.; Rantala, Johanna; Hogervorst, Frans; Peock, Susan; Godwin, Andrew K.; Arason, Adalgeir; Kirchhoff, Tomas; Offit, Kenneth; Isaacs, Claudine; Schmutzler, Rita K.; Wappenschmidt, Barbara; Nevanlinna, Heli; Chen, Xiaoqing; Chenevix-Trench, Georgia; Healey, Sue; Couch, Fergus; Peterlongo, Paolo; Radice, Paolo; Nathanson, Katherine L.; Caligo, Maria Adelaide; Neuhausen, Susan L.; Ganz, Patricia; Sinilnikova, Olga M.; McGuffog, Lesley; Easton, Douglas F.; Antoniou, Antonis C.; Wolf, Ido

    2012-01-01

    Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan® allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93–1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82–1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84–1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66–1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. PMID:22212556

  18. Carriers

    MedlinePlus

    ... Trials Research Publications Support & Care For Newly Diagnosed Care Packages Information Packets Equipment Pool Living With SMA Medical Issues Palliative Breathing Orthopedics Nutrition Equipment Daily Life At School At Home Adults With SMA Play Travel Grief & Loss Community & ...

  19. Protein carriers of conjugate vaccines

    PubMed Central

    Pichichero, Michael E

    2013-01-01

    The immunogenicity of polysaccharides as human vaccines was enhanced by coupling to protein carriers. Conjugation transformed the T cell-independent polysaccharide vaccines of the past to T cell-dependent antigenic vaccines that were much more immunogenic and launched a renaissance in vaccinology. This review discusses the conjugate vaccines for prevention of infections caused by Hemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis. Specifically, the characteristics of the proteins used in the construction of the vaccines including CRM, tetanus toxoid, diphtheria toxoid, Neisseria meningitidis outer membrane complex, and Hemophilus influenzae protein D are discussed. The studies that established differences among and key features of conjugate vaccines including immunologic memory induction, reduction of nasopharyngeal colonization and herd immunity, and antibody avidity and avidity maturation are presented. Studies of dose, schedule, response to boosters, of single protein carriers with single and multiple polysaccharides, of multiple protein carriers with multiple polysaccharides and conjugate vaccines administered concurrently with other vaccines are discussed along with undesirable consequences of conjugate vaccines. The clear benefits of conjugate vaccines in improving the protective responses of the immature immune systems of young infants and the senescent immune systems of the elderly have been made clear and opened the way to development of additional vaccines using this technology for future vaccine products. PMID:23955057

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

    PubMed

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

    2014-09-01

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

  1. 47 CFR 54.904 - Carrier certification.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Carrier certification. 54.904 Section 54.904 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Interstate Common Line Support Mechanism for Rate-of-Return Carriers § 54.904...

  2. 49 CFR 1139.21 - Study carriers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... and/or charges. (b) To corroborate the selection of the above study carriers, and to provide a data base for a continuing evaluation of the validity and usefulness of those carriers as a study group... A, Class I Participating Carriers' Revenue Data....

  3. 7 CFR 33.4 - Carrier.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Carrier. 33.4 Section 33.4 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... ISSUED UNDER AUTHORITY OF THE EXPORT APPLE ACT Definitions § 33.4 Carrier. Carrier means any common...

  4. Responsible implementation of expanded carrier screening

    PubMed Central

    Henneman, Lidewij; Borry, Pascal; Chokoshvili, Davit; Cornel, Martina C; van El, Carla G; Forzano, Francesca; Hall, Alison; Howard, Heidi C; Janssens, Sandra; Kayserili, Hülya; Lakeman, Phillis; Lucassen, Anneke; Metcalfe, Sylvia A; Vidmar, Lovro; de Wert, Guido; Dondorp, Wybo J; Peterlin, Borut

    2016-01-01

    This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners' personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines. PMID:26980105

  5. 5 CFR 890.1308 - Carrier participation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Carrier participation. 890.1308 Section 890.1308 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS... Program Demonstration Project § 890.1308 Carrier participation. (a) All carriers who participate in...

  6. 5 CFR 890.1308 - Carrier participation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Carrier participation. 890.1308 Section 890.1308 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS... Program Demonstration Project § 890.1308 Carrier participation. (a) All carriers who participate in...

  7. 5 CFR 890.1308 - Carrier participation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Carrier participation. 890.1308 Section 890.1308 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS... Program Demonstration Project § 890.1308 Carrier participation. (a) All carriers who participate in...

  8. 5 CFR 890.1308 - Carrier participation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Carrier participation. 890.1308 Section 890.1308 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS... Program Demonstration Project § 890.1308 Carrier participation. (a) All carriers who participate in...

  9. 5 CFR 890.1308 - Carrier participation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Carrier participation. 890.1308 Section 890.1308 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS... Program Demonstration Project § 890.1308 Carrier participation. (a) All carriers who participate in...

  10. Responsible implementation of expanded carrier screening.

    PubMed

    Henneman, Lidewij; Borry, Pascal; Chokoshvili, Davit; Cornel, Martina C; van El, Carla G; Forzano, Francesca; Hall, Alison; Howard, Heidi C; Janssens, Sandra; Kayserili, Hülya; Lakeman, Phillis; Lucassen, Anneke; Metcalfe, Sylvia A; Vidmar, Lovro; de Wert, Guido; Dondorp, Wybo J; Peterlin, Borut

    2016-06-01

    This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners' personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.

  11. 49 CFR 1241.1 - Common carriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Common carriers. 1241.1 Section 1241.1 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT...-CARRIERS SUBJECT TO PART I OF THE INTERSTATE COMMERCE ACT § 1241.1 Common carriers. All common...

  12. 18 CFR 357.1 - Common carriers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Common carriers. 357.1 Section 357.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT... SUBJECT TO PART I OF THE INTERSTATE COMMERCE ACT § 357.1 Common carriers. All common carriers by...

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

    PubMed

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

    2015-09-01

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

  14. Estimating Relatedness in the Presence of Null Alleles

    PubMed Central

    Huang, Kang; Ritland, Kermit; Dunn, Derek W.; Qi, Xiaoguang; Guo, Songtao; Li, Baoguo

    2016-01-01

    Studies of genetics and ecology often require estimates of relatedness coefficients based on genetic marker data. However, with the presence of null alleles, an observed genotype can represent one of several possible true genotypes. This results in biased estimates of relatedness. As the numbers of marker loci are often limited, loci with null alleles cannot be abandoned without substantial loss of statistical power. Here, we show how loci with null alleles can be incorporated into six estimators of relatedness (two novel). We evaluate the performance of various estimators before and after correction for null alleles. If the frequency of a null allele is <0.1, some estimators can be used directly without adjustment; if it is >0.5, the potency of estimation is too low and such a locus should be excluded. We make available a software package entitled PolyRelatedness v1.6, which enables researchers to optimize these estimators to best fit a particular data set. PMID:26500259

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

    PubMed Central

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

    2002-01-01

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

  16. Rare allelic forms of PRDM9 associated with childhood leukemogenesis

    PubMed Central

    Hussin, Julie; Sinnett, Daniel; Casals, Ferran; Idaghdour, Youssef; Bruat, Vanessa; Saillour, Virginie; Healy, Jasmine; Grenier, Jean-Christophe; de Malliard, Thibault; Busche, Stephan; Spinella, Jean-François; Larivière, Mathieu; Gibson, Greg; Andersson, Anna; Holmfeldt, Linda; Ma, Jing; Wei, Lei; Zhang, Jinghui; Andelfinger, Gregor; Downing, James R.; Mullighan, Charles G.; Awadalla, Philip

    2013-01-01

    One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis. PMID:23222848

  17. Rare allelic forms of PRDM9 associated with childhood leukemogenesis.

    PubMed

    Hussin, Julie; Sinnett, Daniel; Casals, Ferran; Idaghdour, Youssef; Bruat, Vanessa; Saillour, Virginie; Healy, Jasmine; Grenier, Jean-Christophe; de Malliard, Thibault; Busche, Stephan; Spinella, Jean-François; Larivière, Mathieu; Gibson, Greg; Andersson, Anna; Holmfeldt, Linda; Ma, Jing; Wei, Lei; Zhang, Jinghui; Andelfinger, Gregor; Downing, James R; Mullighan, Charles G; Awadalla, Philip

    2013-03-01

    One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis.

  18. A Platform for Interrogating Cancer-Associated p53 Alleles

    PubMed Central

    D’Brot, Alejandro; Kurtz, Paula; Regan, Erin; Jakubowski, Brandon; Abrams, John M

    2016-01-01

    p53 is the most frequently mutated gene in human cancer. Compelling evidence argues that full transformation involves loss of growth suppression encoded by wild-type p53 together with poorly understood oncogenic activity encoded by missense mutations. Furthermore, distinguishing disease alleles from natural polymorphisms is an important clinical challenge. To interrogate the genetic activity of human p53 variants, we leveraged the Drosophila model as an in vivo platform. We engineered strains that replace the fly p53 gene with human alleles, producing a collection of stocks that are, in effect, ‘humanized’ for p53 variants. Like the fly counterpart, human p53 transcriptionally activated a biosensor and induced apoptosis after DNA damage. However, all humanized strains representing common alleles found in cancer patients failed to complement in these assays. Surprisingly, stimulus-dependent activation of hp53 occurred without stabilization, demonstrating that these two processes can be uncoupled. Like its fly counterpart, hp53 formed prominent nuclear foci in germline cells but cancer-associated p53 variants did not. Moreover, these same mutant alleles disrupted hp53 foci and inhibited biosensor activity, suggesting that these properties are functionally linked. Together these findings establish a functional platform for interrogating human p53 alleles and suggest that simple phenotypes could be used to stratify disease variants. PMID:26996664

  19. Identification and characterization of variant alleles at CODIS STR loci.

    PubMed

    Allor, Catherine; Einum, David D; Scarpetta, Marco

    2005-09-01

    Short tandem repeat (STR) profiles from 32,671 individuals generated by the ABI Profiler Plus and Cofiler systems were screened for variant alleles not represented within manufacturer-provided allelic ladders. A total of 85 distinct variants were identified at 12 of the 13 CODIS loci, most of which involve a truncated tetranucleotide repeat unit. Twelve novel alleles, identified at D3S1358, FGA, D18S51, D5S818, D7S820 and TPOX, were confirmed by nucleotide sequence analysis and include both insertions and deletions involving the repeat units themselves as well as DNA flanking the repeat regions. Population genetic data were collected for all variants and frequencies range from 0.0003 (many single observations) to 0.0042 (D7S820 '10.3' in North American Hispanics). In total, the variant alleles identified in this study are carried by 1.6% of the estimated 1 million individuals tested annually in the U.S. for the purposes of parentage resolution. A paternity case involving a recombination event of paternal origin is presented and demonstrates how variant alleles can significantly strengthen the genetic evidence in troublesome cases. In such instances, increased costs and turnaround time associated with additional testing may be eliminated.

  20. Conscientiousness is Negatively Associated with Grey Matter Volume in Young APOE ɛ4-Carriers.

    PubMed

    Kunz, Lukas; Reuter, Martin; Axmacher, Nikolai; Montag, Christian

    2017-01-01

    The etiology of late onset Alzheimer's disease (LOAD) depends on multiple factors, among which the APOE ɛ4 allele is the most adverse genetic determinant and conscientiousness represents an influential personality trait. A potential association of both factors with brain structure in young adulthood may constitute a constellation that sets the course toward or against the subtle disease progression of LOAD that starts decades before clinical manifestation. Hence, in the present study, we examined the modulating effects of APOE ɛ4 on the relation between personality dimensions, including conscientiousness, and total grey matter volume (GMV) in young healthy adults using an a priori genotyping design. 105 participants completed an inventory assessing the Five Factor Model of Personality (NEO-FFI) and a structural MRI scan. Total GMV was estimated using both Freesurfer as well as VBM8. Across all participants, total GMV was positively associated with extraversion and negatively related to age. In APOE ɛ4-carriers- but not in APOE ɛ4-non-carriers- conscientiousness was negatively associated with total GMV. In line with the hypothesis of antagonistic pleiotropy of the APOE ɛ4 allele, this result suggests that young APOE ɛ4-carriers with increased total GMV may particularly benefit from cognitive advantages and thus have a lower need to engage in conscientious behavior. In this subset of young APOE ɛ4-carriers, the reduction in conscientiousness could then bring along adverse health behavior in the long run, potentiating the risk for LOAD. Hence, young APOE ɛ4-carriers with increased total GMV may be at a particularly high risk for LOAD.

  1. 49 CFR 376.22 - Exemption for private carrier leasing and leasing between authorized carriers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Exemption for private carrier leasing and leasing... MOTOR CARRIER SAFETY REGULATIONS LEASE AND INTERCHANGE OF VEHICLES Exemptions for the Leasing Regulations § 376.22 Exemption for private carrier leasing and leasing between authorized carriers....

  2. 49 CFR 376.22 - Exemption for private carrier leasing and leasing between authorized carriers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Exemption for private carrier leasing and leasing... MOTOR CARRIER SAFETY REGULATIONS LEASE AND INTERCHANGE OF VEHICLES Exemptions for the Leasing Regulations § 376.22 Exemption for private carrier leasing and leasing between authorized carriers....

  3. 49 CFR 376.22 - Exemption for private carrier leasing and leasing between authorized carriers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Exemption for private carrier leasing and leasing... MOTOR CARRIER SAFETY REGULATIONS LEASE AND INTERCHANGE OF VEHICLES Exemptions for the Leasing Regulations § 376.22 Exemption for private carrier leasing and leasing between authorized carriers....

  4. 49 CFR 376.22 - Exemption for private carrier leasing and leasing between authorized carriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Exemption for private carrier leasing and leasing... MOTOR CARRIER SAFETY REGULATIONS LEASE AND INTERCHANGE OF VEHICLES Exemptions for the Leasing Regulations § 376.22 Exemption for private carrier leasing and leasing between authorized carriers....

  5. 14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... other carriers to pass off by means of activities which are inconsistent with the minimum safeguards...

  6. 49 CFR 376.22 - Exemption for private carrier leasing and leasing between authorized carriers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Exemption for private carrier leasing and leasing... MOTOR CARRIER SAFETY REGULATIONS LEASE AND INTERCHANGE OF VEHICLES Exemptions for the Leasing Regulations § 376.22 Exemption for private carrier leasing and leasing between authorized carriers....

  7. 47 CFR 69.105 - Carrier common line for non-price cap local exchange carriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Carrier common line for non-price cap local...) COMMON CARRIER SERVICES (CONTINUED) ACCESS CHARGES Computation of Charges § 69.105 Carrier common line... shall be assessed upon all interexchange carriers that use local exchange common line facilities for...

  8. Rapid DNA haplotyping using a multiplex heteroduplex approach: Application to Duchenne muscula dystrophy carrier detection

    SciTech Connect

    Prior, T.W.; Wenger, G.D.; Moore, J.

    1994-09-01

    A new strategy has been developed for rapid haplotype analysis. It is based on an initial multiplex amplification of several polymorphic sites, followed by heteroduplex detection. Heteroduplexes formed between two different alleles are detected because they migrate differently than the corresponding homoduplexes in Hydrolink-MDE gel. The method is simple, rapid, does not depend on specific sequences such as restriction enzyme sites or CA boxes and does not require the use of isotope. This approach has been tested using 12 commonly occurring polymorphisms spanning the dystrophin gene as a model. We describe the use of the method to assign the carrier status of females in Duchenne muscular dystrophy (DMD) pedigrees. As a result of expanding the number of detectable polymorphisms throughout the dystrophin gene, we show how the method can easily be combined with dinucleotide analysis to improve the accuracy of carrier detection in the nondeletion cases. The technique is also shown to be used as an effective screen for improving carrier detection in several families with deletions. The finding of heterozygosity within the deletion identifies the at-risk female as a noncarrier. Using this method, we have identified and incorporated 3 new dystrophin polymorphisms (one of which in exon 16 is unique to African Americans). The method may be used other genetic diseases when mutations are unknown, or there are few dinucleotide markers in the gene proximity, or for the identification of haplotype backgrounds of mutant alleles.

  9. The IL23R A/Gln381 Allele Promotes IL-23 Unresponsiveness in Human Memory T-Helper 17 Cells and Impairs Th17 Responses in Psoriasis Patients

    PubMed Central

    Di Meglio, Paola; Villanova, Federica; Napolitano, Luca; Tosi, Isabella; Terranova Barberio, Manuela; Mak, Rose K; Nutland, Sarah; Smith, Catherine H; Barker, Jonathan N W N; Todd, John A; Nestle, Frank O

    2013-01-01

    We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers. PMID:23563201

  10. The role of allelic variation in estrogen receptor genes and major depression in the Nurses Health Study

    PubMed Central

    Keyes, K.; Agnew-Blais, J.; Roberts, A.; Hamilton, A.; De Vivo, I.; Ranu, H.; Koenen, K.

    2015-01-01

    Purpose The role of exogenous and endogenous sex hormones in the etiology of depression remains elusive, in part because sex hormone variation is often correlated with behaviors, life stage changes, and other factors that may influence depression. Estrogen receptor alpha (ESR1) and beta (ESR2) are known to regulate gene expression and estrogen response in areas of the brain associated with major depression and are unlikely to be correlated with exogenous factors that may influence depression. Methods We examined whether functional polymorphisms in these genes are associated with lifetime major depression and chronic major depression among a sample of women from the Nurses’ Health Study II (N=2,576). DSM-IV depressive disorder symptoms were assessed by structured interview in 2007. Genotyping was performed on DNA extracted from blood using Taq-man. Results Women with the AA alleles of ESR2 RS4986938 had the higher prevalence of lifetime major depression than women with other allele frequencies (36.7% for those with AA versus 28.5% with GA and 29.1% with GG, p=0.02) and chronic major depression (14.7% for those with AA versus 9.3% with GA and 9.1 % with GG, p=0.01). History of post-menopausal hormone (PMH) use modified the association of ESR1 polymorphism RS2234693 with any lifetime depression; specifically, those with the TT allele had the highest risk of lifetime depression among PMH users, and the lowest risk of depression among non-PMH users (p-value for interaction=0.02). Further, carriers of the AA alleles in ESR1 polymorphism RS9340799 had increased prevalence of lifetime major depression only among lifetime PMH-users (p=0.007). Conclusions Our findings support the hypothesis that estrogen receptor polymorphisms influence risk for major depression; the role of estrogen receptors and other sex steroid-related genetic factors may provide unique insights into etiology. PMID:26169989

  11. Identification of two novel human CD1E alleles.

    PubMed

    Mirones, I; Oteo, M; Parra-Cuadrado, J F; Martínez-Naves, E

    2000-08-01

    CD1 is a family of proteins structurally related to major histocompatibility complex (MHC) molecules and specialized in presenting lipids or glycolipids to T cells. In humans, there are five CD1 genes (CD1A to CD1E). It has been shown that, in contrast with classical MHC genes, CD1 loci display a very limited polymorphism. In the present work we describe two novel CD1E alleles found in two healthy Caucasian individuals. One allele differs from the wild-type by a point mutation resulting in a replacement of arginine at position 154 by a tryptophan. In the second allele we found a substitution of the leucine 184 by a proline.

  12. Allele surfing promotes microbial adaptation from standing variation.

    PubMed

    Gralka, Matti; Stiewe, Fabian; Farrell, Fred; Möbius, Wolfram; Waclaw, Bartlomiej; Hallatschek, Oskar

    2016-08-01

    The coupling of ecology and evolution during range expansions enables mutations to establish at expanding range margins and reach high frequencies. This phenomenon, called allele surfing, is thought to have caused revolutions in the gene pool of many species, most evidently in microbial communities. It has remained unclear, however, under which conditions allele surfing promotes or hinders adaptation. Here, using microbial experiments and simulations, we show that, starting with standing adaptive variation, range expansions generate a larger increase in mean fitness than spatially uniform population expansions. The adaptation gain results from 'soft' selective sweeps emerging from surfing beneficial mutations. The rate of these surfing events is shown to sensitively depend on the strength of genetic drift, which varies among strains and environmental conditions. More generally, allele surfing promotes the rate of adaptation per biomass produced, which could help developing biofilms and other resource-limited populations to cope with environmental challenges.

  13. Generation and characterization of an analog-sensitive PERK allele.

    PubMed

    Maas, Nancy L; Singh, Nickpreet; Diehl, J Alan

    2014-08-01

    Restriction of nutrients and oxygen in the tumor microenvironment disrupts ER homeostasis and adaptation to such stress is mediated by the key UPR effector PERK. Given its pro-tumorigenic activity, significant efforts have been made to elucidate the molecular mechanisms that underlie PERK function. Chemical-genetic approaches have recently proven instrumental in pathway mapping and interrogating kinase function. To enable a detailed study of PERK signaling we have generated an analog-sensitive PERK allele that accepts N(6)-alkylated ATP analogs. We find that this allele can be regulated by bulky ATP-competitive inhibitors, confirming the identity of the PERK gatekeeper residue as methionine 886. Furthermore, this analog-sensitive allele can be used to specifically label substrates with thiophosphate both in vitro and in cells. These data highlight the potential for using chemical-genetic techniques to identify novel PERK substrates, thereby providing an expanded view of PERK function and further definition of its signaling networks.

  14. Extensive HLA class I allele promiscuity among viral CTL epitopes

    PubMed Central

    Frahm, Nicole; Yusim, Karina; Suscovich, Todd J.; Adams, Sharon; Sidney, John; Hraber, Peter; Hewitt, Hannah S.; Linde, Caitlyn H.; Kavanagh, Daniel G.; Woodberry, Tonia; Henry, Leah M.; Faircloth, Kellie; Listgarten, Jennifer; Kadie, Carl; Jojic, Nebojsa; Sango, Kaori; Brown, Nancy V.; Pae, Eunice; Zaman, M. Tauheed; Bihl, Florian; Khatri, Ashok; John, Mina; Mallal, Simon; Marincola, Francesco M.; Walker, Bruce D.; Sette, Alessandro; Heckerman, David; Korber, Bette T.; Brander, Christian

    2008-01-01

    Summary Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals’ HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I restricted antigen presentation and vaccine development. PMID:17705138

  15. Tunnel and field effect carrier ballistics

    NASA Technical Reports Server (NTRS)

    Kaiser, William J. (Inventor); Bell, L. Douglas (Inventor)

    1989-01-01

    Methods and apparatus for interacting carriers with a structure of matter employ an electrode for emitting said carriers at a distance from a surface of that structure, and cause such carriers to travel along ballistic trajectories inside that structure by providing along the mentioned distance a gap for performance of a process selected from the group of carrier tunneling and field emission and injecting carriers emitted by the mentioned electrode and that process ballistically into the structure through the gap and the mentioned surface. The carriers are collected or analyzed after their travel along ballistic trajectories in the structure of matter. Pertinent information on the inside of the structure is obtained by conducting inside that structure what conventionally would have been considered external ballistics, while performing the carrier-propelling internal ballistics conversely outside that structure.

  16. Non-permeable substrate carrier for electroplating

    DOEpatents

    Abas, Emmanuel Chua; Chen, Chen-An; Ma, Diana Xiaobing; Ganti, Kalyana Bhargava

    2012-11-27

    One embodiment relates to a substrate carrier for use in electroplating a plurality of substrates. The substrate carrier comprises a non-conductive carrier body on which the substrates are to be held. Electrically-conductive lines are embedded within the carrier body, and a plurality of contact clips are coupled to the electrically-conductive lines embedded within the carrier body. The contact clips hold the substrates in place and electrically couple the substrates to the electrically-conductive lines. The non-conductive carrier body is continuous so as to be impermeable to flow of electroplating solution through the non-conductive carrier body. Other embodiments, aspects and features are also disclosed.

  17. Non-permeable substrate carrier for electroplating

    DOEpatents

    Abas, Emmanuel Chua; Chen, Chen-an; Ma, Diana Xiaobing; Ganti, Kalyana; Divino, Edmundo Anida; Ermita, Jake Randal G.; Capulong, Jose Francisco S.; Castillo, Arnold Villamor

    2015-12-29

    One embodiment relates to a substrate carrier for use in electroplating a plurality of substrates. The substrate carrier comprises a non-conductive carrier body on which the substrates are to be held. Electrically-conductive lines are embedded within the carrier body, and a plurality of contact clips are coupled to the electrically-conductive lines embedded within the carrier body. The contact clips hold the substrates in place and electrically couple the substrates to the electrically-conductive lines. The non-conductive carrier body is continuous so as to be impermeable to flow of electroplating solution through the non-conductive carrier body. Other embodiments, aspects and features are also disclosed.

  18. 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.

  19. Rapid DNA haplotyping using a multiplex heteroduplex approach: application to Duchenne muscular dystrophy carrier testing.

    PubMed

    Prior, T W; Wenger, G D; Papp, A C; Snyder, P J; Sedra, M S; Bartolo, C; Moore, J W; Highsmith, W E

    1995-01-01

    A new strategy has been developed for rapid haplotype analysis based on an initial multiplex amplification of several polymorphic sites, followed by heteroduplex detection. Heteroduplexes formed between two different alleles are detected because they migrate differently than the corresponding homoduplexes in Hydrolink-MDE gel. This simple, rapid method does not depend on specific sequences such as restriction enzyme sites or CA boxes and does not require the use of isotope. This approach has been tested using commonly occurring polymorphisms spanning the dystrophin gene as a model. We describe the use of the method to assign the carrier status of females in Duchenne muscular dystrophy (DMD) pedigrees. The method may be used for other genetic diseases when mutations are unknown or there are few dinucleotide markers in the gene proximity, and for the identification of haplotype backgrounds of mutant alleles.

  20. AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo.

    PubMed

    Wang, Xiaowen; Li, Kai; Liu, Ling; Shi, Qiong; Song, Pu; Jian, Zhe; Guo, Sen; Wang, Gang; Li, Chunying; Gao, Tianwen

    2015-09-15

    Vitiligo is an acquired depigmentation disorder largely caused by defective melanocyte- or autoimmunity-induced melanocyte destruction. The aryl hydrocarbon receptor (AHR) is essential for melanocyte homeostasis and immune process, and abnormal AHR was observed in vitiligo. We previously identified the T allele of AHR -129C > T variant as a protective factor against vitiligo. However, biological characterization underlying such effects is not fully certain, further validation by mechanistic research is warranted and was conducted in the present study. We showed that -129T allele promoted AHR transcriptional activity through facilitating its interaction with SP1 transcription factor (SP1) compared with -129C allele. We subsequently found reduced peripheral AHR and SP1 transcript expressions in vitiligo and a negative correlation of AHR level with disease duration. We also investigated AHR-related cytokines and observed increased serum TNF-α concentration and diminished serum levels of IL-10 and TGF-β1 in vitiligo. Further genetic analysis showed that -129T carriers possessed higher levels of AHR and IL-10 than -129C carriers. Therefore, our study indicates that the modulation of AHR transcription by a promoter variant has a profound influence on vitiligo, not only advancing our understanding on AHR function but also providing novel insight into the pathogenesis of degenerative or autoimmune diseases including vitiligo.

  1. Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele.

    PubMed Central

    McGee, T L; Devoto, M; Ott, J; Berson, E L; Dryja, T P

    1997-01-01

    A subset of families with autosomal dominant retinitis pigmentosa (RP) display reduced penetrance with some asymptomatic gene carriers showing no retinal abnormalities by ophthalmic examination or by electroretinography. Here we describe a study of three families with reduced-penetrance RP. In all three families the disease gene appears to be linked to chromosome 19q13.4, the region containing the RP11 locus, as defined by previously reported linkage studies based on five other reduced-penetrance families. Meiotic recombinants in one of the newly identified RP11 families and in two of the previously reported families serve to restrict the disease locus to a 6-cM region bounded by markers D19S572 and D19S926. We also compared the disease status of RP11 carriers with the segregation of microsatellite alleles within 19q13.4 from the noncarrier parents in the newly reported and the previously reported families. The results support the hypothesis that wild-type alleles at the RP11 locus or at a closely linked locus inherited from the noncarrier parents are a major factor influencing the penetrance of pathogenic alleles at this locus. PMID:9345108

  2. Combined effects of current-smoking and the aldehyde dehydrogenase 2*2 allele on the risk of myocardial infarction in Japanese patients.

    PubMed

    Morita, Kazunori; Miyazaki, Hiroko; Saruwatari, Junji; Oniki, Kentaro; Kumagae, Naoki; Tanaka, Takahiro; Kajiwara, Ayami; Otake, Koji; Ogata, Yasuhiro; Arima, Yuichiro; Hokimoto, Seiji; Ogawa, Hisao; Nakagawa, Kazuko

    2015-01-05

    Aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes, e.g. acetaldehyde in cigarette smoke; however, the interactive effects between smoking status and the ALDH2 genotype on coronary artery disease (CAD) have not been reported. We investigated the effects of smoking status and the ALDH2 genotype, and assessed their interactive and combined effects on the risk of myocardial infarction (MI) or stable angina (SA), including 221 MI and 175 SA subjects and 473 age- and sex-matched controls without CAD. Current-smoking and the ALDH2*2 allele additively increased the risk of MI (adjusted odds ratio 4.54, 95% confidence interval 2.25-9.15), although this combination was not associated with the risk of SA. This combination also increased the peak creatine kinase (CK) level synergistically in the acute MI (AMI) subjects. Moreover, current-smoking was found to be a significant risk factor for an increased peak CK level in the ALDH2*2 allele carriers (B 2220.2IU/L, p=0.008), but not the non-carriers. Additionally, a synergistic effect of this combination on the triglycerides levels was also found in the AMI subjects. These preliminary findings suggest that the combination of current-smoking and the inactive ALDH2*2 allele may increase the risk of MI additively and the infarct size synergistically.

  3. At What Cost a Carrier?

    DTIC Science & Technology

    2013-03-01

    expense of unmanned missiles and aircra". If the $eet were designed today , with the technolo- gies now available and the threats now emerging, it likely...brushed At What Cost a Carrier?M A R C H 2 0 1 3 4 | with interest, consequently pushing to convert the coal supply ship Jupiter into an American aircra...mission is to inform and prepare the national security leaders of today and tomorrow. CNAS is located in Washington, and was established in February

  4. External tank aft cargo carrier

    NASA Technical Reports Server (NTRS)

    Mobley, T. B.

    1984-01-01

    The External Tank (ET) Aft Cargo Carrier (ACC) is a low cost, low risk augmentation of the Space Transportation System (STS). It almost doubles the cargo volume of the STS while minimally impacting other STS elements (orbiter, ET and solid rocket boosters SRBs, launch facilities and STS operations. In addition to increasing the potential volume of cargo carried on a Shuttle launch, the ACC provides the following additional benefits: (1) Increased STS competitiveness for payloads; (2) Increased cargo manifest flexibility; (3) Increased spacecraft design options; (4) Alternate manifesting for special payloads; and (5) Future space platform/station design options.

  5. Biocheese: A Food Probiotic Carrier

    PubMed Central

    Castro, J. M.; Tornadijo, M. E.; Fresno, J. M.; Sandoval, H.

    2015-01-01

    This review describes some aspects related to the technological barriers encountered in the development and stability of probiotic cheeses. Aspects concerning the viability of probiotic cultures in this matrix are discussed and the potential of cheese as a biofunctional food carrier is analyzed, outlying some points related to health and safety. In general, the manufacture of probiotic cheese should have little change when compared with the elaboration of cheese in the traditional way. The physicochemical and technological parameters influencing the quality of these products have also to be measured so as to obtain a process optimization. PMID:25802862

  6. 78 FR 66801 - Motor Carrier Safety Advisory Committee; Charter Renewal

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-06

    ... Federal Motor Carrier Safety Administration Motor Carrier Safety Advisory Committee; Charter Renewal AGENCY: Federal Motor Carrier Safety Administration (FMCSA), DOT. ACTION: Announcement of advisory... Committee that provides the Agency with advice and recommendations on motor carrier safety programs...

  7. The Impact of ADH1B Alleles and Educational Status on Levels and Modes of Alcohol Consumption in Russian Male Individuals.

    PubMed

    Borinskaya, S A; Kim, A A; Rubanovich, A V; Yankovsky, N K

    2013-07-01

    Alcohol abuse is one of the main reasons behind the low life span in Russia. Both social and genetic factors affect the alcohol consumption level. The genetic factors are alleles of the alcohol dehydrogenase ADH1B and aldehyde dehydrogenaseALDH2 genes. We have typed and found frequencies for the alleles in a cohort of 642 men, ethnic Russians. The individuals of the cohort were asked to complete a questionnaire in the framework of the Izhevsk Family Study (Leon et al., 2007, 2009) regarding the amount of alcohol consumed and on the type of hazardous alcohol consumption (nonbeverage alcohol consumption and the so-called "zapoï" which is a Russian term for a heavy drinking bout lasting for at least 2 days, when an individual is withdrawn from the normal social life). The ADH1B*48His allele was found among heterozygous individuals only (N=68, 10.6% of the cohort). The ALDH2*504Lys allele was also found among heterozygous individuals only (N=2, 0.3%) The effect of ADH1B alleles and the influence of the education level on the amount and type of alcohol consumed had not previously been studied in Russians. We have found that the amount of consumed alcohol is 21.6% lower (1733 g of ethanol per year) for ADH1B*48His allele carriers in the cohort of Russian men. The amount of consumed alcohol was found to be 9.8% lower (793 g of ethanol per year) in the case when individuals had a higher education as compared to those who had a secondary- or elementary school education level in the same cohort. Hence, the protective effect of the genetic factor (ADH1B*48His allele carriage) has proven to be more pronounced than the influence of the social factor (education level) at the individual level in the cohort of Russian men. Both factors have also proven to have a protective effect against hazardous types of alcohol consumption. Zapoï was not scored among individuals of the cohort with ADH1B*48His allele carriage (OR=12.6, P=0.006), as compared to 8.4% of "zapoï" individuals who

  8. A yeast model reveals biochemical severity associated with each of three variant alleles of galactose-1P uridylyltransferase segregating in a single family.

    PubMed

    Chhay, J S; Openo, K K; Eaton, J S; Gentile, M; Fridovich-Keil, J L

    2008-02-01

    Classic galactosaemia is a potentially lethal inborn error of metabolism that results from profound impairment of galactose-1P uridylyltransferase (GALT). Like many autosomal recessive disorders, classic galactosaemia demonstrates marked allelic heterogeneity; many if not most patients are compound heterozygotes. Owing in part to the fact that most GALT mutations are never observed in patients in the homozygous state, in part to concerns of possible allelic interaction, and in part to the broad range of GALT activity levels associated with the affected, carrier, and control states, definition of the specific functional consequence of individual variant GALT alleles from studies of clinical samples alone can be a challenging task. To overcome this problem we previously developed and applied a null-background yeast system to enable functional analyses of human GALT alleles expressed individually or in defined pairs. We report here the application of this system to characterize three distinct variant alleles of GALT identified within a single family. Of these alleles, one carried a missense mutation (K285N) that has previously been reported and characterized, one carried a nonsense mutation (R204X) that has previously been reported but not characterized, and the third carried a missense substitution (T268N) that was novel. Our studies reported here reconfirm the profound nature of the K285N mutation, demonstrate that the R204X mutation severely compromises both expression and function of human GALT, and finally implicate T268N as one of a very small number of naturally occurring rare but neutral missense polymorphisms in human GALT.

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

    NASA Astrophysics Data System (ADS)

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

    1993-04-01

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

  10. Tuning superconductivity by carrier injection

    NASA Astrophysics Data System (ADS)

    Müller, Paul

    2011-03-01

    All high-Tc cuprates are stacking sequences of Cu O2 layers and charge reservoir layers consisting of metal oxides. Upon doping the Cu O2 layers, antiferromagnetic order is destroyed and metallic conductivity is established. Usually doping is achieved by a non-stoichiometric composition of the charge reservoir layer. However, we already have shown that we can change the carrier concentration of Bi 2 Sr 2 CaCu 2 O8 + δ single crystals by current injection along the c- axis. Critical temperature, c-axis resistivity and critical current of intrinsic Josephson junctions can be tuned in a large range from underdoping to extreme overdoping. This effect is persistent up to annealing temperatures of approximately 270 K. Using current injection at higher bias, we were able to reduce the carrier concentration again. We investigated in detail the superconducting properties by performing macroscopic quantum tunneling experiments of intrinsic Josephson junctions. The experiments have been carried out repeatedly on samples, whose properties were changed only by current injection. An exponential increase of the critical current density with hole concentration was observed. At the same time, the capacitance of intrinsic Josephson junctions increased significantly. Finally, only by current injection, we were able to convert into the superconducting state a nonsuperconducting, oxygen depleted sample. This work was done in collaboration with Y. Koval, X.Y. Jin, S. Probst, Y. Simsek, C. Steiner (Universität Erlangen), H. B. Wang (NIMS, Tsukuba), and G. Behr, B. Büchner (IFW Dresden).

  11. Carrier detection in xeroderma pigmentosum

    SciTech Connect

    Parshad, R.; Sanford, K.K.; Kraemer, K.H.; Jones, G.M.; Tarone, R.E. )

    1990-01-01

    We were able to detect clinically normal carriers of xeroderma pigmentosum (XP) genes with coded samples of either peripheral blood lymphocytes or skin fibroblasts, using a cytogenetic assay shown previously to detect individuals with cancer-prone genetic disorders. Metaphase cells of phytohemagglutinin-stimulated T-lymphocytes from eight individuals who are obligate heterozygotes for XP were compared with those from nine normal controls at 1.3, 2.3, and 3.3 h after x-irradiation (58 R) during the G2 phase of the cell cycle. Lymphocytes from the XP heterozygotes had twofold higher frequencies of chromatid breaks or chromatid gaps than normal (P less than 10(-5)) when fixed at 2.3 or 3.3 h after irradiation. Lymphocytes from six XP homozygotes had frequencies of breaks and gaps threefold higher than normal. Skin fibroblasts from an additional obligate XP heterozygote, when fixed approximately 2 h after x-irradiation (68 R), had a twofold higher frequency of chromatid breaks and a fourfold higher frequency of gaps than fibroblasts from a normal control. This frequency of aberrations in cells from the XP heterozygote was approximately half that observed in the XP homozygote. The elevated frequencies of chromatid breaks and gaps after G2 phase x-irradiation may provide the basis of a test for identifying carriers of the XP gene(s) within known XP families.

  12. Carrier localization in gallium nitride

    SciTech Connect

    Wetzel, C.; Walukiewicz, W.; Haller, E.E.

    1996-09-01

    In wide bandgap GaN, a large number of interesting and important scientific questions remain to be answered. For example, the large free electron concentration reaching 10{sup 19} to 10{sup 20} cm{sup - 3} in nominally undoped material are ascribed to intrinsic defects because no chemical impurity has been found at such high concentrations. According to theoretical models, a nitrogen vacancy acts as a donor but its formation energy is very large in n-type materials, making this suggestion controversial. We have investigated the nature of this yet unidentified donor at large hydrostatic pressure. Results from infrared reflection and Raman scattering indicate strong evidence for localization of free carriers by large pressures. The carrier density is drastically decreased by two orders of magnitude between 20 and 30 GPa. Several techniques provide independent evidence for results in earlier reports and present the first quantitative analysis. A possible interpretation of this effect in terms of the resonant donor level is presented.

  13. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals

    PubMed Central

    Lazarin, Gabriel A.; Haque, Imran S.; Nazareth, Shivani; Iori, Kevin; Patterson, A. Scott; Jacobson, Jessica L.; Marshall, John R.; Seltzer, William K.; Patrizio, Pasquale; Evans, Eric A.; Srinivasan, Balaji S.

    2013-01-01

    Purpose: Recent developments in genomics have led to expanded carrier screening panels capable of assessing hundreds of causal mutations for genetic disease. This new technology enables simultaneous measurement of carrier frequencies for many diseases. As the resultant rank-ordering of carrier frequencies impacts the design and prioritization of screening programs, the accuracy of this ranking is a public health concern. Methods: A total of 23,453 individuals from many obstetric, genetics, and infertility clinics were referred for routine recessive disease carrier screening. Multiplex carrier screening was performed and results were aggregated for this study. Results: Twenty-four percent of individuals were identified as carriers for at least one of 108 disorders, and 5.2% were carriers for multiple disorders. We report tabulations of carrier frequency by self-identified ethnicity and disease. Conclusion: To our knowledge, this study of a large, ethnically diverse clinical sample provides the most accurate measurements to date of carrier frequencies for hundreds of recessive alleles. The study also yields information on the clinical considerations associated with routine use of expanded panels and provides support for a pan-ethnic screening paradigm that minimizes the use of “racial” categories by the physician, as recommended by recent guidelines. PMID:22975760

  14. Silicon ball grid array chip carrier

    DOEpatents

    Palmer, David W.; Gassman, Richard A.; Chu, Dahwey

    2000-01-01

    A ball-grid-array integrated circuit (IC) chip carrier formed from a silicon substrate is disclosed. The silicon ball-grid-array chip carrier is of particular use with ICs having peripheral bond pads which can be reconfigured to a ball-grid-array. The use of a semiconductor substrate such as silicon for forming the ball-grid-array chip carrier allows the chip carrier to be fabricated on an IC process line with, at least in part, standard IC processes. Additionally, the silicon chip carrier can include components such as transistors, resistors, capacitors, inductors and sensors to form a "smart" chip carrier which can provide added functionality and testability to one or more ICs mounted on the chip carrier. Types of functionality that can be provided on the "smart" chip carrier include boundary-scan cells, built-in test structures, signal conditioning circuitry, power conditioning circuitry, and a reconfiguration capability. The "smart" chip carrier can also be used to form specialized or application-specific ICs (ASICs) from conventional ICs. Types of sensors that can be included on the silicon ball-grid-array chip carrier include temperature sensors, pressure sensors, stress sensors, inertia or acceleration sensors, and/or chemical sensors. These sensors can be fabricated by IC processes and can include microelectromechanical (MEM) devices.

  15. Tissue-specific patterns of allelically-skewed DNA methylation.

    PubMed

    Marzi, Sarah J; Meaburn, Emma L; Dempster, Emma L; Lunnon, Katie; Paya-Cano, Jose L; Smith, Rebecca G; Volta, Manuela; Troakes, Claire; Schalkwyk, Leonard C; Mill, Jonathan

    2016-01-01

    While DNA methylation is usually thought to be symmetrical across both alleles, there are some notable exceptions. Genomic imprinting and X chromosome inactivation are two well-studied sources of allele-specific methylation (ASM), but recent research has indicated a more complex pattern in which genotypic variation can be associated with allelically-skewed DNA methylation in cis. Given the known heterogeneity of DNA methylation across tissues and cell types we explored inter- and intra-individual variation in ASM across several regions of the human brain and whole blood from multiple individuals. Consistent with previous studies, we find widespread ASM with > 4% of the ∼220,000 loci interrogated showing evidence of allelically-skewed DNA methylation. We identify ASM flanking known imprinted regions, and show that ASM sites are enriched in DNase I hypersensitivity sites and often located in an extended genomic context of intermediate DNA methylation. We also detect examples of genotype-driven ASM, some of which are tissue-specific. These findings contribute to our understanding of the nature of differential DNA methylation across tissues and have important implications for genetic studies of complex disease. As a resource to the community, ASM patterns across each of the tissues studied are available in a searchable online database: http://epigenetics.essex.ac.uk/ASMBrainBlood.

  16. 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

    2015-04-30

    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.

  17. 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...

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

    PubMed

    Percy, A; Kinghorn, B P

    2005-12-01

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

  19. Natural allelic variations in highly polyploidy Saccharum complex

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sugarcane (Saccharum spp.) as important sugar and biofuel crop are highly polypoid with complex genomes. A large amount of natural phenotypic variation exists in sugarcane germplasm. Understanding its allelic variance has been challenging but is a critical foundation for discovery of the genomic seq...

  20. 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

  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. Tissue-specific patterns of allelically-skewed DNA methylation

    PubMed Central

    Marzi, Sarah J.; Meaburn, Emma L.; Dempster, Emma L.; Lunnon, Katie; Paya-Cano, Jose L.; Smith, Rebecca G.; Volta, Manuela; Troakes, Claire; Schalkwyk, Leonard C.; Mill, Jonathan

    2016-01-01

    ABSTRACT While DNA methylation is usually thought to be symmetrical across both alleles, there are some notable exceptions. Genomic imprinting and X chromosome inactivation are two well-studied sources of allele-specific methylation (ASM), but recent research has indicated a more complex pattern in which genotypic variation can be associated with allelically-skewed DNA methylation in cis. Given the known heterogeneity of DNA methylation across tissues and cell types we explored inter- and intra-individual variation in ASM across several regions of the human brain and whole blood from multiple individuals. Consistent with previous studies, we find widespread ASM with > 4% of the ∼220,000 loci interrogated showing evidence of allelically-skewed DNA methylation. We identify ASM flanking known imprinted regions, and show that ASM sites are enriched in DNase I hypersensitivity sites and often located in an extended genomic context of intermediate DNA methylation. We also detect examples of genotype-driven ASM, some of which are tissue-specific. These findings contribute to our understanding of the nature of differential DNA methylation across tissues and have important implications for genetic studies of complex disease. As a resource to the community, ASM patterns across each of the tissues studied are available in a searchable online database: http://epigenetics.essex.ac.uk/ASMBrainBlood. PMID:26786711

  3. 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.

  4. 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.

  5. Registration of two allelic erect leaf mutants of sorghum

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  6. Frequencies of 32 base pair deletion of the (Delta 32) allele of the CCR5 HIV-1 co-receptor gene in Caucasians: a comparative analysis.

    PubMed

    Lucotte, Gérard

    2002-05-01

    The CCR5 gene encodes for the co-receptor for the major macrophage-tropics strains of human immunodeficiency virus (HIV-1), and a mutant allele of this gene (Delta 32) provide to homozygotes a strong resistance against infection by HIV. The frequency of the Delta 32 allele was investigated in 40 populations of 8842 non-infected subjects coming from Europe, the Middle-East and North Africa. A clear north-south decreasing gradient was evident for Delta 32 frequencies, with a significant correlation coefficient (r=0.83). The main frequency value of Delta 32 for Sweden, Norway, Denmark, Finland and Iceland (0.134) is significantly (chi(2)=63.818, P<0.001) highest than the Delta 32 mean value, indicating that probably the Vikings might have been instrumental in disseminating the Delta 32 allele during the eighth to the tenth centuries during historical times. Possibly variola virus has discriminated the Delta 32 carriers in Europe since the eighth century AD, explaining the high frequency of the Delta 32 allele in Europe today.

  7. Mutation analysis and carrier detection of Hunter syndrome

    SciTech Connect

    Li, P.; Thompson, J.N.; Hug, G.; Chuck, G.

    1994-09-01

    Hunter syndrome, mucopolysaccharidosis type II (MPS II, MIM 309900), is an X-linked lysosomal storage disorder due to a deficiency of iduronate-2-sulfatase (IDS, EC 3.1.6.13) activity. The IDS cDNA sequence and genomic exon/intron sequences have been characterized. In the present investigation, 8 patients with IDS deficiency enzymatically diagnosed by us were used for molecular analysis. Total cellular RNA was isolated from cultured skin fibroblasts and DNA was isolated from cultured skin fibroblasts or leukocytes of the patients and controls. A RT-PCR sequencing method and an exon-by exon PCR amplification of the IDS gene were used for mutation analysis. Six new mutations, from the 8 patients, have been identified: A346V (GCC to GTC) in exon VIII coexistent with T146T silent mutation and a two-nucleotide insertion at codon 423 (CCC to CCCCC) in exon IX coexistent with T146T were found in two patients with a mild Hunter phenotype; S71R (AGC to AGA) in exon II, L279X (TTA to TGA) in exon VI, 406delCT (CTT to --T) in exon IX, and 407delTT (TTT to T--) in exon IX were found in 4 unrelated cases. All mutations detected by RT-PCR sequencing were confirmed by restriction enzyme assay and PCR analysis of the genomic DNA sequence. The mutation L279X eliminated an Mse I site from the mutant allele. Carrier detection for this mutation revealed that the mother of the proband was a carrier; however, neither her mother nor any of her sisters were carriers and none of her brothers were affected. We postulate that the mutation probably originated from a germline mutation. Our studies support previous findings that a large proportion of MPS II families result from new mutations. The RT-PCR sequencing and exon-by-exon PCR method has proven to be a practical approach for mutation analysis and carrier detection in families with an affected MPS II.

  8. Recent Advances in Subunit Vaccine Carriers

    PubMed Central

    Vartak, Abhishek; Sucheck, Steven J.

    2016-01-01

    The lower immunogenicity of synthetic subunit antigens, compared to live attenuated vaccines, is being addressed with improved vaccine carriers. Recent reports indicate that the physio-chemical properties of these carriers can be altered to achieve optimal antigen presentation, endosomal escape, particle bio-distribution, and cellular trafficking. The carriers can be modified with various antigens and ligands for dendritic cells targeting. They can also be modified with adjuvants, either covalently or entrapped in the matrix, to improve cellular and humoral immune responses against the antigen. As a result, these multi-functional carrier systems are being explored for use in active immunotherapy against cancer and infectious diseases. Advancing technology, improved analytical methods, and use of computational methodology have also contributed to the development of subunit vaccine carriers. This review details recent breakthroughs in the design of nano-particulate vaccine carriers, including liposomes, polymeric nanoparticles, and inorganic nanoparticles. PMID:27104575

  9. Carriers of the astronomical 2175 ? extinction feature

    SciTech Connect

    Bradley, J; Dai, Z; Ernie, R; Browning, N; Graham, G; Weber, P; Smith, J; Hutcheon, I; Ishii, H; Bajt, S; Floss, C; Stadermann, F

    2004-07-20

    The 2175 {angstrom} extinction feature is by far the strongest spectral signature of interstellar dust observed by astronomers. Forty years after its discovery the origin of the feature and the nature of the carrier remain controversial. The feature is enigmatic because although its central wavelength is almost invariant its bandwidth varies strongly from one sightline to another, suggesting multiple carriers or a single carrier with variable properties. Using a monochromated transmission electron microscope and valence electron energy-loss spectroscopy we have detected a 5.7 eV (2175 {angstrom}) feature in submicrometer-sized interstellar grains within interplanetary dust particles (IDPs) collected in the stratosphere. The carriers are organic carbon and amorphous silicates that are abundant and closely associated with one another both in IDPs and in the interstellar medium. Multiple carriers rather than a single carrier may explain the invariant central wavelength and variable bandwidth of the astronomical 2175 {angstrom} feature.

  10. KIR2DL2/2DL3-E(35) alleles are functionally stronger than -Q(35) alleles.

    PubMed

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-03-31

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E(35)) are functionally stronger than those with glutamine at the same position (Q(35)). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E(35) could kill more target cells lacking their ligands than NK cells with the weaker -Q(35) alleles, indicating better licensing of KIR2DL2/L3(+) NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.

  11. KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

    NASA Astrophysics Data System (ADS)

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-03-01

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  13. 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.

  14. 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.

  15. Improving accuracy of Tay Sachs carrier screening of the non-Jewish population: analysis of 34 carriers and six late-onset patients with HEXA enzyme and DNA sequence analysis.

    PubMed

    Park, Noh Jin; Morgan, Craig; Sharma, Rajesh; Li, Yuanyin; Lobo, Raynah M; Redman, Joy B; Salazar, Denise; Sun, Weimin; Neidich, Julie A; Strom, Charles M

    2010-02-01

    The purpose of this study was to determine whether combining different testing modalities namely beta-hexosaminidase A (HEXA) enzyme analysis, HEXA DNA common mutation assay, and HEXA gene sequencing could improve the sensitivity for carrier detection in non-Ashkenazi (AJ) individuals. We performed a HEXA gene sequencing assay, a HEXA DNA common mutation assay, and a HEXA enzyme assay on 34 self-reported Tay-Sachs disease (TSD) carriers, six late-onset patients with TSD, and one pseudodeficiency allele carrier. Sensitivity of TSD carrier detection was 91% for gene sequencing compared with 91% for the enzyme assay and 52% for the DNA mutation assay. Gene sequencing combined with enzyme testing had the highest sensitivity (100%) for carrier detection. Gene sequencing detected four novel mutations, three of which are predicted to be disease causing [118.delT, 965A-->T (D322V), and 775A-->G (T259A)]. Gene sequencing is useful in identifying rare mutations in patients with TSD and their families, in evaluating spouses of known carriers for TSD who have indeterminate enzyme analysis and negative for common mutation analysis, and in resolving ambiguous enzyme testing results.

  16. Laboratory Studies of DIB Carriers

    NASA Technical Reports Server (NTRS)

    Allamandola, L. J.

    1995-01-01

    Spectroscopic studies of the following potential diffuse interstellar band (DIB) carriers are reviewed: unspecified organics, carbon chains, polycyclic aromatic hydrocarbons (PAHs), fullerenes and derivatives, as well as porphyrins and related material. An assessment of each is given, along with suggestions for further experimental studies needed to fully test each candidate. Of the experimental techniques in common use matrix isolation spectroscopy with neon matrices is the most appropriate for the DIBs. The low vapor pressure and high reactivity of these materials preclude gas phase studies on many of these species. At this point, given the type and quality of published data available, carbon chains and PARs are the most promising candidates for a number of the DIBs.

  17. CARRIER/CASK HANDLING SYSTEM DESCRIPTION DOCUMENT

    SciTech Connect

    E.F. Loros

    2000-06-23

    The Carrier/Cask Handling System receives casks on railcars and legal-weight trucks (LWTs) (transporters) that transport loaded casks and empty overpacks to the Monitored Geologic Repository (MGR) from the Carrier/Cask Transport System. Casks that come to the MGR on heavy-haul trucks (HHTs) are transferred onto railcars before being brought into the Carrier/Cask Handling System. The system is the interfacing system between the railcars and LWTs and the Assembly Transfer System (ATS) and Canister Transfer System (CTS). The Carrier/Cask Handling System removes loaded casks from the cask transporters and transfers the casks to a transfer cart for either the ATS or CTS, as appropriate, based on cask contents. The Carrier/Cask Handling System receives the returned empty casks from the ATS and CTS and mounts the casks back onto the transporters for reshipment. If necessary, the Carrier/Cask Handling System can also mount loaded casks back onto the transporters and remove empty casks from the transporters. The Carrier/Cask Handling System receives overpacks from the ATS loaded with canisters that have been cut open and emptied and mounts the overpacks back onto the transporters for disposal. If necessary, the Carrier/Cask Handling System can also mount empty overpacks back onto the transporters and remove loaded overpacks from them. The Carrier/Cask Handling System is located within the Carrier Bay of the Waste Handling Building System. The system consists of cranes, hoists, manipulators, and supporting equipment. The Carrier/Cask Handling System is designed with the tooling and fixtures necessary for handling a variety of casks. The Carrier/Cask Handling System performance and reliability are sufficient to support the shipping and emplacement schedules for the MGR. The Carrier/Cask Handling System interfaces with the Carrier/Cask Transport System, ATS, and CTS as noted above. The Carrier/Cask Handling System interfaces with the Waste Handling Building System for building

  18. Charge carrier thermalization in organic diodes

    PubMed Central

    van der Kaap, N. J.; Koster, L. J. A.

    2016-01-01

    Charge carrier mobilities of organic semiconductors are often characterized using steady-state measurements of space charge limited diodes. These measurements assume that charge carriers are in a steady-state equilibrium. In reality, however, energetically hot carriers are introduces by photo-excitation and injection into highly energetic sites from the electrodes. These carriers perturb the equilibrium density of occupied states, and therefore change the overall charge transport properties. In this paper, we look into the effect of energetically hot carriers on the charge transport in organic semiconductors using steady state kinetic Monte Carlo simulations. For injected hot carriers in a typical organic semiconductor, rapid energetic relaxation occurs in the order of tens of nanoseconds, which is much faster than the typical transit time of a charge carrier throught the device. Furthermore, we investigate the impact of photo-generated carriers on the steady-state mobility. For a typical organic voltaic material, an increase in mobility of a factor of 1.1 is found. Therefore, we conclude that the impact of energetically hot carriers on normal device operation is limited. PMID:26791095

  19. Global Carrier Rates of Rare Inherited Disorders Using Population Exome Sequences

    PubMed Central

    Fujikura, Kohei

    2016-01-01

    Exome sequencing has revealed the causative mutations behind numerous rare, inherited disorders, but it is challenging to find reliable epidemiological values for rare disorders. Here, I provide a genetic epidemiology method to identify the causative mutations behind rare, inherited disorders using two population exome sequences (1000 Genomes and NHLBI). I created global maps of carrier rate distribution for 18 recessive disorders in 16 diverse ethnic populations. Out of a total of 161 mutations associated with 18 recessive disorders, I detected 24 mutations in either or both exome studies. The genetic mapping revealed strong international spatial heterogeneities in the carrier patterns of the inherited disorders. I next validated this methodology by statistically evaluating the carrier rate of one well-understood disorder, sickle cell anemia (SCA). The population exome-based epidemiology of SCA [African (allele frequency (AF) = 0.0454, N = 2447), Asian (AF = 0, N = 286), European (AF = 0.000214, N = 4677), and Hispanic (AF = 0.0111, N = 362)] was not significantly different from that obtained from a clinical prevalence survey. A pair-wise proportion test revealed no significant differences between the two exome projects in terms of AF (46/48 cases; P > 0.05). I conclude that population exome-based carrier rates can form the foundation for a prospectively maintained database of use to clinical geneticists. Similar modeling methods can be applied to many inherited disorders. PMID:27219052

  20. Characterization of 18 new BoLA-DRB3 alleles.

    PubMed

    Maillard, J C; Renard, C; Chardon, P; Chantal, I; Bensaid, A

    1999-06-01

    The second exon of the bovine MHC class II DRB3 gene was amplified by polymerase chain reaction (PCR) from DNA samples of 568 zebu Brahman cattle (Bos indicus) from Martinique (French West Indies). Cloning of these PCR products allowed the isolation of both alleles from each animal, which were characterized by the PCR-restriction fragment length polymorphism (RFLP) technique using the restriction enzymes RsaI, BstYI and HaeIII. Four new PCR-RFLP patterns were obtained by digestion with RsaI. These patterns were named 'v', 'w', 'x' and 'y' continuing the accepted nomenclature. Sequencing of each allele allowed the identification of 18 new BoLA-DRB3 exon 2 nucleotide sequences and their deduced amino acid sequences.

  1. Early allelic selection in maize as revealed by ancient DNA.

    PubMed

    Jaenicke-Després, Viviane; Buckler, Ed S; Smith, Bruce D; Gilbert, M Thomas P; Cooper, Alan; Doebley, John; Pääbo, Svante

    2003-11-14

    Maize was domesticated from teosinte, a wild grass, by approximately 6300 years ago in Mexico. After initial domestication, early farmers continued to select for advantageous morphological and biochemical traits in this important crop. However, the timing and sequence of character selection are, thus far, known only for morphological features discernible in corn cobs. We have analyzed three genes involved in the control of plant architecture, storage protein synthesis, and starch production from archaeological maize samples from Mexico and the southwestern United States. The results reveal that the alleles typical of contemporary maize were present in Mexican maize by 4400 years ago. However, as recently as 2000 years ago, allelic selection at one of the genes may not yet have been complete.

  2. Natural Allelic Variations in Highly Polyploidy Saccharum Complex

    PubMed Central

    Song, Jian; Yang, Xiping; Resende, Marcio F. R.; Neves, Leandro G.; Todd, James; Zhang, Jisen; Comstock, Jack C.; Wang, Jianping

    2016-01-01

    Sugarcane (Saccharum spp.) is an important sugar and biofuel crop with high polyploid and complex genomes. The Saccharum complex, comprised of Saccharum genus and a few related genera, are important genetic resources for sugarcane breeding. A large amount of natural variation exists within the Saccharum complex. Though understanding their allelic variation has been challenging, it is critical to dissect allelic structure and to identify the alleles controlling important traits in sugarcane. To characterize natural variations in Saccharum complex, a target enrichment sequencing approach was used to assay 12 representative germplasm accessions. In total, 55,946 highly efficient probes were designed based on the sorghum genome and sugarcane unigene set targeting a total of 6 Mb of the sugarcane genome. A pipeline specifically tailored for polyploid sequence variants and genotype calling was established. BWA-mem and sorghum genome approved to be an acceptable aligner and reference for sugarcane target enrichment sequence analysis, respectively. Genetic variations including 1,166,066 non-redundant SNPs, 150,421 InDels, 919 gene copy number variations, and 1,257 gene presence/absence variations were detected. SNPs from three different callers (Samtools, Freebayes, and GATK) were compared and the validation rates were nearly 90%. Based on the SNP loci of each accession and their ploidy levels, 999,258 single dosage SNPs were identified and most loci were estimated as largely homozygotes. An average of 34,397 haplotype blocks for each accession was inferred. The highest divergence time among the Saccharum spp. was estimated as 1.2 million years ago (MYA). Saccharum spp. diverged from Erianthus and Sorghum approximately 5 and 6 MYA, respectively. The target enrichment sequencing approach provided an effective way to discover and catalog natural allelic variation in highly polyploid or heterozygous genomes. PMID:27375658

  3. Natural Allelic Variations in Highly Polyploidy Saccharum Complex.

    PubMed

    Song, Jian; Yang, Xiping; Resende, Marcio F R; Neves, Leandro G; Todd, James; Zhang, Jisen; Comstock, Jack C; Wang, Jianping

    2016-01-01

    Sugarcane (Saccharum spp.) is an important sugar and biofuel crop with high polyploid and complex genomes. The Saccharum complex, comprised of Saccharum genus and a few related genera, are important genetic resources for sugarcane breeding. A large amount of natural variation exists within the Saccharum complex. Though understanding their allelic variation has been challenging, it is critical to dissect allelic structure and to identify the alleles controlling important traits in sugarcane. To characterize natural variations in Saccharum complex, a target enrichment sequencing approach was used to assay 12 representative germplasm accessions. In total, 55,946 highly efficient probes were designed based on the sorghum genome and sugarcane unigene set targeting a total of 6 Mb of the sugarcane genome. A pipeline specifically tailored for polyploid sequence variants and genotype calling was established. BWA-mem and sorghum genome approved to be an acceptable aligner and reference for sugarcane target enrichment sequence analysis, respectively. Genetic variations including 1,166,066 non-redundant SNPs, 150,421 InDels, 919 gene copy number variations, and 1,257 gene presence/absence variations were detected. SNPs from three different callers (Samtools, Freebayes, and GATK) were compared and the validation rates were nearly 90%. Based on the SNP loci of each accession and their ploidy levels, 999,258 single dosage SNPs were identified and most loci were estimated as largely homozygotes. An average of 34,397 haplotype blocks for each accession was inferred. The highest divergence time among the Saccharum spp. was estimated as 1.2 million years ago (MYA). Saccharum spp. diverged from Erianthus and Sorghum approximately 5 and 6 MYA, respectively. The target enrichment sequencing approach provided an effective way to discover and catalog natural allelic variation in highly polyploid or heterozygous genomes.

  4. Allelic exchange in Mycobacterium tuberculosis with long linear recombination substrates.

    PubMed Central

    Balasubramanian, V; Pavelka, M S; Bardarov, S S; Martin, J; Weisbrod, T R; McAdam, R A; Bloom, B R; Jacobs, W R

    1996-01-01

    Genetic studies of Mycobacterium tuberculosis have been greatly hampered by the inability to introduce specific chromosomal mutations. Whereas the ability to perform allelic exchanges has provided a useful method of gene disruption in other organisms, in the clinically important species of mycobacteria, such as M. tuberculosis and Mycobacterium bovis, similar approaches have thus far been unsuccessful. In this communication, we report the development of a shuttle mutagenesis strategy that involves the use of long linear recombination substrates to reproducibly obtain recombinants by allelic exchange in M. tuberculosis. Long linear recombination substrates, approximately 40 to 50 kb in length, were generated by constructing libraries in the excisable cosmid vector pYUB328. The cosmid vector could be readily excised from the recombinant cosmids by digestion with PacI, a restriction endonuclease for which there exist few, if any, sites in mycobacterial genomes. A cosmid containing the mycobacterial leuD gene was isolated, and a selectable marker conferring resistance to kanamycin was inserted into the leuD gene in the recombinant cosmid by interplasmid recombination in Escherichia coli. A long linear recombination substrate containing the insertionally mutated leuD gene was generated by PacI digestion. Electroporation of this recombination substrate containing the insertionally mutated leuD allele resulted in the generation of leucine auxotrophic mutants by homologous recombination in 6% of the kanamycin-resistant transformants for both the Erdman and H37Rv strains of M. tuberculosis. The ability to perform allelic exchanges provides an important approach for investigating the biology of this pathogen as well as developing new live-cell M. tuberculosis-based vaccines. PMID:8550428

  5. Citrobacter spp. as a source of qnrB Alleles.

    PubMed

    Jacoby, George A; Griffin, Caitlin M; Hooper, David C

    2011-11-01

    qnrB is the most common of the five qnr families and has the greatest number of allelic variants. Almost two-thirds of the qnrB alleles have been reported in Citrobacter spp., and several were shown to be located on the chromosome. In this study, PCR was used to investigate the prevalence of plasmid-mediated quinolone resistance genes in 71 clinical isolates belonging to the Citrobacter freundii complex. Thirty-seven percent contained qnrB alleles, including 7 (qnrB32 to qnrB38) that were novel and 1 pseudogene, while none contained qnrA, qnrC, qnrD, qnrS, or aac(6')-Ib-cr. When the strains were arrayed by related 16S rRNA sequence and further separated into subspecies by biochemical criteria, clustering of qnrB-positive strains was evident. In only two strains with qnrB2 and qnrB4 was quinolone resistance transferable by conjugation, and only these strains contained the ISCR1 sequence that is often associated with qnrB on plasmids. Five of 26 qnrB-positive strains contained integrase genes, but these included the strains with qnrB2 and qnrB4 as well as two strains with other transmissible plasmids. In a fully sequenced genome of Citrobacter youngae, a member of the C. freundii complex, another novel qnrB allele, qnrB39, occurs in a sequence of genes that is 90% identical to sequence surrounding integron-associated qnrB4 incorporated into plasmids. The chromosome of Citrobacter is the likely source of plasmid-mediated qnrB.

  6. Fast spatial ancestry via flexible allele frequency surfaces

    PubMed Central

    Rañola, John Michael; Novembre, John; Lange, Kenneth

    2014-01-01

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

  7. 14 CFR 271.5 - Carrier revenues.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Carrier revenues. 271.5 Section 271.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS GUIDELINES FOR SUBSIDIZING AIR CARRIERS PROVIDING ESSENTIAL AIR TRANSPORTATION § 271.5...

  8. 14 CFR 271.4 - Carrier costs.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Carrier costs. 271.4 Section 271.4 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS GUIDELINES FOR SUBSIDIZING AIR CARRIERS PROVIDING ESSENTIAL AIR TRANSPORTATION § 271.4...

  9. 29 CFR 1202.13 - Air carriers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... terms of title II of the Railway Labor Act, which was approved April 10, 1936, all of title I, except section 3, which relates to the National Railroad Adjustment Board, was extended to cover every common carrier by air engaged in interstate or foreign commerce, and every carrier by air transporting mail...

  10. 29 CFR 1202.13 - Air carriers.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... terms of title II of the Railway Labor Act, which was approved April 10, 1936, all of title I, except section 3, which relates to the National Railroad Adjustment Board, was extended to cover every common carrier by air engaged in interstate or foreign commerce, and every carrier by air transporting mail...

  11. 49 CFR 1139.21 - Study carriers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 8 2014-10-01 2014-10-01 false Study carriers. 1139.21 Section 1139.21 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION RULES OF PRACTICE PROCEDURES IN MOTOR CARRIER REVENUE PROCEEDINGS Intercity...

  12. 49 CFR 1139.21 - Study carriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Study carriers. 1139.21 Section 1139.21 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION RULES OF PRACTICE PROCEDURES IN MOTOR CARRIER REVENUE PROCEEDINGS Intercity...

  13. 49 CFR 1139.21 - Study carriers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 8 2012-10-01 2012-10-01 false Study carriers. 1139.21 Section 1139.21 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION RULES OF PRACTICE PROCEDURES IN MOTOR CARRIER REVENUE PROCEEDINGS Intercity...

  14. 49 CFR 1139.21 - Study carriers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 8 2011-10-01 2011-10-01 false Study carriers. 1139.21 Section 1139.21 Transportation Other Regulations Relating to Transportation (Continued) SURFACE TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION RULES OF PRACTICE PROCEDURES IN MOTOR CARRIER REVENUE PROCEEDINGS Intercity...

  15. Data-aided carrier tracking loops

    NASA Technical Reports Server (NTRS)

    Lindsey, W. C.; Simon, M. K.

    1973-01-01

    Power in composite signal sidebands is used to enhance signal-to-noise ratio in carrier tracking loop, thereby reducing radio loss and decreasing probability of receiver error. By adding quadrature channel to phase-lock-loop detector circuit of receiver, dc component can be fed back into carrier tracking loop.

  16. Pollution-tolerant allele in fingernail clams (Musculium transversum).

    PubMed

    Sloss, B L; Romano, M A; Anderson, R V

    1998-08-01

    For nearly 50 years, the fingernail clam (Musculium transversum) was believed to be virtually eliminated from the Illinois River. In 1991, workers began finding substantial populations of M. transversum in the Illinois River including several beds in and around the highly polluted Chicago Sanitary District. In order to determine if populations of M. transversum from polluted sites exhibited any genetic response to the high levels of toxins and to examine the genetic structure of several populations of M. transversum for any changes due to the population crash, starch-gel electrophoresis was performed on M. transversum from three Illinois River localities and four Mississippi River basin locations. The sampled populations produced an inbreeding coefficient (FIS) of 0.929, indicating that the populations were highly inbred. The results of a suspected founder effect due to a bottleneck was suggested by an FST = 0.442. The isozyme Glucose-6-phosphate isomerase-2 (Gpi-2) produced allelic frequency patterns that were consistent with expected patterns of a pollution-tolerant allele. Polluted sites exhibited elevated frequencies of Gpi-2(100) whereas nonpolluted sites exhibited elevated frequencies of Gpi-2(74). This frequency pattern suggested that natural selection was occurring in populations under severe toxic pressures, leading to an increase in the frequency of the allele Gpi-2(100). Therefore, Gpi-2(100) is a possible pollution-tolerant mutation in M. transversum.

  17. RNA-FISH to analyze allele-specific expression.

    PubMed

    Braidotti, G

    2001-01-01

    One of the difficulties associated with the analysis of imprinted gene expression is the need to distinguish RNA synthesis occurring at the maternal vs the paternally inherited copy of the gene. Most of the techniques used to examine allele-specific expression exploit naturally occurring polymorphisms and measure steady-state levels of RNA isolated from a pool of cells. Hence, a restriction fragment length polymorphism (RFLP) an be exploited in a heterozygote, by a reverse transcriptase polymerase chain reaction (RT-PCR)- based procedure, to analyze maternal vs paternal gene expression. The human IGF2R gene was analyzed in this way. Smrzka et al. (1) were thus able to show that the IGF2R gene possesses a hemimethylated, intronic CpG island analogous to the mouse imprinting box. However, IGF2R mRNA was detected that possessed the RFLP from both the maternal and paternal alleles in all but one of the 70 lymphoblastoid samples. (The one monoallelic sample reactivated its paternal allele with continued cell culturing.) It was concluded that monoallelic expression of the human gene is a polymorphic trait occurring in a small minority of all tested samples (reviewed in refs. 2,3). Although this is a sound conclusion, the question remains: Is the human IGF2R gene imprinted?

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

    PubMed

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

    2014-04-14

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

  19. A survey of FRAXE allele sizes in three populations

    SciTech Connect

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

    1996-08-09

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

  20. Mutant power: using mutant allele collections for yeast functional genomics.

    PubMed

    Norman, Kaitlyn L; Kumar, Anuj

    2016-03-01

    The budding yeast has long served as a model eukaryote for the functional genomic analysis of highly conserved signaling pathways, cellular processes and mechanisms underlying human disease. The collection of reagents available for genomics in yeast is extensive, encompassing a growing diversity of mutant collections beyond gene deletion sets in the standard wild-type S288C genetic background. We review here three main types of mutant allele collections: transposon mutagen collections, essential gene collections and overexpression libraries. Each collection provides unique and identifiable alleles that can be utilized in genome-wide, high-throughput studies. These genomic reagents are particularly informative in identifying synthetic phenotypes and functions associated with essential genes, including those modeled most effectively in complex genetic backgrounds. Several examples of genomic studies in filamentous/pseudohyphal backgrounds are provided here to illustrate this point. Additionally, the limitations of each approach are examined. Collectively, these mutant allele collections in Saccharomyces cerevisiae and the related pathogenic yeast Candida albicans promise insights toward an advanced understanding of eukaryotic molecular and cellular biology.

  1. The frequency of different CGG-repeat alleles in the FMR-1 gene in the general population and special populations

    SciTech Connect

    Holden, J.J.A. |; Chalifoux, M.; Wing, M.

    1994-09-01

    The fragile X (FRAXA) syndrome is the most common inherited form of developmental disability and was the first genetic disorder in which the mechanism of mutation is triplet repeat expansion. The normal fragile X mental retardation-1 gene has 6-52 copies of the CGG-repeat; affected males have extensive amplification, coupled with methylation and gene inactivation; and carriers have between about 55 and 200 copies. There is some overlap in the 45-55 repeat range, with some alleles showing stable and othres unstable transmission. There have been several estimates of the incidence of the FRAXA syndrome, based on testing of special populations using chromosome analysis and the range is 1/750-1/2000. Because of the high burden associated with this syndrome, and in the face of discussions about population screening, it is important to know the actual incidence of mutations in this gene, as well as the distribution of unstable repeats above 45 copes. We have initiated a general population screening to examine 50,000 newborn samples using PCR, and have developed a rapid, inexpensive and reliable method for amplifying the CGG-repeat from Guthrie spots. In the first 1600 samples examined, we found 15 alleles with greater than 45 CGG-repeats, with the highest being 61 repeats.

  2. A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis

    PubMed Central

    Fjeld, Karianne; Johansson, Bente B.; Kirsten, Holger; Ruffert, Claudia; Masson, Emmanuelle; Steine, Solrun J.; Bugert, Peter; Cnop, Miriam; Grützmann, Robert; Mayerle, Julia; Mössner, Joachim; Ringdal, Monika; Schulz, Hans-Ulrich; Sendler, Matthias; Simon, Peter; Sztromwasser, Paweł; Torsvik, Janniche; Scholz, Markus; Tjora, Erling; Férec, Claude; Witt, Heiko; Lerch, Markus M.; Njølstad, Pål R.; Johansson, Stefan; Molven, Anders

    2015-01-01

    Carboxyl-ester lipase is a digestive pancreatic enzyme encoded by the highly polymorphic CEL gene1. Mutations in CEL cause maturity-onset diabetes of the young (MODY) with pancreatic exocrine dysfunction2. Here we identified a hybrid allele (CEL-HYB), originating from a crossover between CEL and its neighboring pseudogene CELP. In a discovery cohort of familial chronic pancreatitis cases, the carrier frequency of CEL-HYB was 14.1% (10/71) compared with 1.0% (5/478) in controls (odds ratio [OR] = 15.5, 95% confidence interval [CI] = 5.1-46.9, P = 1.3 × 10−6). Three replication studies in non-alcoholic chronic pancreatitis cohorts identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2, 95% CI = 3.2-8.5, P = 1.2 × 10−11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models revealed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. The hybrid variant of CEL is the first chronic pancreatitis gene identified outside the protease/antiprotease system of pancreatic acinar cells. PMID:25774637

  3. Prevalence of PI*Z and PI*S alleles of alpha-1-antitrypsin deficiency in Finland.

    PubMed

    Häggblom, Jan; Kettunen, Kaisa; Karjalainen, Jussi; Heliövaara, Markku; Jousilahti, Pekka; Saarelainen, Seppo

    2015-01-01

    The prevalence of PI*Z and PI*S alleles of SERPINA1 gene related to alpha-1-antitrypsin deficiency has previously been estimated to be lower in Finland than in the other countries of Northern Europe. The prevalence of PI*M (Malton) has not been studied in Finland before. We determined alpha-1-antitrypsin PI*Z and PI*S and PI*M (Malton) genotypes from a representative population sample. The number of subjects was 6,354 in the PI*S and PI*M (Malton) genotyping. PI*Z genotyping was performed in a subsample of 2,482 subjects. The allele frequencies were PI*Z 19.7/1,000 and PI*S 10.2/1,000. No PI*M (Malton) was found. The number of carriers of PI*Z and PI*S is significantly higher than previously estimated. The prevalences are in line with the findings in the neighboring countries.

  4. Effect of metallothionein 2A gene polymorphism on allele-specific gene expression and metal content in prostate cancer

    SciTech Connect

    Krześlak, Anna; Forma, Ewa; Jóźwiak, Paweł; Szymczyk, Agnieszka; Bryś, Magdalena

    2013-05-01

    Metallothioneins (MTs) are highly conserved, small molecular weight, cysteine rich proteins. The major physiological functions of metallothioneins include homeostasis of essential metals Zn and Cu and protection against cytotoxicity of heavy metals. The aim of this study was to determine whether there is an association between the − 5 A/G single nucleotide polymorphism (SNP; rs28366003) in core promoter region and expression of metallothionein 2A (MT2A) gene and metal concentration in prostate cancer tissues. MT2A polymorphism was determined by the polymerase chain reaction–restriction fragment length polymorphism technique (PCR–RFLP) using 412 prostate cancer tissue samples. MT2A gene expression analysis was performed by real-time RT-PCR method. A significant association between rs28366003 genotype and MT2A expression level was found. The average mRNA level was found to be lower among minor allele carriers (the risk allele) than average expression among homozygotes for the major allele. Metal levels were analyzed by flamed atomic absorption spectrometer system. Highly statistically significant associations were detected between the SNP and Cd, Zn, Cu and Pb levels. The results of Spearman's rank correlation showed that the expressions of MT2A and Cu, Pb and Ni concentrations were negatively correlated. On the basis of the results obtained in this study, we suggest that SNP polymorphism may affect the MT2A gene expression in prostate and this is associated with some metal accumulation. - Highlights: • MT2A gene expression and metal content in prostate cancer tissues • Association between SNP (rs28366003) and expression of MT2A • Significant associations between the SNP and Cd, Zn, Cu and Pb levels • Negative correlation between MT2A gene expression and Cu, Pb and Ni levels.

  5. Hydrogen: the future energy carrier.

    PubMed

    Züttel, Andreas; Remhof, Arndt; Borgschulte, Andreas; Friedrichs, Oliver

    2010-07-28

    Since the beginning of the twenty-first century the limitations of the fossil age with regard to the continuing growth of energy demand, the peaking mining rate of oil, the growing impact of CO2 emissions on the environment and the dependency of the economy in the industrialized world on the availability of fossil fuels became very obvious. A major change in the energy economy from fossil energy carriers to renewable energy fluxes is necessary. The main challenge is to efficiently convert renewable energy into electricity and the storage of electricity or the production of a synthetic fuel. Hydrogen is produced from water by electricity through an electrolyser. The storage of hydrogen in its molecular or atomic form is a materials challenge. Some hydrides are known to exhibit a hydrogen density comparable to oil; however, these hydrides require a sophisticated storage system. The system energy density is significantly smaller than the energy density of fossil fuels. An interesting alternative to the direct storage of hydrogen are synthetic hydrocarbons produced from hydrogen and CO2 extracted from the atmosphere. They are CO2 neutral and stored like fossil fuels. Conventional combustion engines and turbines can be used in order to convert the stored energy into work and heat.

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

    PubMed

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

    2012-06-01

    Transgenic and conditional knockout mouse models play an important role in biomedical research and their use has grown exponentially in the last 5-10 years. Generating conditional knockouts often requires breeding multiple alleles onto the background of a single mouse or group of mice. Breeding these mice depends on parental genotype, litter size, transmission frequency, and the number of breeding rounds. Therefore, a well planned breeding strategy is critical for keeping costs to a minimum. However, designing a viable breeding strategy can be challenging. With so many different variables this would be an ideal task for a computer program. To facilitate this process, we created a Java-based program called Conditional Allele Mouse Planner (CAMP). CAMP is designed to provide an estimate of the number of breeders, amount of time, and costs associated with generating mice of a particular genotype. We provide a description of CAMP, how to use it, and offer it freely as an application.

  7. Novel method for analysis of allele specific expression in triploid Oryzias latipes reveals consistent pattern of allele exclusion.

    PubMed

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

    2014-01-01

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

  8. 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 θ, the population-scaled mutation rate, based on simulated data. Discovered relationships between θ, the number of alleles, and the frequency spectrum support the development of three new estimators of microsatellite θ. The three estimators exhibit roughly similar mean squared errors (MSEs) and all are biased. However, across a broad range of sample sizes and θ 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.

  9. 77 FR 46555 - Motor Carrier Safety Advisory Committee: Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-03

    ... Federal Motor Carrier Safety Administration Motor Carrier Safety Advisory Committee: Public Meeting AGENCY: Federal Motor Carrier Safety Administration (FMCSA), DOT. ACTION: Notice of meeting of Motor Carrier... major motor carrier safety provisions of the recently enacted Moving Ahead for Progress in the...

  10. APOE E4 Carriers show prospective memory enhancement under nicotine, and evidence for specialisation within medial BA10.

    PubMed

    Evans, Simon; Gray, Marcus A; Dowell, Nicholas G; Tabet, Naji; Tofts, Paul S; King, Sarah L; Rusted, Jennifer M

    2013-03-01

    There is evidence to suggest that the APOE ɛ4 allele (which confers an increased risk of developing dementia) might be associated with cognitive advantages earlier in life. Further, nicotine might selectively benefit ɛ4 carriers. We used fMRI to explore performance on a prospective memory (PM) task in young adults (age 18-30) with and without nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in ɛ4 carriers, but not in ɛ3 carriers. In an event-related analysis, extrastriate responses to PM trials were enhanced by nicotine only in ɛ4 carriers. These differences in early visual processing may contribute to the behavioral findings. Activity in medial BA10 (previously implicated in PM) differentiated ɛ4 from ɛ3 carriers. One BA10 subregion showed greater deactivation in ɛ4 carriers during PM trials. Activity in other BA10 subregions was modulated by PM reaction time, pointing to region-specific effects within medial BA10. In addition, activity in right hippocampal formation was only seen in ɛ4 carriers receiving nicotine. These results demonstrate that cognitive enhancement by nicotine can selectively benefit APOE ɛ4 carriers, and point to genotype-specific differences in neural activity during PM. In addition, these results show that the role of medial BA10 in PM likely involves varying contributions from functionally specific subregions.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  12. Allele Mining Strategies: Principles and Utilisation for Blast Resistance Genes in Rice (Oryza sativa L.).

    PubMed

    Ashkani, Sadegh; Yusop, Mohd Rafii; Shabanimofrad, Mahmoodreza; Azady, Amin; Ghasemzadeh, Ali; Azizi, Parisa; Latif, Mohammad Abdul

    2015-01-01

    Allele mining is a promising way to dissect naturally occurring allelic variants of candidate genes with essential agronomic qualities. With the identification, isolation and characterisation of blast resistance genes in rice, it is now possible to dissect the actual allelic variants of these genes within an array of rice cultivars via allele mining. Multiple alleles from the complex locus serve as a reservoir of variation to generate functional genes. The routine sequence exchange is one of the main mechanisms of R gene evolution and development. Allele mining for resistance genes can be an important method to identify additional resistance alleles and new haplotypes along with the development of allele-specific markers for use in marker-assisted selection. Allele mining can be visualised as a vital link between effective utilisation of genetic and genomic resources in genomics-driven modern plant breeding. This review studies the actual concepts and potential of mining approaches for the discovery of alleles and their utilisation for blast resistance genes in rice. The details provided here will be important to provide the rice breeder with a worthwhile introduction to allele mining and its methodology for breakthrough discovery of fresh alleles hidden in hereditary diversity, which is vital for crop improvement.

  13. Hot carrier relaxation dynamics in zinc selenide

    NASA Astrophysics Data System (ADS)

    Mehendale, Manjusha

    The ultrafast relaxation dynamics of hot carriers are monitored in a high-quality ZnSe epilayer grown on GaAs substrate by employing a novel femtosecond pump-probe differential reflectivity technique which exploits the intrinsic interferometric asymmetric Fabry-Perot sample structure. The ultrashort femtosecond pulses used in these timeresolved pump-probe experiments are derived from a hard-apertured Kerr-lens modelocked Ti:sapphire laser. The effect of pump-laser-induced thermal lensing on the stability and operational characteristics of such solid-state Femtosecond lasers is discussed. A theoretical model, which assumes the exponential cooling of electrons and holes towards the band edge and a simple two parabolic band structure, is used to estimate the hot carrier cooling times for various photoexcited carrier densities. This model shows the results to be consistent with the expected characteristic electronic LO-phonon emission time of 35-40 fs and provide evidence for the influence of a non-equilibrium LO-phonon population, known as ``hot phonon effect'', on the electron cooling dynamics for carrier densities higher than 3 × 1017 cm-3. Another model, which is based on a balance equation approach, is used to analyze the experimental data more accurately, by including the effects of various processes such as screened carrier-phonon, carrier-carrier scattering and hot phonon effects on the relaxation dynamics. Comparison of the experimental data with this latter theoretical model indicates that the observed reduction in the electron cooling rate with increasing carrier density is due to both screening of the Fröhlich interaction and hot phonon effect. Finally, a comparison of hot carrier relaxation processes at various lattice temperatures is presented. This study provides an evidence of a more pronounced hot phonon effect at a lattice temperature of 80K than at 300K, which is complicated by temperature-dependent changes in optical and physical properties of the

  14. The influence of HLA alleles and HBV subgenotyes on the outcomes of HBV infections in Northeast China.

    PubMed

    Li, Xingku; Liu, Wei; Wang, Hongyan; Jin, Xi; Fang, Shaohong; Shi, Yuguang; Liu, Zhen; Zhang, Shuyun; Yang, Shufen

    2012-01-01

    Hepatitis B virus (HBV) infection has a wide variety of clinical outcomes, it could be spontaneouly recovered and also could develop fulminant liver failure or cirrhosis with hepatocellular carcinoma. Human leukocyte antigen (HLA) polymorphism and HBV (sub)genotypes have been speculated to associate with the outcome of HBV infection because the data obtained from various populations who bear different HLA alleles have shown a HLA polymorphism associated outcome of HBV infection. However, as the most important viral and host genetic factors, the impact of HBV (sub)genotypes in combination with HLA polymorphism on the clinical outcomes of HBV infections remains unclear. To demonstrate the association of HLA allele polymorphism in combination with HBV subgenotypes with the outcome of HBV infection in Northeastern Han Chinese population, a total of 230 HBV-infected individuals (Infection group) were compared to 210 random selected controls (Control group) who are negative for HBV infection for their HLA alleles frequency as well as the associations with the virus infection, clearance and persistence in combination with HBV subgenotypes. Of the 230 HBV-infected subjects, 54 were acute self-limited hepatitis (ASH) with HBV subgenotype C2 (ASH-C2), 144 were chronic hepatitis (CH) with HBV subgenotype C2 and B2 (CH-C2 and CH-B2), and 32 were spontaneously recovered (SR) without subgenotype results. When two groups are compared, the results suggest that B*48, B*51 and DRB1*12 carrier may have a high risk for HBV infection, but B*51 is likely association with spontaneous recovery and DRB1*07, 12 may be implied in viral persistence. HLA-B*15, DRB1*11 and 14 associated with viral clearance in the cases of HBV-C2 infection; HLA-B*54 carriers in chronic group are more sensitive to with the infection of HBV subgenotype B2; HLA-B*07 and DRB1*13 may protect subjects from HBV infection. The data presented a link between HLA polymorphism and HBV pathogenesis and suggested potential

  15. Advancing allele group-specific amplification of the complete HLA-C gene--isolation of novel alleles from three allele groups (C*04, C*07 and C*08).

    PubMed

    Cisneros, E; Martínez-Pomar, N; Vilches, M; Martín, P; de Pablo, R; Nuñez Del Prado, N; Nieto, A; Matamoros, N; Moraru, M; Vilches, C

    2013-10-01

    A variety of strategies have been designed for sequence-based HLA typing (SBT) and for the isolation of new human leucocyte antigen (HLA) alleles, but unambiguous characterization of complete genomic sequences remains a challenge. We recently reported a simple method for the group-specific amplification (GSA) and sequencing of a full-length C*04 genomic sequence in isolation from the accompanying allele. Here we build on this strategy and present homologous methods that enable the isolation of HLA-C alleles belonging to another two allele groups. Using this approach, which can be applied to sequence-based typing in some clinical settings, we have successfully characterized three novel HLA-C alleles (C*04:128, C*07:01:01:02, and C*08:62).

  16. Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium.

    PubMed

    Allikmets, R

    2000-08-01

    Age-related macular degeneration (AMD) accounts for >50% of the registered visual disability among North American and Western European populations and has been associated both with environmental factors, such as smoking, and with genetic factors. Previously we have reported disease-associated variants in the ABCR (also called ABCA4) gene in a subset of patients affected with this complex disorder. We have now tested our original hypothesis, that ABCR is a dominant susceptibility locus for AMD, by screening 1,218 unrelated AMD patients of North American and Western European origin and 1,258 comparison individuals from 15 centers in North America and Europe for the two most frequent AMD-associated variants found in ABCR. These two sequence changes, G1961E and D2177N, were found in one allele of ABCR in 40 patients ( approximately 3.4%), and in 13 control subjects ( approximately 0.95%). Fisher's two-sided exact test confirmed that these two variants are associated with AMD at a statistically significant level (P<.0001). The risk of AMD is elevated approximately threefold in D2177N carriers and approximately fivefold in G1961E carriers. The identification of a gene that confers risk of AMD is an important step in unraveling this complex disorder.

  17. Biogenesis of endosome-derived transport carriers.

    PubMed

    Chi, Richard J; Harrison, Megan S; Burd, Christopher G

    2015-09-01

    Sorting of macromolecules within the endosomal system is vital for physiological control of nutrient homeostasis, cell motility, and proteostasis. Trafficking routes that export macromolecules from the endosome via vesicle and tubule transport carriers constitute plasma membrane recycling and retrograde endosome-to-Golgi pathways. Proteins of the sorting nexin family have been discovered to function at nearly every step of endosomal transport carrier biogenesis and it is becoming increasingly clear that they form the core machineries of cargo-specific transport pathways that are closely integrated with cellular physiology. Here, we summarize recent progress in elucidating the pathways that mediate the biogenesis of endosome-derived transport carriers.

  18. Tunable Carrier Multiplication and Cooling in Graphene

    NASA Astrophysics Data System (ADS)

    Johannsen, Jens Christian; Ulstrup, Søren; Crepaldi, Alberto; Cilento, Federico; Zacchigna, Michele; Miwa, Jill A.; Cacho, Cephise; Chapman, Richard T.; Springate, Emma; Fromm, Felix; Raidel, Christian; Seyller, Thomas; King, Phil D. C.; Parmigiani, Fulvio; Grioni, Marco; Hofmann, Philip

    2015-01-01

    Time- and angle-resolved photoemission measurements on two doped graphene samples displaying different doping levels reveal remarkable differences in the ultrafast dynamics of the hot carriers in the Dirac cone. In the more strongly ($n$-)doped graphene, we observe larger carrier multiplication factors ($>$ 3) and a significantly faster phonon-mediated cooling of the carriers back to equilibrium compared to in the less ($p$-)doped graphene. These results suggest that a careful tuning of the doping level allows for an effective manipulation of graphene's dynamical response to a photoexcitation.

  19. Personality traits in Huntington's disease: An exploratory study of gene expansion carriers and non-carriers.

    PubMed

    Larsen, Ida Unmack; Mortensen, Erik Lykke; Vinther-Jensen, Tua; Nielsen, Jørgen Erik; Knudsen, Gitte Moos; Vogel, Asmus

    2016-12-01

    Huntington's disease (HD) is associated with risk for developing psychiatric symptoms. Vulnerability or resilience to psychiatric symptoms may be associated with personality traits. This exploratory study, aimed to investigate personality traits in a large cohort of HD carriers and at risk gene-expansion negative individuals (HD non-carriers), exploring whether carrying the HD gene or growing up in an HD family influences personality traits. Forty-seven HD carriers, Thirty-nine HD non-carriers, and 121 healthy controls answered the Danish version of the revised NEO personality inventory. Comparisons between HD carriers and HD non-carriers were mostly non-significant but the combined group of HD carriers and non-carriers showed significantly higher scores on the facets: "hostility," "assertiveness," and "activity" and on the trait "Conscientiousness" relative to controls, "Conscientiousness" have been associated with resilience to psychiatric symptoms. Twelve HD carriers and non-carriers were classified as depressed and showed significantly lower scores on "Extraversion" and "Conscientiousness" and significantly higher scores on "Neuroticism," which are associated with vulnerability to psychiatric symptoms. Our findings suggest that, there is no direct effect of the HD gene on personality traits, but that personality assessment may be relevant to use when identifying individuals from HD families who are vulnerable to develop psychiatric symptoms. © 2016 Wiley Periodicals, Inc.

  20. Common Kibra alleles are associated with human memory performance.

    PubMed

    Papassotiropoulos, Andreas; Stephan, Dietrich A; Huentelman, Matthew J; Hoerndli, Frederic J; Craig, David W; Pearson, John V; Huynh, Kim-Dung; Brunner, Fabienne; Corneveaux, Jason; Osborne, David; Wollmer, M Axel; Aerni, Amanda; Coluccia, Daniel; Hänggi, Jürgen; Mondadori, Christian R A; Buchmann, Andreas; Reiman, Eric M; Caselli, Richard J; Henke, Katharina; de Quervain, Dominique J-F

    2006-10-20

    Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele-dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

  1. Allelic melanism in American and British peppered moths.

    PubMed

    Grant, B S

    2004-01-01

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

  2. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers

    PubMed Central

    2010-01-01

    Introduction Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. Methods We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Results SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, Ptrend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, Ptrend = 0.018). Conclusions This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations. PMID:21114847

  3. Analysis of FMR1 gene expression in female premutation carriers using robust segmented linear regression models

    PubMed Central

    García-Alegría, Eva; Ibáñez, Berta; Mínguez, Mónica; Poch, Marisa; Valiente, Alberto; Sanz-Parra, Arantza; Martinez-Bouzas, Cristina; Beristain, Elena; Tejada, Maria-Isabel

    2007-01-01

    Fragile X syndrome is caused by the absence or reduction of the fragile X mental retardation protein (FMRP) because FMR1 gene expression is reduced. Alleles with repeat sizes of 55–200 are classified as premutations, and it has been demonstrated that FMR1 expression is elevated in the premutation range. However, the majority of the studies reported were performed in males. We studied FMR1 expression in 100 female fragile X family members from the northern region of Spain using quantitative (fluorescence) real-time polymerase chain reaction. Of these 100 women, 19 had normal alleles, 19 were full mutation carriers, and 62 were premutation carriers. After confirming differences between the three groups of females, and increased levels of the FMR1 transcript among premutation carriers, we found that the relationship between mRNA levels and repeat size is nonlinear. These results were obtained using a novel methodology that, based on the size of the CGG repeats, allows us to find out the most probable threshold from which the relationship between CGG repeat number and mRNA levels changes. Using this approach, a significant positive correlation between CGG repeats and total mRNA levels has been found in the premutation range <100 CGG, but this correlation diminishes from 100 onward. However, when correcting by the X inactivation ratio, mRNA levels increase as the number of CGG repeats increases, and this increase is highly significant over 100 CGG. We suggest that due to skewed X inactivation, mRNA levels tend to normalize in females when the number of CGG repeats increases. PMID:17449730

  4. Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

    PubMed Central

    Soontornniyomkij, Virawudh; Moore, David J.; Gouaux, Ben; Soontornniyomkij, Benchawanna; Tatro, Erick T.; Umlauf, Anya; Masliah, Eliezer; Levine, Andrew J.; Singer, Elyse J.; Vinters, Harry V.; Gelman, Benjamin B.; Morgello, Susan; Cherner, Mariana; Grant, Igor; Achim, Cristian L.

    2013-01-01

    Objective The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer’s disease (AD). We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition. Design Clinico-pathological study of HIV-infected adults from four prospective cohorts in the U.S. National NeuroAIDS Tissue Consortium. Methods We used multivariable logistic regressions to model outcomes (Aβ plaques [immunohistochemistry] and HAND [standard criteria]) on predictors (APOE ε4 [allelic discrimination assay], older age [≥ 50 years], Aβ plaques, and their two-way interactions) and co-morbid factors. Results Isocortical Aβ deposits generally occurred as diffuse plaques and mild to moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques (adjusted odds ratio [OR] 10.16 and 5.77 [95% confidence interval (CI) 2.89–35.76 and 1.91–17.48], P=0.0003 and 0.0019, respectively, n=96). The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00 [95% CI 1.41–638.63], P=0.029, n=15), but not in non-ε4 carriers (n=57). Conclusion The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally Aβ plaques in HIV brains were immunohistologically different from those in symptomatic AD brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND subjects who could benefit from Aβ-targeted therapies. PMID:23018443

  5. 47 CFR 54.809 - Carrier certification.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SERVICE Interstate Access Universal Service Support Mechanism § 54.809 Carrier certification. (a... mechanism, on or before the filing deadlines set forth in paragraph (c) of this section. All of...

  6. Carrier cooling in colloidal quantum wells.

    PubMed

    Pelton, Matthew; Ithurria, Sandrine; Schaller, Richard D; Dolzhnikov, Dmitriy S; Talapin, Dmitri V

    2012-12-12

    It has recently become possible to chemically synthesize atomically flat semiconductor nanoplatelets with monolayer-precision control over the platelet thickness. It has been suggested that these platelets are quantum wells; that is, carriers in these platelets are confined in one dimension but are free to move in the other two dimensions. Here, we report time-resolved photoluminescence and transient-absorption measurements of carrier relaxation that confirm the quantum-well nature of these nanomaterials. Excitation of the nanoplatelets by an intense laser pulse results in the formation of a high-temperature carrier population that cools back down to ambient temperature on the time scale of several picoseconds. The rapid carrier cooling indicates that the platelets are well-suited for optoelectronic applications such as lasers and modulators.

  7. Intraoral radiation carrier for edentulous patients

    SciTech Connect

    Sela, M.; Taicher, S.

    1983-12-01

    The principles of fabricating an intraoral radioactive carrier have been described to treat malignant diseases of the oral cavity. The prosthesis provides consistent direction and fixation of the radioactive source into the same location.

  8. NASA's Original Shuttle Carrier Departs Dryden

    NASA Video Gallery

    NASA's Space Shuttle Carrier Aircraft (SCA) No. 905, departed NASA's Dryden Flight Research Center on Oct. 24, 2012 for the final time, ending a 38-year association with the NASA field center at Ed...

  9. Precise frequency calibration using television video carriers

    NASA Technical Reports Server (NTRS)

    Burkhardt, Edward E.

    1990-01-01

    The availability of inexpensive and quick precise frequency calibration methods is limited. VLF and GPS do offer precise calibration. However, antenna placement, cost of equipment, and calibration time place many restrictions on the user. The USNO maintained line-10 television Time of Coincidence (TOC) of station WTTG, channel 5, Washington, DC requires a frequency stable video carrier. This video carrier, 77.24 MHz is controlled by the same cesium beam standard controlling the TOC of line-10. Excellent frequency comparisons against this video carrier have been accomplished at 95 miles (153 km). With stable propagation and a three foot wire antenna, a part in 10(exp 9) can be determined in a few minutes. Inexpensive field equipment with a synthesized 1 kHz offset from the video carrier offers parts in 10(exp 11) calibrations in a few minutes using an oscilloscope as a phase comparator.

  10. What It Means to be a Carrier

    MedlinePlus

    ... Toolkits Advocacy National Fragile X Foundation Advocacy Day STAR Local Advocacy Agenda and Accomplishments Community Community Support ... premutation carriers were an increased rate of twin births and of premature ovarian failure (POI). .. We now ...

  11. Optical carrier wave shocking: detection and dispersion.

    PubMed

    Kinsler, P; Radnor, S B P; Tyrrell, J C A; New, G H C

    2007-06-01

    Carrier wave shocking is studied using the pseudospectral spatial-domain (PSSD) technique. We describe the shock detection diagnostics necessary for this numerical study and verify them against theoretical shocking predictions for the dispersionless case. These predictions show a carrier envelope phase and pulse bandwidth sensitivity in the single-cycle regime. The flexible dispersion management offered by the PSSD enables us to independently control the linear and nonlinear dispersion. Customized dispersion profiles allow us to analyze the development of both carrier self-steepening and shocks. The results exhibit a marked asymmetry between normal and anomalous dispersion, both in the limits of the shocking regime and in the (near) shocked pulse wave forms. Combining these insights, we offer some suggestions on how carrier shocking (or at least extreme self-steepening) might be realized experimentally.

  12. Accurate size comparison of short tandem repeat alleles amplified by PCR.

    PubMed

    Smith, R N

    1995-01-01

    A strategy is presented for classifying complex short tandem repeat (STR) alleles by size. Such alleles can differ in length by only 1 bp. The HUMACTBP2 locus was used as a model. Dye-labeled, PCR-amplified alleles were analyzed on an automated DNA sequencer with laser-induced fluorescence detection and fragment-sizing software. Between-gel allele sizes calculated against an in-lane allelic ladder or viral DNA size standard were too imprecise to distinguish a 1-bp difference. However, the size difference between a sample allele and its matching ladder allele provided a reliable criterion for size classification. The mean size difference +/- 3 SDs was 0.5 bp, and so an individual result within this interval signified a match. Statistically, 99.7% of the results should lie within +/- 3 SDs with virtually no chance of encountering the 9-SD difference from the mean necessary to misclassify an allele by 1 bp. The method was valid for sample alleles sized against the allelic ladder and for both sample and ladder alleles sized against the viral DNA standard. A correction for the effect of different dye labels on mobility was included in the calculations.

  13. Polymorphism of Mhc-DRB alleles in Cercopithecus aethiops (green monkey): generation and functionality.

    PubMed

    Rosal-Sánchez, M; Paz-Artal, E; Moreno-Pelayo, M A; Martínez-Quiles, N; Martínez-Laso, J; Martín-Villa, J M; Arnaiz-Villena, A

    1998-05-01

    DRB genes have been studied for the first time in green monkeys (Cercopithecus aethiops). Eleven new DRB alleles (exon 2, exon 3) have been obtained and sequenced from cDNA. A limited number of lineages have been identified: DRB1*03 (4 alleles), DRB1*07 (3 alleles), DRB5 (1 allele), DRB*w6 (1 allele), and DRB*w7 (2 alleles). The existence of Ceae-DRB1 duplications is supported by the finding of 3 DRB1 alleles in 3 different individuals. Ceae-DRB1*0701 may be non-functional because it bears serine at position 82, which hinders molecule surface expression in mice; the allele is only found in Ceae-DRB duplicated haplotypes. Base changes in cDNA Ceae-DRB alleles are consistent with the generation of polymorphism by point mutations or short segment exchanges between alleles. The eleven green monkey DRB alleles meet the requirements for functionality as antigen-presenting molecules (perhaps, excluding DRB1*0701), since: 1) they have been isolated from cDNA and do not present deletions, insertions or stop codons: 2) structural motifs necessary for a correct folding of the molecule, for the formation of DR/DR dimers and for CD4 interactions are conserved, and 3) the number of non-synonymous substitutions is higher than the number of synonymous substitutions in the peptide binding region (PBR), while the contrary holds true for the non-PBR region.

  14. Common polymorphisms of the peroxisome proliferator-activated receptor-gamma (Pro12Ala) and peroxisome proliferator-activated receptor-gamma coactivator-1 (Gly482Ser) and the response to pioglitazone in Chinese patients with type 2 diabetes mellitus.

    PubMed

    Hsieh, Ming-Chia; Lin, Kun-Der; Tien, Kai-Jen; Tu, Shih-Te; Hsiao, Jeng-Yueh; Chang, Shun-Jen; Lin, Shiu-Ru; Shing, Shih-Jang; Chen, Hung-Chun

    2010-08-01

    We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma; Pro12Ala) and in PPAR-gamma coactivator-1(PGC-1; Gly482Ser) genes on the response to pioglitazone in Chinese with type 2 diabetes mellitus. A total of 250 patients with type 2 diabetes mellitus were treated with pioglitazone (30 mg/d) for 24 weeks without a change in previous medications. All patients were genotyped for the PPAR-gamma Pro12Ala and PGC-1 Gly482Ser polymorphisms. The Ala12Ala and Pro12Ala genotypes (26.0% vs 13.5%, P = .025) and Ala allele (15.6% vs 7.3%, P = .008) were significantly more frequent in pioglitazone responders than in nonresponders. The distribution of PGC-1 genotypes and alleles was not significantly different between responders and nonresponders. The decrease in fasting glucose (50.4 +/- 52.2 vs 43.3 +/- 51.7 mg/dL, P < .001) and hemoglobin A(1c) (0.57% +/- 1.44% vs 0.35% +/- 1.10%, P = .004) levels was significantly greater in subjects with the Ala12 carriers (Pro12Ala and Ala12Ala) than in those without the allele (Pro12Pro). Baseline fasting glucose and triglyceride levels were related to the response of pioglitazone. Only the PPAR-gamma Pro12Ala polymorphism was found to be associated with the response of pioglitazone by multiple logistic regression analysis. The PPAR-gamma Pro12Ala gene polymorphism is associated with the response to pioglitazone in Chinese patients with type 2 diabetes mellitus. These findings may be helpful for targeted treatment of diabetes by identifying patients who are likely to respond to pioglitazone.

  15. Hemoglobin-Based Nanoarchitectonic Assemblies as Oxygen Carriers.

    PubMed

    Jia, Yi; Duan, Li; Li, Junbai

    2016-02-10

    Safe and effective artificial oxygen carriers are the subject of great interest due to the problems of traditional blood transfusion and enormous demand in clinical use. In view of its unique oxygen-transport ability and normal metabolic pathways, hemoglobin is regarded as an ideal oxygen-carrying unit. With advances in nano-biotechnology, hemoglobin assemblies as artificial oxygen carriers achieve great development. Here, recent progress on hemoglobin-based oxygen carriers is highlighted in view of two aspects: acellular hemoglobin-based oxygen carriers and cellular hemoglobin-based oxygen carriers. These novel oxygen carriers exhibit advantages over traditional carriers and will greatly promote research on reliable and feasible oxygen carriers.

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

    PubMed

    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.

  17. Real-Time PCR Genotyping Assay for GM2 Gangliosidosis Variant 0 in Toy Poodles and the Mutant Allele Frequency in Japan

    PubMed Central

    RAHMAN, Mohammad Mahbubur; YABUKI, Akira; KOHYAMA, Moeko; MITANI, Sawane; MIZUKAMI, Keijiro; UDDIN, Mohammad Mejbah; CHANG, Hye-Sook; KUSHIDA, Kazuya; KISHIMOTO, Miori; YAMABE, Remi; YAMATO, Osamu

    2013-01-01

    ABSTRACT GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the HEXB gene. In canine SD, a pathogenic mutation (c.283delG) of the canine HEXB gene has been identified in toy poodles. In the present study, a TaqMan probe-based real-time PCR genotyping assay was developed and evaluated for rapid and large-scale genotyping and screening for this mutation. Furthermore, a genotyping survey was carried out in a population of toy poodles in Japan to determine the current mutant allele frequency. The real-time PCR assay clearly showed all genotypes of canine SD. The assay was suitable for large-scale survey as well as diagnosis, because of its high throughput and rapidity. The genotyping survey demonstrated a carrier frequency of 0.2%, suggesting that the current mutant allele frequency is low in Japan. However, there may be population stratification in different places, because of the founder effect by some carriers. Therefore, this new assay will be useful for the prevention and control of SD in toy poodles. PMID:24161966

  18. Minority carrier lifetime in indium phosphide

    NASA Technical Reports Server (NTRS)

    Jenkins, Phillip; Landis, Geoffrey A.; Weinberg, Irving; Kneisel, Keith

    1991-01-01

    Transient photoluminescence is used to measure the minority carrier lifetime on n-type and p-type InP wafers. The measurements show that unprocessed InP wafers have very high minority carrier lifetimes. Lifetimes of 200 ns and 700 ns were observed for lightly-doped p- and n-type material respectively. Lifetimes over 5 ns were found in heavily doped n-type material.

  19. Hot-Carrier Seebeck Effect: Diffusion and Remote Detection of Hot Carriers in Graphene

    NASA Astrophysics Data System (ADS)

    Sierra, Juan F.; Neumann, Ingmar; Costache, Marius V.; Valenzuela, Sergio O.

    2015-06-01

    We investigate hot carrier propagation across graphene using an electrical nonlocal injection/detection method. The device consists of a monolayer graphene flake contacted by multiple metal leads. Using two remote leads for electrical heating, we generate a carrier temperature gradient that results in a measurable thermoelectric voltage VNL across the remaining (detector) leads. Due to the nonlocal character of the measurement, VNL is exclusively due to the Seebeck effect. Remarkably, a departure from the ordinary relationship between Joule power P and VNL, VNL ~ P, becomes readily apparent at low temperatures, representing a fingerprint of hot-carrier dominated thermoelectricity. By studying VNL as a function of bias, we directly determine the carrier temperature and the characteristic cooling length for hot-carrier propagation, which are key parameters for a variety of new applications that rely on hot-carrier transport.

  20. Hot-Carrier Seebeck Effect: Diffusion and Remote Detection of Hot Carriers in Graphene.

    PubMed

    Sierra, Juan F; Neumann, Ingmar; Costache, Marius V; Valenzuela, Sergio O

    2015-06-10

    We investigate hot carrier propagation across graphene using an electrical nonlocal injection/detection method. The device consists of a monolayer graphene flake contacted by multiple metal leads. Using two remote leads for electrical heating, we generate a carrier temperature gradient that results in a measurable thermoelectric voltage V(NL) across the remaining (detector) leads. Due to the nonlocal character of the measurement, V(NL) is exclusively due to the Seebeck effect. Remarkably, a departure from the ordinary relationship between Joule power P and V(NL), V(NL) ∼ P, becomes readily apparent at low temperatures, representing a fingerprint of hot-carrier dominated thermoelectricity. By studying V(NL) as a function of bias, we directly determine the carrier temperature and the characteristic cooling length for hot-carrier propagation, which are key parameters for a variety of new applications that rely on hot-carrier transport.

  1. Presymptomatic signs in healthy CJD mutation carriers.

    PubMed

    Gigi, Ariela; Vakil, Eli; Kahana, Ester; Hadar, Uri

    2005-01-01

    Creutzfeldt-Jacob disease (CJD) is a rapidly progressing dementia with neurological, psychiatric and cognitive symptoms. We focused our study on the familial CJD form among Libyan Jews (the E200K mutation), trying to identify preclinical neuropsychological signs in mutation carriers to facilitate early diagnosis of the disease. A wide range of neuropsychological tests was administered to 27 healthy volunteers, all first-degree relatives of genetic CJD patients. Thirteen of our participants were gene mutation carriers (E200K) and 14 controls. The healthy mutation carriers reported significantly lower Trait and higher State anxiety scores. Repeated Measure analysis showed statistical significance. The Anxiety Index (State-Trait Anxiety Score) progressed with age in the carriers' group but not in the controls. Since this was more pronounced in the older subjects, we suggest that abnormal stress mechanisms precede the clinical onset of CJD. Cognitive differences have also been found between carriers and controls, especially in visual recognition of pictured objects. Both kinds of differences (anxiety levels and cognitive deficits) were most pronounced in elderly subjects. This study is the first to show any dysfunction in healthy CJD mutation carriers.

  2. Radio science measurements with suppressed carrier

    NASA Astrophysics Data System (ADS)

    Asmar, S.; Divsalar, D.; Oudrhiri, K.; Hamkins, J.

    Radio Science started when it became apparent with early deep space missions that occultations by planetary atmospheres would affect the quality of radio communications. Since then the atmospheric properties and other aspects of planetary science, solar science, and fundamental physics were studied by scientists. Radio Science data was always extracted from a received pure residual carrier (without data modulation). For some missions, it is very desirable to obtain Radio Science data from a suppressed carrier modulation. In this paper we propose a method to extract Radio Science data when a coded suppressed carrier modulation is used in deep space communications. The type of modulation can be BPSK, QPSK, OQPSK, MPSK or even GMSK. However we concentrate mostly on BPSK modulation. The proposed method for suppressed carrier simply tries to wipe out data that acts as an interference for Radio Science measurements. In order to measure the estimation errors in amplitude and phase of the Radio Science data we use the Cramer-Rao bound (CRB). The CRB for suppressed carrier modulation with non-ideal data wiping is then compared with residual carrier modulation under the same noise condition. The method of derivation of the CRB for non-ideal data wiping is an innovative method that is presented here. Some numerical results are provided for a coded system.

  3. Radio Science Measurements with Suppressed Carrier

    NASA Technical Reports Server (NTRS)

    Asmar, Sami; Divsalar, Dariush; Oudrhiri, Kamal

    2013-01-01

    Radio Science started when it became apparent with early Solar missions that occultations by planetary atmospheres would affect the quality of radio communications. Since then the atmospheric properties and other aspects of planetary science, solar science, and fundamental physics were studied by scientists. Radio Science data was always extracted from a received pure residual carrier (without data modulation). For some missions, it is very desirable to obtain Radio Science data from a suppressed carrier modulation. In this paper we propose a method to extract Radio Science data when a coded suppressed carrier modulation is used in deep space communications. Type of modulation can be BPSK, QPSK, OQPSK, MPSK or even GMSK. However we concentrate mostly on BPSK modulation. The proposed method for suppressed carrier simply tries to wipe out data that acts as an interference for Radio Science measurements. In order to measure the estimation errors in amplitude and phase of the Radio Science data we use Cramer-Rao bound (CRB). The CRB for the suppressed carrier modulation with non-ideal data wiping is then compared with residual carrier modulation under the same noise condition. The method of derivation of CRB for non-ideal data wiping is an innovative method that presented here. Some numerical results are provided for coded system.

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

    PubMed

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

    2012-02-01

    A promoter polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to confer relative risk for phenotypes (depression/anxiety) and endophenotypes (amygdala reactivity). In this report, we identify and characterize three rare 5-HTTLPR alleles not previously described in the human literature. The three novel alleles were identified while genotyping 5-HTTLPR in a family-based attention deficit hyperactivity disorder clinical population. Two of the novel alleles are longer than the common 16-repeat long (L) allele (17 and 18 repeats) and the third is significantly smaller than the 14-repeat short (S) allele (11 repeats). The sequence and genetic architecture of each novel allele is described in detail. We report a significant decrease in the expression between the XL₁₇ (17r) allele and the L(A) (16r) allele. The XS₁₁ (11r) allele showed similar expression with the S (14r) allele. A 1.8-fold increase in expression was observed with the L(A)(16r) allele compared with the L(G) (16r) allele, which replicates results from earlier 5-HTTLPR expression experiments. In addition, transcription factor binding site (TFBS) analysis was performed using MatInspector (Genomatix) that showed the presence or absence of different putative TFBSs between the novel alleles and the common L (16r) and S (14r) alleles. The identification of rare variants and elucidation of their functional impact could potentially lead to understanding the contribution that the rare variant may have on the inheritance/susceptibility of multifactorial common diseases.

  5. Cytochrome allelic variants and clopidogrel metabolism in cardiovascular diseases therapy.

    PubMed

    Jarrar, Mohammed; Behl, Shalini; Manyam, Ganiraju; Ganah, Hany; Nazir, Mohammed; Nasab, Reem; Moustafa, Khaled

    2016-06-01

    Clopidogrel and aspirin are among the most prescribed dual antiplatelet therapies to treat the acute coronary syndrome and heart attacks. However, their potential clinical impacts are a subject of intense debates. The therapeutic efficiency of clopidogrel is controlled by the actions of hepatic cytochrome P450 (CYPs) enzymes and impacted by individual genetic variations. Inter-individual polymorphisms in CYPs enzymes affect the metabolism of clopidogrel into its active metabolites and, therefore, modify its turnover and clinical outcome. So far, clinical trials fail to confirm higher or lower adverse cardiovascular effects in patients treated with combinations of clopidogrel and proton pump inhibitors, compared with clopidogrel alone. Such inconclusive findings may be due to genetic variations in the cytochromes CYP2C19 and CYP3A4/5. To investigate potential interactions/effects of these cytochromes and their allele variants on the treatment of acute coronary syndrome with clopidogrel alone or in combination with proton pump inhibitors, we analyze recent literature and discuss the potential impact of the cytochrome allelic variants on cardiovascular events and stent thrombosis treated with clopidogrel. The diversity of CYP2C19 polymorphisms and prevalence span within various ethnic groups, subpopulations and demographic areas are also debated.

  6. A bird's eye view of a deleterious recessive allele.

    PubMed

    Ekblom, Robert

    2016-07-01

    In the endangered Scottish chough (Pyrrhocorax pyrrhocorax) population, a lethal blindness syndrome is found to be caused by a deleterious recessive allele. Photo: Gordon Yates. In Focus: Trask, A.E., Bignal, E.M., McCracken, D.I., Monaghan, P., Piertney, S.B. & Reid, J.M. (2016) Evidence of the phenotypic expression of a lethal recessive allele under inbreeding in a wild population of conservation concern. Journal of Animal Ecology, 85, 879-891. In this issue of Journal of Animal Ecology, Trask et al. () report on a strange, lethal, blindness that regularly affects chicks of an endangered bird population. The authors show that the inheritance mode of this blindness disease precisely matches the expectations of a recessive deleterious mutation. Intriguingly, there is also an indication that the disease-causing variant might be maintained in the population by balancing selection, due to a selective advantage for heterozygotes. Could this finding have consequences for conservation actions implemented for the population?

  7. Allele mining and enhanced genetic recombination for rice breeding.

    PubMed

    Leung, Hei; Raghavan, Chitra; Zhou, Bo; Oliva, Ricardo; Choi, Il Ryong; Lacorte, Vanica; Jubay, Mona Liza; Cruz, Casiana Vera; Gregorio, Glenn; Singh, Rakesh Kumar; Ulat, Victor Jun; Borja, Frances Nikki; Mauleon, Ramil; Alexandrov, Nickolai N; McNally, Kenneth L; Sackville Hamilton, Ruaraidh

    2015-12-01

    Traditional rice varieties harbour a large store of genetic diversity with potential to accelerate rice improvement. For a long time, this diversity maintained in the International Rice Genebank has not been fully used because of a lack of genome information. The publication of the first reference genome of Nipponbare by the International Rice Genome Sequencing Project (IRGSP) marked the beginning of a systematic exploration and use of rice diversity for genetic research and breeding. Since then, the Nipponbare genome has served as the reference for the assembly of many additional genomes. The recently completed 3000 Rice Genomes Project together with the public database (SNP-Seek) provides a new genomic and data resource that enables the identification of useful accessions for breeding. Using disease resistance traits as case studies, we demonstrated the power of allele mining in the 3,000 genomes for extracting accessions from the GeneBank for targeted phenotyping. Although potentially useful landraces can now be identified, their use in breeding is often hindered by unfavourable linkages. Efficient breeding designs are much needed to transfer the useful diversity to breeding. Multi-parent Advanced Generation InterCross (MAGIC) is a breeding design to produce highly recombined populations. The MAGIC approach can be used to generate pre-breeding populations with increased genotypic diversity and reduced linkage drag. Allele mining combined with a multi-parent breeding design can help convert useful diversity into breeding-ready genetic resources.

  8. Characterization of ROP18 alleles in human toxoplasmosis.

    PubMed

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

    2014-04-01

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

  9. Allelic loss and linkage studies in prostate cancer

    SciTech Connect

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

    1994-09-01

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

  10. Allelic variations of glut-1 deficiency syndrome: the chinese experience.

    PubMed

    Liu, Yanyan; Bao, Xinhua; Wang, Dong; Fu, Na; Zhang, Xiaoying; Cao, Guangna; Song, Fuying; Wang, Shuang; Zhang, Yuehua; Qin, Jiong; Yang, Hong; Engelstad, Kristin; De Vivo, Darryl C; Wu, Xiru

    2012-07-01

    Glucose transporter type 1 deficiency syndrome is characterized by infantile onset seizures, development delay, movement disorders, and acquired microcephaly. The phenotype includes allelic variants such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia of childhood with or without epilepsy. Dystonias involve allelic variants of glucose transporter type 1 deficiency syndrome. Three Chinese patients presented with paroxysmal behavioral disturbance, weakness, ataxia (especially after fasting), and exercise intolerance. Electroencephalogram findings did not correlate with clinical manifestations. Cranial magnetic resonance imaging produced normal results or mild hypomyelination. Hypoglycorrhachia was evident in all cases. Cerebrospinal fluid glucose ranged from 1.63-2.45 mmol/L. Erythrocyte 3-O-methyl-d-glucose uptake was decreased to 58% in patient 1. Three SLC2A1 disease-causing mutations (761delA, P383H, and R400C) were observed. No patient tolerated ketogenic diets. Two patients responded to frequent meals with snacks. Cerebrospinal fluid evaluation constitutes the diagnostic testing permitting early treatment of glucose transporter type 1 deficiency syndrome. Early diagnosis and treatment improve prognoses.

  11. A genetic model of melanoma tumorigenesis based on allelic losses

    SciTech Connect

    Hayward, N.K.; Palmer, J.M.; Walters, M.K.

    1994-09-01

    Previous karyotypic studies have indicated a possible series of non-random chromosomal events involved in the progression of melanoma. We sought to define a model of melanocyte tumorigenesis by studying allelic deletions of polymorphic simple tandem repeat markers mapping to chromosome 1, 6q, 7, 9p, 10, 11, 17, and 21 in thirty matched pairs of melanoma and constitutional DNAs. The most frequent and earliest deletions were found on 9p (57%) and 10q (32%) and with the exception of one case, no sample has loss of markers on another chromosome without concomitant loss of markers on 9p and/or 10q. Losses on 6q were also a frequent (32%) event that sometimes occurred in primary melanomas, whereas losses of loci on distal 1p (26%) or 11q (26%) occurred only in metastic melanomas. A background rate (0-17%) of allele loss was seen on chromosomes 7, 17, and 21. Homozygous deletions in a panel of 31 melanoma cell lines were only detected for markers on 9p (4 cases). These data strongly support the previous model of melanoma tumorigenesis based primarily on karyotypic findings in melanocytic lesions. However, we have been able to further augment the model by delimiting the regions of loss on 10q to a region distal to D10S254, and on 1p, to between D1S243 and D1S160.

  12. 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.

  13. Allele frequency of CODIS 13 in Indonesian population.

    PubMed

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

    2009-04-01

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

  14. [TUB9 polymorphism in the CFTR gene of cystic fibrosis patients, carriers, and healthy donors from the Moscow region. SSCP and restriction analyses].

    PubMed

    Amosenko, F A; Trubnikova, I S; Zakhar'ev, V M; Bannikov, V M; Sazonova, M A; Petrova, N V; Kapranov, N I; Kaplinin, V N

    1997-02-01

    Data on the screening of 266 non-delta F508 chromosomes (42 cystic fibrosis patients, 43 carriers, and 48 healthy donors from the Moscow region) for the presence of structural abnormalities within the tenth exon of the CFTR gene conducted by means of the single-stranded conformation polymorphism (SSCP) technique in nonisotope modification are presented. The method used made it possible to detect three SSCP variants, one of which was present in cystic fibrosis patients (23.8%) and carriers (9.3%), but not in healthy donors. Sequencing of the 5 amplified DNA fragments carrying this SSCP variant revealed an A-->G substitution in the 1525-61 position, which indicated the presence of TUB9 polymorphism with allele 1 in the homozygous state in all cases tested. The three SSCP variants described corresponded to the three allelic variants of TUB9 polymorphism as judged by MnlI restriction analysis of the amplified tenth exon sequence. The modified SSCP technique is also suitable for routine screening for the G542X, G55ID, and W1282X point mutations within the CFTR gene. The frequency distribution of polymorphic TUB9 marker alleles across the non-delta F508 chromosomes in the three studied groups were estimated. Homozygotes for the TUB9 allele 1 were shown to have identical GATT-TUB9-M470V haplotypes.

  15. Carriers of a common variant in the dopamine transporter gene have greater dementia risk, cognitive decline, and faster ventricular expansion

    PubMed Central

    Roussotte, Florence F.; Gutman, Boris A.; Hibar, Derrek P.; Madsen, Sarah K.; Narr, Katherine L.; Thompson, Paul M.

    2015-01-01

    Background Genetic variants in DAT1, the gene encoding the dopamine transporter protein (DAT), have been implicated in many brain disorders. In a recent case-control study of Alzheimer’s disease (AD), a regulatory polymorphism in DAT1 showed a significant association with the clinical stages of dementia. Methods We tested whether this variant was associated with increased AD risk, and with measures of cognitive decline and longitudinal ventricular expansion, in a large sample of elderly participants with genetic, neurocognitive, and neuroimaging data from the Alzheimer’s Disease Neuroimaging Initiative. Results The minor allele – previously linked with increased DAT expression in vitro – was More common in AD patients than in both individuals with mild cognitive impairment and Healthy elderly controls. The same allele was also associated with poorer cognitive performance and faster ventricular expansion, independently of diagnosis. Conclusion These results may be due to reduced dopaminergic transmission in carriers of the DAT1 mutation. PMID:25496873

  16. Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers

    PubMed Central

    Perkins, Michelle; Wolf, Andrew B.; Chavira, Bernardo; Shonebarger, Daniel; Meckel, J.P.; Leung, Lana; Ballina, Lauren; Ly, Sarah; Saini, Aman; Jones, T. Bucky; Vallejo, Johana; Jentarra, Garilyn; Valla, Jon

    2016-01-01

    The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer’s disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD. PMID:27128370

  17. Human leukocyte antigen-DRB1*1101 correlates with less severe hepatitis in Taiwanese male carriers of hepatitis B virus.

    PubMed

    Huang, Yi-Wen; Hu, Chung-Yi; Chen, Chi-Lin; Liao, Ya-Tang; Liu, Chun-Jen; Lai, Ming-Yang; Chen, Pei-Jer; Yang, Sien-Sing; Hu, Jui-Ting; Chen, Ding-Shinn; Kao, Jia-Horng

    2009-04-01

    Human leukocyte antigen (HLA) class II molecules are associated with host immune responses against hepatitis B virus infection. Male gender is the apparent host factor when someone encounters with the severity of hepatitis. The aim of this study was to investigate the association of the most polymorphic HLA class II allele, human leukocyte antigen-DRB1, with the severity of hepatitis in male carriers of hepatitis B virus. In this prospective cohort study, a total of 204 carriers of hepatitis B virus (131 men and 73 women) who have been followed-up for more than 1 year at the outpatient clinic of a university hospital were collected consecutively. Fifty carriers of hepatitis B virus (group I) with alanine aminotransferase <2x upper limit of normal (mean follow-up 83.6 months) were compared with 154 chronic hepatitis B patients (group II) with alanine aminotransferase >/=2x upper limit of normal (mean follow-up 81.3 months). Alleles of HLA-DRB1 were typed by the polymerase chain reaction-sequence specific oligonucleotide probe hybridization and genotypes of hepatitis B virus by melting curve analysis. HLA-DRB1*1101 was found in 18% of group I versus 8% of group II in male carriers (OR 0.23, P = 0.020, after adjustment for age) and 4% versus 9.4% in female carriers (P = 0.094). In male carriers harboring DRB1*1101, the distribution of hepatitis B viral genotype was comparable between the two groups. HLA-DRB1*1101 correlates with less severe hepatitis in Taiwanese male carriers of hepatitis B virus.

  18. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

    PubMed

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Ramón y Cajal, Teresa; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K; Toland, Amanda E; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Greene, Mark H; Mai, Phuong L; Nussbaum, Robert L; Andrulis, Irene L; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Barkardottir, Rosa B; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R; Hogervorst, Frans B L; van der Hout, Annemarie H; Seynaeve, Caroline; van der Luijt, Rob B; Ligtenberg, Marjolijn J L; Devilee, Peter; Wijnen, Juul T; Rookus, Matti A; Meijers-Heijboer, Hanne E J; Blok, Marinus J; van den Ouweland, Ans M W; Aalfs, Cora M; Rodriguez, Gustavo C; Phillips, Kelly-Anne A; Piedmonte, Marion; Nerenstone, Stacy R; Bae-Jump, Victoria L; O'Malley, David M; Ratner, Elena S; Schmutzler, Rita K; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M; Miron, Alex; Neuhausen, Susan L; Terry, Mary Beth; Chung, Wendy K; Daly, Mary B; Goldgar, David E; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elisabeth J; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K; Olah, Edith; Narod, Steven A; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N; Hamann, Ute; Spurdle, Amanda B; Healey, Sue; Weitzel, Jeffrey N; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M; Maxwell, Christopher A; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J; Antoniou, Antonis C; Pujana, Miguel Angel

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  19. Characterization of Mhc-DRB allelic diversity in white-tailed deer (Odocoileus virginianus) provides insight into Mhc-DRB allelic evolution within Cervidae.

    PubMed

    Van Den Bussche, R A; Hoofer, S R; Lochmiller, R L

    1999-05-01

    Although white-tailed deer (Odocoileus virginianus) are one of North America's best studied mammals, no information is available concerning allelic diversity at any locus of the major histocompatibility complex in this taxon. Using the polymerase chain reaction, single-stranded conformation polymorphism analysis, and DNA sequencing techniques, 15 DRB exon 2 alleles were identified among 150 white-tailed deer from a single population in southeastern Oklahoma. These alleles represent a single locus and exhibit a high degree of nucleotide and amino acid polymorphism, with most amino acid variation occurring at positions forming the peptide binding sites. Furthermore, twenty-seven amino acid residues unique to white-tailed deer DRB alleles were detected, with 19 of these occurring at residues forming contact points of the peptide binding region. Significantly higher rates of nonsynonymous than synonymous substitutions were detected among these DRB alleles. In contrast to other studies of Artiodactyla DRB sequences, interallelic recombination does not appear to be playing a significant role in the generation of allelic diversity at this locus in white-tailed deer. To examine evolution of white-tailed deer (Odvi-DRB) alleles within Cervidae, we performed a phylogenetic analysis of all published red deer (Ceel-DRB), roe deer (Caca-DRB), and moose (Alal-DRB) DRB alleles. The phylogenetic tree clearly shows a trans-species persistence of DRB lineages among these taxa. Moreover, this phylogenetic tree provides insight into evolution of DRB allelic lineages within Cervidae and may aid in assignment of red deer DRB alleles to specific loci.

  20. Lack of association of apoE ε4 allele with insulin resistance.

    PubMed

    Ragogna, Francesca; Lattuada, Guido; Ruotolo, Giacomo; Luzi, Livio; Perseghin, Gianluca

    2012-02-01

    ApoE is a polymorphic protein involved in the metabolism of plasma lipoproteins; the ε4 allele was shown to be associated with coronary and aortic atherosclerosis in age-dependent fashion mediated by unknown mechanisms. This study was undertaken to assess whether the apoE isoforms in humans were associated with normal glucose tolerance and with metabolic and inflammatory risk factors of CVD. ApoE genotype was assessed in 365 individuals. Of those, 309 were studied in the postabsorptive conditions and 142 of them also underwent a 3h-OGTT; 56 additional subjects were studied by means of the insulin clamp in combination with [6,6-2H2] glucose infusion. ApoE genotype frequencies were similar to those previously reported and were not influenced by age and BMI. Fasting plasma glucose, insulin, FFA, the lipid profile, surrogate markers (HOMA-IR, OGTT-derived index) as well as the clamp-derived parameters or insulin sensitivity and insulin secretion were not different by apoE genotypes. Serum adipokines concentrations (leptin, adiponectin, resistin) and markers of inflammation (serum fasting hsCRP and MCP1/CCL2) were also not different by apoE genotypes. In the subgroup of young ε4 carriers which underwent the clamp procedure, a higher fasting endogenous glucose production was detected. ApoE genotype was not associated with insulin resistance or altered insulin secretion, and no abnormalities in the typical circulating endocrine, metabolic, and inflammatory features of the insulin resistance syndrome were detected.

  1. Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics.

    PubMed

    Javors, Martin A; Seneviratne, Chamindi; Roache, John D; Ait-Daoud, Nassima; Bergeson, Susan E; Walss-Bass, M Consuelo; Akhtar, Fatema Z; Johnson, Bankole A

    2005-01-01

    Expression rates of long (L) and short (S) alleles of the serotonin (5-HT) transporter (5-HTT) gene have been shown to differ under various circumstances. We compared 5-HTT uptake (function) level and paroxetine binding (density) in platelets of alcoholics as indices of 5-HTT expression rate among LL, LS, and SS genotypes. Concentration curves of [3H]5-HT and [3H]paroxetine were used to quantify the equilibrium constant (Km) and maximum 5-HT uptake rate (Vmax) for 5-HTT uptake into intact platelets and the dissociation constant (Kd) and maximum specific binding density (Bmax) for paroxetine binding to platelet membranes, respectively. Genotypes were determined using electrophoresis with fluorescent markers. Vmax for 5-HTT uptake did not correlate with Bmax for paroxetine binding (r=-0.095, P=0.415). Means of Vmax and Bmax did not differ in a statistically significant manner among LL, LS, and SS genotypes in these alcoholic subjects. However, Vmax for LL and SS appeared to have a bimodal distribution, so the percentage of subjects with Vmax <200 fmol/min-10(7) platelets was statistically significantly higher in LL than in SS (51.5% vs. 22.7%, respectively), with an odds ratio of 3.6 (P<0.05). The percentage of Vmax <200 fmol/min-10(7) platelets for LS was 39.3% (not significant vs. LL or SS). Previous studies of healthy human controls have shown that 5-HTT density in raphe nuclei and 5-HTT uptake in platelets are higher in the LL genotype than in S carriers. Our findings in currently drinking alcoholics support the hypothesis that those with the LL genotype of the 5'-HTTLPR region of the 5-HTT gene have reduced 5-HTT function.

  2. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    PubMed Central

    2010-01-01

    Background CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. Methods We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. Results The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Conclusion Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations. PMID:20701755

  3. 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

  4. Effective marker alleles associated with type 2 resistance to Fusarium head blight infection in fields

    PubMed Central

    Li, Tao; Luo, Meng; Zhang, Dadong; Wu, Di; Li, Lei; Bai, Guihua

    2016-01-01

    Molecular markers associated with known quantitative trait loci (QTLs) for type 2 resistance to Fusarium head blight (FHB) in bi-parental mapping population usually have more than two alleles in breeding populations. Therefore, understanding the association of each allele with FHB response is particularly important to marker-assisted enhancement of FHB resistance. In this paper, we evaluated FHB severities of 192 wheat accessions including landraces and commercial varieties in three field growing seasons, and genotyped this panel with 364 genome-wide informative molecular markers. Among them, 11 markers showed reproducible marker-trait association (p < 0.05) in at least two experiments using a mixed model. More than two alleles were identified per significant marker locus. These alleles were classified into favorable, unfavorable and neutral alleles according to the normalized genotypic values. The distributions of effective alleles at these loci in each wheat accession were characterized. Mean FHB severities increased with decreased number of favorable alleles at the reproducible loci. Chinese wheat landraces and Japanese accessions have more favorable alleles at the majority of the reproducible marker loci. FHB resistance levels of varieties can be greatly improved by introduction of these favorable alleles and removal of unfavorable alleles simultaneously at these QTL-linked marker loci. PMID:27436944

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

    PubMed

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

    2014-01-01

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

  6. SNP-Based Quantification of Allele-Specific DNA Methylation Patterns by Pyrosequencing®.

    PubMed

    Busato, Florence; Tost, Jörg

    2015-01-01

    The analysis of allele-specific DNA methylation patterns has recently attracted much interest as loci of allele-specific DNA methylation overlap with known risk loci for complex diseases and the analysis might contribute to the fine-mapping and interpretation of non-coding genetic variants associated with complex diseases and improve the understanding between genotype and phenotype. In the presented protocol, we present a method for the analysis of DNA methylation patterns on both alleles separately using heterozygous Single Nucleotide Polymorphisms (SNPs) as anchor for allele-specific PCR amplification followed by analysis of the allele-specific DNA methylation patterns by Pyrosequencing(®). Pyrosequencing is an easy-to-handle, quantitative real-time sequencing method that is frequently used for genotyping as well as for the analysis of DNA methylation patterns. The protocol consists of three major steps: (1) identification of individuals heterozygous for a SNP in a region of interest using Pyrosequencing; (2) analysis of the DNA methylation patterns surrounding the SNP on bisulfite-treated DNA to identify regions of potential allele-specific DNA methylation; and (3) the analysis of the DNA methylation patterns associated with each of the two alleles, which are individually amplified using allele-specific PCR. The enrichment of the targeted allele is re-enforced by modification of the allele-specific primers at the allele-discriminating base with Locked Nucleic Acids (LNA). For the proof-of-principle of the developed approach, we provide assay details for three imprinted genes (IGF2, IGF2R, and PEG3) within this chapter. The mean of the DNA methylation patterns derived from the individual alleles corresponds well to the overall DNA methylation patterns and the developed approach proved more reliable compared to other protocols for allele-specific DNA methylation analysis.

  7. Differential Analysis of the Nasal Microbiome of Pig Carriers or Non-Carriers of Staphylococcus aureus

    PubMed Central

    Espinosa-Gongora, Carmen; Larsen, Niels; Schønning, Kristian; Fredholm, Merete; Guardabassi, Luca

    2016-01-01

    Staphylococcus aureus is presently regarded as an emerging zoonotic agent due to the spread of specific methicillin-resistant S. aureus (MRSA) clones in pig farms. Studying the microbiota can be useful for the identification of bacteria that antagonize such opportunistic veterinary and zoonotic pathogen in animal carriers. The aim of this study was to determine whether the nasal microbiome of pig S. aureus carriers differs from that of non-carriers. The V3-V5 region of the 16S rRNA gene was sequenced from nasal swabs of 44 S. aureus carriers and 56 non-carriers using the 454 GS FLX titanium system. Carriers and non-carriers were selected on the basis of quantitative longitudinal data on S. aureus carriage in 600 pigs sampled at 20 Danish herds included in two previous studies in Denmark. Raw sequences were analysed with the BION meta package and the resulting abundance matrix was analysed using the DESeq2 package in R to identify operational taxonomic units (OTUs) with differential abundance between S. aureus carriers and non-carriers. Twenty OTUs were significantly associated to non-carriers, including species with known probiotic potential and antimicrobial effect such as lactic acid-producing isolates described among Leuconostoc spp. and some members of the Lachnospiraceae family, which is known for butyrate production. Further 5 OTUs were significantly associated to carriage, including known pathogenic bacteria such as Pasteurella multocida and Klebsiella spp. Our results show that the nasal microbiome of pigs that are not colonized with S. aureus harbours several species/taxa that are significantly less abundant in pig carriers, suggesting that the nasal microbiota may play a role in the individual predisposition to S. aureus nasal carriage in pigs. Further research is warranted to isolate these bacteria and assess their possible antagonistic effect on S. aureus for the pursuit of new strategies to control MRSA in pig farming. PMID:27509169

  8. Influence of sex of the transmitting parent as well as of parental allel size on the CTG expansion in myotonic dystrophy (DM)

    SciTech Connect

    Brunner, H.G.; Brueggenwirth, H.T.; Nillesen, W.; Hamel, B.C.J.; Hoppe, R.L.E.; Oost, B.A. van; Ropers, H.H.; Smeets, H.J.M.; Jansen, G.; Die, C.E.M. de; Hoeweler, C.J. Wieringa, B.

    1993-11-01

    In patients with myotonic dystrophy (DM), the severity of clinical signs is correlated with the length of a (CTG)[sub n] trinucleotide repeat sequence. This sequence tends to expand in subsequent generations. In order to examine the kinetics of this process and, in particular, the influence of the mutant-allele size and the sex of the transmitting parent, the authors have studied (CTG)[sub n] repeat lengths in the offspring of 38 healthy carriers with small mutations (less than 100 CTG trinucleotides, mean length [CTG][sub 67]). In these studies, the authors found a weakly positive correlation between the size of the mutation in the carrier parents and that in their offspring. Furthermore, the authors observed that, in the offspring of male transmitters, repeat lengths exceeding 100 CTG trinucleotides were much more frequent than in the offspring of carrier females (48 [92%] of 52 vs. 7 [44%] of 16, P = .0002). Similarly, in genealogical studies performed in 38 Dutch DM kindreds, an excess of nonmanifesting male transmitters was noted, which was most conspicuous in the generation immediately preceding that with phenotypic expression of DM. Thus, two separate lines of evidence suggest that the sex of the transmitting parent is an important factor that determines DM allele size in the offspring. On the basis of the data, the authors estimate that when both parents are asymptomatic, the odds are approximately 2:1 that the father carries the DM mutation. Because expansion of the CTG repeat is more rapid with male transmission, negative selection during spermatogenesis may be required to explain the exclusive maternal inheritance of severe congenital onset DM. 42 refs., 1 fig., 2 tabs.

  9. Genetically-mediated Grey and White Matter Alteration in Normal 
Elderly Individuals with the CLU-C Allele Gene

    PubMed Central

    Qiu, Lihua; He, Yong; Tang, Hehan; Zhou, Yi; Wang, Jinhong; Zhang, Weiwei; Chen, Guangxiang; Zhao, Fei; Ouyang, Tingxue; Ju, Bin; Li, Zhengyan; Wang, Lanlan; Zou, Ling; Gong, Qiyong

    2016-01-01

    Abstract: Background Several genome-wide association studies have found that the rs11136000 polymorphism of the C allele (CLU-C) is associated with the risk for developing late-onset Alzheimer’s disease (LOAD). However, the effects of the CLU-C/C genotype on brain structure, including gray and white matter, are not adequately understood. Objectives We aimed to clarify the gray matter and white matter integrity changes in non-demented ageing individuals with the AD risk gene of the rs11136000 polymorphism of the C allele (CLU-C) and the correlation with cognitive performance. Methods Voxel-based analysis was used to compare the differences in high-resolution structural T1 and diffusion tensor imaging data between 31 CLU-C/C and 15 non-CLU-C/C carriers in non-demented older adults. Results Compared to non-CLU-C/C carriers, CLU-C homozygotes showed a reduced gray matter concentration (GMC) in the left parahippocampal gyrus, right middle frontal and temporal middle gyri, increased GMC in the left middle frontal and right fusiform gyri and increased gray matter volume (GMV) in the left middle frontal gyrus (P < 0.001). Decreased fractional anisotropy (FA) in the sub-gyral white matter of the left external capsule and left anterior cingulate and increased FA in the sub-gyral white matter of the left temporal lobe were also found in CLU-C/C genotype carriers. Moreover, the FA value in the left external capsule correlated with several cognitive measures. Conclusion Our findings provide further evidence for the CLU risk variant as a candidate gene for AD and may serve as a pre-clinical neuroimaging phenotype of late-onset AD. PMID:27396407

  10. 46 CFR 565.3 - Classification as controlled carrier.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 9 2010-10-01 2010-10-01 false Classification as controlled carrier. 565.3 Section 565... MARITIME PRACTICES CONTROLLED CARRIERS § 565.3 Classification as controlled carrier. (a) Notification. The... States and will notify any ocean common carrier of any change in its classification as a...

  11. 46 CFR 565.3 - Classification as controlled carrier.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 9 2013-10-01 2013-10-01 false Classification as controlled carrier. 565.3 Section 565... MARITIME PRACTICES CONTROLLED CARRIERS § 565.3 Classification as controlled carrier. (a) Notification. The... States and will notify any ocean common carrier of any change in its classification as a...

  12. 47 CFR 73.1540 - Carrier frequency measurements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 73.1540 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES... measurements. (a) The carrier frequency of each AM and FM station and the visual carrier frequency and the difference between the visual carrier and the aural carrier or center frequency of each TV and Class A...

  13. 14 CFR 389.24 - Foreign air carriers.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Foreign air carriers. 389.24 Section 389.24...) ORGANIZATION FEES AND CHARGES FOR SPECIAL SERVICES Filing and Processing License Fees § 389.24 Foreign air carriers. A foreign air carrier, or such carriers, if from the same country, acting jointly, may apply...

  14. 76 FR 32390 - Motor Carrier Safety Advisory Committee Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-06

    ... Federal Motor Carrier Safety Administration Motor Carrier Safety Advisory Committee Public Meeting AGENCY: Federal Motor Carrier Safety Administration (FMCSA), DOT. ACTION: Notice of Motor Carrier Safety Advisory... MCSAC will complete action on Task 11-01, regarding Patterns of Safety Violations by Motor...

  15. Theileria annulata: carrier state and immunity.

    PubMed

    Ilhan, T; Williamson, S; Kirvar, E; Shiels, B; Brown, C G

    1998-06-29

    Recovery from primary infection of Theileria annulata results in the development of a persistent carrier state in the vertebrate host. The carrier state is of great importance in the maintenance of the life cycle by alternate tick/cattle challenge and both contributes to and may be necessary for maintenance of immunity. Therefore, an accurate determination of carrier animals could be useful in determining immune status and may allow the necessary control measures to be implemented. Detailed information on the carrier state of animals following immunization with attenuated cell lines is lacking. In this study, relationship between immune response, persistence of the parasite, and the antibody response has been investigated. Calves were infected with T. annulata sporozoites, low passage (non-attenuated) or high passage (attenuated, vaccine) cell lines and later challenged with a lethal dose of heterologous sporozoites. The presence and persistence of the parasite were monitored by PCR using primers derived from genes coding for ssrRNA and a 30 kDa major merozoite surface protein, by Giemsa stained blood smears to detect the presence of piroplasms and also by attempting to establish infected mononuclear cell cultures from venous blood. Antibody responses were measured by indirect ELISA using a merozoite recombinant antigen and IFAT using piroplasm and macroschizont antigens. Results showed that there was an evident relationship between the persistence of carrier status, antibody response in ELISA and immune response to challenge.

  16. Extracting hot carriers from photoexcited semiconductor nanocrystals

    SciTech Connect

    Zhu, Xiaoyang

    2014-12-10

    This research program addresses a fundamental question related to the use of nanomaterials in solar energy -- namely, whether semiconductor nanocrystals (NCs) can help surpass the efficiency limits, the so-called “Shockley-Queisser” limit, in conventional solar cells. In these cells, absorption of photons with energies above the semiconductor bandgap generates “hot” charge carriers that quickly “cool” to the band edges before they can be utilized to do work; this sets the solar cell efficiency at a limit of ~31%. If instead, all of the energy of the hot carriers could be captured, solar-to-electric power conversion efficiencies could be increased, theoretically, to as high as 66%. A potential route to capture this energy is to utilize semiconductor nanocrystals. In these materials, the quasi-continuous conduction and valence bands of the bulk semiconductor become discretized due to confinement of the charge carriers. Consequently, the energy spacing between the electronic levels can be much larger than the highest phonon frequency of the lattice, creating a “phonon bottleneck” wherein hot-carrier relaxation is possible via slower multiphonon emission. For example, hot-electron lifetimes as long as ~1 ns have been observed in NCs grown by molecular beam epitaxy. In colloidal NCs, long lifetimes have been demonstrated through careful design of the nanocrystal interfaces. Due to their ability to slow electronic relaxation, semiconductor NCs can in principle enable extraction of hot carriers before they cool to the band edges, leading to more efficient solar cells.

  17. Non-Equilibrium Allele Frequency Spectra Via Spectral Methods

    PubMed Central

    Hey, Jody; Chen, Kevin

    2011-01-01

    A major challenge in the analysis of population genomics data consists of isolating signatures of natural selection from background noise caused by random drift and gene flow. Analyses of massive amounts of data from many related populations require high-performance algorithms to determine the likelihood of different demographic scenarios that could have shaped the observed neutral single nucleotide polymorphism (SNP) allele frequency spectrum. In many areas of applied mathematics, Fourier Transforms and Spectral Methods are firmly established tools to analyze spectra of signals and model their dynamics as solutions of certain Partial Differential Equations (PDEs). When spectral methods are applicable, they have excellent error properties and are the fastest possible in high dimension; see [15]. In this paper we present an explicit numerical solution, using spectral methods, to the forward Kolmogorov equations for a Wright-Fisher process with migration of K populations, influx of mutations, and multiple population splitting events. PMID:21376069

  18. 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

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

    PubMed

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

    2010-02-10

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

  20. Cytochrome P450 allele CYP3A7*1C associates with adverse outcomes in chronic lymphocytic leukemia, breast and lung cancer

    PubMed Central

    Orr, Nick; Broderick, Peter; Catovsky, Daniel; Matakidou, Athena; Eisen, Timothy; Goldsmith, Christy; Dudbridge, Frank; Peto, Julian; dos-Santos-Silva, Isabel; Ashworth, Alan; Ross, Gillian; Houlston, Richard S; Fletcher, Olivia

    2016-01-01

    CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially impacting drug effectiveness. Here we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated single nucleotide polymorphism (SNP) was rs45446698, a SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (hazard ratio [HR]=1.74, P=0.03), all-cause mortality in lung cancer patients (HR=1.43, P=0.009), and CLL progression (HR=1.62, P=0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate and clinical outcome (Pinteraction=0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers. PMID:26964624

  1. The variant allele of the rs188140481 polymorphism confers a moderate increase in the risk of prostate cancer in Polish men.

    PubMed

    Antczak, Andrzej; Wokołorczyk, Dominika; Kluźniak, Wojciech; Kashyap, Aniruddh; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Dębniak, Tadeusz; Masojć, Bartłomiej; Górski, Bohdan; Gromowski, Tomasz; Gołąb, Adam; Sikorski, Andrzej; Słojewski, Marcin; Gliniewicz, Bartłomiej; Borkowski, Tomasz; Borkowski, Andrzej; Przybyła, Jacek; Sosnowski, Marek; Małkiewicz, Bartosz; Zdrojowy, Romuald; Sikorska-Radek, Paulina; Matych, Józef; Wilkosz, Jacek; Różański, Waldemar; Kiś, Jacek; Bar, Krzysztof; Janiszewska, Hanna; Stawicka, Małgorzata; Milecki, Piotr; Lubiński, Jan; Narod, Steven A; Cybulski, Cezary

    2015-03-01

    A number of single nucleotide polymorphisms (SNPs) in the human genome have been associated with increased risk of prostate cancer. Recently, a single SNP in the region of chromosome 8q24 (rs188140481) has been associated with a three-fold increased risk of prostate cancer in Europe and North America. To establish whether rs188140481 is associated with the risk of prostate cancer in Poland, we genotyped 3467 men with prostate cancer and 1958 controls. The A allele of rs188140481 was detected in 44 of 3467 (1.3%) men with prostate cancer and in seven of 1958 (0.4%) controls (odds ratio=3.6; 95% confidence interval 1.6-7.9; P=0.0006). The allele was present in eight of 390 (2.1%) men with familial prostate cancer (odds ratio=5.8; 95% confidence interval 2.1-16.2; P=0.001). A positive family history of cancers at sites other than the prostate was observed in 27% of men who carried the rs188140481 risk allele and in 44% of noncarriers (P=0.04). No cancer at a site other than the prostate was more common in first-degree or second-degree relatives of carriers of the rs188140481 risk allele than relatives of noncarriers. The rs188140481 polymorphism in the 8q24 region confers a moderate increase in the risk of prostate cancer in Polish men. The SNP does not appear to be associated with susceptibility to cancers of other types.

  2. 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.

  3. The Microcephalin Ancestral Allele in a Neanderthal Individual

    PubMed Central

    Lari, Martina; Rizzi, Ermanno; Milani, Lucio; Corti, Giorgio; Balsamo, Carlotta; Vai, Stefania; Catalano, Giulio; Pilli, Elena; Longo, Laura; Condemi, Silvana; Giunti, Paolo; Hänni, Catherine; De Bellis, Gianluca; Orlando, Ludovic; Barbujani, Guido; Caramelli, David

    2010-01-01

    Background The high frequency (around 0.70 worlwide) and the relatively young age (between 14,000 and 62,000 years) of a derived group of haplotypes, haplogroup D, at the microcephalin (MCPH1) locus led to the proposal that haplogroup D originated in a human lineage that separated from modern humans >1 million years ago, evolved under strong positive selection, and passed into the human gene pool by an episode of admixture circa 37,000 years ago. The geographic distribution of haplogroup D, with marked differences between Africa and Eurasia, suggested that the archaic human form admixing with anatomically modern humans might have been Neanderthal. Methodology/Principal Findings Here we report the first PCR amplification and high- throughput sequencing of nuclear DNA at the microcephalin (MCPH1) locus from Neanderthal individual from Mezzena Rockshelter (Monti Lessini, Italy). We show that a well-preserved Neanderthal fossil dated at approximately 50,000 years B.P., was homozygous for the ancestral, non-D, allele. The high yield of Neanderthal mtDNA sequences of the studied specimen, the pattern of nucleotide misincorporation among sequences consistent with post-mortem DNA damage and an accurate control of the MCPH1 alleles in all personnel that manipulated the sample, make it extremely unlikely that this result might reflect modern DNA contamination. Conclusions/Significance The MCPH1 genotype of the Monti Lessini (MLS) Neanderthal does not prove that there was no interbreeding between anatomically archaic and modern humans in Europe, but certainly shows that speculations on a possible Neanderthal origin of what is now the most common MCPH1 haplogroup are not supported by empirical evidence from ancient DNA. PMID:20498832

  4. Generation of humoral immune responses to multi-allele PfAMA1 vaccines; effect of adjuvant and number of component alleles on the breadth of response.

    PubMed

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

    2010-11-03

    There is increasing interest in multi-allele vaccines to overcome strain-specificity against polymorphic vaccine targets such as Apical Membrane Antigen 1 (AMA1). These have been shown to induce broad inhibitory antibodies in vitro and formed the basis for the design of three Diversity-Covering (DiCo) proteins with similar immunological effects. The antibodies produced are to epitopes that are shared between vaccine alleles and theoretically, increasing the number of component AMA1 alleles is expected to broaden the antibody response. A plateau effect could however impose a limit on the number of alleles needed to achieve the broadest specificity. Moreover, production cost and the vaccine formulation process would limit the number of component alleles. In this paper, we compare rabbit antibody responses elicited with multi-allele vaccines incorporating seven (three DiCos and four natural AMA1 alleles) and three (DiCo mix) antigens for gains in broadened specificity. We also investigate the effect of three adjuvant platforms on antigen specificity and antibody functionality. Our data confirms a broadened response after immunisation with DiCo mix in all three adjuvants. Higher antibody titres were elicited with either CoVaccine HT™ or Montanide ISA 51, resulting in similar in vitro inhibition (65-82%) of five out of six culture-adapted P. falciparum strains. The antigen binding specificities of elicited antibodies were also similar and independent of the adjuvant used or the number of vaccine component alleles. Thus neither the four extra antigens nor adjuvant had any observable benefits with respect to specificity broadening, although adjuvant choice influenced the absolute antibody levels and thus the extent of parasite inhibition. Our data confirms the feasibility and potential of multi-allele PfAMA1 formulations, and highlights the need for adjuvants with improved antibody potentiation properties for AMA1-based vaccines.

  5. An Allele Real-Coded Quantum Evolutionary Algorithm Based on Hybrid Updating Strategy.

    PubMed

    Zhang, Yu-Xian; Qian, Xiao-Yi; Peng, Hui-Deng; Wang, Jian-Hui

    2016-01-01

    For improving convergence rate and preventing prematurity in quantum evolutionary algorithm, an allele real-coded quantum evolutionary algorithm based on hybrid updating strategy is presented. The real variables are coded with probability superposition of allele. A hybrid updating strategy balancing the global search and local search is presented in which the superior allele is defined. On the basis of superior allele and inferior allele, a guided evolutionary process as well as updating allele with variable scale contraction is adopted. And H ε gate is introduced to prevent prematurity. Furthermore, the global convergence of proposed algorithm is proved by Markov chain. Finally, the proposed algorithm is compared with genetic algorithm, quantum evolutionary algorithm, and double chains quantum genetic algorithm in solving continuous optimization problem, and the experimental results verify the advantages on convergence rate and search accuracy.

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

    PubMed

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

    2006-10-01

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

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

    PubMed Central

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

    2012-01-01

    In the dog, previous analyses of major histocompatibility complex (MHC) class I genes suggest a single polymorphic locus, Dog Leukocyte Antigen (DLA)-88. While 51 alleles have been reported, estimates of prevalence have not been made. We hypothesized that, within a breed, DLA-88 diversity would be restricted, and one or more dominant alleles could be identified. Accordingly, we determined allele usage in 47 Golden Retrievers and 39 Boxers. In each population, 10 alleles were found; 4 were shared. Seven novel alleles were identified. DLA-88*05101 and *50801 predominated in Golden Retrievers, while most Boxers carried *03401. In these breeds DLA-88 polymorphisms are limited and largely non-overlapping. The finding of highly prevalent alleles fulfills an important prerequisite for studying canine CD8+ T-cell responses. PMID:22571293

  8. A Novel Dominant Transformer Allele of the Sex-Determining Gene Her-1 of Caenorhabditis Elegans

    PubMed Central

    Trent, C.; Wood, W. B.; Horvitz, H. R.

    1988-01-01

    We have characterized a novel dominant allele of the sex-determining gene her-1 of Caenorhabditis elegans. This allele, called n695, results in the incomplete transformation of XX animals into phenotypic males. Previously characterized recessive her-1 alleles transform XO animals into phenotypic hermaphrodites. We have identified five new recessive her-1 mutations as intragenic suppressors of n695. Three of these suppressors are weak, temperature-sensitive alleles. We show that the recessive her-1 mutations are loss-of-function alleles, and that the her-1(n695) mutation results in a gain-of-function at the her-1 locus. The existence of dominant and recessive alleles that cause opposite phenotypic transformations demonstrates that the her-1 gene acts to control sexual identity in C. elegans. PMID:3220248

  9. Identification and characterization of novel HLA alleles: Utility of next-generation sequencing methods.

    PubMed

    Brown, Nicholas K; Kheradmand, Taba; Wang, Jinguo; Marino, Susana R

    2016-04-01

    The HLA genes are the most polymorphic of the human genome, and novel HLA alleles are continuously identified, often by clinical Sanger sequencing-based typing (SBT) assays. Introduction of next-generation sequencing (NGS) technologies for clinical HLA typing may significantly improve this process. Here we compare four cases of novel HLA alleles identified and characterized by both SBT and NGS. The tested NGS system sequenced broader regions of the HLA loci, and identified novel polymorphisms undetected by SBT. Subsequent characterization of the novel alleles in isolation of coencoded alleles by SBT required custom-designed primers, while the NGS system was able to sequence both alleles in phase. However, the tested assay was unable to amplify buccal cell DNA for subsequent NGS sequencing, presumably due to the lower quality of these samples. While NGS assays will undoubtedly increase novel allele identification, more stringent DNA sample requirements may be necessary for this new technology.

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

    PubMed Central

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

    2004-01-01

    Natural populations carry deleterious recessive alleles which cause inbreeding depression. We compared mortality and growth of inbred and outbred zebrafish, Danio rerio, between 6 and 48 days of age. Grandparents of the studied fish were caught in the wild. Inbred fish were generated by brother-sister mating. Mortality was 9% in outbred fish, and 42% in inbred fish, which implies at least 3.6 lethal equivalents of deleterious recessive alleles per zygote. There was no significant inbreeding depression in the growth, perhaps because the surviving inbred fish lived under less crowded conditions. In contrast to alleles that cause embryonic and early larval mortality in the same population, alleles responsible for late larval and early juvenile mortality did not result in any gross morphological abnormalities. Thus, deleterious recessive alleles that segregate in a wild zebrafish population belong to two sharply distinct classes: early-acting, morphologically overt, unconditional lethals; and later-acting, morphologically cryptic, and presumably milder alleles. PMID:15451692

  11. Ovine MHC class II DRB1 alleles associated with resistance or susceptibility to development of bovine leukemia virus-induced ovine lymphoma.

    PubMed

    Nagaoka, Y; Kabeya, H; Onuma, M; Kasai, N; Okada, K; Aida, Y

    1999-02-15

    For the further characterization of bovine leukemia virus (BLV)-induced leukemogenesis, we investigated the association between polymorphism of ovine leukocyte antigen (OLA)-DRB1 gene and tumor development after infection of sheep with BLV. We infected 28 sheep with BLV and cloned exon 2 of the OLA-DRB1 gene from asymptomatic animals and from animals with lymphoma Sequence analysis revealed that, among 12 healthy sheep without any evidence of tumor, ten (83.3%) carried DRB1 alleles encoding Arg-Lys (RK) at positions beta70/71 as compared with only 6 (37.5%) of the 16 sheep with lymphoma, which suggested that alleles encoding the RK motif might protect against development of tumors after infection by BLV. By contrast, alleles encoding Ser-Arg (SR) at positions beta70/71 were present at a significantly elevated frequency in sheep with lymphoma as compared with the healthy carriers, which indicated that OLA-DRB1 alleles encoding the SR motif might be positively related to susceptibility to tumor development. The two amino acids in these motifs line a pocket that accommodates the side chain of a bound peptide according to a model of the crystal structure of human leukocyte antigen (HLA)-DR1. To analyze immunoreactions of sheep with alleles that encoded RK or SR at beta70/71, we selected sheep with either the RK/SR genotypes or the SR/SR genotypes and immunized them with a mixture of multiple synthetic antigenic peptides that corresponded to T-helper, T-cytotoxic, and B-cell epitopes of the BLV envelope glycoprotein gp51. Two weeks after the last immunization, all of the sheep were challenged with BLV. Sheep with the RK/SR genotype produced neutralizing antibodies against BLV; they eliminated BLV completely within 28 weeks of the BLV challenge, and they gave strong lymphocyte-proliferative responses to the peptides used for immunization. Moreover, such animals did not develop lymphoma. By contrast, sheep with the SR/SR genotype continued to produce BLV throughout the

  12. Prevalence of -alpha(3.7) and alpha alpha alpha(anti3.7) alleles in sickle cell trait and beta-thalassemia patients in Mexico.

    PubMed

    Nava, María Paulina; Ibarra, Bertha; Magaña, María Teresa; de la Luz Chávez, María; Perea, F Javier

    2006-01-01

    The aim of this study was to determine the frequency of alpha-globin gene mutations in three groups of Mexican unrelated individuals. The first two groups were normal and sickle cell trait individuals from the Costa Chica region, a place with a 12.8% frequency of HbS carriers, and the third group comprised of Mexican mestizo patients with beta-thalassemia. We searched for -alpha(3.7) and -alpha(4.2) alpha(+)-thalassemia deletion alleles, as well as the alpha alpha alpha(anti3.7) triplication through long-gap PCR. The alleles -alpha(3.7) and alpha alpha alpha(anti3.7) were found in the heterozygote state only; 19% of the normal subjects had the -alpha(3.7) allele, and 2% showed the alpha alpha alpha(anti3.7) allele. In individuals with the sickle cell trait, 17% had the -alpha(3.7) deletion, and the alpha alpha alpha(anti3.7) triplication was observed in 3% of these individuals. We revealed that 16% of the subjects with beta-thalassemia showed the -alpha(3.7) deletion and 28% the alpha alpha alpha(anti3.7) triplication. The -alpha(4.2) deletion was not detected in any individual. The frequency of the -alpha(3.7) allele was roughly the same in the three groups studied; this can be explained by the fact that the three groups have common genes from Africa and the Mediterranean, where a high prevalence of alpha(+)-thalassemia has been observed. To our knowledge, the frequency of alpha alpha alpha(anti3.7) triplication observed in the Mexican beta-thalassemia patients is the highest reported. As the -alpha(3.7) and alpha alpha alpha(anti3.7) alleles are very common in our selected populations, we believe that there is a need to investigate systematically the alpha-globin gene mutations in all hemoglobinopathies in the Mexican population.

  13. Carrier lifetimes in thin-film photovoltaics

    NASA Astrophysics Data System (ADS)

    Baek, Dohyun

    2015-09-01

    The carrier lifetimes in thin-film solar cells are reviewed and discussed. Shockley-Read-Hall recombination is dominant at low carrier density, Auger recombination is dominant under a high injection condition and high carrier density, and surface recombination is dominant under any conditions. Because the surface photovoltage technique is insensitive to the surface condition, it is useful for bulk lifetime measurements. The photoconductance decay technique measures the effective recombination lifetime. The time-resolved photoluminescence technique is very useful for measuring thin-film semiconductor or solar-cell materials lifetime, because the sample is thin, other techniques are not suitable for measuring the lifetime. Many papers have provided time-resolved photoluminescence (TRPL) lifetimes for copper-indium-gallium-selenide (CIGS) and CdTe thin-film solar cell. The TRPL lifetime strongly depends on open-circuit voltage and conversion efficiency; however, the TRPL life time is insensitive to the short-circuit current.

  14. Inorganic Nanomaterials as Carriers for Drug Delivery.

    PubMed

    Chen, Shizhu; Hao, Xiaohong; Liang, Xingjie; Zhang, Qun; Zhang, Cuimiao; Zhou, Guoqiang; Shen, Shigang; Jia, Guang; Zhang, Jinchao

    2016-01-01

    For safe and effective therapy, drugs must be delivered efficiently and with minimal systemic side effects. Nanostructured drug carriers enable the delivery of small-molecule drugs as well as nucleic acids and proteins. Inorganic nanomaterials are ideal for drug delivery platforms due to their unique physicochemical properties, such as facile preparation, good storage stability and biocompatibility. Many inorganic nanostructure-based drug delivery platforms have been prepared. Although there are still many obstacles to overcome, significant advances have been made in recent years. This review focuses on the status and development of inorganic nanostructures, including silica, quantum dots, gold, carbon-based and magnetic iron oxide-based nanostructures, as carriers for chemical and biological drugs. We specifically highlight the extensive use of these inorganic drug carriers for cancer therapy. Finally, we discuss the most important areas in the field that urgently require further study.

  15. Nanogel Carrier Design for Targeted Drug Delivery

    PubMed Central

    Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

    2014-01-01

    Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

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

    PubMed

    Gorlov, Ivan P; Gorlova, Olga Y; Amos, Christopher I

    2015-07-01

    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.

  17. Sequence of a novel HLA-B*51 allele in a volunteer haematopoietic stem cell donor.

    PubMed

    Cosentini, E; Longhi, E; Frison, S; Luongo, V; Mantovani, M; Ciardiello, G; Bruno, P; Poli, F

    2010-10-01

    We describe a novel HLA-B*51 allele detected by DNA direct sequencing. The sequence of this allele has been officially named B*51:78 as a confirmatory sequence. This new allele nucleotide sequence differs from HLA-B*51:01:01 for two point mutations in exon 2 where codons 79-80 change from CGG-ATC to CGC-ACC (p.Ile80Thr).

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

    PubMed

    Coffee, Erin M; Yerkes, Laura; Ewen, Elizabeth P; Zee, Tiffany; Tolan, Dean R

    2010-02-01

    Mutations in the aldolase B gene (ALDOB) impairing enzyme activity toward fructose-1-phosphate cleavage cause hereditary fructose intolerance (HFI). Diagnosis of the disease is possible by identifying known mutant ALDOB alleles in suspected patients; however, the frequencies of mutant alleles can differ by population. Here, 153 American HFI patients with 268 independent alleles were analyzed to identify the prevalence of seven known HFI-causing alleles (A149P, A174D, N334K, Delta4E4, R59Op, A337V, and L256P) in this population. Allele-specific oligonucleotide hybridization analysis was performed on polymerase chain reaction (PCR)-amplified genomic DNA from these patients. In the American population, the missense mutations A149P and A174D are the two most common alleles, with frequencies of 44% and 9%, respectively. In addition, the nonsense mutations Delta4E4 and R59Op are the next most common alleles, with each having a frequency of 4%. Together, the frequencies of all seven alleles make up 65% of HFI-causing alleles in this population. Worldwide, these same alleles make up 82% of HFI-causing mutations. This difference indicates that screening for common HFI alleles is more difficult in the American population. Nevertheless, a genetic screen for diagnosing HFI in America can be improved by including all seven alleles studied here. Lastly, identification of HFI patients presenting with classic symptoms and who have homozygous null genotypes indicates that aldolase B is not required for proper development or metabolic maintenance.

  19. Giant SCA8 alleles in nine children whose mother has two moderately large ones.

    PubMed

    Corral, Jordi; Genís, David; Banchs, Isabel; San Nicolás, Hector; Armstrong, Judith; Volpini, Víctor

    2005-04-01

    We report here a family in which each of nine children has inherited giant SCA8 CTG expansions from a homozygous mother who has two moderately large SCA8 CTG alleles. In contrast, three homozygous male individuals and a case of coexistence of two expansions of the FRDA gene and one of SCA8, all of them with moderately large alleles, have transmitted their respective SCA8 expanded alleles with minor changes, as usually occurs in heterozygous male transmissions.

  20. 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.

  1. 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

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

    PubMed Central

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

    2010-01-01

    Mutations in the aldolase B gene (ALDOB) impairing enzyme activity toward fructose-1-phosphate cleavage cause hereditary fructose intolerance (HFI). Diagnosis of the disease is possible by identifying known mutant ALDOB alleles in suspected patients; however, the frequencies of mutant alleles can differ by population. Here, 153 American HFI patients with 268 independent alleles were analyzed to identify the prevalence of seven known HFI-causing alleles (A149P, A174D, N334K, Δ4E4, R59Op, A337V, and L256P) in this population. Allele-specific oligonucleotide hybridization analysis was performed on polymerase chain reaction (PCR)-amplified genomic DNA from these patients. In the American population, the missense mutations A149P and A174D are the two most common alleles, with frequencies of 44% and 9%, respectively. In addition, the nonsense mutations Δ4E4 and R59Op are the next most common alleles, with each having a frequency of 4%. Together, the frequencies of all seven alleles make up 65% of HFI-causing alleles in this population. Worldwide, these same alleles make up 82% of HFI-causing mutations. This difference indicates that screening for common HFI alleles is more difficult in the American population. Nevertheless, a genetic screen for diagnosing HFI in America can be improved by including all seven alleles studied here. Lastly, identification of HFI patients presenting with classic symptoms and who have homozygous null genotypes indicates that aldolase B is not required for proper development or metabolic maintenance. PMID:20033295

  3. BISMUTH PHOSPHATE CARRIER PROCESS FOR Pu RECOVERY

    DOEpatents

    Finzel, T.G.

    1959-02-01

    An improvement in the bismuth phosphate carrier precipitation process for recovering plutonium is described. It has been found that a more granular and more easily filterable carrier precipitiite is formed if the addition of the bismuth and phosphate ions is effected by first adding 9/10 of the bismuth ions necessary, then slowly adding all of the source of the phosphate ions to be incorporated in the precipitate, while digesting at 75 C and afterwards incorporating the remainder of the total bismuth ions necessary

  4. Spacelab Hitchhiker, a quick reaction carrier

    NASA Technical Reports Server (NTRS)

    James, E. F.; Moye, J. E.; Lohman, R. L.

    1985-01-01

    It is pointed out that NASA is developing a new way to get payloads into orbit in a short time and at a low cost. The 'Spacelab Hitchhiker' is the carrier program which will accomplish this objective. The Spacelab Hitchhiker carrier is a Shuttle payload. The primary application of the considered program will be related to science and technology payloads. Attention is given to the Hitchhiker concept, details regarding the Hitchhiker-G and Hitchhiker-M, aspects of integration and operations, Orbiter resources and STS interfaces, the conduction of Hitchhiker flights as 'flights of opportunity', questions of payload selection, and organizational interfaces.

  5. Carrier molecules for use in veterinary vaccines.

    PubMed

    Gerdts, Volker; Mutwiri, George; Richards, James; van Drunen Littel-van den Hurk, Sylvia; Potter, Andrew A

    2013-01-11

    The practice of immunization of animals and humans has been carried out for centuries and is generally accepted as the most cost effective and sustainable method of infectious disease control. Over the past 20 years there have been significant changes in our ability to produce antigens by conventional extraction and purification, recombinant DNA and synthesis. However, many of these products need to be combined with carrier molecules to generate optimal immune responses. This review covers selected topics in the development of carrier technologies for use in the veterinary vaccine field, including glycoconjugate and peptide vaccines, microparticle and nanoparticle formulations, and finally virus-like particles.

  6. CONCENTRATION OF Pu USING OXALATE TYPE CARRIER

    DOEpatents

    Ritter, D.M.; Black, R.P.S.

    1960-04-19

    A method is given for dissolving and reprecipitating an oxalate carrier precipitate in a carrier precipitation process for separating and recovering plutonium from an aqueous solution. Uranous oxalate, together with plutonium being carried thereby, is dissolved in an aqueous alkaline solution. Suitable alkaline reagents are the carbonates and oxulates of the alkali metals and ammonium. An oxidizing agent selected from hydroxylamine and hydrogen peroxide is then added to the alkaline solution, thereby oxidizing uranium to the hexavalent state. The resulting solution is then acidified and a source of uranous ions provided in the acidified solution, thereby forming a second plutoniumcarrying uranous oxalate precipitate.

  7. Transient carrier transfer in tunnel injection structures

    NASA Astrophysics Data System (ADS)

    Talalaev, V. G.; Tomm, J. W.; Zakharov, N. D.; Werner, P.; Gösele, U.; Novikov, B. V.; Sokolov, A. S.; Samsonenko, Y. B.; Egorov, V. A.; Cirlin, G. E.

    2008-07-01

    InGaAs tunnel injection nanostructures consisting of a single quantum well as injector and a quantum dot layer as emitter are studied by time-resolved photoluminescence spectroscopy. The quantum dot photoluminescence undergoes substantial changes when proceeding from direct quantum dot excitation to quantum well excitation, which causes an indirect population of the dot ground states. This results in a lowered effective carrier temperature within the dots. Results on the carrier transfer versus barrier thickness are discussed within the Wentzel-Kramers-Brillouin approximation. Deviations for barrier thicknesses <5nm are assigned to the formation of nanobridges that are actually detected by transmission electron microscopy.

  8. Viruses - from pathogens to vaccine carriers.

    PubMed

    Small, Juliana C; Ertl, Hildegund C J

    2011-10-01

    Vaccination is mankind's greatest public health success story. By now vaccines to many of the viruses that once caused fatal childhood diseases are routinely used throughout the world. Traditional methods of vaccine development through inactivation or attenuation of viruses have failed for some of the most deadly human pathogens, necessitating new approaches. Genetic modification of viruses not only allows for their attenuation but also for incorporation of sequences from other viruses, turning one pathogen into a vaccine carrier for another. Recombinant viruses have pros and cons as vaccine carriers, as discussed below using vectors based on adenovirus, herpesvirus, flavivirus, and rhabdovirus as examples.

  9. Effective Charge Carrier Utilization in Photocatalytic Conversions.

    PubMed

    Zhang, Peng; Wang, Tuo; Chang, Xiaoxia; Gong, Jinlong

    2016-05-17

    Continuous efforts have been devoted to searching for sustainable energy resources to alleviate the upcoming energy crises. Among various types of new energy resources, solar energy has been considered as one of the most promising choices, since it is clean, sustainable, and safe. Moreover, solar energy is the most abundant renewable energy, with a total power of 173 000 terawatts striking Earth continuously. Conversion of solar energy into chemical energy, which could potentially provide continuous and flexible energy supplies, has been investigated extensively. However, the conversion efficiency is still relatively low since complicated physical, electrical, and chemical processes are involved. Therefore, carefully designed photocatalysts with a wide absorption range of solar illumination, a high conductivity for charge carriers, a small number of recombination centers, and fast surface reaction kinetics are required to achieve a high activity. This Account describes our recent efforts to enhance the utilization of charge carriers for semiconductor photocatalysts toward efficient solar-to-chemical energy conversion. During photocatalytic reactions, photogenerated electrons and holes are involved in complex processes to convert solar energy into chemical energy. The initial step is the generation of charge carriers in semiconductor photocatalysts, which could be enhanced by extending the light absorption range. Integration of plasmonic materials and introduction of self-dopants have been proved to be effective methods to improve the light absorption ability of photocatalysts to produce larger amounts of photogenerated charge carriers. Subsequently, the photogenerated electrons and holes migrate to the surface. Therefore, acceleration of the transport process can result in enhanced solar energy conversion efficiency. Different strategies such as morphology control and conductivity improvement have been demonstrated to achieve this goal. Fine-tuning of the

  10. Chitotriosidase Activity and Gene Polymorphism in Iranian Patients with Gaucher Disease and Sibling Carriers

    PubMed Central

    MOZAFARI, Hadi; TAGHIKHANI, Mohammad; KHATAMI, Shohreh; ALAEI, Mohammad Reza; VAISI-RAYGANI, Asad; RAHIMI, Zohreh

    2016-01-01

    Objective Chitotriosidase (CT) activity is a useful biomarker for diagnosis and monitoring of Gaucher disease (GD). Its application is limited by some variants in the CT gene. Two main polymorphisms are 24 bp duplication and G102S led to reduce CT activity. The aim of this study was to determine these variants influencing on plasma CT activity. Materials & Methods Blood samples were collected from 33 patients with GD, 15 sibling carriers and 105 healthy individuals serving as controls. CT activity was measured using 4-methylumbelliferyl-β-D-N,N′,N″triacetylchitotrioside substrate in plasma samples. The CT genotypes of 24 bp duplication and G102S variants were determined using PCR and PCR-RFLP. Results Untreated GD patients had a significantly higher CT activity compared to treated patients (P = 0.021). In addition, chitotriosidase activity in carriers was higher rather than controls. Allele frequencies of 24 bp duplication in GD patients, sibling carriers and controls were 0.21, 0.266 and 0.29 and for G102S were 0.318, 0.366 and 0.219, respectively. Different G102S genotypes had not significant effect on CT activity. Chitotriosidase activity has a positive correlation with age in normal group, carriers, and negative correlation with hemoglobin in GD patients. Using cut-off level of 80.75 nmol/ml/h, sensitivity and specificity of CT activity were 93.9% and 100%, respectively. Conclusion Chitotriosidase activity is a suitable biomarker for diagnosis and monitoring of GD. Determination of 24 bp duplication is helpful for more accurate monitoring the GD patient’s therapy. However, it seems that, specifying of the G102S polymorphism is not required for Iranian GD patients. PMID:27843468

  11. Altered neural activity in the 'when' pathway during temporal processing in fragile X premutation carriers.

    PubMed

    Kim, So-Yeon; Tassone, Flora; Simon, Tony J; Rivera, Susan M

    2014-03-15

    Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). Large expansions of the CGG repeat (>200 repeats) consequently result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55-200 of CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA. Recent studies have shown that infants with FXS exhibit severely reduced resolution of temporal attention, whereas spatial resolution of attention is not impaired. Following from these findings in the full mutation, the current study used fMRI to examine whether premutation carriers would exhibit atypical temporal processing at behavioral and/or neural levels. Using spatial and temporal working memory (SWM and TWM) tasks, separately tagging spatial and temporal processing, we demonstrated that neurotypical adults showed greater activation in the 'when pathway' (i.e., the right temporoparietal junction: TPJ) during TWM retrieval than SWM retrieval. However, premutation carriers failed to show this increased involvement of the right TPJ during retrieval of temporal information. Further, multiple regression analyses on right TPJ activation and FMR1 gene expression (i.e., CGG repeat size and FMR1 mRNA) suggests that elevated FMR1 mRNA level is a powerful predictor accounting for reduced right TPJ activation associated with temporal processing in premutation carriers. In conclusion, the current study provides the first evidence on altered neural correlates of temporal processing in adults with the premutation, explained by their FMR1 gene expression.

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

    PubMed Central

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

    1992-01-01

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

  13. RAET1/ULBP alleles and haplotypes among Kolla South American Indians.

    PubMed

    Cox, Steven T; Arrieta-Bolaños, Esteban; Pesoa, Susanna; Vullo, Carlos; Madrigal, J Alejandro; Saudemont, Aurore

    2013-06-01

    NK cell cytolysis of infected or transformed cells can be mediated by engagement of the activating immunoreceptor NKG2D with one of eight known ligands (MICA, MICB and RAET1E-N) and is essential for innate immunity. As well as diversity of NKG2D ligands having the same function, allelic polymorphism and ethnic diversity has been reported. We previously determined HLA class I allele and haplotype frequencies in Kolla South American Indians who inhabit the northwest provinces of Argentina, and were found to have a similar restricted allelic profile to other South American Indians and novel alleles not seen in other tribes. In our current study, we characterized retinoic acid early transcription-1 (RAET1) alleles by sequencing 58 unrelated Kolla people. Only three of six RAET1 ligands were polymorphic. RAET1E was most polymorphic with five alleles in the Kolla including an allele we previously described, RAET1E*009 (allele frequency (AF) 5.2%). Four alleles of RAET1L were also found and RAET1E*002 was most frequent (AF=78%). Potential functional diversity only affected RAET1E and RAET1L, which were in linkage disequilibrium indicating a selective advantage. The results suggest that limited RAET1 polymorphism in the Kolla was not detrimental to human survival but still necessary and may affect disease susceptibility or severity.

  14. FMR1 alleles in Tasmania: a screening study of the special educational needs population.

    PubMed

    Mitchell, R J; Holden, J J A; Zhang, C; Curlis, Y; Slater, H R; Burgess, T; Kirkby, K C; Carmichael, A; Heading, K D; Loesch, D Z

    2005-01-01

    The distribution of fragile X mental retardation-1 (FMR1) allele categories, classified by the number of CGG repeats, in the population of Tasmania was investigated in 1253 males with special educational needs (SEN). The frequencies of these FMR1 categories were compared with those seen in controls as represented by 578 consecutive male births. The initial screening was based on polymerase chain reaction analysis of dried blood spots. Inconclusive results were verified by Southern analysis of a venous blood sample. The frequencies of common FMR1 alleles in both samples, and of grey zone alleles in the controls, were similar to those in other Caucasian populations. Consistent with earlier reports, we found some (although insignificant) increase of grey zone alleles in SEN subjects compared with controls. The frequencies of predisposing flanking haplotypes among grey zone males FMR1 alleles were similar to those seen in other Caucasian SEN samples. Contrary to expectation, given the normal frequency of grey zone alleles, no premutation (PM) or full mutation (FM) allele was detected in either sample, with only 15 fragile X families diagnosed through routine clinical admissions registered in Tasmania up to 2002. An explanation of this discrepancy could be that the C19th founders of Tasmania carried few PM or FM alleles. The eight to ten generations since white settlement of Tasmania has been insufficient time for susceptible grey zone alleles to evolve into the larger expansions.

  15. Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles

    PubMed Central

    Lockhart, David W.; Listgarten, Jennifer; Maley, Stephen N.; Kadie, Carl; Learn, Gerald H.; Nickle, David C.; Heckerman, David E.; Deng, Wenjie; Brander, Christian; Ndung'u, Thumbi; Coovadia, Hoosen; Goulder, Philip J.R.; Korber, Bette T.; Walker, Bruce D.; Mullins, James I.

    2009-01-01

    Abstract HIV-1 can evolve HLA-specific escape variants in response to HLA-mediated cellular immunity. HLA alleles that are common in the host population may increase the frequency of such escape variants at the population level. When loss of viral fitness is caused by immune escape variation, these variants may revert upon infection of a new host who does not have the corresponding HLA allele. Furthermore, additional escape variants may appear in response to the nonconcordant HLA alleles. Because individuals with rare HLA alleles are less likely to be infected by a partner with concordant HLA alleles, viral populations infecting hosts with rare HLA alleles may undergo a greater amount of evolution than those infecting hosts with common alleles due to the loss of preexisting escape variants followed by new immune escape. This hypothesis was evaluated using maximum likelihood phylogenetic trees of each gene from 272 full-length HIV-1 sequences. Recent viral evolution, as measured by the external branch length, was found to be inversely associated with HLA frequency in nef (p < 0.02), env (p < 0.03), and pol (p ≤ 0.05), suggesting that rare HLA alleles provide a disproportionate force driving viral evolution compared to common alleles, likely due to the loss of preexisting escape variants during early stages postinfection. PMID:19327049

  16. Validation study of the TrueAllele automated data review system.

    PubMed

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

    2004-07-01

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

  17. eSensor®: A Microarray Technology Based on Electrochemical Detection of Nucleic Acids and Its Application to Cystic Fibrosis Carrier Screening

    NASA Astrophysics Data System (ADS)

    Reed, Michael R.; Coty, William A.

    We have developed a test for identification of carriers for cystic fibrosis using the eSensor® DNA detection technology. Oligonucleotide probes are deposited within self-assembled monolayers on gold electrodes arrayed upon printed circuit boards. These probes allow sequence-specific capture of amplicons containing a panel of mutation sites associated with cystic fibrosis. DNA targets are detected and mutations genotyped using a “sandwich” assay methodology employing electrochemical detection of ferrocene-labeled oligonucleotides for discrimination of carrier and non-carrier alleles. Performance of the cystic fibrosis application demonstrates sufficient accuracy and reliability for clinical diagnostic use, and the procedure can be performed by trained medical technologists available in the hospital laboratory.

  18. Proline affects brain function in 22q11DS children with the low activity COMT 158 allele.

    PubMed

    Vorstman, Jacob A S; Turetsky, Bruce I; Sijmens-Morcus, Monique E J; de Sain, Monique G; Dorland, Bert; Sprong, Mirjam; Rappaport, Eric F; Beemer, Frits A; Emanuel, Beverly S; Kahn, René S; van Engeland, Herman; Kemner, Chantal

    2009-02-01

    The association between the 22q11.2 deletion syndrome (22q11DS) and psychiatric disorders, particularly psychosis, suggests a causal relationship between 22q11DS genes and abnormal brain function. The genes catechol-O-methyl-transferase (COMT) and proline dehydrogenase both reside within the commonly deleted region of 22q11.2. COMT activity and proline levels may therefore be altered in 22q11DS individuals. Associations of both COMT(158) genotype and elevated serum proline levels with abnormal brain function have been reported. Fifty-six 22q11DS children and 75 healthy controls were assessed on physiological measures of brain function, including prepulse inhibition (PPI) of startle, P50 auditory sensory gating and smooth pursuit eye movements (SPEM). COMT(158) genotype and plasma proline levels were determined in the 22q11DS children. We hypothesized an interaction between the COMT(158) genotype and proline, predicting the strongest negative effect of high proline on brain function to occur in 22q11DS children who are carriers of the COMT(met) allele. Of the three physiological measures, only SPEM and PPI were abnormal in the patient sample. With regard to the SPEM performance, there was a significant interaction between the COMT(158) genotype and proline level with significantly decreased SPEM performance in children with high plasma proline levels and the low activity COMT(met) allele. A similar interaction effect was not observed with regard to PPI. These findings are consistent with a model in which elevated proline negatively affects brain function by an increase in dopamine in the prefrontal cortex. 22q11DS patients with low dopamine catabolic capacity are therefore especially vulnerable to this functional disruption.

  19. The Sp1-mediaded allelic regulation of MMP13 expression by an ESCC susceptibility SNP rs2252070

    PubMed Central

    Shi, Meng; Xia, Jianhong; Xing, Huaixin; Yang, Wenjun; Xiong, Xiangyu; Pan, Wenting; Han, Sichong; Shang, Jinhua; Zhou, Changchun; Zhou, Liqing; Yang, Ming

    2016-01-01

    Metallopeptidase 13 (MMP13), a well-known and highly regulated zinc-dependent MMP collagenase, plays a crucial part in development and progression of esophageal squamous cell carcinoma (ESCC). Therefore, we examined associations between ESCC susceptibility and four haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed by logistic regression model. After analyzing 1588 ESCC patients and frequency-matched 1600 unaffected controls, we found that MMP13 rs2252070 G > A genetic polymorphism is significantly associated with ESCC risk in Chinese Han populations (GA: OR = 0.63, 95% CI = 0.54–0.74, P = 1.7 × 10−6, AA: OR = 0.73, 95% CI = 0.66–0.81, P = 1.8 × 10−6). Interestingly, the rs2252070 G-to-A change was shown to diminish a Sp1-binding site in ESCC cells. Reporter gene assays indicated that the rs2252070 A allele locating in a potential MMP13 promoter has low promoter activities. After measuring MMP13 gene expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2252070 A protective allele carriers showed decreased oncogene MMP13 expression. Results of these analyses underline the support of the notion that MMP13 might function as a key oncogene in esophageal carcinogenesis. PMID:27245877

  20. The Sp1-mediaded allelic regulation of MMP13 expression by an ESCC susceptibility SNP rs2252070.

    PubMed

    Shi, Meng; Xia, Jianhong; Xing, Huaixin; Yang, Wenjun; Xiong, Xiangyu; Pan, Wenting; Han, Sichong; Shang, Jinhua; Zhou, Changchun; Zhou, Liqing; Yang, Ming

    2016-06-01

    Metallopeptidase 13 (MMP13), a well-known and highly regulated zinc-dependent MMP collagenase, plays a crucial part in development and progression of esophageal squamous cell carcinoma (ESCC). Therefore, we examined associations between ESCC susceptibility and four haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed by logistic regression model. After analyzing 1588 ESCC patients and frequency-matched 1600 unaffected controls, we found that MMP13 rs2252070 G > A genetic polymorphism is significantly associated with ESCC risk in Chinese Han populations (GA: OR = 0.63, 95% CI = 0.54-0.74, P = 1.7 × 10(-6), AA: OR = 0.73, 95% CI = 0.66-0.81, P = 1.8 × 10(-6)). Interestingly, the rs2252070 G-to-A change was shown to diminish a Sp1-binding site in ESCC cells. Reporter gene assays indicated that the rs2252070 A allele locating in a potential MMP13 promoter has low promoter activities. After measuring MMP13 gene expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2252070 A protective allele carriers showed decreased oncogene MMP13 expression. Results of these analyses underline the support of the notion that MMP13 might function as a key oncogene in esophageal carcinogenesis.

  1. Distribution of BoLA-DRB3 allelic frequencies and identification of a new allele in the iranian cattle breed sistani (Bos indicus).

    PubMed

    Mohammadi, A; Nassiry, M R; Mosafer, J; Mohammadabadi, M R; Sulimova, G E

    2009-02-01

    The distribution of the frequencies of BoLA-DRB3 gene alleles in the Iranian cattle breed Sistani was studied by the PCR-RFLP ("hemi-nested") assay using restriction endonucleases RsaI, HaeIII and BstYI. In the examined cattle breed (65 animals) 32 alleles have been identified one of which being described for the first time (6.15% frequency). The nucleotide sequence of the polymorphic region of exon 2 of this allele has been determined and submitted in the GeneBank database under accession number DQ486519. The submitted sequence has maximum homology (92%) with the previously described sequence DRB3-mRNA from Bos indicus (AccN X79346) and differs from it by 24 nucleotide substitutions which result in 16 amino acid substitutions. The peptide (on the basis of the reconstructed amino acid sequence) has 89% identity to the sequence encoded by the BIDRBF 188 locus (Bos indicus). The results obtained permit the sequence described by us to be considered as a new allele of the BoLA-DRB3 gene (DRB3.2**X). The total frequency of the main six alleles (DRB3.2*X, *10, *11, *20, *34 and *X) occurring with a frequency of over 5% is about 60% in Iranian Sistani cattle. Fifteen alleles have <1% frequency. The highest frequency was observed for DRB3.2*8 allele (21.54%) like in other previously described breeds of Bos indicus (up to 23.07%). The Iranian breed Sistani has a high level of similarity by the spectrum of BoLA-DRB3 alleles and their frequencies to other Bos indicus breeds and significantly differs by these criteria from the Bos taurus breeds. The Iranian Sistani herd under study includes alleles associated with to resistance to leukemia (DRB3.2*ll and *23) and to different forms of mastitis (DRB3.2*2, *7, *11, *23 and *24) although their frequencies are low (from 0.77 to 5.37%). On the whole, a high level of diversity of BoLA-DRB3 gene alleles and the availability of alleles associated with resistance to different diseases makes this breed of interest for breeding practice.

  2. Allele specific-PCR and melting curve analysis showed relatively high frequency of β-casein gene A1 allele in Iranian Holstein, Simmental and native cows.

    PubMed

    Gholami, M; Hafezian, S H; Rahimi, G; Farhadi, A; Rahimi, Z; Kahrizi, D; Kiani, S; Karim, H; Vaziri, S; Muhammadi, S; Veisi, F; Ghadiri, K; Shetabi, H; Zargooshi, J

    2016-10-31

    There are two allelic forms of A1 and A2 of β-casein gene in dairy cattle. Proteolytic digestion of bovine β-casein A1 type produces bioactive peptide of β-casomorphin-7 known as milk devil. β-casomorphin-7 causes many diseases, including type 1 diabetes, cardiovascular disease syndrome, sudden death and madness. The aim of the present study was to determine the different allelic forms of β-casein gene in Iranian Holstein, Simmental and native cattle in order to identify A1 and A2 variants. The blood samples were collected randomly and DNA was extracted using modified salting out method. An 854 bp fragment including part of exon 7 and part of intron 6 of β-casein gene was amplified by allele specific polymerase chain reaction (AS-PCR). Also, the accuracy of AS-PCR genotyping has been confirmed by melting temperature curve analysis using Real-time PCR machinery. The comparison of observed allele and genotype frequency among the studied breeds was performed using the Fisher exact and Chi-squared test, respectively by SAS program. Obtained results showed the A1 allele frequencies of 50, 51.57, 54.5, 49.4 and 46.6% in Holstein, Simmental, Sistani, Taleshi and Mazandarani cattle populations, respectively. The chi-square test was shown that no any populations were in Hardy-Weinberg equilibrium for studied marker locus. Comparison and analysis of the test results for allelic frequency showed no any significant differences between breeds (P>0.05). The frequency of observed genotypes only differs significantly between Holstein and Taleshi breeds but no any statistically significant differences were found for other breeds (P>0.05). A relatively high frequency of β-casein A1 allele was observed in Iranian native cattle. Therefore, determine the genotypes and preference alleles A2 in these native and commercial cattle is recommended.

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

    PubMed

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

    2013-06-01

    Campylobacter jejuni is 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.

  4. 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.

  5. 42 CFR 421.200 - Carrier functions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 3 2010-10-01 2010-10-01 false Carrier functions. 421.200 Section 421.200 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... a channel of communication to and from CMS of information, instructions, and other material...

  6. 14 CFR 221.2 - Carrier's duty.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Carrier's duty. 221.2 Section 221.2 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC..., and provide and keep open to public inspection, tariffs showing all fares, and charges for foreign...

  7. 76 FR 63561 - Common Carriers; Editorial Amendments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-13

    ...] [Pages 63561-63563] [FR Doc No: 2011-26515] FEDERAL COMMUNICATIONS COMMISSION 47 CFR Part 64 [DA 11-1649... Disabilities; Truth-in-Billing Requirements for Common Carriers, Order (Order), document DA 11-1649, adopted September 30, 2011, and released September 30, 2011. The full text of document DA 11-1649 and copies of...

  8. 14 CFR 223.6 - Carrier's rules.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS FREE AND REDUCED-RATE TRANSPORTATION General Provisions § 223.6 Carrier's rules. (a) Each air... interchange of free and reduced-rate transportation passes or a statement describing those practices. (b)...

  9. 7 CFR 35.4 - Carrier.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 2 2014-01-01 2014-01-01 false Carrier. 35.4 Section 35.4 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE COMMODITY STANDARDS AND STANDARD CONTAINER REGULATIONS EXPORT...

  10. Carrier recovery techniques on satellite mobile channels

    NASA Technical Reports Server (NTRS)

    Vucetic, B.; Du, J.

    1990-01-01

    An analytical method and a stored channel model were used to evaluate error performance of uncoded quadrature phase shift keying (QPSK) and M-ary phase shift keying (MPSK) trellis coded modulation (TCM) over shadowed satellite mobile channels in the presence of phase jitter for various carrier recovery techniques.

  11. OCP: Opportunistic Carrier Prediction for Wireless Networks

    DTIC Science & Technology

    2008-08-01

    Many protocols have been proposed for medium access control in wireless networks. MACA [13], MACAW [3], and FAMA [8] are the earlier proposals for...world performance of carrier sense. In Proceedings of ACM SIGCOMM E-WIND Workshop, 2005. [13] P. Karn. MACA : A new channel access method for packet radio

  12. Nuclear Submarines and Aircraft Carriers | Radiation ...

    EPA Pesticide Factsheets

    2016-02-23

    Nuclear submarines and aircraft carriers are powered by onboard nuclear reactors. Heat from the nuclear reaction makes the steam needed to power the submarine. When a nuclear vessel is taken out of service, its radioactive parts are disposed of and monitored.

  13. Suppressed Carrier Synchronizers for ISI Channels

    NASA Technical Reports Server (NTRS)

    Hinedi, Sami M.; Simon, Marvin K.

    1996-01-01

    We demonstrate a class of suppressed carrier synchronization loops that are motivated by MAP estimation theory and in the presence of ISI outperform the conventional I-Q loop which is designed on the basis of zero ISI (wideband assumption). The measure of comparison used is the so-called.

  14. 7 CFR 35.4 - Carrier.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 2 2013-01-01 2013-01-01 false Carrier. 35.4 Section 35.4 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE COMMODITY STANDARDS AND STANDARD CONTAINER REGULATIONS EXPORT...

  15. 7 CFR 35.4 - Carrier.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 2 2011-01-01 2011-01-01 false Carrier. 35.4 Section 35.4 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE COMMODITY STANDARDS AND STANDARD CONTAINER REGULATIONS EXPORT...

  16. 18 CFR 357.1 - Common carriers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Common carriers. 357.1 Section 357.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY APPROVED FORMS, INTERSTATE COMMERCE ACT ANNUAL SPECIAL OR PERIODIC REPORTS:...

  17. 48 CFR 1602.170-1 - Carrier.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Carrier. 1602.170-1 Section 1602.170-1 Federal Acquisition Regulations System OFFICE OF PERSONNEL MANAGEMENT FEDERAL EMPLOYEES HEALTH BENEFITS ACQUISITION REGULATION GENERAL DEFINITIONS OF WORDS AND TERMS Definitions of FEHBP...

  18. URANOUS IODATE AS A CARRIER FOR PLUTONIUM

    DOEpatents

    Miller, D.R.; Seaborg, G.T.; Thompson, S.G.

    1959-12-15

    A process is described for precipitating plutonium on a uranous iodate carrier from an aqueous acid solution conA plutonium solution more concentrated than the original solution can then be obtained by oxidizing the uranium to the hexavalent state and dissolving the precipitate, after separating the latter from the original solution, by means of warm nitric acid.

  19. Paraoxonase Arg 192 allele is an independent risk factor for three-vessel stenosis of coronary artery disease.

    PubMed

    Vaisi-Raygani, Asad; Ghaneialvar, Hori; Rahimi, Zohreh; Tavilani, Haidar; Pourmotabbed, Tayebeh; Shakiba, Ebrahim; Vaisi-Raygani, Aliakbar; Kiani, Amir; Aminian, Mahdi; Alibakhshi, Reza; Bartels, Cynthia

    2011-11-01

    The role of the paraoxonase (PON1) codon 192 polymorphism [glutamine (Q)/arginine (R)] in coronary artery disease (CAD) is controversial. The aim of the present study was to evaluate whether the PON1 gene polymorphism is an independent risk factor for severity of coronary artery disease in patients from west of Iran. The PON1-Arg-192 genotypes were detected by PCR-RFLP in 414 individuals undergoing their first coronary angiography. Patients were placed into one of two groups: CAD and control without CAD or diabetes. The frequency of PON1-Arg-192 allele was significantly higher in the CAD (23.4 vs. 16%, P = 0.032) than in the control group and there was a higher risk of developing CAD (OR = 1.6, P = 0.02). In addition, this difference remained significant after adjustment for without history of diabetes (OR = 1.47, P = 0.048), presence of normolipidemia and absence of history of blood pressure (OR = 1.4, P = 0.05). This result indicated PON1-Arg-192 allele is a risk factor of CAD also when correcting for conventional risk factors. We found a significant association between the PON1-Arg-192 genotype (QR + RR) and the extent of CAD in CAD patients and CAD subjects without diabetes, represented by the increased frequency of three-vessel disease with OR = 1.49, P = 0.046; χ2 = 3.82, P = 0.048 and OR = 1.46, P = 0.05; χ2 = 3.48, P = 0.051, respectively. The CAD patients carrying PON1-Arg-192 genotype (QR + RR) had lower plasma HDL-C level (P = 0.019) and higher plasma LDL-C(P = 0.01) and TG(P = 0.05). Our results indicated that PON1-Arg-192 allele can be important independent risk factor of CAD in a west population of Iran, with carriers of PON1-Arg-192 having an increased frequency of three-vessel disease and also having a distinct plasma lipids profile. Larger collaborative studies are needed to confirm these results.

  20. Terahertz carrier dynamics and dielectric properties of GaN epilayers with different carrier concentrations

    NASA Astrophysics Data System (ADS)

    Guo, H. C.; Zhang, X. H.; Liu, W.; Yong, A. M.; Tang, S. H.

    2009-09-01

    Using terahertz time-domain spectroscopy, we measured the complex conductivity and dielectric function of n-type GaN with various carrier concentrations on sapphire substrate. The measured complex conductivity, which is due to the free carriers, is well fitted by simple Drude model. The contribution from the lattice vibration to the complex dielectric function inc