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Sample records for additional protective haplotype

  1. Understanding the contrasting spatial haplotype patterns of malaria-protective β-globin polymorphisms.

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    Hockham, Carinna; Piel, Frédéric B; Gupta, Sunetra; Penman, Bridget S

    2015-12-01

    The malaria-protective β-globin polymorphisms, sickle-cell (β(S)) and β(0)-thalassaemia, are canonical examples of human adaptation to infectious disease. Occurring on distinct genetic backgrounds, they vary markedly in their patterns of linked genetic variation at the population level, suggesting different evolutionary histories. β(S) is associated with five classical restriction fragment length polymorphism haplotypes that exhibit remarkable specificity in their geographical distributions; by contrast, β(0)-thalassaemia mutations are found on haplotypes whose distributions overlap considerably. Here, we explore why these two polymorphisms display contrasting spatial haplotypic distributions, despite having malaria as a common selective pressure. We present a meta-population genetic model, incorporating individual-based processes, which tracks the evolution of β-globin polymorphisms on different haplotypic backgrounds. Our simulations reveal that, depending on the rate of mutation, a large population size and/or high population growth rate are required for both the β(S)- and the β(0)-thalassaemia-like patterns. However, whilst the β(S)-like pattern is more likely when population subdivision is high, migration low and long-distance migration absent, the opposite is true for β(0)-thalassaemia. Including gene conversion has little effect on the overall probability of each pattern; however, when inter-haplotype fitness variation exists, gene conversion is more likely to have contributed to the diversity of haplotypes actually present in the population. Our findings highlight how the contrasting spatial haplotype patterns exhibited by β(S) and β(0)-thalassaemia may provide important indications as to the evolution of these adaptive alleles and the demographic history of the populations in which they have evolved.

  2. An NOS3 Haplotype Is Protective against Hypertension in a Caucasian Population

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    Georgios D. Kitsios

    2010-01-01

    Full Text Available The endothelial nitric oxide synthase gene (NOS3 has been implicated in the development of hypertension, although the specific role of variants and haplotypes has not been clarified. In this study, the association of three polymorphisms (promoter T786C, intronic 4a/b, and nonsynonymous G894T was tested in a case-control sample of 230 patients with essential hypertension and 306 healthy controls. Haplotype analysis was also performed. The mutant allele a∗ of the 4a/b polymorphism showed a protective effect against hypertension under a dominant model (odds ratio=0.64, 95% confidence interval (0.44–0.93, although this effect was not significant after the adjustment for covariates (=0.06. The estimated frequency of the haplotype composed of the T786∗, 4a∗, and G894∗ alleles was significantly higher in controls (5.5% compared to cases (2%. These results indicate that although individual NOS3 polymorphisms are not associated with hypertension, a rare haplotype of the gene might be protective against the development of hypertension.

  3. Understanding the contrasting spatial haplotype patterns of malaria-protective β-globin polymorphisms

    OpenAIRE

    Hockham, Carinna; Piel, Frédéric B; Gupta, Sunetra; Penman, Bridget S.

    2015-01-01

    The malaria-protective β-globin polymorphisms, sickle-cell (βS) and β0-thalassaemia, are canonical examples of human adaptation to infectious disease. Occurring on distinct genetic backgrounds, they vary markedly in their patterns of linked genetic variation at the population level, suggesting different evolutionary histories. βS is associated with five classical restriction fragment length polymorphism haplotypes that exhibit remarkable specificity in their geographical distributions; by con...

  4. Osteoprotegerin CGA haplotype protection against cerebrovascular complications in anti-CCP negative patients with rheumatoid arthritis.

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    Fernanda Genre

    Full Text Available Rheumatoid arthritis is an inflammatory disease with high incidence of cardiovascular disease due to accelerated atherosclerosis. Osteoprotegerin (OPG has been associated with increased risk of atherosclerotic disease in the general population. Several polymorphisms in the OPG gene with functional effects on cardiovascular disease in non-rheumatic individuals have been described. Therefore, we aimed to analyze the effect of three of these functional OPG polymorphisms on the risk of cardiovascular disease in a large and well-characterized cohort of Spanish patients with rheumatoid arthritis.Three OPG gene variants (rs3134063, rs2073618 and rs3134069 were genotyped by TaqMan assays in 2027 Spanish patients with rheumatoid arthritis. Anti-cyclic citrullinated peptide (anti-CCP antibody testing was positive in 997 of 1714 tested. Also, 18.3% of the whole series had experienced cardiovascular events, including 5.4% with cerebrovascular accidents. The relationship between OPG variants and cardiovascular events was assessed using Cox regression.No association between OPG gene variants and cardiovascular disease was observed in the whole group of rheumatoid arthritis patients or in anti-CCP positive patients. Nevertheless, a protective effect of CGA haplotype on the risk of cardiovascular disease in general, and specifically in the risk of cerebrovascular complications after adjusting for sex, age at disease diagnosis and traditional cardiovascular risk factors was disclosed in anti-CCP negative patients (HR = 0.54; 95%CI: 0.31-0.95; p = 0.032 and HR = 0.17; 95%CI: 0.04-0.78; p = 0.022, respectively.Our results indicate a protective effect of the OPG CGA haplotype on cardiovascular risk, mainly due to a protective effect against cerebrovascular events in anti-CCP negative rheumatoid arthritis patients.

  5. Evidence for HLA class II susceptible and protective haplotypes for osteomyelitis in pediatric patients with sickle cell anemia.

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    Al-Ola, K; Mahdi, N; Al-Subaie, A M; Ali, M E; Al-Absi, I K; Almawi, W Y

    2008-05-01

    We investigated the association of human leukocyte antigen (HLA) class II alleles and haplotypes with the pathogenesis of sickle cell anemia (SCA) osteomyelitis. SCA patients comprised 42 patients with osteomyelitis and 150 patients without osteomyelitis; HLA-DRB1* and HLA-DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming (SSP). DRB1*100101 (P value corrected for the number of different alleles tested, Pc=0.003) was positively associated with osteomyelitis. At the haplotype level, DRB1*100101-DQB1*050101 (Pc=0.001) was more prevalent among patients, while DRB1*030101-DQB1*0201 (Pc=0.020) and DRB1*040101-DQB1*0302 (Pc=0.039) were more prevalent among SCA controls, thereby conferring disease susceptibility or protection to these haplotypes, respectively. These results show that specific HLA haplotypes influence SCA osteomyelitis risk and that specific HLA types may serve as markers for identifying SCA patients at high risk for osteomyelitis.

  6. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

    DEFF Research Database (Denmark)

    Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves;

    2010-01-01

    Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing ...

  7. The Additive Risk Model for Estimation of Effect of Haplotype Match in BMT Studies

    DEFF Research Database (Denmark)

    Scheike, Thomas; Martinussen, T; Zhang, MJ

    2011-01-01

    leads to a missing data problem. We show how Aalen's additive risk model can be applied in this setting with the benefit that the time-varying haplomatch effect can be easily studied. This problem has not been considered before, and the standard approach where one would use the expected-maximization (EM...... be developed using product-integration theory. Small sample properties are investigated using simulations in a setting that mimics the motivating haplomatch problem....

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

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    Anderson Michelle A

    2008-11-01

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

  9. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

    DEFF Research Database (Denmark)

    Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves;

    2010-01-01

    Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing...... narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1...... ratio = 0.02; P narcolepsy susceptibility....

  10. Control of HIV-1 by an HLA-B*52:01-C*12:02 protective haplotype.

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    Chikata, Takayuki; Murakoshi, Hayato; Koyanagi, Madoka; Honda, Kazutaka; Gatanaga, Hiroyuki; Oka, Shinichi; Takiguchi, Masafumi

    2017-09-14

    HLA-B*52:01-C*12:02, which is found in approximately 20 % of all Japanese, is well known to be associated with ulcerative colitis and Takayasu arteritis. This haplotype is also known to be a protective one in HIV-1-infective individuals. Recent studies showed that HLA-B*52:01-restricted HIV-1-specific T cells suppress HIV-1 and that HLA-C*12:02 together with KIR2DL2 play an important role in NK cell-mediated control of HIV-1. However, the role of HLA-C*12:02-restricted CTLs in suppression of HIV-1 replication remains unknown. In the present study, we demonstrated that HLA-C*12:02-restricted CTLs specific for 2 immunodominant epitopes, Pol IY11 and Nef MY9, contributed to the suppression of HIV-1 replication in HIV-1-infected individuals. Further analysis demonstrated that these 2 HLA-C*12:02-restricted CTLs together with 4 HLA-B*52:01-restricted ones effectively suppressed HIV-1 in individuals having the HLA-B*52:01-C*12:02 haplotype. Thus, both HLA-C*12:02 and HLA-B*52:01 alleles contribute to HIV-1 suppression via both HIV-1-specific CTLs and NK cells in individuals having this haplotype. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  11. Combining haplotypers

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    Kääriäinen, Matti; Lappalainen, Sampsa; Mielikäinen, Taneli

    2007-01-01

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

  12. Enhancing thermostability of β-mannanase by protective additives

    Institute of Scientific and Technical Information of China (English)

    Zhaohui LIU; Wei QI; Weina WU; Yue LIU; Zhimin HE

    2008-01-01

    The effects of some sugars (glucose, mannose, fructose, sucrose and chitosan) and polyols (glycol, gly-cerol and sorbitol) as protective additive on the thermo-stability of β-mannanase were studied. The optimal reaction temperatures of β-mannanase and the ther-modynamics and the deactivation kinetics with or without additives were also investigated. The experimental results show that sucrose, chitosan and sorbitol could apparently improve the thermal stability of β-mannanase when their concentration was kept at 2 g/L. The optimal combina-tion additive proportion was sucrose: chitosan : sorbi-tol = 1 : 2 : 2 (molar ratio) using the orthogonal experimental design. The sucrose, chitosan, glycerol, sor-bitol and the combination additive might increase the optimal reaction temperature from 50℃ to about 60℃ due to their good protection effect. The thermal deactiva-tion curves of βmannanase accorded with the kinetic rules of first order reaction, and the corresponding kinetic and thermodynamic parameters were calculated. Meanwhile, the protective mechanism of the additives against deactivation of enzyme was also discussed.

  13. DLA class II alleles and haplotypes are associated with risk for and protection from chronic hepatitis in the English Springer spaniel.

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    Nicholas H Bexfield

    Full Text Available Chronic hepatitis (CH is common in dogs in the United Kingdom. An increased prevalence of the disease is seen in the English Springer spaniel (ESS, and this breed suffer from a severe form with young to middle aged female dogs being predisposed. The disease shares histological features with those of human viral hepatitis, although the specific aetiological agent has not yet been identified. The aim of the current study was to investigate whether dog leucocyte antigen (DLA class II alleles and haplotypes are associated with susceptibility/resistance to CH in the ESS. Sequence-based genotyping of the polymorphic exon 2 from DLA-DRB1, -DQA1 and -DQB1 class II loci were performed in 66 ESSs with CH and 84 healthy controls. There was a significant difference in the distribution of the protective alleles DRB1*00501 (3.0% vs. 12.0%, odds ratio [OR] = 0.23, 95% confidence interval [CI] = 0.06-0.74 and DQB1*00501 (3.8% vs. 12.0%, OR = 0.29, 95% CI = 0.09-0.85 between cases and controls. The haplotype DLA-DRB1*00501/DQA1*00301/DQB1*00501 was present in 11.9% of controls and 3.0% of cases and was significantly associated with protection against disease development (OR = 0.26, 95% CI = 0.08-0.80. There was a significant difference in the distribution of the risk alleles DRB1*00601 (14.4% vs. 6.5%, OR = 2.40, 95% CI = 1.10-5.63 and DQB1*00701 (14.4% vs. 6.5%, OR = 2.40, 95% CI = 1.10-5.63 between cases and controls. A risk haplotype (DLA-DRB1*00601/DQA1*005011/DQB1*00701 was present in 14.4% of cases and 6.5% of controls and conferred an elevated risk of developing CH with an OR of 3.13 (95% CI = 1.20-8.26. These results demonstrate that DLA class II is significantly associated with risk and protection from developing CH in ESSs.

  14. Protective human leucocyte antigen haplotype, HLA-DRB1*01-B*14, against chronic Chagas disease in Bolivia.

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    Florencia del Puerto

    Full Text Available BACKGROUND: Chagas disease, caused by the flagellate parasite Trypanosoma cruzi affects 8-10 million people in Latin America. The mechanisms that underlie the development of complications of chronic Chagas disease, characterized primarily by pathology of the heart and digestive system, are not currently understood. To identify possible host genetic factors that may influence the clinical course of Chagas disease, Human Leucocyte Antigen (HLA regional gene polymorphism was analyzed in patients presenting with differing clinical symptoms. METHODOLOGY: Two hundred and twenty nine chronic Chagas disease patients in Santa Cruz, Bolivia, were examined by serological tests, electrocardiogram (ECG, and Barium enema colon X-ray. 31.4% of the examinees showed ECG alterations, 15.7% megacolon and 58.1% showed neither of them. A further 62 seropositive megacolon patients who had undergone colonectomy due to acute abdomen were recruited. We analyzed their HLA genetic polymorphisms (HLA-A, HLA-B, MICA, MICB, DRB1 and TNF-alpha promoter region mainly through Sequence based and LABType SSO typing test using LUMINEX Technology. PRINCIPAL FINDINGS: The frequencies of HLA-DRB1*01 and HLA-B*14:02 were significantly lower in patients suffering from megacolon as well as in those with ECG alteration and/or megacolon compared with a group of patients with indeterminate symptoms. The DRB1*0102, B*1402 and MICA*011 alleles were in strong Linkage Disequilibrium (LD, and the HLA-DRB1*01-B*14-MICA*011 haplotype was associated with resistance against chronic Chagas disease. CONCLUSIONS: This is the first report of HLA haplotype association with resistance to chronic Chagas disease.

  15. Protective human leucocyte antigen haplotype, HLA-DRB1*01-B*14, against chronic Chagas disease in Bolivia.

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    Florencia del Puerto

    Full Text Available BACKGROUND: Chagas disease, caused by the flagellate parasite Trypanosoma cruzi affects 8-10 million people in Latin America. The mechanisms that underlie the development of complications of chronic Chagas disease, characterized primarily by pathology of the heart and digestive system, are not currently understood. To identify possible host genetic factors that may influence the clinical course of Chagas disease, Human Leucocyte Antigen (HLA regional gene polymorphism was analyzed in patients presenting with differing clinical symptoms. METHODOLOGY: Two hundred and twenty nine chronic Chagas disease patients in Santa Cruz, Bolivia, were examined by serological tests, electrocardiogram (ECG, and Barium enema colon X-ray. 31.4% of the examinees showed ECG alterations, 15.7% megacolon and 58.1% showed neither of them. A further 62 seropositive megacolon patients who had undergone colonectomy due to acute abdomen were recruited. We analyzed their HLA genetic polymorphisms (HLA-A, HLA-B, MICA, MICB, DRB1 and TNF-alpha promoter region mainly through Sequence based and LABType SSO typing test using LUMINEX Technology. PRINCIPAL FINDINGS: The frequencies of HLA-DRB1*01 and HLA-B*14:02 were significantly lower in patients suffering from megacolon as well as in those with ECG alteration and/or megacolon compared with a group of patients with indeterminate symptoms. The DRB1*0102, B*1402 and MICA*011 alleles were in strong Linkage Disequilibrium (LD, and the HLA-DRB1*01-B*14-MICA*011 haplotype was associated with resistance against chronic Chagas disease. CONCLUSIONS: This is the first report of HLA haplotype association with resistance to chronic Chagas disease.

  16. Haplotypes in the lipoprotein lipase gene influence fasting insulin and discovery of a new risk haplotype.

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    Goodarzi, Mark O; Taylor, Kent D; Guo, Xiuqing; Hokanson, John E; Haffner, Steven M; Cui, Jinrui; Chen, Yii-Der I; Wagenknecht, Lynne E; Bergman, Richard N; Rotter, Jerome I

    2007-01-01

    Prior studies of Mexican Americans described association of lipoprotein lipase (LPL) gene haplotypes with insulin sensitivity/resistance and atherosclerosis. The most common haplotype (haplotype 1) was protective, whereas the fourth most common haplotype (haplotype 4) conferred risk for insulin resistance and atherosclerosis. In this study of Hispanics in the Insulin Resistance Atherosclerosis Study Family Study, we sought to replicate LPL haplotype association with insulin sensitivity/resistance. LPL haplotypes based on 12 single nucleotide polymorphisms were analyzed for association with indexes of insulin sensitivity and other metabolic and adiposity measures. This study was conducted in the general community of San Antonio, Texas, and San Luis Valley, Colorado. Participants in this study were 978 members of 86 Hispanic families. LPL haplogenotype, metabolic phenotypes, and adiposity were measured in this study. The haplotype structure was identical with that observed in prior studies. Among 978 phenotyped subjects, haplotype 1 was associated with decreased fasting insulin (P = 0.01), and haplotype 4 was associated with increased fasting insulin (P = 0.02) and increased visceral fat mass (P = 0.002). Insulin sensitivity, derived from iv glucose tolerance testing, tended (P > 0.1) to be higher with haplotype 1 (S(I) = 1.72) and lower with haplotype 4 (S(I)=1.38). Haplotype 2 was associated with increases in fasting insulin, triglycerides (TGs), TG to high-density lipoprotein-cholesterol ratio, and apolipoprotein B (P = 0.01-0.04). This study independently replicates our prior results of LPL haplotypes 1 and 4 as associated with measures of insulin sensitivity and resistance, respectively. Haplotype 4 may confer insulin resistance by increasing visceral fat. Haplotype 2 was identified as a new risk haplotype, suggesting the complex nature of LPL's effect on features of the insulin resistance syndrome.

  17. Protection of astaxanthin in astaxanthin nanodispersions using additional antioxidants.

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    Anarjan, Navideh; Nehdi, Imededdine Arbi; Tan, Chin Ping

    2013-07-02

    The protective effects of α-tocopherol and ascorbic acid on astaxanthin in astaxanthin nanodispersions produced via a solvent-diffusion technique and stabilized by a three-component stabilizer system, were studied either individually or in combination by using response surface methodology. Generally, both α-tocopherol and ascorbic acid could retard the astaxanthin degradation in astaxanthin nanodispersions. The results showed that the using α-tocopherol and ascorbic acid can be more efficient in increasing the chemical stability of nanodispersions in comparison to using them individually. Using a response surface methodology (RSM) response optimizer, it was seen that addition of ascorbic acid (ascorbic acid/astaxanthin w/w) and α-tocopherol (α-tocopherol/astaxanthin w/w) in proportions of 0.4 and 0.6, respectively, would give the maximum chemical stability to the studied astaxanthin nanodispersions.

  18. Protection of Astaxanthin in Astaxanthin Nanodispersions Using Additional Antioxidants

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    Chin Ping Tan

    2013-07-01

    Full Text Available The protective effects of α-tocopherol and ascorbic acid on astaxanthin in astaxanthin nanodispersions produced via a solvent-diffusion technique and stabilized by a three-component stabilizer system, were studied either individually or in combination by using response surface methodology. Generally, both α-tocopherol and ascorbic acid could retard the astaxanthin degradation in astaxanthin nanodispersions. The results showed that the using α-tocopherol and ascorbic acid can be more efficient in increasing the chemical stability of nanodispersions in comparison to using them individually. Using a response surface methodology (RSM response optimizer, it was seen that addition of ascorbic acid (ascorbic acid/astaxanthin w/w and α-tocopherol (α-tocopherol/astaxanthin w/w in proportions of 0.4 and 0.6, respectively, would give the maximum chemical stability to the studied astaxanthin nanodispersions.

  19. Malaria haplotype frequency estimation.

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    Wigger, Leonore; Vogt, Julia E; Roth, Volker

    2013-09-20

    We present a Bayesian approach for estimating the relative frequencies of multi-single nucleotide polymorphism (SNP) haplotypes in populations of the malaria parasite Plasmodium falciparum by using microarray SNP data from human blood samples. Each sample comes from a malaria patient and contains one or several parasite clones that may genetically differ. Samples containing multiple parasite clones with different genetic markers pose a special challenge. The situation is comparable with a polyploid organism. The data from each blood sample indicates whether the parasites in the blood carry a mutant or a wildtype allele at various selected genomic positions. If both mutant and wildtype alleles are detected at a given position in a multiply infected sample, the data indicates the presence of both alleles, but the ratio is unknown. Thus, the data only partially reveals which specific combinations of genetic markers (i.e. haplotypes across the examined SNPs) occur in distinct parasite clones. In addition, SNP data may contain errors at non-negligible rates. We use a multinomial mixture model with partially missing observations to represent this data and a Markov chain Monte Carlo method to estimate the haplotype frequencies in a population. Our approach addresses both challenges, multiple infections and data errors.

  20. 46 CFR 308.204 - Additional war risk protection and indemnity insurance.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Additional war risk protection and indemnity insurance... OPERATIONS WAR RISK INSURANCE War Risk Protection and Indemnity Insurance § 308.204 Additional war risk protection and indemnity insurance. Owners or charterers may obtain, on an excess basis, additional war...

  1. Haplotype association between haptoglobin (Hp2 and Hp promoter SNP (A-61C may explain previous controversy of haptoglobin and malaria protection.

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    Sharon E Cox

    Full Text Available BACKGROUND: Malaria is one of the strongest recent selective pressures on the human genome, as evidenced by the high levels of varying haemoglobinopathies in human populations-despite the increased risk of mortality in the homozygous states. Previously, functional polymorphisms of Hp, coded by the co-dominant alleles Hp1 and Hp2, have been variously associated with several infectious diseases, including malaria susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: Risk of a clinical malarial episode over the course of a malarial transmission season was assessed using active surveillance in a cohort of Gambian children aged 10-72 months. We report for the first time that the major haplotype for the A-61C mutant allele in the promoter of haptoglobin (Hp-an acute phase protein that clears haemoglobin released from haemolysis of red cells-is associated with protection from malarial infection in older children, (children aged >or=36 months, >500 parasites/ul and temperature >37.5 degrees C; OR = 0.42; [95% CI 0.24-0.73] p = 0.002 (lr test for interaction, or=36 months, p = 0.014. Protection was also observed using two other definitions, including temperature >37.5 degrees C, dipstick positive, plus clinical judgement of malaria blinded to dipstick result (all ages, OR = 0.48, [95% CI 0.30-0.78] p = 0.003; >or=36 months, OR = 0.31, [95% CI 0.15-0.62] p = 0.001. A similar level of protection was observed for the known protective genetic variant, sickle cell trait (HbAS. CONCLUSIONS/SIGNIFICANCE: We propose that previous conflicting results between Hp phenotypes/genotypes and malaria susceptibility may be explained by differing prevalence of the A-61C SNP in the populations studied, which we found to be highly associated with the Hp2 allele. We report the -61C allele to be associated with decreased Hp protein levels (independent of Hp phenotype, confirming in vitro studies. Decreased Hp expression may lead to increased oxidant stress and increased red cell

  2. Protection of Astaxanthin in Astaxanthin Nanodispersions Using Additional Antioxidants

    OpenAIRE

    Chin Ping Tan; Imededdine Arbi Nehdi; Navideh Anarjan

    2013-01-01

    The protective effects of α-tocopherol and ascorbic acid on astaxanthin in astaxanthin nanodispersions produced via a solvent-diffusion technique and stabilized by a three-component stabilizer system, were studied either individually or in combination by using response surface methodology. Generally, both α-tocopherol and ascorbic acid could retard the astaxanthin degradation in astaxanthin nanodispersions. The results showed that the using α-tocopherol and ascorbic acid can be more efficient...

  3. Land protection plan Ellicott Slough National Wildlife Refuge proposed Buena Vista addition [2004

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Land Protection Plan, as part of the Environmental Assessment, Land Protection Plan and Conceptual Management Plan for the proposed Buena Vista addition to the...

  4. N-phenylmaleimide as a New Ploymerizable Additive for Overcharge Protection of Lithium-ion Batteries

    Institute of Scientific and Technical Information of China (English)

    B.Wang; Q.Xia; Y.P.Wu

    2007-01-01

    1 Results In persuit of better safety controls of lithium batteries,much efforts has been focused on the development of the internal and self-actuating overcharge protection additives.We report a novel electropolymerizable electrolyte additive for overcharge protection of lithium batteries. Electrochemical properties and overcharge behavior of NPM as a new polymerizable electrolyte additive for overcharge protection of lithium ion batteries are studied by cyclic voltammetry,charge-discharge measurements...

  5. HaplotypeCN: copy number haplotype inference with Hidden Markov Model and localized haplotype clustering.

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    Yen-Jen Lin

    Full Text Available Copy number variation (CNV has been reported to be associated with disease and various cancers. Hence, identifying the accurate position and the type of CNV is currently a critical issue. There are many tools targeting on detecting CNV regions, constructing haplotype phases on CNV regions, or estimating the numerical copy numbers. However, none of them can do all of the three tasks at the same time. This paper presents a method based on Hidden Markov Model to detect parent specific copy number change on both chromosomes with signals from SNP arrays. A haplotype tree is constructed with dynamic branch merging to model the transition of the copy number status of the two alleles assessed at each SNP locus. The emission models are constructed for the genotypes formed with the two haplotypes. The proposed method can provide the segmentation points of the CNV regions as well as the haplotype phasing for the allelic status on each chromosome. The estimated copy numbers are provided as fractional numbers, which can accommodate the somatic mutation in cancer specimens that usually consist of heterogeneous cell populations. The algorithm is evaluated on simulated data and the previously published regions of CNV of the 270 HapMap individuals. The results were compared with five popular methods: PennCNV, genoCN, COKGEN, QuantiSNP and cnvHap. The application on oral cancer samples demonstrates how the proposed method can facilitate clinical association studies. The proposed algorithm exhibits comparable sensitivity of the CNV regions to the best algorithm in our genome-wide study and demonstrates the highest detection rate in SNP dense regions. In addition, we provide better haplotype phasing accuracy than similar approaches. The clinical association carried out with our fractional estimate of copy numbers in the cancer samples provides better detection power than that with integer copy number states.

  6. HaplotypeCN: Copy Number Haplotype Inference with Hidden Markov Model and Localized Haplotype Clustering

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    Lin, Yen-Jen; Chen, Yu-Tin; Hsu, Shu-Ni; Peng, Chien-Hua; Tang, Chuan-Yi; Yen, Tzu-Chen; Hsieh, Wen-Ping

    2014-01-01

    Copy number variation (CNV) has been reported to be associated with disease and various cancers. Hence, identifying the accurate position and the type of CNV is currently a critical issue. There are many tools targeting on detecting CNV regions, constructing haplotype phases on CNV regions, or estimating the numerical copy numbers. However, none of them can do all of the three tasks at the same time. This paper presents a method based on Hidden Markov Model to detect parent specific copy number change on both chromosomes with signals from SNP arrays. A haplotype tree is constructed with dynamic branch merging to model the transition of the copy number status of the two alleles assessed at each SNP locus. The emission models are constructed for the genotypes formed with the two haplotypes. The proposed method can provide the segmentation points of the CNV regions as well as the haplotype phasing for the allelic status on each chromosome. The estimated copy numbers are provided as fractional numbers, which can accommodate the somatic mutation in cancer specimens that usually consist of heterogeneous cell populations. The algorithm is evaluated on simulated data and the previously published regions of CNV of the 270 HapMap individuals. The results were compared with five popular methods: PennCNV, genoCN, COKGEN, QuantiSNP and cnvHap. The application on oral cancer samples demonstrates how the proposed method can facilitate clinical association studies. The proposed algorithm exhibits comparable sensitivity of the CNV regions to the best algorithm in our genome-wide study and demonstrates the highest detection rate in SNP dense regions. In addition, we provide better haplotype phasing accuracy than similar approaches. The clinical association carried out with our fractional estimate of copy numbers in the cancer samples provides better detection power than that with integer copy number states. PMID:24849202

  7. Polyfibroblast Phase 4: A Self-Healing and Galvanic Protection Additive

    Science.gov (United States)

    2014-11-26

    8/98) Prescribed by ANSI Std. Z39.18 REDD-2014-387 POLYFIBROBLAST PHASE IV: A SELF- HEALING AND GALVANIC PROTECTION ADDITIVE Progress Report #10...Performance/Technical Report (Monthly) 4. TITLE AND SUBTITLE Polyfibroblast: A Self- Healing and Galvanic Protection Additive 6. AUTHOR{S) Benkoski, Jason...14. ABSTRACT The goal of this project is to develop a primer additive that mimics the self- healing ability of skin by forming a polymer scar across

  8. Advax-adjuvanted recombinant protective antigen provides protection against inhalational anthrax that is further enhanced by addition of murabutide adjuvant.

    Science.gov (United States)

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita; Merkel, Tod J

    2014-04-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.

  9. Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant

    Science.gov (United States)

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita

    2014-01-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy. PMID:24554695

  10. Haplotype studies in Wilson disease

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.R.; Bull, P.C.; Roberts, E.A.; Cox, D.W.; Walshe, J.M. (Univ. of Toronto (Canada))

    1994-01-01

    In 51 families with Wilson disease, the authors have studied DNA haplotypes of dinucleotide repeat polymorphisms (CA repeats) in the 13q14.3 region, to examine these markers for association with the Wilson disease gene (WND). In addition to a marker (D13S133) described elsewhere, the authors have developed three new highly polymorphic markers (D13S314, D13S315, and D13S316) close to the WND locus. The authors have examined the distribution of marker alleles at the loci studied and have found that D13S314, D13S133, and D13S316 each show nonrandom distribution on chromosomes carrying the WND mutation. The authors have studied haplotypes of these three markers and have found that there are highly significant differences between WND and normal haplotypes in northern European families. These findings have important implications for mutation detection and molecular diagnosis in families with Wilson disease. 25 refs., 2 figs., 5 tabs.

  11. Xylene as a New Polymerizable Additive for Overcharge Protection of Lithium Ion Batteries

    Institute of Scientific and Technical Information of China (English)

    ZHANG Qianyu; QIU Chenchen; FU Yanbao; MA Xiaohua

    2009-01-01

    The electrochemical properties and overcharge protection mechanism of xylene as a new polymerizable electrolyte additive for overcharge protection of lithium ion batteries were studied by cyclic voltammetry tests,chargedischarge performance and battery power capacity measurements.It was found that when the battery was overcharged,xylene could electrochemically polymerize at the overcharge potential of 4.3-4.7 V (vs.Li/Li+) to form a thin polymer film on the surface of the cathode,thus preventing voltage runaway.On the other hand,the use of xylene as an overcharge protection electrolyte additive did not influence the normal performance of lithium ion batteries.

  12. Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments.

    Science.gov (United States)

    Palo, Outi M; Antila, Mervi; Silander, Kaisa; Hennah, William; Kilpinen, Helena; Soronen, Pia; Tuulio-Henriksson, Annamari; Kieseppä, Tuula; Partonen, Timo; Lönnqvist, Jouko; Peltonen, Leena; Paunio, Tiina

    2007-10-15

    Bipolar disorder (BPD) and schizophrenia (SCZ) have at least a partially convergent aetiology and thus may share genetic susceptibility loci. Multiple lines of evidence emphasize the role of disrupted-in-schizophrenia-1 (DISC1) gene in psychotic disorders such as SCZ. We monitored the association of allelic variants of translin-associated factor X (TSNAX)/DISC1 gene cluster using 13 single-nucleotide polymorphisms (SNPs) in 723 members of 179 Finnish BPD families. Consistent with an earlier finding in Finnish SCZ families, the haplotype T-A of rs751229 and rs3738401 at the 5' end of DISC1 was over-transmitted to males with psychotic disorder (P = 0.008; for an extended haplotype P = 0.0007 with both genders). Haplotypes at the 3' end of DISC1 associated with bipolar spectrum disorder (P = 0.0002 for an under-transmitted haplotype T-T of rs821616 and rs1411771, for an extended haplotype P = 0.0001), as did a two-SNP risk haplotype at the 5' end of TSNAX (P = 0.007). The risk haplotype for psychotic disorder also associated to perseverations (P = 0.035; for rs751229 alone P = 0.0012), and a protective haplotype G-T-G with rs1655285 in addition to auditory attention (P = 0.0059). The 3' end variants associated with several cognitive traits, with the most robust signal for rs821616 and verbal fluency and rs980989 and psychomotor processing speed (P = 0.011 for both). These results support involvement of DISC1 in the genetic aetiology of BPD and suggest that its distinct variants contribute to variation in the dimensional features of psychotic and bipolar spectrum disorders. Finding of alternative associating haplotypes in the same set of BPD families gives evidence for allelic heterogeneity within DISC1, eventually leading to heterogeneity in the clinical outcome as well.

  13. Functional Haplotypes in Interleukin 4 Gene Associated with Periodontitis

    Science.gov (United States)

    Mayer, Marcia Pinto Alves; Rossa, Carlos

    2017-01-01

    Chronic periodontitis (CP) is an infectious inflammatory disease that affects tooth-supporting structures and in which dental plaque bacteria, immune mechanisms and genetic predisposition play important roles. Interleukin 4 (IL-4) is a key anti-inflammatory cytokine with relevant action in imbalances in inflamed periodontal tissue. Individuals carrying the TCI/CCI genotype (S-haplotype) of the IL-4 gene are 5 times more susceptible to CP, whereas the CTI/TTD genotype (P-haplotype) confers protection against CP. Compared with the S-haplotype, subjects with the P-haplotype produce higher levels of the IL-4 protein after non-surgical periodontal therapy. The present in vitro study aimed to investigate the functionality of IL-4 haplotypes in immune cells to obtain insight into the influence of these genetic variations in regulating immune responses to CP-associated bacteria. Peripheral blood was collected from 6 subjects carrying each haplotype, and their immune cells were challenged with periodontopathogens to compare responses of the different haplotypes with regard to gene expression, protein secretion and the immunophenotype of T helper responses. We found higher IL-4 mRNA and protein levels in the P-haplotype, which also presented higher levels of anti-inflammatory cytokines. In contrast, cells from S-haplotype subjects responded with higher levels of pro-inflammatory cytokines. S-haplotype individuals exhibited significantly greater polarization toward the Th1 phenotype, whereas the P-haplotype was associated with an attenuated response to periodontopathogens, with suggestive skewing toward Th2/M2 phenotypes. In conclusion, IL-4 genetic variations associated with susceptibility to or protection against chronic periodontitis are directly associated with influencing the response of immune cells to periodontopathogens. PMID:28114408

  14. The effect of genealogy-based haplotypes on genomic prediction

    DEFF Research Database (Denmark)

    Edriss, Vahid; Fernando, Rohan L.; Su, Guosheng

    2013-01-01

    Background Genomic prediction uses two sources of information: linkage disequilibrium between markers and quantitative trait loci, and additive genetic relationships between individuals. One way to increase the accuracy of genomic prediction is to capture more linkage disequilibrium by regression...... on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. Methods A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using...... local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (pi) of the haplotype covariates had zero effect...

  15. Haplotypes versus genotypes on pedigrees

    Directory of Open Access Journals (Sweden)

    Kirkpatrick Bonnie B

    2011-04-01

    Full Text Available Abstract Background Genome sequencing will soon produce haplotype data for individuals. For pedigrees of related individuals, sequencing appears to be an attractive alternative to genotyping. However, methods for pedigree analysis with haplotype data have not yet been developed, and the computational complexity of such problems has been an open question. Furthermore, it is not clear in which scenarios haplotype data would provide better estimates than genotype data for quantities such as recombination rates. Results To answer these questions, a reduction is given from genotype problem instances to haplotype problem instances, and it is shown that solving the haplotype problem yields the solution to the genotype problem, up to constant factors or coefficients. The pedigree analysis problems we will consider are the likelihood, maximum probability haplotype, and minimum recombination haplotype problems. Conclusions Two algorithms are introduced: an exponential-time hidden Markov model (HMM for haplotype data where some individuals are untyped, and a linear-time algorithm for pedigrees having haplotype data for all individuals. Recombination estimates from the general haplotype HMM algorithm are compared to recombination estimates produced by a genotype HMM. Having haplotype data on all individuals produces better estimates. However, having several untyped individuals can drastically reduce the utility of haplotype data.

  16. Evaluation of additional lead shielding in protecting the physician from radiation during cardiac interventional procedures.

    Science.gov (United States)

    Chida, Koichi; Morishima, Yoshiaki; Katahira, Yoshiaki; Chiba, Hiroo; Zuguchi, Masayuki

    2005-12-20

    Since cardiac interventional procedures deliver high doses of radiation to the physician, radiation protection for the physician in cardiac catheterization laboratories is very important. One of the most important means of protecting the physician from scatter radiation is to use additional lead shielding devices, such as tableside lead drapes and ceiling-mounted lead acrylic protection. During cardiac interventional procedures (cardiac IVR), however, it is not clear how much lead shielding reduces the physician dose. This study compared the physician dose [effective dose equivalent (EDE) and dose equivalent (DE)] with and without additional shielding during cardiac IVR. Fluoroscopy scatter radiation was measured using a human phantom, with an ionization chamber survey meter, with and without additional shielding. With the additional shielding, fluoroscopy scatter radiation measured with the human phantom was reduced by up to 98%, as compared with that without. The mean EDE (whole body, mean+/-SD) dose to the operator, determined using a Luxel badge, was 2.55+/-1.65 and 4.65+/-1.21 mSv/year with and without the additional shielding, respectively (p=0.086). Similarly, the mean DE (lens of the eye) to the operator was 15.0+/-9.3 and 25.73+/-5.28 mSv/year, respectively (p=0.092). In conclusion, although tableside drapes and lead acrylic shields suspended from the ceiling provided extra protection to the physician during cardiac IVR, the reduction in the estimated physician dose (EDE and DE) during cardiac catheterization with additional shielding was lower than we expected. Therefore, there is a need to develop more ergonomically useful protection devices for cardiac IVR.

  17. Modification of silicone sealant to improve gamma radiation resistance, by addition of protective agents

    Science.gov (United States)

    González-Pérez, Giovanni; Burillo, Guillermina

    2013-09-01

    Poly (dimethylsiloxane) (PDMS) sealant (SS) was modified with the addition of different protective compounds to conserve its physical-chemical properties during gamma irradiation. 2-Vinyl naphthalene (2-VN), bisphenol-A (BPA) and poly (vinyl carbazole) (PVK) were used to evaluate radiation protection through the crosslinking effect of radiation. The samples were irradiated with doses from 100 kGy to 500 kGy at room temperature in air, with a 60Co gamma source, and the changes in molecular weight, thermal behavior, elastic properties and infrared spectra (FTIR-ATR) absorbance analysis were determined. The molecular weight of unmodified silicone sealant increases with the absorbed dose because of crosslinking as predominant effect. However, the crosslinking effect was inhibited with the addition of protective agent due to the aromatic compounds present. Modified silicone sealant films present better radiation resistance than unmodified system.

  18. Pure Parsimony Xor Haplotyping

    CERN Document Server

    Bonizzoni, Paola; Dondi, Riccardo; Pirola, Yuri; Rizzi, Romeo

    2010-01-01

    The haplotype resolution from xor-genotype data has been recently formulated as a new model for genetic studies. The xor-genotype data is a cheaply obtainable type of data distinguishing heterozygous from homozygous sites without identifying the homozygous alleles. In this paper we propose a formulation based on a well-known model used in haplotype inference: pure parsimony. We exhibit exact solutions of the problem by providing polynomial time algorithms for some restricted cases and a fixed-parameter algorithm for the general case. These results are based on some interesting combinatorial properties of a graph representation of the solutions. Furthermore, we show that the problem has a polynomial time k-approximation, where k is the maximum number of xor-genotypes containing a given SNP. Finally, we propose a heuristic and produce an experimental analysis showing that it scales to real-world large instances taken from the HapMap project.

  19. Pure parsimony xor haplotyping.

    Science.gov (United States)

    Bonizzoni, Paola; Della Vedova, Gianluca; Dondi, Riccardo; Pirola, Yuri; Rizzi, Romeo

    2010-01-01

    The haplotype resolution from xor-genotype data has been recently formulated as a new model for genetic studies. The xor-genotype data is a cheaply obtainable type of data distinguishing heterozygous from homozygous sites without identifying the homozygous alleles. In this paper, we propose a formulation based on a well-known model used in haplotype inference: pure parsimony. We exhibit exact solutions of the problem by providing polynomial time algorithms for some restricted cases and a fixed-parameter algorithm for the general case. These results are based on some interesting combinatorial properties of a graph representation of the solutions. Furthermore, we show that the problem has a polynomial time k-approximation, where k is the maximum number of xor-genotypes containing a given single nucleotide polymorphisms (SNP). Finally, we propose a heuristic and produce an experimental analysis showing that it scales to real-world large instances taken from the HapMap project.

  20. Creating Protected Areas on Public Lands: Is There Room for Additional Conservation?

    Science.gov (United States)

    Arriagada, Rodrigo A.; Echeverria, Cristian M.; Moya, Danisa E.

    2016-01-01

    Most evaluations of the effectiveness of PAs have relied on indirect estimates based on comparisons between protected and unprotected areas. Such methods can be biased when protection is not randomly assigned. We add to the growing literature on the impact of PAs by answering the following research questions: What is the impact of Chilean PAs on deforestation which occurred between 1986 and 2011? How do estimates of the impact of PAs vary when using only public land as control units? We show that the characteristics of the areas in which protected and unprotected lands are located differ significantly. To satisfactorily estimate the effects of PAs, we use matching methods to define adequate control groups, but not as in previous research. We construct control groups using separately non-protected private areas and non-protected public lands. We find that PAs avoid deforestation when using unprotected private lands as valid controls, however results show no impact when the control group is based only on unprotected public land. Different land management regimes, and higher levels of enforcement inside public lands may reduce the opportunity to add additional conservation benefits when the national systems for PAs are based on the protection of previously unprotected public lands. Given that not all PAs are established to avoid deforestation, results also admit the potential for future studies to include other outcomes including forest degradation (not just deforestation), biodiversity, wildlife, primary forests (not forests in general), among others. PMID:26848856

  1. Creating Protected Areas on Public Lands: Is There Room for Additional Conservation?

    Directory of Open Access Journals (Sweden)

    Rodrigo A Arriagada

    Full Text Available Most evaluations of the effectiveness of PAs have relied on indirect estimates based on comparisons between protected and unprotected areas. Such methods can be biased when protection is not randomly assigned. We add to the growing literature on the impact of PAs by answering the following research questions: What is the impact of Chilean PAs on deforestation which occurred between 1986 and 2011? How do estimates of the impact of PAs vary when using only public land as control units? We show that the characteristics of the areas in which protected and unprotected lands are located differ significantly. To satisfactorily estimate the effects of PAs, we use matching methods to define adequate control groups, but not as in previous research. We construct control groups using separately non-protected private areas and non-protected public lands. We find that PAs avoid deforestation when using unprotected private lands as valid controls, however results show no impact when the control group is based only on unprotected public land. Different land management regimes, and higher levels of enforcement inside public lands may reduce the opportunity to add additional conservation benefits when the national systems for PAs are based on the protection of previously unprotected public lands. Given that not all PAs are established to avoid deforestation, results also admit the potential for future studies to include other outcomes including forest degradation (not just deforestation, biodiversity, wildlife, primary forests (not forests in general, among others.

  2. Founder mitochondrial haplotypes in Amerindian populations.

    Science.gov (United States)

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

    1994-07-01

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

  3. Haplotyping using a combination of polymerase chain reaction-single-strand conformational polymorphism analysis and haplotype-specific PCR amplification.

    Science.gov (United States)

    Zhou, Huitong; Li, Shaobin; Liu, Xiu; Wang, Jiqing; Luo, Yuzhu; Hickford, Jon G H

    2014-12-01

    A single nucleotide polymorphism (SNP) may have an impact on phenotype, but it may also be influenced by multiple SNPs within a gene; hence, the haplotype or phase of multiple SNPs needs to be known. Various methods for haplotyping SNPs have been proposed, but a simple and cost-effective method is currently unavailable. Here we describe a haplotyping approach using two simple techniques: polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) and haplotype-specific PCR. In this approach, individual regions of a gene are analyzed by PCR-SSCP to identify variation that defines sub-haplotypes, and then extended haplotypes are assembled from the sub-haplotypes either directly or with the additional use of haplotype-specific PCR amplification. We demonstrate the utility of this approach by haplotyping ovine FABP4 across two variable regions that contain seven SNPs and one indel. The simplicity of this approach makes it suitable for large-scale studies and/or diagnostic screening.

  4. Haplotyping as perfect phylogeny: a direct approach.

    Science.gov (United States)

    Bafna, Vineet; Gusfield, Dan; Lancia, Giuseppe; Yooseph, Shibu

    2003-01-01

    list of "future work" in Gusfield (2002) began with the task of developing a simpler, more direct, yet still efficient algorithm. This paper accomplishes that goal, for both the rooted and unrooted PPH problems. It establishes a simple, easy-to-program, O(nm(2))-time algorithm that determines whether there is a PPH solution for input genotypes and produces a linear-space data structure to represent all of the solutions. The approach allows complete, self-contained proofs. In addition to algorithmic simplicity, the approach here makes the representation of all solutions more intuitive than in Gusfield (2002), and solves another goal from that paper, namely, to prove a nontrivial upper bound on the number of PPH solutions, showing that that number is vastly smaller than the number of haplotype solutions (each solution being a set of n pairs of haplotypes that can generate the genotypes) when the perfect phylogeny requirement is not imposed.

  5. Investigation of Pm-75 carbon black addition on the properties of protective polymer coatings

    Science.gov (United States)

    Sapronov, Oleksandr; Maruschak, Pavlo; Buketova, Natalia; Leschenko, Oleksandr; Panin, Sergey

    2016-11-01

    The influence of the loading of fine furnace carbon black on the physical-mechanical, thermal-physical properties and structure of protective coatings was investigated. It is shown that for the formation of coatings with enhanced adhesion characteristics, the optimal weight fraction of additives should make q = 25 wt %, while for the formation of coatings with enhanced cohesive characteristics, that of additives should be q = 20 wt %. The optical-microscopy-based technique was employed to investigate the structure of the fracture patterns. A uniform fracture surface topology was revealed, which characterizes the viscous character of material fracture when content of the additives is equal to q = 10-30 wt %, which provides a significant improvement of physical and mechanical properties of the developed materials.

  6. Solid polymer electrolyte electrochemical storage cell containing a redox shuttle additive for overcharge protection

    Science.gov (United States)

    Richardson, Thomas J.; Ross, Philip N.

    1999-01-01

    A class of organic redox shuttle additives is described, preferably comprising nitrogen-containing aromatics compounds, which can be used in a high temperature (85.degree. C. or higher) electrochemical storage cell comprising a positive electrode, a negative electrode, and a solid polymer electrolyte to provide overcharge protection to the cell. The organic redox additives or shuttles are characterized by a high diffusion coefficient of at least 2.1.times.10.sup.-8 cm.sup.2 /second and a high onset potential of 2.5 volts or higher. Examples of such organic redox shuttle additives include an alkali metal salt of 1,2,4-triazole, an alkali metal salt of imidazole, 2,3,5,6-tetramethylpyrazine, 1,3,5-tricyanobenzene, and a dialkali metal salt of 3-4-dihydroxy-3-cyclobutene-1,2-dione.

  7. Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations

    Directory of Open Access Journals (Sweden)

    Jallow Muminatou

    2007-08-01

    Full Text Available Abstract Background The sickle (βs mutation in the beta-globin gene (HBB occurs on five "classical" βs haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the βs allele – a consequence of protection from severe malarial infection afforded by heterozygotes – has been associated with a high degree of extended haplotype similarity. The relationship between classical βs haplotypes and long-range haplotype similarity may have both anthropological and clinical implications, but to date has not been explored. Here we evaluate the haplotype similarity of classical βs haplotypes over 400 kb in population samples from Jamaica, The Gambia, and among the Yoruba of Nigeria (Hapmap YRI. Results The most common βs sub-haplotype among Jamaicans and the Yoruba was the Benin haplotype, while in The Gambia the Senegal haplotype was observed most commonly. Both subtypes exhibited a high degree of long-range haplotype similarity extending across approximately 400 kb in all three populations. This long-range similarity was significantly greater than that seen for other haplotypes sampled in these populations (P s mutation. Conclusion Two different classical βs haplotypes, sampled from different populations, exhibit comparable and extensive long-range haplotype similarity and strong LD. This LD extends across the adjacent recombination hotspot, and is discernable at distances in excess of 400 kb. Although the multi-centric geographic distribution of βs haplotypes indicates strong subdivision among early Holocene sub-Saharan populations, we find no evidence that selective pressures imposed by falciparum malaria varied in intensity or timing between these subpopulations. Our observations also suggest that cis-acting loci, which may influence outcomes in sickle cell disease, could lie considerable distances away from β-globin.

  8. ASSOCIATION BETWEEN GAB2 HAPLOTYPE AND HIGHER GLUCOSE METABOLISM IN ALZHEIMER'S DISEASE-AFFECTED BRAIN REGIONS IN COGNITIVELY NORMAL APOEε4 CARRIERS

    Science.gov (United States)

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

    2010-01-01

    In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative presymptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk. PMID:20888920

  9. Fast and accurate haplotype frequency estimation for large haplotype vectors from pooled DNA data

    Directory of Open Access Journals (Sweden)

    Iliadis Alexandros

    2012-10-01

    Full Text Available Abstract Background Typically, the first phase of a genome wide association study (GWAS includes genotyping across hundreds of individuals and validation of the most significant SNPs. Allelotyping of pooled genomic DNA is a common approach to reduce the overall cost of the study. Knowledge of haplotype structure can provide additional information to single locus analyses. Several methods have been proposed for estimating haplotype frequencies in a population from pooled DNA data. Results We introduce a technique for haplotype frequency estimation in a population from pooled DNA samples focusing on datasets containing a small number of individuals per pool (2 or 3 individuals and a large number of markers. We compare our method with the publicly available state-of-the-art algorithms HIPPO and HAPLOPOOL on datasets of varying number of pools and marker sizes. We demonstrate that our algorithm provides improvements in terms of accuracy and computational time over competing methods for large number of markers while demonstrating comparable performance for smaller marker sizes. Our method is implemented in the "Tree-Based Deterministic Sampling Pool" (TDSPool package which is available for download at http://www.ee.columbia.edu/~anastas/tdspool. Conclusions Using a tree-based determinstic sampling technique we present an algorithm for haplotype frequency estimation from pooled data. Our method demonstrates superior performance in datasets with large number of markers and could be the method of choice for haplotype frequency estimation in such datasets.

  10. Land protection plan Ellicott Slough National Wildlife Refuge proposed Buena Vista addition [2005

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This Land Protection Plan (LPP) describes the resource protection needs and habitat protection methods the U.S. Fish and Wildlife Service (Service) would use for the...

  11. Land protection plan Ellicott Slough National Wildlife Refuge proposed Buena Vista addition [2005

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This Land Protection Plan (LPP) describes the resource protection needs and habitat protection methods the U.S. Fish and Wildlife Service (Service) would use for...

  12. Are molecular haplotypes worth the time and expense? A cost-effective method for applying molecular haplotypes.

    Directory of Open Access Journals (Sweden)

    Mark A Levenstien

    2006-08-01

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

  13. Mapping Haplotype-haplotype Interactions with Adaptive LASSO

    Directory of Open Access Journals (Sweden)

    Li Ming

    2010-08-01

    Full Text Available Abstract Background The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it presents daunting challenges in statistical modeling and testing of the interaction effects, largely due to the complicated higher order epistatic complexity. Results In this article, we propose a new strategy in modeling haplotype-haplotype interactions under the penalized logistic regression framework with adaptive L1-penalty. We consider interactions of sequence variants between haplotype blocks. The adaptive L1-penalty allows simultaneous effect estimation and variable selection in a single model. We propose a new parameter estimation method which estimates and selects parameters by the modified Gauss-Seidel method nested within the EM algorithm. Simulation studies show that it has low false positive rate and reasonable power in detecting haplotype interactions. The method is applied to test haplotype interactions involved in mother and offspring genome in a small for gestational age (SGA neonates data set, and significant interactions between different genomes are detected. Conclusions As demonstrated by the simulation studies and real data analysis, the approach developed provides an efficient tool for the modeling and testing of haplotype interactions. The implementation of the method in R codes can be

  14. Mapping haplotype-haplotype interactions with adaptive LASSO.

    Science.gov (United States)

    Li, Ming; Romero, Roberto; Fu, Wenjiang J; Cui, Yuehua

    2010-08-27

    The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs) have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it presents daunting challenges in statistical modeling and testing of the interaction effects, largely due to the complicated higher order epistatic complexity. In this article, we propose a new strategy in modeling haplotype-haplotype interactions under the penalized logistic regression framework with adaptive L1-penalty. We consider interactions of sequence variants between haplotype blocks. The adaptive L1-penalty allows simultaneous effect estimation and variable selection in a single model. We propose a new parameter estimation method which estimates and selects parameters by the modified Gauss-Seidel method nested within the EM algorithm. Simulation studies show that it has low false positive rate and reasonable power in detecting haplotype interactions. The method is applied to test haplotype interactions involved in mother and offspring genome in a small for gestational age (SGA) neonates data set, and significant interactions between different genomes are detected. As demonstrated by the simulation studies and real data analysis, the approach developed provides an efficient tool for the modeling and testing of haplotype interactions. The implementation of the method in R codes can be freely downloaded from http://www.stt.msu.edu/~cui/software.html.

  15. Understanding Y haplotype matching probability.

    Science.gov (United States)

    Brenner, Charles H

    2014-01-01

    The Y haplotype population-genetic terrain is better explored from a fresh perspective rather than by analogy with the more familiar autosomal ideas. For haplotype matching probabilities, versus for autosomal matching probabilities, explicit attention to modelling - such as how evolution got us where we are - is much more important while consideration of population frequency is much less so. This paper explores, extends, and explains some of the concepts of "Fundamental problem of forensic mathematics - the evidential strength of a rare haplotype match". That earlier paper presented and validated a "kappa method" formula for the evidential strength when a suspect matches a previously unseen haplotype (such as a Y-haplotype) at the crime scene. Mathematical implications of the kappa method are intuitive and reasonable. Suspicions to the contrary raised in rest on elementary errors. Critical to deriving the kappa method or any sensible evidential calculation is understanding that thinking about haplotype population frequency is a red herring; the pivotal question is one of matching probability. But confusion between the two is unfortunately institutionalized in much of the forensic world. Examples make clear why (matching) probability is not (population) frequency and why uncertainty intervals on matching probabilities are merely confused thinking. Forensic matching calculations should be based on a model, on stipulated premises. The model inevitably only approximates reality, and any error in the results comes only from error in the model, the inexactness of the approximation. Sampling variation does not measure that inexactness and hence is not helpful in explaining evidence and is in fact an impediment. Alternative haplotype matching probability approaches that various authors have considered are reviewed. Some are based on no model and cannot be taken seriously. For the others, some evaluation of the models is discussed. Recent evidence supports the adequacy of

  16. HaploForge: A Comprehensive Pedigree Drawing and Haplotype Visualisation Web Application.

    Science.gov (United States)

    Tekman, Mehmet; Medlar, Alan; Mozere, Monika; Kleta, Robert; Stanescu, Horia

    2017-08-14

    Haplotype reconstruction is an important tool for understanding the aetiology of human disease. Haplotyping infers the most likely phase of observed genotypes conditional on constraints imposed by the genotypes of other pedigree members. The results of haplotype reconstruction, when visualised appropriately, show which alleles are identical by descent despite the presence of untyped individuals. When used in concert with linkage analysis, haplotyping can help delineate a locus of interest and provide a succinct explanation for the transmission of the trait locus. Unfortunately, the design choices made by existing haplotype visualisation programs do not scale to large numbers of markers. Indeed, following haplotypes from generation to generation requires excessive scrolling back and forth. In addition, the most widely-used program for haplotype visualisation produces inconsistent recombination artefacts for the X chromosome. To resolve these issues, we developed HaploForge, a novel web application for haplotype visualisation and pedigree drawing. HaploForge takes advantage of HTML5 to be fast, portable and avoid the need for local installation. It can accurately visualise autosomal and X-linked haplotypes from both outbred and consanguineous pedigrees. Haplotypes are coloured based on identity by descent using a novel A* search algorithm and we provide a flexible viewing mode to aid visual inspection. HaploForge can currently process haplotype reconstruction output from Allegro, GeneHunter, Merlin and Simwalk. HaploForge is licensed under GPLv3 and is hosted and maintained via GitHub. Supplementary data is available from Bioinformatics online.

  17. iHAP – integrated haplotype analysis pipeline for characterizing the haplotype structure of genes

    Directory of Open Access Journals (Sweden)

    Lim Yun Ping

    2006-12-01

    Full Text Available Abstract Background The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. Results To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. Conclusion The iHAP resource, available at http://ihap.bii.a-star.edu.sg, provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies.

  18. Transgenic mice with -6A haplotype of the human angiotensinogen gene have increased blood pressure compared with -6G haplotype.

    Science.gov (United States)

    Jain, Sudhir; Tillinger, Andrej; Mopidevi, Brahmaraju; Pandey, Varunkumar G; Chauhan, Chetankumar K; Fiering, Steven N; Warming, Soren; Kumar, Ashok

    2010-12-24

    Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at -6, and the -6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with -6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with -6G. We have found that the hAGT gene has three additional SNPs (A/G at -1670, C/G at -1562, and T/G at -1561). Variants -1670A, -1562C, and -1561T almost always occur with -6A, and variants -1670G, -1562G, and -1561G almost always occur with -6G. Therefore, the hAGT gene may be subdivided into either -6A or -6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with -6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with -6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the -6A or -6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing -6A haplotype. Our studies also show that transgenic mice containing -6A haplotype have increased plasma AGT level and increased blood pressure as compared with -6G haplotype. Our studies explain the molecular mechanism involved in association of the -6A allele of the hAGT gene with hypertension.

  19. Functionality and opposite roles of two interleukin 4 haplotypes in immune cells

    Science.gov (United States)

    Anovazzi, G; Medeiros, M C; Pigossi, S C; Finoti, L S; Souza Moreira, T M; Mayer, M P A; Zanelli, C F; Valentini, S R; Rossa-Junior, C; Scarel-Caminaga, R M

    2017-01-01

    Cytokines expression can be influenced by polymorphisms in their respective coding genes. We associated the CTI/TTD haplotype (Hap-1) and TCI/CCI haplotype (Hap-2) in the IL4 gene formed by the −590, +33 and variable number of tandem repeat polymorphisms with the severity of chronic periodontitis in humans. The functionality of these IL4 haplotypes in the response of immune cells to phorbol 12-myristate 13-acetate (PMA) with Ionomycin and IL-1β (as inflammatory stimuli) was evaluated. Gene expression (quantitative real-time PCR), profile of secreted cytokines (multiplex) and phenotypic polarization of T cells (flow cytometry) were the outcomes assessed. Green fluorescent protein reporter plasmid constructs containing specific IL4 haplotype were transiently transfected into JM cells to assess the influence of the individual haplotypes on promoter activity. In response to inflammatory stimuli the immune cells from Hap-1 haplotype had increased expression of anti-inflammatory IL4; conversely, the Hap-2 haplotype showed higher levels of pro-inflammatory cytokines. The haplotype CTI proved to be the most important for the regulation of IL4 promoter, regardless of the nature of the inflammatory stimulation; whereas the polymorphism in the promoter region had the least functional effect. In conclusion, IL4 haplotypes studied are functional and trigger opposite immune responses: anti-inflammatory (Hap-1) and pro-inflammatory (Hap-2). In addition, we identified the CTI haplotype as the main responsible for the regulation of IL4 transcriptional activity. PMID:28053321

  20. Approximation properties of haplotype tagging

    Directory of Open Access Journals (Sweden)

    Dreiseitl Stephan

    2006-01-01

    Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs are locations at which the genomic sequences of population members differ. Since these differences are known to follow patterns, disease association studies are facilitated by identifying SNPs that allow the unique identification of such patterns. This process, known as haplotype tagging, is formulated as a combinatorial optimization problem and analyzed in terms of complexity and approximation properties. Results It is shown that the tagging problem is NP-hard but approximable within 1 + ln((n2 - n/2 for n haplotypes but not approximable within (1 - ε ln(n/2 for any ε > 0 unless NP ⊂ DTIME(nlog log n. A simple, very easily implementable algorithm that exhibits the above upper bound on solution quality is presented. This algorithm has running time O((2m - p + 1 ≤ O(m(n2 - n/2 where p ≤ min(n, m for n haplotypes of size m. As we show that the approximation bound is asymptotically tight, the algorithm presented is optimal with respect to this asymptotic bound. Conclusion The haplotype tagging problem is hard, but approachable with a fast, practical, and surprisingly simple algorithm that cannot be significantly improved upon on a single processor machine. Hence, significant improvement in computatational efforts expended can only be expected if the computational effort is distributed and done in parallel.

  1. Dengue fever virus and Japanese encephalitis virus synthetic peptides, with motifs to fit HLA class I haplotypes prevalent in human populations in endemic regions, can be used for application to skin Langerhans cells to prime antiviral CD8+ cytotoxic T cells (CTLs)--a novel approach to the protection of humans.

    Science.gov (United States)

    Becker, Y

    1994-09-01

    Flaviviruses were reported to induce CD8+ cytotoxic T cells in infected individuals, indicating that nonapeptides, proteolytic cleavage products of the viral precursor protein, enter the endoplasmic reticulum in infected cells and interact with HLA class I molecules. The assembled HLA class I molecules are transported to the plasma membrane and prime CD8+ T cells. Current knowledge of the interaction of viral peptides with HLA molecules is reviewed. Based on this review, an idea is presented to use synthetic flavivirus peptides with an amino acid motif to fit with the HLA class I peptide binding group of HLA haplotypes prevalent in a given population in an endemic area. These synthetic viral peptides may be introduced into the human skin using a lotion containing the peptides ("Peplotion") together with substances capable of enhancing the penetration of these peptides into the skin to reach Langerhans cells. The peptide-treated Langerhans cells, professional antigen-presenting cells, may bind the synthetic viral peptides by their HLA class I peptide-binding grooves. Antigens carrying Langerhans cells are able to migrate and induce the cellular immune response in the lymph nodes. This approach to the priming of antiviral CD8+ cytotoxic T cells may provide cellular immune protection from flavivirus infection without inducing the humoral immune response, which can lead to the shock syndrome in Dengue fever patients. To be able to develop anti-Dengue virus synthetic peptides for populations with different HLA class I haplotypes, it is necessary to develop computational studies to design HLA class I Dengue virus synthetic peptides with motifs to fit the HLA haplotypes of the population living in an endemic region for Dengue fever. Experiments to study Dengue virus and Japanese encephalitis peptides vaccines and their effectiveness in protection against Dengue fever and Japanese encephalitis are needed. The development of human antiviral vaccines for application of viral

  2. The Potential for Achieving Freeze/Thaw Protection in Concrete through the addition of Rubber Crumb

    OpenAIRE

    Richardson, Alan; Coventry, Kathryn; Pienaar, Jaques

    2011-01-01

    This paper evaluates the use of recycled rubber tyres in the form of rubber crumb as a freeze/thaw protection agent when used in concrete. Reusing scrap tyres in the form of rubber crumb, in concrete could benefi t the environment by reducing landfi ll and reducing the chemical usage of air entraining agents. The test procedure involved subjecting concrete to freeze/thaw cycles at 5 days of age. Thawing was conducted in water to ensure full saturation of pores and maximum stress on the concre...

  3. Association of polymorphisms and haplotypes in the cytochrome P450 1B1 gene with uterine leiomyoma: A case control study.

    Science.gov (United States)

    Salimi, Saeedeh; Khodamian, Maryam; Narooie-Nejad, Mehrnaz; Hajizadeh, Azam; Fazeli, Kimia; Namazi, Lida; Yaghmaei, Minoo

    2015-03-01

    Uterine leiomyoma (UL) is an estrogen-dependent neoplasm of the uterus and estrogen metabolizing enzymes affect its promotion and progression. The aim of the present study was to evaluate the association between four single-nucleotide polymorphisms (SNPs) of the cytochrome P450 1B1 (CYP1B1) gene and UL risk. Four SNPs of the CYP1B1 gene in 105 UL patients and 112 unrelated healthy controls were genotyped using a direct sequencing method. Haplotype analyses were performed with UNPHASED software and linkage disequilibrium (LD) was assessed by Haploview software. There were no associations between Leu432Val (rs1056836), Asp449Asp (rs1056837) and Asn453Ser (rs1800440) polymorphisms of the CYP1B1 gene and UL. Although the genotypic frequencies of the Arg368His (rs79204362) polymorphism did not differ between the two groups, the frequency of A (His) allele was significantly higher in UL females (P=0.02). In addition, the frequency of GTAA haplotype was significantly higher in the controls and played a protective role in UL susceptibility. A strong LD between the three common SNPs (rs1056836, rs1056837 and rs1800440) in the CYP1B1 gene was observed in the population. In conclusion, a higher frequency of the CYP1B1 368His (A) allele was observed in UL females. The frequency of the GTAA haplotype was significantly higher in healthy females and this haplotype played a protective role in UL susceptibility.

  4. Special report. Upgrading security: hospitals opt for new equipment; new approaches; heavy investments in additional patient, employee protection.

    Science.gov (United States)

    1994-07-01

    An increasing number of hospitals are taking steps to prevent the violence that plagues both urban and rural areas from spilling over into their emergency rooms and nursing units. Four facilities--Duke Medical University Center, Durham, NC; Children's Hospital, Columbus, OH; Ingalls Hospital, Harvey, IL; and University Medical Center, Las Vegas, NV--have recently installed new equipment or implemented innovative security procedures in an effort to better protect patients and employees. Although the price tag for additional protection is often high, officials at the hospitals agree that providing a safe environment is worth the investment.

  5. Detecting disease-predisposing variants: The haplotype method

    Energy Technology Data Exchange (ETDEWEB)

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

    1997-03-01

    For many HLA-associated diseases, multiple alleles - and, in some cases, multiple loci - have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some - compared with none - of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1 No. 52 (Arg predisposing) DQB1 No. 57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class H DRB1 data, the results were consistent with the shared-epitope hypothesis. 35 refs., 2 figs., 6 tabs.

  6. Kullback-Leibler divergence for detection of rare haplotype common disease association.

    Science.gov (United States)

    Lin, Shili

    2015-11-01

    Rare haplotypes may tag rare causal variants of common diseases; hence, detection of such rare haplotypes may also contribute to our understanding of complex disease etiology. Because rare haplotypes frequently result from common single-nucleotide polymorphisms (SNPs), focusing on rare haplotypes is much more economical compared with using rare single-nucleotide variants (SNVs) from sequencing, as SNPs are available and 'free' from already amassed genome-wide studies. Further, associated haplotypes may shed light on the underlying disease causal mechanism, a feat unmatched by SNV-based collapsing methods. In recent years, data mining approaches have been adapted to detect rare haplotype association. However, as they rely on an assumed underlying disease model and require the specification of a null haplotype, results can be erroneous if such assumptions are violated. In this paper, we present a haplotype association method based on Kullback-Leibler divergence (hapKL) for case-control samples. The idea is to compare haplotype frequencies for the cases versus the controls by computing symmetrical divergence measures. An important property of such measures is that both the frequencies and logarithms of the frequencies contribute in parallel, thus balancing the contributions from rare and common, and accommodating both deleterious and protective, haplotypes. A simulation study under various scenarios shows that hapKL has well-controlled type I error rates and good power compared with existing data mining methods. Application of hapKL to age-related macular degeneration (AMD) shows a strong association of the complement factor H (CFH) gene with AMD, identifying several individual rare haplotypes with strong signals.

  7. Haplotype-based association analysis of the MAPT locus in Late Onset Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morris John C

    2007-01-01

    Full Text Available Abstract Background Late onset Alzheimer's disease (LOAD is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a β-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c with AD. The current study is an attempt to replicate this association in an independently ascertained cohort. Results In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD. Conclusion In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD.

  8. Native and European haplotypes of Phragmites Australis (common reed) in the central Platte River, Nebraska

    Science.gov (United States)

    Larson, D.L.; Galatowitsch, S.M.; Larson, J.L.

    2011-01-01

    Phragmites australis (common reed) is known to have occurred along the Platte River historically, but recent rapid increases in both distribution and density have begun to impact habitat for migrating sandhill cranes and nesting piping plovers and least terns. Invasiveness in Phragmites has been associated with the incursion of a European genotype (haplotype M) in other areas; determining the genotype of Phragmites along the central Platte River has implications for proper management of the river system. In 2008 we sampled Phragmites patches along the central Platte River from Lexington to Chapman, NE, stratified by bridge segments, to determine the current distribution of haplotype E (native) and haplotype M genotypes. In addition, we did a retrospective analysis of historical Phragmites collections from the central Platte watershed (1902-2006) at the Bessey Herbarium. Fresh tissue from the 2008 survey and dried tissue from the herbarium specimens were classified as haplotype M or E using the restriction fragment length polymorphism procedure. The European haplotype was predominant in the 2008 samples: only 14 Phragmites shoots were identified as native haplotype E; 224 were non-native haplotype M. The retrospective analysis revealed primarily native haplotype individuals. Only collections made in Lancaster County, near Lincoln, NE, were haplotype M, and the earliest of these was collected in 1973. ?? 2011 Copyright by the Center for Great Plains Studies, University of Nebraska-Lincoln.

  9. Linear-XOR and Additive Checksums Don't Protect Damgard-Merkle Hashes

    DEFF Research Database (Denmark)

    Gauravaram, Praveen; Kelsey, John

    2008-01-01

    We consider the security of Damg\\aa{}rd-Merkle variants which compute linear-XOR or additive checksums over message blocks, intermediate hash values, or both, and process these checksums in computing the final hash value. We show that these Damg\\aa{}rd-Merkle variants gain almost no security agai...

  10. Quantitative trait loci and the relevance of phased haplotypes

    DEFF Research Database (Denmark)

    Gregersen, Vivi Raundahl

    underlying gentic control both as traditional linkage studies relying on genetic maps and as GWAS where an approach of phasing haplotypes within the QTL have been conducted to validate the regions. Overall, regions of interest have been identified for chronic pleuritis and osteochondrosis in addition to meat...

  11. Effect of the addition of 3-glycidoxypropyltrimethoxysilane to tetraethoxyorthosilicate-based stone protective coating using -octylamine as a catalyst

    Indian Academy of Sciences (India)

    Dan Li; Feigao Xu; Li Shao; Min Wang

    2015-02-01

    A tetraethoxyorthosilicate (TEOS)-based stone protective coating containing functional 3-glycidoxypropyltrimethoxysilane (GPTMS) has been prepared in order to reduce gel crack formation during the drying phase using -octylamine as a catalyst. The effect of gel time and viscosity on GPTMS concentration were studied.We have demonstrated that the addition of GPTMS accelerated the gel process and improve viscosity of sol. It was found that GPTMS was chemically incorporated into the gel matrix via Si–O bonds by Fourier transform infrared spectroscopy (FTIR) analysis. Nitrogen adsorption–desorption isotherms of xerogels were measured, they showed that the pore size of xerogels decreased with the addition of GPTMS. Atomic force microscopy (AFM) showed the surface roughness increased as content of GPTMS was higher. The Scotch Tape test and the hardness values showed improvement of cohesion and consolidation ability of hybrid sol. The protective performance evaluation of the treated stones with hybrid sol indicated its acid rain resistance.

  12. Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families.

    Science.gov (United States)

    Desjardins, Sylvie; Belleau, Pascal; Labrie, Yvan; Ouellette, Geneviève; Bessette, Paul; Chiquette, Jocelyne; Laframboise, Rachel; Lépine, Jean; Lespérance, Bernard; Pichette, Roxane; Plante, Marie; Durocher, Francine

    2008-01-01

    Our current understanding of breast cancer susceptibility involves mutations in the 2 major genes BRCA1 and BRCA2, found in about 25% of high-risk families, as well as few other low penetrance genes such as ATM and CHEK2. Approximately two-thirds of the multiple cases families remain to be explained by mutations in still unknown genes. In a candidate gene approach to identify new genes potentially involved in breast cancer susceptibility, we analyzed genomic variants in the ZBRK1 gene, a co-repressor implicated in BRCA1-mediated repression of GADD45. Direct sequencing of ZBRK1 entire coding region in affected breast cancer individuals from 97 high-risk French Canadian breast/ovarian cancer families and 94 healthy controls led to the identification of 18 genomic variants. Haplotype analyses, using PHASE, COCAPHASE and HaploStats programs, put in evidence 3 specific haplotypes which could potentially modulate breast cancer risk, and among which 2 that are associated with a potential protective effect (p = 0.01135 and p = 0.00268), while another haplotype is over-represented in the case group (p = 0.00143). Further analyses of these haplotypes indicated that a strong component of the observed difference between both groups emerge from the first 5 variants (out of 12 used for haplotype determination). The present study also permitted to determine a set of tagging SNPs that could be useful for subsequent analyses in large scale association studies. Additional studies in large cohorts and other populations will however be needed to further evaluate if common and/or rare ZBRK1 sequence variants and haplotypes could be associated with a modest/intermediate breast cancer risk.

  13. The effects of latex additions on centrifugally cast concrete for internal pipeline protection

    Energy Technology Data Exchange (ETDEWEB)

    Buchheit, R.G.; Hinkebein, T.E.; Hlava, P.F. [Sandia National Labs., Albuquerque, NM (United States); Melton, D.G. [LaQue Center for Corrosion Technology, Inc., Wrightsville Beach, NC (United States)

    1993-07-01

    Centrifugally-cast concrete liners applied to the interiors of plain steel pipe sections were tested for corrosion performance in brine solutions. An American Petroleum Institute (API) standard concrete, with and without additions of a styrene-butadiene copolymer latex, was subjected to simulated service and laboratory tests. Simulated service tests used a mechanically pumped test manifold containing sections of concrete-lined pipe. Linear polarization probes embedded at steel-concrete interfaces tracked corrosion rates of these samples as a function of exposure time. Laboratory tests used electrochemical impedance spectroscopy to study corrosion occurring at the steel-concrete interfaces. Electron probe microanalysis (EPMA) determined ingress and distribution of damaging species, such as Cl, in concrete liners periodically returned from the field. Observations of concrete-liner fabrication indicate that latex loading levels were difficult to control in the centrifugal-casting process. Overall, test results indicate that latex additions do not impart significant improvements to the performance of centrifugally cast liners and may even be detrimental. Corrosion at steel-concrete interfaces appears to be localized and the area fraction of corroding interfaces can be greater in latex-modified concretes than in API baseline material. EPMA shows higher interfacial Cl concentration in the latex-modified concretes than in the API standard due to rapid brine transport through cracks to the steel surface.

  14. HLA class II haplotypes distinctly associated with vaso-occlusion in children with sickle cell disease.

    Science.gov (United States)

    Mahdi, Najat; Al-Ola, Khadija; Al-Subaie, Abeer M; Ali, Muhallab E; Al-Irhayim, Zaid; Al-Irhayim, A Qader; Almawi, Wassim Y

    2008-04-01

    We investigated the association of HLA class II alleles and haplotypes with sickle cell anemia vaso-occlusive crisis (VOC). DRB1*100101 was positively associated, while DRB1*140101, DRB1*150101, and DQB1*060101 were negatively associated, with VOC. Both susceptible (DRB1*100101-DQB1*050101) and protective (DRB1*110101-DQB1*030101 and DRB1*150101-DQB1*060101) haplotypes were identified, indicating that HLA class II haplotypes influence VOC risk.

  15. Protective Effect of Two Yeast Based Feed Additives on Pigs Chronically Exposed to Deoxynivalenol and Zearalenone

    Science.gov (United States)

    Weaver, Alexandra C.; See, M. Todd; Kim, Sung Woo

    2014-01-01

    To evaluate the effects of the mycotoxins deoxynivalenol (DON) and zearalenone (ZEA) on pigs and the benefits of two mycotoxin mitigation strategies, gilts (n = 84, 9.1 ± 0.1 kg) were allotted to four treatments: CON (control); MT (4.8 mg/kg feed DON and 0.3 mg/kg feed ZEA); MT-YC (MT + 2 g/kg of yeast cell wall product); and MT-YF (MT + 2 g/kg of yeast fermentation product). After 42 days of feeding, pigs fed MT had reduced (p < 0.05) growth performance compared with pigs fed CON. Pigs fed MT-YF had greater (p < 0.05) average daily gain and tended to have greater (p = 0.080) average daily feed intake than MT, whereas pigs fed MT-YC did not differ from MT. Oxidative DNA damage increased (p < 0.05) in MT, whereas pigs fed MT-YF tended to have lower (p = 0.067) oxidative stress. Liver hydropic degeneration was increased (p < 0.05) in MT in contrast to CON and MT-YF, and tended to be greater (p = 0.079) than MT-YC. Collectively, feeding diets contaminated with mycotoxins significantly reduced growth performance and impacted pig health. The yeast additives had varied ability to reduce mycotoxin effects on pig growth and health, but may still play a beneficial role in reducing the overall impacts of a mycotoxin challenge on pigs. PMID:25533517

  16. Addition of ulinastatin to preservation solution promotes protection against ischemia-reperfusion injury in rabbit lung

    Institute of Scientific and Technical Information of China (English)

    XU Ming; WEN Xiao-hong; CHEN Shu-ping; AN Xiao-xia; XU He-yun

    2011-01-01

    Background The composition of the lung preservation solution used in lung graft procurement has been considered the key to minimize lung injury during the period of ischemia. Low-potassium dextran glucose (LPDG), an extracellular-type solution, has been adopted by most lung transplantation centers, due to the experimental and clinical evidences that LPDG is superior to intracellular-type solutions. Ulinastatin has been shown to attenuate ischemia-reperfusion (I/R) injury in various organs in animals. We supposed that the addition of ulinastatin to LPDG as a flushing solution, would further ameliorate I/R lung injury than LPDG solution alone.Methods Twelve male New Zealand white rabbits were randomly divided into 2 groups. Using an alternative in situ lung I/R model, the left lung in the control group was supplied and preserved with LPDG solution for 120 minutes. In the study group 50 000 U/kg of ulinastatin was added to the LPDG solution for lung preservation. Then re-ventilation and reperfusion of the left lung were performed for 90 minutes. Blood gas analysis (PaO2, PaCO2), mean pulmonary artery pressure (MPAP) and serum TNF-α level were measured intermittently. The pulmonary water index (D/W), tissue myeloperoxidase (MPO) activity, tissue malondialdehyde (MDA) content and morphologic changes were analyzed.Results The study group showed significantly higher PaO2 and lower MPAP at the end of reperfusion. Serum TNF-α level, left lung tissue MPO and MDA in the study group were significantly lower than those in the control group. D/W and pathologic evaluation were also remarkably different between the two groups.Conclusions This study indicated that better lung preservation could be achieved with the use of an ulinastatin modified LPDG solution. Ulinastatin further attenuated lung I/R injury, at least partly by reducing oxidative reactions,inhibiting the release of inflammatory factors and neutrophils immigration.

  17. Haplotype block structure is conserved across mammals

    NARCIS (Netherlands)

    Guryev, Victor; Smits, Bart M G; van de Belt, Jose; Verheul, Mark; Hubner, Norbert; Cuppen, Edwin

    2006-01-01

    Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium i

  18. Estimating haplotype effects for survival data

    DEFF Research Database (Denmark)

    Scheike, Thomas; Martinussen, Torben; Silver, J

    2010-01-01

    Genetic association studies often investigate the effect of haplotypes on an outcome of interest. Haplotypes are not observed directly, and this complicates the inclusion of such effects in survival models. We describe a new estimating equations approach for Cox's regression model to assess haplo...

  19. Most parsimonious haplotype allele sharing determination

    Directory of Open Access Journals (Sweden)

    Xu Jiaofen

    2009-04-01

    Full Text Available Abstract Background The "common disease – common variant" hypothesis and genome-wide association studies have achieved numerous successes in the last three years, particularly in genetic mapping in human diseases. Nevertheless, the power of the association study methods are still low, in particular on quantitative traits, and the description of the full allelic spectrum is deemed still far from reach. Given increasing density of single nucleotide polymorphisms available and suggested by the block-like structure of the human genome, a popular and prosperous strategy is to use haplotypes to try to capture the correlation structure of SNPs in regions of little recombination. The key to the success of this strategy is thus the ability to unambiguously determine the haplotype allele sharing status among the members. The association studies based on haplotype sharing status would have significantly reduced degrees of freedom and be able to capture the combined effects of tightly linked causal variants. Results For pedigree genotype datasets of medium density of SNPs, we present two methods for haplotype allele sharing status determination among the pedigree members. Extensive simulation study showed that both methods performed nearly perfectly on breakpoint discovery, mutation haplotype allele discovery, and shared chromosomal region discovery. Conclusion For pedigree genotype datasets, the haplotype allele sharing status among the members can be deterministically, efficiently, and accurately determined, even for very small pedigrees. Given their excellent performance, the presented haplotype allele sharing status determination programs can be useful in many downstream applications including haplotype based association studies.

  20. The frequency of an IL-18-associated haplotype in Africans.

    Science.gov (United States)

    Thompson, Simon R; Humphries, Steve E; Thomas, Mark G; Ekong, Rosemary; Tarekegn, Ayele; Bekele, Endeshaw; Creemer, Olivia; Bradman, Neil; Veeramah, Krishna R

    2013-04-01

    Variation within the gene for the proinflammatory cytokine interleukin (IL)-18 has been associated with inter-individual differences in levels of free protein and disease risk. We investigated the frequency of function-associated IL18 gene haplotypes in an extensive sample (n=2357) of African populations from across the continent. A previously identified five tagging SNP (single-nucleotide polymorphism) haplotype (here designated hGTATA), known to be associated with lower levels of IL-18, was observed at a frequency of 27% in a British population of recent European ancestry, but was found at low frequency (African populations. Potentially protective variants may, as a consequence, be found at low frequency in African individuals and may confer a difference in disease risk.

  1. Evidence for the molecular heterogeneity of sickle cell anemia chromosomes bearing the betaS/Benin haplotype.

    Science.gov (United States)

    Patrinos, George P; Samperi, Piera; Lo Nigro, Luca; Kollia, Panagoula; Schiliro, Gino; Papadakis, Manoussos N

    2005-09-01

    There are at least four distinct African and one Asian chromosomal backgrounds (haplotypes) on which the sickle cell mutation has arisen. Additionally, previous data suggest that the beta(S)/Bantu haplotype is heterogeneous at the molecular level. Here, we report the presence of the (A)gamma -499 T-->A variation in sickle cell anemia chromosomes of Sicilian and North African origin bearing the beta(S)/Benin haplotype. Being absent from North American beta(S)/Benin chromosomes, which were studied previously, this variation is indicative for the molecular heterogeneity of the beta(S)/Benin haplotype.

  2. Haplotype block structure is conserved across mammals.

    Directory of Open Access Journals (Sweden)

    Victor Guryev

    2006-07-01

    Full Text Available Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium in populations and have important applications in the design and interpretation of genetic experiments. Although evolutionary processes are known to drive the selection of individual polymorphisms, their effect on haplotype block structure dynamics has not been shown. Here, we present a high-resolution haplotype map for a 5-megabase genomic region in the rat and compare it with the orthologous human and mouse segments. Although the size and fine structure of haplotype blocks are species dependent, there is a significant interspecies overlap in structure and a tendency for blocks to encompass complete genes. Extending these findings to the complete human genome using haplotype map phase I data reveals that linkage disequilibrium values are significantly higher for equally spaced positions in genic regions, including promoters, as compared to intergenic regions, indicating that a selective mechanism exists to maintain combinations of alleles within potentially interacting coding and regulatory regions. Although this characteristic may complicate the identification of causal polymorphisms underlying phenotypic traits, conservation of haplotype structure may be employed for the identification and characterization of functionally important genomic regions.

  3. Analysis of Swine Leukocyte Antigen Haplotypes in Yucatan Miniature Pigs Used as Biomedical Model Animal.

    Science.gov (United States)

    Choi, Nu-Ri; Seo, Dong-Won; Choi, Ki-Myung; Ko, Na-Young; Kim, Ji-Ho; Kim, Hyun-Il; Jung, Woo-Young; Lee, Jun-Heon

    2016-03-01

    The porcine major histocompatibility complex (MHC) is called swine leukocyte antigen (SLA), which controls immune responses and transplantation reactions. The SLA is mapped on pig chromosome 7 (SSC7) near the centromere. In this study, 3 class I (SLA-1, SLA-3, and SLA-2) and 3 class II (DRB1, DQB1, and DQA) genes were used for investigation of SLA haplotypes in Yucatan miniature pigs in Korea. This pig breed is a well-known model organism for biomedical research worldwide. The current study indicated that Korean Yucatan pig population had 3 Class I haplotypes (Lr-4.0, Lr-6.0, and Lr-25.0) and 3 class II haplotypes (Lr-0.5, Lr-0.7, and Lr-0.25). The combinations of SLA class I and II haplotype together, 2 homozygous (Lr-4.5/4.5 and Lr-6.7/6.7) and 3 heterozygous (Lr-4.5/6.7, Lr-4.5/25.25, and Lr-6.7/25.25) haplotypes were identified, including previously unidentified new heterozygous haplotypes (Lr-4.5/4.7). In addition, a new SLA allele typing method using Agilent 2100 bioanalyzer was developed that permitted more rapid identification of SLA haplotypes. These results will facilitate the breeding of SLA homozygous Yucatan pigs and will expedite the possible use of these pigs for the biomedical research, especially xenotransplantation research.

  4. An Efficient Trio-Based Mini-Haplotyping Method for Genetic Diagnosis of Phenylketonuria

    OpenAIRE

    Saeed Talebi; Mona Entezam; Neda Mohajer; Golnaz-Ensieh Kazemi-sefat; Masoumeh Razipour; Somayeh Ahmadloo; Aria Setoodeh; Mohammad Keramatipour

    2016-01-01

    Objective The phenylalanine hydroxylase (PAH) locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficient method for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explain how to resolve the dye shift challenge in multiplex short tandem repeat (STR) genotyping. Materials and Methods One...

  5. Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.

    Directory of Open Access Journals (Sweden)

    Andrea G Nackley

    Full Text Available Catechol-O-methyltransferase (COMT is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158met position, designated as low (LPS, average (APS, and high pain sensitive (HPS, are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs, accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224 is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488 are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.

  6. Correlation between haplotype of apolipoprotein B gene and natural longevity persons in Uygur Nationality

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    This paper investigated the correlation between polymorphisms and haplotypes in the apolipoprotein B (apoB) gene (SP-I/D, XbaI-RFLP, VNTR) and natural longevity persons among the Uygur people in Xin-jiang. For this purpose, 191 healthy Uygur individuals aged above 90 from Hetian area of Xinjiang were recruited, and another 53 persons aged 65—70 from the same nationality, the same region and with the same gender ratio, served as the control group. Genotyping was performed by PCR-SSP, PCR-RFLP and PCR-sequencing methods. Logistic regression analyses revealed that the frequencies of X+X+ genotype, M and L alleles and the genetypes composed of M and L were significantly higher in the longevity group than in the control group. In haplotype analyses, we found that, in the long-lived people, the frequency of haplotypes composed of the X+ and M alleles was significantly higher whereas the frequency of haplotypes composed of the X- and S alleles was significantly lower (both P<0.05) I than those of their controls. These results indicated that the S allele, SS genotype and X+-S, D-S, D-X+-S haplotypes were the possible adverse factors, whereas the M, L alleles, X+X+, MM, ML, LL genotypes and I-X+-M, X+-M haplotypes were the possibe protective factors for the naturally long-lived Uygur people in China.

  7. Correlation between haplotype of apolipoprotein B gene and natural longevity persons in Uygur Nationality

    Institute of Scientific and Technical Information of China (English)

    JIANG WenXi; QIU ChangChun; CHENG ZuHeng; ZHOU WenYu; GU MingLiang; XU Qun; FANG MingWu; NIU WenQuan

    2007-01-01

    This paper investigated the correlation between polymorphisms and haplotypes in the apolipoprotein B (apoB) gene (SP-I/D, XbaI-RFLP, VNTR) and natural longevity persons among the Uygur people in Xinjiang. For this purpose, 191 healthy Uygur individuals aged above 90 from Hetian area of Xinjiang were recruited, and another 53 persons aged 65-70 from the same nationality, the same region and with the same gender ratio, served as the control group. Genotyping was performed by PCR-SSP, PCR-RFLP and PCR-sequencing methods. Logistic regression analyses revealed that the frequencies of X+X+ genotype, M and L alleles and the genetypes composed of M and L were significantly higher in the longevity group than in the control group. In haplotype analyses, we found that, in the long-lived people, the frequency of haplotypes composed of the X+ and M alleles was significantly higher whereas the frequency of haplotypes composed of the X- and S alleles was significantly lower (both P<0.05) I than those of their controls. These results indicated that the S allele, SS genotype and X+-S, D-S, D-X+-S haplotypes were the possible adverse factors, whereas the M, L alleles, X+X+, MM, ML, LL genotypes and I-X+-M, X+-M haplotypes were the possibe protective factors for the naturally long-lived Uygur people in China.

  8. Complementarity of Binding Motifs is a General Property of HLA-A and HLA-B Molecules and Does Not Seem to Effect HLA Haplotype Composition.

    Science.gov (United States)

    Rao, Xiangyu; De Boer, Rob J; van Baarle, Debbie; Maiers, Martin; Kesmir, Can

    2013-01-01

    Different human leukocyte antigen (HLA) haplotypes (i.e., the specific combinations of HLA-A, -B, -DR alleles inherited together from one parent) are observed in different frequencies in human populations. Some haplotypes, like HLA-A1-B8, are very frequent, reaching up to 10% in the Caucasian population, while others are very rare. Numerous studies have identified associations between HLA haplotypes and diseases, and differences in haplotype frequencies can in part be explained by these associations: the stronger the association with a severe (autoimmune) disease, the lower the expected HLA haplotype frequency. The peptide repertoires of the HLA molecules composing a haplotype can also influence the frequency of a haplotype. For example, it would seem advantageous to have HLA molecules with non-overlapping binding specificities within a haplotype, as individuals expressing such an haplotype would present a diverse set of peptides from viruses and pathogenic bacteria on the cell surface. To test this hypothesis, we collect the proteome data from a set of common viruses, and estimate the total ligand repertoire of HLA class I haplotypes (HLA-A-B) using in silico predictions. We compare the size of these repertoires to the HLA haplotype frequencies reported in the National Marrow Donor Program (NMDP). We find that in most HLA-A and HLA-B pairs have fairly distinct binding motifs, and that the observed haplotypes do not contain HLA-A and -B molecules with more distinct binding motifs than random HLA-A and HLA-B pairs. In addition, the population frequency of a haplotype is not correlated to the distinctness of its HLA-A and HLA-B peptide binding motifs. These results suggest that there is a not a strong selection pressure on the haplotype level favoring haplotypes having HLA molecules with distinct binding motifs, which would result the largest possible presented peptide repertoires in the context of infectious diseases.

  9. Complementarity of binding motifs is a general property of HLA-A and HLA-B molecules and does not seem to effect HLA haplotype composition

    Directory of Open Access Journals (Sweden)

    Xiangyu eRao

    2013-11-01

    Full Text Available Different HLA haplotypes (i.e., the specific combinations of HLA-A, -B, -DR alleles inherited together from one parent are observed in different frequencies in human populations. Some haplotypes, like HLA-A1-B8, are very frequent, reaching up to 10% in the Caucasian population, while others are very rare. Numerous studies have identified associations between HLA haplotypes and diseases, and differences in haplotype frequencies can in part be explained by these associations: the stronger the association with a severe (autoimmune disease, the lower the expected HLA haplotype frequency. The peptide repertoires of the HLA molecules composing a haplotype can also influence the frequency of a haplotype. For example, it would seem advantageous to have HLA molecules with non-overlapping binding specificities within a haplotype, as individuals expressing such an haplotype would present a diverse set of peptides from viruses and pathogenic bacteria on the cell surface. To test this hypothesis, we collect the proteome data from a set of common viruses, and estimate the total ligand repertoire of HLA class I haplotypes (HLA-A-B using in silico predictions. We compare the size of these repertoires to the HLA haplotype frequencies reported in the National Marrow Donor Program (NMDP. We find that in most HLA-A and HLA-B pairs have fairly distinct binding motifs, and that the observed haplotypes do not contain HLA-A and –B molecules with more distinct binding motifs than random HLA-A and HLA-B pairs. In addition, the population frequency of a haplotype is not correlated to the distinctness of its HLA-A and HLA-B peptide binding motifs. These results suggest that there is a not a strong selection pressure on the haplotype level favouring haplotypes having HLA molecules with distinct binding motifs, which would result the largest possible presented peptide repertoires in the context of infectious diseases.

  10. HEMO2life as a protective additive to Celsior solution for static storage of donor hearts prior to transplantation.

    Science.gov (United States)

    Teh, Elaine S; Zal, Franck; Polard, Valérie; Menasché, Philippe; Chambers, David J

    2017-06-01

    Prior to heart transplantation, static storage of donor hearts is currently limited to 4-5 h, despite profound hypothermia (4-8 °C). Because heart transplantation is an emergency procedure, improved protection to extend safe storage duration would be advantageous. We investigated whether the naturally respiratory pigment HEMO2life(®), which is effective at hypothermia for the passive release of oxygen via oxygen gradient, could improve long-term preservation. Isolated Langendorff-perfused rat hearts (n = 12/group) were equilibrated (20 min) and function (left ventricular developed pressure: LVDP) measured by intraventricular balloon before arrest with cold (7.5 °C) Celsior(®) solution, either alone (control) or with the addition of HEMO2life(®) (Hemarina SA, Morlaix, France) at 1 g/L. Cold storage lasted 8 h prior to reperfusion (60 min) and recovery (as % of pre-ischemic function) was assessed. Hearts (minced and homogenized) were also assessed by TTC staining as a measure of viability and two hearts from each group were sliced and assessed by TTC staining for infarct size. Values are expressed as mean ± standard error of mean and analyzed by Student's t-test. Hearts recovered rapidly in both groups to a plateau by 20 min of reperfusion; control and HEMO2life(®) final recovery (60 min) was 45 ± 2% and 57 ± 1% (P natural oxygen releasing pigment HEMO2life(®) to Celsior(®) preservation solution significantly improved post-ischemic recovery of heart function. This additive may have major therapeutic potential for clinical heart transplantation.

  11. The Chemical Basis of Thiol Addition to Nitro-conjugated Linoleic Acid, a Protective Cell-signaling Lipid*♦

    Science.gov (United States)

    Turell, Lucía; Vitturi, Darío A.; Coitiño, E. Laura; Lebrato, Lourdes; Möller, Matías N.; Sagasti, Camila; Salvatore, Sonia R.; Woodcock, Steven R.; Alvarez, Beatriz; Schopfer, Francisco J.

    2017-01-01

    Nitroalkene fatty acids are formed in vivo and exert protective and anti-inflammatory effects via reversible Michael addition to thiol-containing proteins in key signaling pathways. Nitro-conjugated linoleic acid (NO2-CLA) is preferentially formed, constitutes the most abundant nitrated fatty acid in humans, and contains two carbons that could potentially react with thiols, modulating signaling actions and levels. In this work, we examined the reactions of NO2-CLA with low molecular weight thiols (glutathione, cysteine, homocysteine, cysteinylglycine, and β-mercaptoethanol) and human serum albumin. Reactions followed reversible biphasic kinetics, consistent with the presence of two electrophilic centers in NO2-CLA located on the β- and δ-carbons with respect to the nitro group. The differential reactivity was confirmed by computational modeling of the electronic structure. The rates (kon and koff) and equilibrium constants for both reactions were determined for different thiols. LC-UV-Visible and LC-MS analyses showed that the fast reaction corresponds to β-adduct formation (the kinetic product), while the slow reaction corresponds to the formation of the δ-adduct (the thermodynamic product). The pH dependence of the rate constants, the correlation between intrinsic reactivity and thiol pKa, and the absence of deuterium solvent kinetic isotope effects suggested stepwise mechanisms with thiolate attack on NO2-CLA as rate-controlling step. Computational modeling supported the mechanism and revealed additional features of the transition states, anionic intermediates, and final neutral products. Importantly, the detection of cysteine-δ-adducts in human urine provided evidence for the biological relevance of this reaction. Finally, human serum albumin was found to bind NO2-CLA both non-covalently and to form covalent adducts at Cys-34, suggesting potential modes for systemic distribution. These results provide new insights into the chemical basis of NO2-CLA

  12. How well do HapMap haplotypes identify common haplotypes of genes? A comparison with haplotypes of 334 genes resequenced in the environmental genome project.

    Science.gov (United States)

    Taylor, Jack A; Xu, Zong-Li; Kaplan, Norman L; Morris, Richard W

    2006-01-01

    One of the goals of the International HapMap Project is the identification of common haplotypes in genes. However, HapMap uses an incomplete catalogue of single nucleotide polymorphisms (SNPs) and might miss some common haplotypes. We examined this issue using data from the Environmental Genome Project (EGP) which resequenced 335 genes in 90 people, and thus, has a nearly complete catalogue of gene SNPs. The EGP identified a total of 45,243 SNPs, of which 10,780 were common SNPs (minor allele frequency >or=0.1). Using EGP common SNP genotype data, we identified 1,459 haplotypes with frequency >or=0.05 and we use these as "benchmark" haplotypes. HapMap release 16 had genotype information for 1,573 of 10,780 (15%) EGP common SNPs. Using these SNPs, we identified common HapMap haplotypes (frequency >or=0.05) in each of the four HapMap ethnic groups. To compare common HapMap haplotypes to EGP benchmark haplotypes, we collapsed benchmark haplotypes to the set of 1,573 SNPs. Ninety-eight percent of the collapsed benchmark haplotypes could be found as common HapMap haplotypes in one or more of the four HapMap ethnic groups. However, collapsing benchmark haplotypes to the set of SNPs available in HapMap resulted in a loss of haplotype information: 545 of 1,459 (37%) benchmark haplotypes were uniquely identified, and only 25% of genes had all their benchmark haplotypes uniquely identified. We resampled the EGP data to examine the effect of increasing the number of HapMap SNPs to 5 million, and estimate that approximately 40% of common SNPs in genes will be sampled and that half of the genes will have sufficient SNPs to identify all common haplotypes. This inability to distinguish common haplotypes of genes may result in loss of power when examining haplotype-disease association.

  13. IL7Rα expression and upregulation by IFNβ in dendritic cell subsets is haplotype-dependent.

    Directory of Open Access Journals (Sweden)

    Fiona C McKay

    Full Text Available The IL7Rα gene is unequivocally associated with susceptibility to multiple sclerosis (MS. Haplotype 2 (Hap 2 confers protection from MS, and T cells and dendritic cells (DCs of Hap 2 exhibit reduced splicing of exon 6, resulting in production of relatively less soluble receptor, and potentially more response to ligand. We have previously shown in CD4 T cells that IL7Rα haplotypes 1 and 2, but not 4, respond to interferon beta (IFNβ, the most commonly used immunomodulatory drug in MS, and that haplotype 4 (Hap 4 homozygotes have the highest risk of developing MS. We now show that IL7R expression increases in myeloid cells in response to IFNβ, but that the response is haplotype-dependent, with cells from homozygotes for Hap 4 again showing no response. This was shown using freshly derived monocytes, in vitro cultured immature and mature monocyte-derived dendritic cells, and by comparing homozygotes for the common haplotypes, and relative expression of alleles in heterozygotes (Hap 4 vs not Hap 4. As for T cells, in all myeloid cell subsets examined, Hap 2 homozygotes showed a trend for reduced splicing of exon 6 compared to the other haplotypes, significantly so in most conditions. These data are consistent with increased signaling being protective from MS, constitutively and in response to IFNβ. We also demonstrate significant regulation of immune response, chemokine activity and cytokine biosynthesis pathways by IL7Rα signaling in IFNβ -treated myeloid subsets. IFNβ-responsive genes are over-represented amongst genes associated with MS susceptibility. IL7Rα haplotype may contribute to MS susceptibility through reduced capacity for IL7Rα signalling in myeloid cells, especially in the presence of IFNβ, and is currently under investigation as a predictor of therapeutic response.

  14. Haplotype-phenotype relationships of paraoxonase-1.

    Science.gov (United States)

    Chen, Jia; Chan, Wendy; Wallenstein, Sylvan; Berkowitz, Gertrud; Wetmur, James G

    2005-03-01

    Paraoxonase 1 (PON1) is an enzyme with multiple activities, including detoxification of organophosphates. It is believed to be important in preventing neurotoxic damage and has also been implicated in atherosclerosis. The PON1 gene contains five common polymorphisms, three in the promoter (-909G > C, -162A > G, -108C > T) and two in the coding region (M55L, Q192R) with varying but incomplete linkage disequilibrium. Our previous study showed that functional polymorphisms in PON1 were strongly associated with enzymatic activity in both pregnant women [26-30 weeks of gestation] and neonates. However, there was substantial overlapping of enzyme activities between genotypes. In this study, we investigated whether haplotype (genotype + phase) information would strengthen the genotype-phenotype relationship for PON1. The study consisted of a multiethnic population of 402 mothers and 229 neonates. Haplotypes were imputed by two widely used programs, PHASE and tagSNPs, which yielded very similar results. There were seven haplotypes with a frequency of 5% or higher in at least one ethnic group of the study population. Haplotype composition varied substantially with respect to ethnicity. Haplotypes in Caucasians and African-Americans showed the largest difference, and Caribbean Hispanics seemed to be a mixture of Caucasian and African ancestry. Collectively, the genetic (genotype or haplotype) contribution to PON1 enzymatic activity (measured as phenylacetate hydrolysis) was greater in neonates compared with mothers. Specifically, 16.6% of PON1 variability was explained by genotypes in mothers compared with 30.9% in neonates. Haplotype information offered a slightly increased power in predicting PON1 activity; they explained 35.5% and 19.3% of PON1 variability in neonates and mothers, respectively.

  15. Evaluation of the efficacy of additional measures introduced for the protection of healthcare personnel handling antineoplastic drugs.

    Science.gov (United States)

    Odraska, Pavel; Dolezalova, Lenka; Kuta, Jan; Oravec, Michal; Piler, Pavel; Blaha, Ludek

    2013-03-01

    Due to their adverse effects, antineoplastic drugs are considered as a potential health risk to healthcare personnel. The objective of the study was to compare the surface contamination level of the conventional preparation room and outpatient clinic before and after the implementation of a set of additional protective measures. The measures were targeted at eliminating potential sources of environmental contamination, and modification of the cleaning procedure. The measures introduced into the preparation room consisted of (i) the introduction of manual cleaning of drug vials before they enter the preparation room, (ii) the modification of the routine cleaning procedure performed at the end of each working day (i.e. shifting the cleaning of the isolators as the most contaminated objects from the beginning of the cleaning process to the end), and (iii) the introduction of regular cleaning of the work table every 2 h. The measures introduced into the outpatient clinic consisted of (i) replacement of the standard infusion sets with multichannel sets for safe drug administration, (ii) the introduction of self-cleaning seats to the patient lavatories supporting hygienic and contamination-free seated urination, and (iii) replacement of standard infusion stands with wall-mounted stands, supporting the regular and proper cleaning of the floor beneath. To determine the surface contamination level with antineoplastic drugs, cyclophosphamide and platinum were determined in wipe samples with high performance liquid chromatography with tandem mass spectrometry and inductively coupled plasma mass spectrometry. In the preparation room, depending on the sampling spot and analyte, median concentrations ranged from 5 to 267 pg cm(-2) and from 2 to 368 pg cm(-2) before and after implementation of the measures, respectively. In the outpatient clinic, median concentrations ranged from 5 to 5310 pg cm(-2) and from antineoplastic drugs are administered. In contrast, measures implemented

  16. Investigation of extended Y chromosome STR haplotypes in Sardinia.

    Science.gov (United States)

    Lacerenza, D; Aneli, S; Di Gaetano, C; Critelli, R; Piazza, A; Matullo, G; Culigioni, C; Robledo, R; Robino, C; Calò, C

    2017-03-01

    Y-chromosomal variation of selected single nucleotide polymorphisms (SNPs) and 32 short tandem repeat (STR) loci was evaluated in Sardinia in three open population groups (Northern Sardinia, n=40; Central Sardinia, n=56; Southern Sardinia, n=91) and three isolates (Desulo, n=34; Benetutti, n=45, Carloforte, n=42). The tested Y-STRs consisted of Yfiler(®) Plus markers and the seven rapidly mutating (RM) loci not included in the YFiler(®) Plus kit (DYF399S1, DYF403S1ab, DYF404S1, DYS526ab, DYS547, DYS612, and DYS626). As expected, inclusion of additional Y-STR loci increased haplotype diversity (h), though complete differentiation of male lineages was impossible even by means of RM Y-STRs (h=0.99997). Analysis of molecular variance indicated that the three open populations were fairly homogeneous, whereas signs of genetic heterogeneity could be detected when the three isolates were also included in the analysis. Multidimensional scaling analysis showed that, even for extended haplotypes including RM Y-STR markers, Sardinians were clearly differentiated from populations of the Italian peninsula and Sicily. The only exception was represented by the Carloforte sample that, in accordance with its peculiar population history, clustered with Northern/Central Italian populations. The introduction of extended forensic Y-STR panels, including highly variable RM Y-STR markers, is expected to reduce the impact of population structure on haplotype frequency estimations. However, our results show that the availability of geographically detailed reference databases is still important for the assessment of the evidential value of a Y-haplotype match.

  17. A candidate transacting modulator of fetal hemoglobin gene expression in the Arab-Indian haplotype of sickle cell anemia.

    Science.gov (United States)

    Vathipadiekal, Vinod; Farrell, John J; Wang, Shuai; Edward, Heather L; Shappell, Heather; Al-Rubaish, A M; Al-Muhanna, Fahad; Naserullah, Z; Alsuliman, A; Qutub, Hatem Othman; Simkin, Irene; Farrer, Lindsay A; Jiang, Zhihua; Luo, Hong-Yuan; Huang, Shengwen; Mostoslavsky, Gustavo; Murphy, George J; Patra, Pradeep K; Chui, David H K; Alsultan, Abdulrahman; Al-Ali, Amein K; Sebastiani, Paola; Steinberg, Martin H

    2016-11-01

    Fetal hemoglobin (HbF) levels are higher in the Arab-Indian (AI) β-globin gene haplotype of sickle cell anemia compared with African-origin haplotypes. To study genetic elements that effect HbF expression in the AI haplotype we completed whole genome sequencing in 14 Saudi AI haplotype sickle hemoglobin homozygotes-seven selected for low HbF (8.2% ± 1.3%) and seven selected for high HbF (23.5% ± 2.6%). An intronic single nucleotide polymorphism (SNP) in ANTXR1, an anthrax toxin receptor (chromosome 2p13), was associated with HbF. These results were replicated in two independent Saudi AI haplotype cohorts of 120 and 139 patients, but not in 76 Saudi Benin haplotype, 894 African origin haplotype and 44 AI haplotype patients of Indian origin, suggesting that this association is effective only in the Saudi AI haplotype background. ANTXR1 variants explained 10% of the HbF variability compared with 8% for BCL11A. These two genes had independent, additive effects on HbF and together explained about 15% of HbF variability in Saudi AI sickle cell anemia patients. ANTXR1 was expressed at mRNA and protein levels in erythroid progenitors derived from induced pluripotent stem cells (iPSCs) and CD34(+) cells. As CD34(+) cells matured and their HbF decreased ANTXR1 expression increased; as iPSCs differentiated and their HbF increased, ANTXR1 expression decreased. Along with elements in cis to the HbF genes, ANTXR1 contributes to the variation in HbF in Saudi AI haplotype sickle cell anemia and is the first gene in trans to HBB that is associated with HbF only in carriers of the Saudi AI haplotype. Am. J. Hematol. 91:1118-1122, 2016. © 2016 Wiley Periodicals, Inc.

  18. Quantitated transcript haplotypes (QTH) of AGTR1, reduced abundance of mRNA haplotypes containing 1166C (rs5186:A>C), and relevance to metabolic syndrome traits.

    Science.gov (United States)

    Abdollahi, Mohammad R; Lewis, Rohan M; Gaunt, Tom R; Cumming, Debbie V E; Rodriguez, Santiago; Rose-Zerilli, Matthew; Collins, Andrew R; Syddall, Holly E; Howell, William M; Cooper, Cyrus; Godfrey, Keith M; Cameron, Iain T; Day, Ian N M

    2007-04-01

    The angiotensin II type 1 receptor (AGTR1) is the main target through which angiotensin II influences cardiovascular tone, cell growth, and fluid and electrolyte balance. AGTR1 polymorphism has been reported to associate with hypertension, myocardial infarction (MI), and metabolic traits. Here we describe a novel approach to quantitation of transcript haplotypes (QTH) of AGTR1. To determine relative allelic expression from haplotypes, within-individual-between-allele ratiometric analyses in placental cDNA were developed for the transcribed SNPs rs5182:C>T (encoding p.L191) and rs5186:A>C (3'-noncoding "A1166C"). Additionally, between-individual comparisons were made using TaqMan assays applied to both homozygous and heterozygous genotypes and haplotypes. In conjunction, linkage disequilibrium (LD) and genomic haplotype associations with metabolic syndrome were examined. There was no significant difference of mRNA level for alleles of rs5182:C>T, but allele and mRNA haplotypes carrying 1166C exhibited reduced abundance. The effect was much greater in CC homozygotes than in heterozygotes. The promoter region was confirmed to be in a separate haplotype block from the AGTR1 3' region containing rs5182:C>T and rs5186:A>C. Metabolic syndrome trait associations were strongest for the 3' block generally and for the C allele of rs5186:A>C specifically. All effects were much more prominent in homozygotes, possibly reflecting interallelic interaction through feedback loops of mRNA regulation. Differential abundance of AGTR1 mRNA haplotypes may mediate clinical phenotypic observations of the AGTR1 genotype. Copyright 2007 Wiley-Liss, Inc.

  19. Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

    Science.gov (United States)

    Vacic, Vladimir; Ozelius, Laurie J; Clark, Lorraine N; Bar-Shira, Anat; Gana-Weisz, Mali; Gurevich, Tanya; Gusev, Alexander; Kedmi, Merav; Kenny, Eimear E; Liu, Xinmin; Mejia-Santana, Helen; Mirelman, Anat; Raymond, Deborah; Saunders-Pullman, Rachel; Desnick, Robert J; Atzmon, Gil; Burns, Edward R; Ostrer, Harry; Hakonarson, Hakon; Bergman, Aviv; Barzilai, Nir; Darvasi, Ariel; Peter, Inga; Guha, Saurav; Lencz, Todd; Giladi, Nir; Marder, Karen; Pe'er, Itsik; Bressman, Susan B; Orr-Urtreger, Avi

    2014-09-01

    The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.

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

    Science.gov (United States)

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

    2011-01-01

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

  1. Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction.

    Science.gov (United States)

    Mannila, Maria Nastase; Eriksson, Per; Lundman, Pia; Samnegård, Ann; Boquist, Susanna; Ericsson, Carl-Göran; Tornvall, Per; Hamsten, Anders; Silveira, Angela

    2005-03-01

    Fibrinogen has consistently been recognized as an independent predictor of myocardial infarction (MI). Multiple mechanisms link fibrinogen to MI; therefore disentangling the factors underlying variation in plasma fibrinogen concentration is essential. Candidate regions in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes were screened for single nucleotide polymorphisms (SNPs). Several novel SNPs were detected in the FGG and FGA genes in addition to the previously known SNPs in the fibrinogen genes. Tight linkage disequilibrium extending over various physical distances was observed between most SNPs. Consequently, eight SNPs were chosen and determined in 377 postinfarction patients and 387 healthy individuals. None of the SNPs were associated with plasma fibrinogen concentration or MI. Haplotype analyses revealed a consistent pattern of haplotypes associated with variation in risk of MI. Of the four haplotypes inferred using the FGA -58G>A and FGG 1299 +79T>C SNPs, the most frequent haplotype, FGG-FGA*1 (prevalence 46.6%), was associated with increased risk of MI (OR 1.51; 95%CI 1.18, 1.93), whereas the least frequent haplotype, FGG-FGA*4 (11.8%), was associated with lower risk of MI (OR 0.79 95%CI 0.64, 0.98). In conclusion, fibrinogen haplotypes, but not SNPs in isolation, are associated with variation in risk of MI.

  2. Environmental Assessment, Land Protection Plan and Conceptual Management Plan: Ellicott Slough National Wildlife Refuge proposed Buena Vista addition

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Ellicott Slough National Wildlife Refuge (Refuge) was established in 1975 for the protection of the endangered Santa Cruz long-toed salamander (SCLTS). There are 170...

  3. Functional promoter haplotypes of interleukin-18 condition susceptibility to severe malarial anemia and childhood mortality.

    Science.gov (United States)

    Anyona, Samuel B; Kempaiah, Prakasha; Raballah, Evans; Ouma, Collins; Were, Tom; Davenport, Gregory C; Konah, Stephen N; Vulule, John M; Hittner, James B; Gichuki, Charity W; Ong'echa, John M; Perkins, Douglas J

    2011-12-01

    Severe malarial anemia (SMA) is a leading cause of morbidity and mortality in children residing in regions where Plasmodium falciparum transmission is holoendemic. Although largely unexplored in children with SMA, interleukin-18 (IL-18) is important for regulating innate and acquired immunity in inflammatory and infectious diseases. As such, we selected two functional single-nucleotide polymorphisms (SNPs) in the IL-18 promoter (-137G→C [rs187238] and -607C→A [rs1946518]) whose haplotypes encompass significant genetic variation due to the presence of strong linkage disequilibrium among these variants. The relationship between the genotypes/haplotypes, SMA (hemoglobin [Hb], sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency, HIV-1, and bacteremia revealed that carriage of the -607AA genotype was associated with protection against SMA (odds ratio [OR] = 0.440 [95% confidence interval {CI} = 0.21 to 0.90], P = 0.031) in children with acute infection. In contrast, carriers of the -137G/-607C (GC) haplotype had increased susceptibility to SMA (OR = 2.050 [95% CI = 1.04 to 4.05], P = 0.039). Measurement of IL-18 gene expression in peripheral blood leukocytes demonstrated that elevated IL-18 transcripts were associated with reduced hemoglobin concentrations (ρ = -0.293, P = 0.010) and that carriers of the "susceptible" GC haplotype had elevated IL-18 transcripts (P = 0.026). Longitudinal investigation of clinical outcomes over a 3-year follow-up period revealed that carriers of the rare CC haplotype (∼1% frequency) had 5.76 times higher mortality than noncarriers (P = 0.001). Results presented here demonstrate that IL-18 promoter haplotypes that condition elevated IL-18 gene products during acute infection are associated with increased risk of SMA. Furthermore, carriage of the rare CC haplotype significantly increases the risk of childhood mortality.

  4. Separation of Y-chromosomal haplotypes from male DNA mixtures via multiplex haplotype-specific extraction.

    Science.gov (United States)

    Rothe, Jessica; Nagy, Marion

    2015-11-01

    In forensic analysis, the interpretation of DNA mixtures is the subject of ongoing debate and requires expertise knowledge. Haplotype-specific extraction (HSE) is an alternative method that enables the separation of large chromosome fragments or haplotypes by using magnetic beads in conjunction with allele-specific probes. HSE thus allows physical separation of the components of a DNA mixture. Here, we present the first multiplex HSE separation of a Y-chromosomal haplotype consisting of six Yfiler short tandem repeat markers from a mixture of male DNA.

  5. Interaction between HLA-DRB1-DQB1 Haplotypes in Sardinian Multiple Sclerosis Population

    Science.gov (United States)

    Cocco, Eleonora; Murru, Raffaele; Costa, Gianna; Kumar, Amit; Pieroni, Enrico; Melis, Cristina; Barberini, Luigi; Sardu, Claudia; Lorefice, Lorena; Fenu, Giuseppe; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Marrosu, Maria Giovanna

    2013-01-01

    We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13∶03-*03∶01 OR = 3.3, Pc 5.1×10−5, *04∶05-*03∶01 OR = 2.1, Pc 9.7×10−8, *15∶01-*06∶02 OR = 2.0, Pc = 9.1×10−3, *03∶01-*02∶01 OR = 1.7 Pc = 7.9×10−22) and protection (*11, OR = 0.8, Pc = 2.7×10−2, *16∶01-*05∶02 OR = 0.6, Pc = 4.8×10−16, *14∶01-4-*05∶031 = OR = 0.5, Pc = 9.8×10−4 and *15∶02-*06∶01 OR = 0.4, Pc = 5.1×10−4). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14∶01, *04∶05, *13∶03, *08∶01 and *03∶01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85–99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms. PMID:23593151

  6. 77 FR 8892 - Detailed Planning To Consider Additional Land Protection on the Missouri River From Fort Randall...

    Science.gov (United States)

    2012-02-15

    ... 25486, DFC, Denver, CO 80225. FOR FURTHER INFORMATION CONTACT: Nick Kaczor, Planning Team Leader... and that their Outstandingly Remarkable Values shall be protected for the benefit and enjoyment of... habitats for fish and wildlife will provide benefits to visitors, neighbors, and local communities of...

  7. Haplotypes, sub-haplotypes and geographical distribution in Omani patients with sickle cell disease

    Directory of Open Access Journals (Sweden)

    Suha Mustafa Hassan

    2015-05-01

    Full Text Available Despite the fact that patients homozygous for the sickle cell disease (SCD mutation have an identical genotype, the severity of the disease can be extremely variable. The hemoglobin (Hb S mutation has been described on five different haplotypes with different clinical expression. Identifying the genotypes, haplotypes and sub-haplotypes of the β gene cluster in Oman needs to be studied in more details to establish a correlation between the genotype/haplotype and phenotype diversity observed in SCD patients for prognostic purposes, accurate diagnosis and thus planning for the best tailored treatment. We have investigated 125 HbS homozygotes from different parts of Oman and determined their haplotypes and sub-haplotypes and correlated this to the hematological and clinical expression. We have found 11 haplotype combinations differently distributed in the country, with the Asian/Asian HbS haplotype being the most predominant. Sub-haplotypes was only found among patients with CAR/OmanI haplotype. As expected, the correlation between haplotypes, sub-haplotypes and disease severity was mainly associated with HbF expression. Our study on haplotype/phenotype correlation has shown which major haplotypes occur in the different regions of Oman. Furthermore, neither the haplotype or sub-haplotype nor the HbF alone appeared to be fully associable with the variable clinical phenotypes. External factors do occur and are associated with the expression of the disease.  尽管镰状细胞突变病(SCD)患者拥有相同的基因类型,但患者的病患程度却大相径庭。血红蛋白(Hb)S突变有五种不同的单体型,各种类型在临床表现上也不相同。为了识别在阿曼地区β基因簇的基因型、单体型,亚单体型,需要研究更多以SCD患者预后为目的,关于其观察到的基因型、单体型,表型多样性之间联系的更多细节,以便作出准确的诊断,为各

  8. Determination of haplotypes at structurally complex regions using emulsion haplotype fusion PCR

    Directory of Open Access Journals (Sweden)

    Tyson Jess

    2012-12-01

    Full Text Available Abstract Background Genotyping and massively-parallel sequencing projects result in a vast amount of diploid data that is only rarely resolved into its constituent haplotypes. It is nevertheless this phased information that is transmitted from one generation to the next and is most directly associated with biological function and the genetic causes of biological effects. Despite progress made in genome-wide sequencing and phasing algorithms and methods, problems assembling (and reconstructing linear haplotypes in regions of repetitive DNA and structural variation remain. These dynamic and structurally complex regions are often poorly understood from a sequence point of view. Regions such as these that are highly similar in their sequence tend to be collapsed onto the genome assembly. This is turn means downstream determination of the true sequence haplotype in these regions poses a particular challenge. For structurally complex regions, a more focussed approach to assembling haplotypes may be required. Results In order to investigate reconstruction of spatial information at structurally complex regions, we have used an emulsion haplotype fusion PCR approach to reproducibly link sequences of up to 1kb in length to allow phasing of multiple variants from neighbouring loci, using allele-specific PCR and sequencing to detect the phase. By using emulsion systems linking flanking regions to amplicons within the CNV, this led to the reconstruction of a 59kb haplotype across the DEFA1A3 CNV in HapMap individuals. Conclusion This study has demonstrated a novel use for emulsion haplotype fusion PCR in addressing the issue of reconstructing structural haplotypes at multiallelic copy variable regions, using the DEFA1A3 locus as an example.

  9. A CCL5 Haplotype Is Associated with Low Seropositivity Rate of HCV Infection in People Who Inject Drugs.

    Directory of Open Access Journals (Sweden)

    Kristi Huik

    Full Text Available The role of CC chemokine receptor 5 (CCR5 and its ligand CCL5 on the pathogenesis of HIV infection has been well studied but not for HCV infection. Here, we investigated whether CCL5 haplotypes influence HIV and HCV seropositivity among 373 Caucasian people who inject drugs (PWID from Estonia.Study included 373 PWID; 56% were HIV seropositive, 44% HCV seropositive and 47% co-infected. Four CCL5 haplotypes (A-D were derived from three CCL5 polymorphisms (rs2107538/rs2280788/rs2280789 typed by Taqman allelic discrimination assays. The data of CCR5 haplotypes were used from our previous study. The association between CCL5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis.Possessing CCL5 haplotype D (defined by rs2107538A/rs2280788G/rs2280789C decreased the odds of HCV seropositivity compared to those not possessing it (OR = 0.19; 95% CI 0.09-0.40, which remained significant after adjustment to co-variates (OR = 0.08; 95% CI 0.02-0.29. An association of this haplotype with HIV seropositivity was not found. In step-wise logistic regression with backward elimination CCL5 haplotype D and CCR5 HHG*1 had reduced odds for HCV seropositivity (OR = 0.28 95% CI 0.09-0.92; OR = 0.23 95% CI 0.08-0.68, respectively compared to those who did not possess these haplotypes, respectively.Our results suggest that among PWID CCL5 haplotype D and CCR5 HHG*1 independently protects against HCV. Our findings highlight the importance of CCL5 genetic variability and CCL5-CCR5 axis on the susceptibility to HCV.

  10. Haplotype reconstruction and estimation of haplotype frequencies from nuclear families with only one parent available.

    Science.gov (United States)

    Ding, Xiangdong; Zhang, Qin; Flury, Christine; Simianer, Henner

    2006-01-01

    Recent literature has suggested that haplotype inference through close relatives, especially from nuclear families can be an alternative strategy in determining the linkage phase. In this paper, haplotype reconstruction and estimation of haplotype frequencies via expectation maximization (EM) algorithm including nuclear families with only one parent available is proposed. Parent and his (her) child are treated as parent-child pair with one shared haplotype. This reduces the number of potential haplotype pairs for both parent and child separately, resulting in a higher accuracy of the estimation. In a series of simulations, the comparisons of PHASE, GENEHUNTER, EM-based approach for complete nuclear families and our approach are carried out. In all situations, EM-based approach for trio data is comparable but slightly worse error rate than PHASE, our approach is slightly better and much faster than PHASE for incomplete trios, the performance of GENEHUNTER is very bad in simple nuclear family settings and dramatically decreased with the number of markers being increased. On the other hand, the comparison result of different sampling designs demonstrates that sampling trios is the most efficient design to estimate haplotype frequencies in populations under same genotyping cost.

  11. Effects of IL-10 haplotype and atomic bomb radiation exposure on gastric cancer risk.

    Science.gov (United States)

    Hayashi, Tomonori; Ito, Reiko; Cologne, John; Maki, Mayumi; Morishita, Yukari; Nagamura, Hiroko; Sasaki, Keiko; Hayashi, Ikue; Imai, Kazue; Yoshida, Kengo; Kajimura, Junko; Kyoizumi, Seishi; Kusunoki, Yoichiro; Ohishi, Waka; Fujiwara, Saeko; Akahoshi, Masazumi; Nakachi, Kei

    2013-07-01

    Gastric cancer (GC) is one of the cancers that reveal increased risk of mortality and incidence in atomic bomb survivors. The incidence of gastric cancer in the Life Span Study cohort of the Radiation Effects Research Foundation (RERF) increased with radiation dose (gender-averaged excess relative risk per Gy = 0.28) and remains high more than 65 years after exposure. To assess a possible role of gene-environment interaction, we examined the dose response for gastric cancer incidence based on immunosuppression-related IL-10 genotype, in a cohort study with 200 cancer cases (93 intestinal, 96 diffuse and 11 other types) among 4,690 atomic bomb survivors participating in an immunological substudy. Using a single haplotype block composed of four haplotype-tagging SNPs (comprising the major haplotype allele IL-10-ATTA and the minor haplotype allele IL-10-GGCG, which are categorized by IL-10 polymorphisms at -819A>G and -592T>G, +1177T>C and +1589A>G), multiplicative and additive models for joint effects of radiation and this IL-10 haplotyping were examined. The IL-10 minor haplotype allele(s) was a risk factor for intestinal type gastric cancer but not for diffuse type gastric cancer. Radiation was not associated with intestinal type gastric cancer. In diffuse type gastric cancer, the haplotype-specific excess relative risk (ERR) for radiation was statistically significant only in the major homozygote category of IL-10 (ERR = 0.46/Gy, P = 0.037), whereas estimated ERR for radiation with the minor IL-10 homozygotes was close to 0 and nonsignificant. Thus, the minor IL-10 haplotype might act to reduce the radiation related risk of diffuse-type gastric cancer. The results suggest that this IL-10 haplotyping might be involved in development of radiation-associated gastric cancer of the diffuse type, and that IL-10 haplotypes may explain individual differences in the radiation-related risk of gastric cancer. © 2013 by Radiation Research Society

  12. Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis.

    Directory of Open Access Journals (Sweden)

    Rakesh Chettier

    Full Text Available Adolescent idiopathic scoliosis (AIS is a clinically significant disorder with high heritability that affects 2-4% of the population. Genome-wide association studies have identified LBX1 as a strong susceptibility locus for AIS in Asian and Caucasian populations. Here we further dissect the genetic association with AIS in a Caucasian population. To identify genetic markers associated with AIS we employed a genome-wide association study (GWAS design comparing 620 female Caucasian patients who developed idiopathic scoliosis during adolescence with 1,287 ethnically matched females who had normal spinal curves by skeletal maturity. The genomic region around LBX1 was imputed and haplotypes investigated for genetic signals under different inheritance models. The strongest signal was identified upstream of LBX1 (rs11190878, P(trend = 4.18 × 10(-9, OR = 0.63[0.54-0.74]. None of the remaining SNPs pass the genome-wide significance threshold. We found rs11190870, downstream of LBX1 and previously associated with AIS in Asian populations, to be in modest linkage disequilibrium (LD with rs11190878 (r(2 = 0.40, D' = 0.81. Haplotype analysis shows that rs11190870 and rs11190878 track a single risk factor that resides on the ancestral haplotype and is shared across ethnic groups. We identify six haplotypes at the LBX1 locus including two strongly associated haplotypes; a recessive risk haplotype (TTA, Control(freq = 0.52, P = 1.25 × 10(-9, OR = 1.56, and a co-dominant protective haplotype (CCG, Control(freq = 0.28, P = 2.75 × 10(-7, OR = 0.65. Together the association signals from LBX1 explain 1.4% of phenotypic variance. Our results identify two clinically relevant haplotypes in the LBX1-region with opposite effects on AIS risk. The study demonstrates the utility of haplotypes over un-phased SNPs for individualized risk assessment by more strongly delineating individuals at risk for AIS without compromising the effect size.

  13. Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis.

    Science.gov (United States)

    Chettier, Rakesh; Nelson, Lesa; Ogilvie, James W; Albertsen, Hans M; Ward, Kenneth

    2015-01-01

    Adolescent idiopathic scoliosis (AIS) is a clinically significant disorder with high heritability that affects 2-4% of the population. Genome-wide association studies have identified LBX1 as a strong susceptibility locus for AIS in Asian and Caucasian populations. Here we further dissect the genetic association with AIS in a Caucasian population. To identify genetic markers associated with AIS we employed a genome-wide association study (GWAS) design comparing 620 female Caucasian patients who developed idiopathic scoliosis during adolescence with 1,287 ethnically matched females who had normal spinal curves by skeletal maturity. The genomic region around LBX1 was imputed and haplotypes investigated for genetic signals under different inheritance models. The strongest signal was identified upstream of LBX1 (rs11190878, P(trend) = 4.18 × 10(-9), OR = 0.63[0.54-0.74]). None of the remaining SNPs pass the genome-wide significance threshold. We found rs11190870, downstream of LBX1 and previously associated with AIS in Asian populations, to be in modest linkage disequilibrium (LD) with rs11190878 (r(2) = 0.40, D' = 0.81). Haplotype analysis shows that rs11190870 and rs11190878 track a single risk factor that resides on the ancestral haplotype and is shared across ethnic groups. We identify six haplotypes at the LBX1 locus including two strongly associated haplotypes; a recessive risk haplotype (TTA, Control(freq) = 0.52, P = 1.25 × 10(-9), OR = 1.56), and a co-dominant protective haplotype (CCG, Control(freq) = 0.28, P = 2.75 × 10(-7), OR = 0.65). Together the association signals from LBX1 explain 1.4% of phenotypic variance. Our results identify two clinically relevant haplotypes in the LBX1-region with opposite effects on AIS risk. The study demonstrates the utility of haplotypes over un-phased SNPs for individualized risk assessment by more strongly delineating individuals at risk for AIS without compromising the effect size.

  14. Association of KIR Genotypes and Haplotypes with Susceptibility to Chronic Hepatitis B Virus Infection in Chinese Han Population

    Institute of Scientific and Technical Information of China (English)

    Zhiming Lu; Yulian Jiao; Chunyan Ma; Song Shao; Xiangfa Cui; Guojian Chen; Jianfeng Li; Yueran Zhao; Bingchang Zhang; Shijun Chen; Zhongtao Gai; Zhaolei Feng; Xiangdong Liu; Yiqing Liu; Xin Wen; Li Li

    2008-01-01

    Killer immunoglobulin-like receptor (KIR) genes can regulate the activation of NK and T cells upon interaction with HLA class I molecules. Hepatitis B virus (HBV) infection has been regarded as a multi-factorial disorder disease. Previous studies revealed that KIRs were involved in HCV and HIV infection or clearance. The aim of this study was to explore the possibility of the inheritance of KIR genotypes and haplotypes as a candidate for susceptibility to persistent HBV infection or HBV clearance. The sequence specific primer polymerase chain reaction (SSP-PCR) was employed to identify the KIR genes and pseudogenes in 150 chronic hepatitis B (CHB) patients, 251 spontaneously recovered (SR) controls, and 412 healthy controls. The frequencies of genotype G, M,FZI increased in CHB patients compared with healthy control subjects. The frequency of genotype AH was higher in SR controls than that in both CHB patients and healthy controls. The carriage frequencies of genotype G and AH were higher; while, the frequencies of AF and AJ were lower in SR controls than those in healthy control subjects. The frequency of A hapiotype was lower, whereas, the frequency of B haplotype was higher in CHB patients and SR controls than those in healthy controls. In healthy controls, haplotype 4 was found lower compared with that in CHB patients and SR controls and the frequency of haplotype 5 was higher in SR controls than that in other two groups. Based on these findings, it seems that the genotypes M and FZI are HBV susceptive genotypes;AH, on the other hand, may be protective genotypes that facilitate the clearance of HBV. It appears that the haplotype 4 is HBV susceptive haplotype, whereas, haplotype 5 may be the protective haplotype that facilitates the clearance of HBV. Cellular & Molecular Immunology. 2008;5(6):457-463.

  15. Enhanced protection against malaria by indoor residual spraying in addition to insecticide treated nets: is it dependent on transmission intensity or net usage?

    Directory of Open Access Journals (Sweden)

    Philippa A West

    Full Text Available Insecticide treated nets (ITNs and indoor residual spraying (IRS are effective vector control tools that protect against malaria. There is conflicting evidence regarding whether using ITNs and IRS in combination provides additional benefit over using either of these methods alone. This study investigated factors that may modify the effect of the combined use of IRS and ITNs compared to using ITNs alone on malaria infection prevalence.Secondary analysis was carried out on data from a cluster randomised trial in north-west Tanzania. 50 clusters received ITNs from a universal coverage campaign; of these 25 were randomly allocated to additionally receive two rounds of IRS in 2012. In cross-sectional household surveys children 0.5-14 years old were tested for Plasmodium falciparum infections (PfPR two, six and ten months after the first IRS round.IRS protected those sleeping under nets (OR = 0.38, 95%CI 0.26-0.57 and those who did not (OR = 0.43, 95%CI 0.29-0.63. The protective effect of IRS was not modified by community level ITN use (ITN use = 50%, OR = 0.46, 95%CI 0.28-0.74. The additional protection from IRS was similar in low (<10% PfPR, OR = 0.38, 95%CI 0.19-0.75 and high transmission areas (≥10% PfPR, OR = 0.34, 95%CI 0.18-0.67. ITN use was protective at the individual-level regardless of whether the village had been sprayed (OR = 0.83, 95%CI 0.70-0.98. Living in a sprayed village was protective regardless of whether the individual slept under an ITN last night (OR = 0.41, 95%CI 0.29-0.58.Implementing IRS in addition to ITNs was beneficial for individuals from villages with a wide range of transmission intensities and net utilisation levels. Net users received additional protection from IRS. ITNs were providing some individual protection, even in this area with high levels of pyrethroid insecticide resistance. These results demonstrate that there is a supplementary benefit of IRS even when ITNs are effective.ClinicalTrials.gov NCT01697852.

  16. Interleukin-6 (IL-6) haplotypes and the response to therapy of chronic hepatitis C virus infection

    Science.gov (United States)

    Yee, Leland J.; Im, KyungAh; Borg, Brian; Yang, Huiying; Liang, T. Jake

    2009-01-01

    Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-α-2a is successful in eradicating virus from only 30%–80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) (RR=0.80; 95%C.I.: 0.66– 0.98; p=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95%C.I.: 0.66–0.94; p=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95%C.I.: 0.66–0.94; p=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% C.I.: 0.62–1.0; p=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy. PMID:19387461

  17. Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection.

    Science.gov (United States)

    Yee, L J; Im, K; Borg, B; Yang, H; Liang, T J

    2009-06-01

    Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-alpha-2a is successful in eradicating virus from only 30 to 80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to the therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) ((relative risk) RR=0.80; 95% CI: 0.66-0.98; P=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95% CI: 0.66-0.94; P=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95% CI: 0.66-0.94; P=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% CI: 0.62-1.0; P=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy.

  18. Evaluation of the protective effect of chemical additives in the oxidation of phenolic compounds catalysed by peroxidase.

    Science.gov (United States)

    Torres, Juliana Arriel; Chagas, Pricila Maria Batista; Silva, Maria Cristina; Dos Santos, Custódio Donizete; Corrêa, Angelita Duarte

    2016-01-01

    The use of oxidoredutive enzymes in removing organic pollutants has been the subject of much research. The oxidation of phenolic compounds in the presence of chemical additives has been the focus of this study. In this investigation, the influence of the additives polyethylene glycol and Triton X-100 was evaluated in the phenol oxidation, caffeic acid, chlorogenic acid and total phenolic compounds present in coffee processing wastewater (CPW) at different pH values, performed by turnip peroxidase and peroxidase extracted from soybean seed hulls. The influence of these additives was observed only in the oxidation of phenol and caffeic acid. In the oxidation of other studied phenolic compounds, the percentage of oxidation remained unchanged in the presence of these chemical additives. In the oxidation of CPW in the presence of additives, no change in the oxidation of phenolic compounds was observed. Although several studies show the importance of evaluating the influence of additives on the behaviour of enzymes, this study found a positive response from the economic point of view for the treatment of real wastewater, since the addition of these substances showed no influence on the oxidation of phenolic compounds, which makes the process less costly.

  19. HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

    Science.gov (United States)

    Cocco, Eleonora; Sardu, Claudia; Pieroni, Enrico; Valentini, Maria; Murru, Raffaele; Costa, Gianna; Tranquilli, Stefania; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Floris, Matteo; Contu, Paolo; Marrosu, Maria Giovanna

    2012-01-01

    Introduction Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS. Methods and Results A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10−3), *04:05-*03:01 (OR = 2.4, P = 4.4×10−6) and *03:01-*02:01 (OR = 2.1, P = 1.0×10−15) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10−11) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10−3) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05

  20. Transgenic Mice with −6A Haplotype of the Human Angiotensinogen Gene Have Increased Blood Pressure Compared with −6G Haplotype*

    Science.gov (United States)

    Jain, Sudhir; Tillinger, Andrej; Mopidevi, Brahmaraju; Pandey, Varunkumar G.; Chauhan, Chetankumar K.; Fiering, Steven N.; Warming, Soren; Kumar, Ashok

    2010-01-01

    Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at −6, and the −6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with −6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with −6G. We have found that the hAGT gene has three additional SNPs (A/G at −1670, C/G at −1562, and T/G at −1561). Variants −1670A, −1562C, and −1561T almost always occur with −6A, and variants −1670G, −1562G, and −1561G almost always occur with −6G. Therefore, the hAGT gene may be subdivided into either −6A or −6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with −6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with −6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the −6A or −6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing −6A haplotype. Our studies also show that transgenic mice containing −6A haplotype have increased plasma AGT level and increased blood pressure as compared with −6G haplotype. Our studies explain the molecular mechanism involved in association of the −6A allele of the hAGT gene with hypertension. PMID:20978123

  1. Identification of HAVCR1 gene haplotypes associated with mRNA expression levels and susceptibility to autoimmune diseases.

    Science.gov (United States)

    García-Lozano, José Raúl; Abad, Cristina; Escalera, Ana; Torres, Belén; Fernández, Olga; García, Alicia; Sánchez-Román, Julio; Sabio, José-Mario; Ortego-Centeno, Norberto; Raya-Alvarez, Enrique; Núñez-Roldán, Antonio; Martín, Javier; González-Escribano, María Francisca

    2010-08-01

    Human HAVCR1 gene maps on 5q33.2, a region linked with susceptibility to allergic and autoimmune diseases. The aims of the present study were to define the haplotypes of HAVCR1 gene taking into account both HapMap Project SNP haplotypes and exon 4 variants, to investigate a possible relationship between these haplotypes and mRNA expression levels, and to assess whether HAVCR1 gene is involved in susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Genotyping of three ins/del variants in the exon 4 was performed by fragment length analysis. Five tag SNPs genotypes and mRNA levels were determined using TaqMan assays. We defined four major haplotypes in our population: the two major haplotypes (named haplotypes A and B) bear both the 5383_5397del variant and the two most common SNP sets found in the CEU population. Quantification analysis revealed that genotype B/B had the highest median of mRNA expression levels (vs. BX + XX, p < 0.0001). Additionally, frequency of the genotype BB was significantly higher in RA patients than in controls (12.3 vs. 5.9% in controls, p = 0.0046, p (c) = 0.014, OR = 2.23, 95% CI 1.23-4.10). Our results support a relationship between HAVCR1 haplotypes and mRNA expression levels, and suggest an association of this gene with autoimmune diseases.

  2. Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition

    Directory of Open Access Journals (Sweden)

    Ollier William

    2005-04-01

    Full Text Available Abstract Background The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs, at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs were identified for each map. Results Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. Conclusion For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results.

  3. Genetic differences in the two main groups of the Japanese population based on autosomal SNPs and haplotypes.

    Science.gov (United States)

    Yamaguchi-Kabata, Yumi; Tsunoda, Tatsuhiko; Kumasaka, Natsuhiko; Takahashi, Atsushi; Hosono, Naoya; Kubo, Michiaki; Nakamura, Yusuke; Kamatani, Naoyuki

    2012-05-01

    Although the Japanese population has a rather low genetic diversity, we recently confirmed the presence of two main clusters (the Hondo and Ryukyu clusters) through principal component analysis of genome-wide single-nucleotide polymorphism (SNP) genotypes. Understanding the genetic differences between the two main clusters requires further genome-wide analyses based on a dense SNP set and comparison of haplotype frequencies. In the present study, we determined haplotypes for the Hondo cluster of the Japanese population by detecting SNP homozygotes with 388,591 autosomal SNPs from 18,379 individuals and estimated the haplotype frequencies. Haplotypes for the Ryukyu cluster were inferred by a statistical approach using the genotype data from 504 individuals. We then compared the haplotype frequencies between the Hondo and Ryukyu clusters. In most genomic regions, the haplotype frequencies in the Hondo and Ryukyu clusters were very similar. However, in addition to the human leukocyte antigen region on chromosome 6, other genomic regions (chromosomes 3, 4, 5, 7, 10 and 12) showed dissimilarities in haplotype frequency. These regions were enriched for genes involved in the immune system, cell-cell adhesion and the intracellular signaling cascade. These differentiated genomic regions between the Hondo and Ryukyu clusters are of interest because they (1) should be examined carefully in association studies and (2) likely contain genes responsible for morphological or physiological differences between the two groups.

  4. Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition.

    Science.gov (United States)

    Zeggini, Eleftheria; Barton, Anne; Eyre, Stephen; Ward, Daniel; Ollier, William; Worthington, Jane; John, Sally

    2005-04-25

    The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results.

  5. The Wilson disease gene: Haplotypes and mutations

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.R.; Roberts, E.A.; Cox, D.W. [Hospital for Sick Children, Toronto (Canada); Walshe, J.M. [Middlesex Hospital, London (United Kingdom)

    1994-09-01

    Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

  6. SNP Analysis and Haplotype Identification in Chymotrypsin Inhibitor-2 (CI-2) Gene of Barley

    Institute of Scientific and Technical Information of China (English)

    ZENG Xiang-hui; WEI Yu-ming; JIANG Qian-tao; QI Peng-fei; ZHENG You-liang

    2009-01-01

    Barley chymotrypsin inhibitor-2 (CI-2) was considered to be a promising candidate for enhancing the nutritional value of other cereals by increasing its concentration as it is rich in lysine than any other storage protein. Also, it was proposed that CI-2 might play an important role in the inhibition of proteolytic enzymes from pests or pathogens as CI-2 can strongly inhibit chymotrypsin and subtilisin. In this study, a total of 93 CI-2 gene sequences were isolated from wild and cultivated barley. 48 SNPs and 4 indels were detected across the entire sequences. The frequency of SNPs in the non-coding region (1 out of 9 bases) was slightly higher than that in the coding region (1 out of 10.7 bases). In all, 33.3% of the candidate cSNPs resulted in amino acid changes. As a total, the 24 cSNPs resulted in 15 amino acid changes. Ten distinguishable haplotypes were detected, among which 3 haplotypes were shared in the most barley accessions, whereas the rest of the haplotypes appeared at a lower frequency. In addition, three haplotypes (haplotype 4, 8, and 9) were unique for single accessions. These results suggested that low diversity at the CI-2 locus was detected among the cultivated and wild barley.

  7. Molecular Pathology and Haplotype Analysis of Wilson Disease in Mediterranean Populations

    Science.gov (United States)

    Figus, Annalena; Angius, Andrea; Loudianos, Georgios; Bertini, Chiara; Dessì, Valeria; Loi, Angela; Deiana, Manila; Lovicu, Mario; Olla, Nazario; Sole, Gabriella; De Virgiliis, Stefano; Lilliu, Franco; Farci, Anna Maria Giulia; Nurchi, Annamaria; Giacchino, Raffaella; Barabino, Arrigo; Marazzi, Maria; Zancan, Lucia; Greggio, Nella A.; Marcellini, Matilde; Solinas, Antonello; Deplano, Angelo; Barbera, Cristiana; Devoto, Marcella; Ozsoylu, Sinasi; Kocak, Nurten; Akar, Nejat; Karayalcin, Selin; Mokini, Vahe; Cullufi, Paskal; Balestrieri, Angelo; Cao, Antonio; Pirastu, Mario

    1995-01-01

    We analyzed mutations and defined the chromosomal haplotype in 127 patients of Mediterranean descent who were affected by Wilson disease (WD), 39 Sardinians, 49 Italians, 33 Turks, and 6 Albanians. Haplotypes were derived by use of the microsatellite markers D13S301, D13S296, D13S297, and D13S298, which are linked to the WD locus. There were five common haplotypes in Sardinians, three in Italians, and two in Turks, which accounted for 85%, 32%, and 30% of the WD chromosomes, respectively. We identified 16 novel mutations: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, we detected the previously described mutations: 2302insC, 3404delC, Argl320ter, Gly944-Ser, and Hisl070Gin. Of the new mutations detected, two, the 1515insT on haplotype I and 2464delC on haplotype XVI, accounted for 6% and 13%, respectively, of the mutations in WD chromosomes in the Sardinian population. Mutations H1070Q, 2302insC, and 2533delA represented 13%, 8%, and 8%, respectively, of the mutations in WD chromosomes in other Mediterranean populations. The remaining mutations were rare and limited to one or two patients from different populations. Thus, WD results from some frequent mutations and many rare defects. ImagesFigure 1 PMID:8533760

  8. Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations

    Energy Technology Data Exchange (ETDEWEB)

    Figus, A.; Farcia, A.M.G.; Nurchi, A. [Universita degli Studi di Cagliari (Italy)] [and others

    1995-12-01

    We analyzed mutations and defined the chromosomal haplotype in 127 patients of Mediterranean descent who were affected in Wilson disease (WD): 39 Sardinians, 49 Italians, 33 Turks, and 6 Albanians. Haplotypes were derived by use of the microsatellite markers D13S301, D13S296, D13S297, and D13S298, which are linked to the WD locus. There were five common haplotypes in Sardinians, three in Italians, and two in Turks, which accounted for 85%, 32%, and 30% of the WD chromosomes, respectively. We identified 16 novel mutations: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, we detected the previously described mutations: 2302insC, 3404delC, Arg1320ter, Gly944Ser, and His1070Gin. Of the new mutations detected, two, the 1515insT on haplotype I and 2464delC on haplotype XVI, accounted for 6% and 13%, respectively, of the mutations in WD chromsomes in the Sardinian populations. Mutations H1070Q, 2302insC, and 2533delA represented 13%, 8%, and 8%, respectively, of the mutations in WD chromsomes in other Mediterranean populations. The remaining mutations were rare and limited to one or two patients from different populations. Thus, WD results from some frequent mutations and many rare defects. 28 refs., 1 fig., 3 tabs.

  9. Discrete Fourier Transform (DFT algorithm, ultra-saturation phenomenon, unloaded transformer energizing with additional line/load from the supplying side, transformer differential protection.

    Directory of Open Access Journals (Sweden)

    bahram noshad

    2012-11-01

    Full Text Available One of mal-operations of the transformer differential protection during the unload transformer energizing with additional line/load from the supplying side is ultra-saturation phenomenon. In this paper, first a new model according to Discrete Fourier Transform (DFT algorithm for investigating the ultra-saturation phenomenon during the unload transformer energizing with additional line/load from the supplying side is presented and its effect on the differential protection of the transformer is considered. In this model, the nonlinear characteristic of the transformer core and the effect of current transformer are taken into account. It is assumed that the additional line/load from the supplying side of the power transformer is a resistive-inductive load. Also, the effect of the residual flux, inception angle and additional line/load from the supplying side on the ultra-saturation phenomenon is investigated. Then, the mal-operation of differential protection by using DFT algorithm is described.

  10. Double Conjugate Addition of Dithiols to Propargylic Carbonyl Systems To Generate Protected 1,3-Dicarbonyl Compounds

    NARCIS (Netherlands)

    Sneddon, Helen F.; Heuvel, Alexandra van den; Hirsch, Anna K.H.; Booth, Richard A.; Shaw, David M.; Gaunt, Matthew J.; Ley, Steven V.

    2006-01-01

    The work describes the efficient double conjugate addition of ethane and propane dithiols in the presence of sodium methoxide to a wide variety of propargylic carbonyl containing compounds. The products of these reactions are differentiated, 1,3-dicarbonyl systems useful for various synthesis progra

  11. Serotype specificity of B-haplotype influence on the relative efficacy of Marek's disease vaccines.

    Science.gov (United States)

    Bacon, L D; Witter, R L

    1994-01-01

    B-haplotype genes in the chicken were previously shown to differentially influence vaccine efficacy against challenge with very virulent Marek's disease virus according to the type of Marek's disease (MD) vaccine used. To determine whether MD vaccines of the same serotype gave comparable levels of protection against MD in chickens of the same haplotype challenged with MD virus strain Md5, two serotype 1 and two serotype 2 vaccines were compared with one serotype 3 vaccine using chickens of 15-B-congenic lines. There was a strong correlation in development of MD lesions among chickens of the different lines receiving the two serotype 2 vaccines (r = 0.94) as well as among chickens receiving the two serotype 1 vaccines (r = 0.76). The serotype 1 vaccines were preferable for B2, B13, B15, and B21, but serotype 2 vaccines were more protective for B5 chickens. The two serotype 2 vaccines gave equivalent protection; however, of the serotype 1 vaccines, CVI988/Rispens provided more protection than Md11/75c/R2/23. We conclude that the B-haplotype influence on MD vaccine efficacy is dependent on the serotype of the vaccine.

  12. A linear-time algorithm for reconstructing zero-recombinant haplotype configuration on a pedigree

    Science.gov (United States)

    2012-01-01

    Background When studying genetic diseases in which genetic variations are passed on to offspring, the ability to distinguish between paternal and maternal alleles is essential. Determining haplotypes from genotype data is called haplotype inference. Most existing computational algorithms for haplotype inference have been designed to use genotype data collected from individuals in the form of a pedigree. A haplotype is regarded as a hereditary unit and therefore input pedigrees are preferred that are free of mutational events and have a minimum number of genetic recombinational events. These ideas motivated the zero-recombinant haplotype configuration (ZRHC) problem, which strictly follows the Mendelian law of inheritance, namely that one haplotype of each child is inherited from the father and the other haplotype is inherited from the mother, both without any mutation. So far no linear-time algorithm for ZRHC has been proposed for general pedigrees, even though the number of mating loops in a human pedigree is usually very small and can be regarded as constant. Results Given a pedigree with n individuals, m marker loci, and k mating loops, we proposed an algorithm that can provide a general solution to the zero-recombinant haplotype configuration problem in O(kmn + k2m) time. In addition, this algorithm can be modified to detect inconsistencies within the genotype data without loss of efficiency. The proposed algorithm was subject to 12000 experiments to verify its performance using different (n, m) combinations. The value of k was uniformly distributed between zero and six throughout all experiments. The experimental results show a great linearity in terms of execution time in relation to input size when both n and m are larger than 100. For those experiments where n or m are less than 100, the proposed algorithm runs very fast, in thousandth to hundredth of a second, on a personal desktop computer. Conclusions We have developed the first deterministic linear

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-08-01

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

  14. Mitochondrial haplotypes associated with biomarkers for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Perry G Ridge

    Full Text Available Various studies have suggested that the mitochondrial genome plays a role in late-onset Alzheimer's disease, although results are mixed. We used an endophenotype-based approach to further characterize mitochondrial genetic variation and its relationship to risk markers for Alzheimer's disease. We analyzed longitudinal data from non-demented, mild cognitive impairment, and late-onset Alzheimer's disease participants in the Alzheimer's Disease Neuroimaging Initiative with genetic, brain imaging, and behavioral data. We assessed the relationship of structural MRI and cognitive biomarkers with mitochondrial genome variation using TreeScanning, a haplotype-based approach that concentrates statistical power by analyzing evolutionarily meaningful groups (or clades of haplotypes together for association with a phenotype. Four clades were associated with three different endophenotypes: whole brain volume, percent change in temporal pole thickness, and left hippocampal atrophy over two years. This is the first study of its kind to identify mitochondrial variation associated with brain imaging endophenotypes of Alzheimer's disease. Our results provide additional evidence that the mitochondrial genome plays a role in risk for Alzheimer's disease.

  15. D-loop haplotype diversity in Brazilian horse breeds.

    Science.gov (United States)

    Ianella, Patrícia; Albuquerque, Maria do Socorro Maués; Paiva, Samuel Rezende; Egito, Andréa Alves do; Almeida, Leonardo Daniel; Sereno, Fabiana T P S; Carvalho, Luiz Felipe Ramos; Mariante, Arthur da Silva; McManus, Concepta Margaret

    2017-08-31

    The first horses were brought to Brazil by the colonizers after 1534. Over the centuries, these animals evolved and adapted to local environmental conditions usually unsuitable for exotic breeds, thereby originating locally adapted Brazilian breeds. The present work represents the first description of maternal genetic diversity in these horse breeds based on D-loop sequences. A D-Loop HSV-I fragment of 252 bp, from 141 horses belonging to ten Brazilian breeds / genetic groups (locally adapted and specialized breeds) were analysed. Thirty-five different haplotypes belonging to 18 haplogroups were identified with 33 polymorphic sites. Haplotype diversity (varying from 0.20 to 0.96) and nucleotide diversity (varying from 0.0039 to 0.0239) was lower for locally adapted than for specialized breeds, with the same pattern observed for FST values. Haplogroups identified in Brazilian breeds are in agreement with previous findings in South American samples. The low variability observed mainly in locally adapted breeds, indicates that, to ensure conservation of these breeds, careful reproductive management is needed. Additional genetic characterization studies are required to support accurate decision-making.

  16. Protective

    Directory of Open Access Journals (Sweden)

    Wessam M. Abdel-Wahab

    2013-10-01

    Full Text Available Many active ingredients extracted from herbal and medicinal plants are extensively studied for their beneficial effects. Antioxidant activity and free radical scavenging properties of thymoquinone (TQ have been reported. The present study evaluated the possible protective effects of TQ against the toxicity and oxidative stress of sodium fluoride (NaF in the liver of rats. Rats were divided into four groups, the first group served as the control group and was administered distilled water whereas the NaF group received NaF orally at a dose of 10 mg/kg for 4 weeks, TQ group was administered TQ orally at a dose of 10 mg/kg for 5 weeks, and the NaF-TQ group was first given TQ for 1 week and was secondly administered 10 mg/kg/day NaF in association with 10 mg/kg TQ for 4 weeks. Rats intoxicated with NaF showed a significant increase in lipid peroxidation whereas the level of reduced glutathione (GSH and the activity of superoxide dismutase (SOD, catalase (CAT, glutathione S-transferase (GST and glutathione peroxidase (GPx were reduced in hepatic tissues. The proper functioning of the liver was also disrupted as indicated by alterations in the measured liver function indices and biochemical parameters. TQ supplementation counteracted the NaF-induced hepatotoxicity probably due to its strong antioxidant activity. In conclusion, the results obtained clearly indicated the role of oxidative stress in the induction of NaF toxicity and suggested hepatoprotective effects of TQ against the toxicity of fluoride compounds.

  17. B haplotype influence on the relative efficacy of Marek's disease vaccines in commercial chickens.

    Science.gov (United States)

    Bacon, L D; Witter, R L

    1994-04-01

    The objectives were to investigate whether or not B haplotypes influence vaccinal immunity against Marek's disease (MD) in commercial chickens and to evaluate whether retrospective analysis would detect the influence. This method involved evaluating the B haplotypes of turkey herpesvirus (HVT)-vaccinated sick vs normal chickens from a flock afflicted with MD symptoms. An analysis of the retrospective data disclosed that MD symptoms were present in a higher proportion of B2B19 than B2B21 chickens. A prospective study was then conducted with blood-typed chickens of the strain vaccinated with HVT or HVT + 301B bivalent MD vaccines prior to inoculation of the very virulent Md5 virus. The bivalent vaccine provided better protection than HVT alone, but with either vaccine fewer B2B21 chickens developed MD lesions. We conclude that the B haplotype influence on vaccinal immunity against MD previously demonstrated in B-congenic strains of chickens is also significant in commercial chickens and that the influence can be detected through analysis of B haplotypes in sick vs normal chickens of an affected flock.

  18. Genomic sequence of 'Candidatus Liberibacter solanacearum' haplotype C and its comparison with haplotype A and B genomes

    Science.gov (United States)

    Haapalainen, Minna; Schott, Thomas; Thompson, Sarah M.; Smith, Grant R.; Nissinen, Anne I.; Pirhonen, Minna

    2017-01-01

    Haplotypes A and B of ‘Candidatus Liberibacter solanacearum’ (CLso) are associated with diseases of solanaceous plants, especially Zebra chip disease of potato, and haplotypes C, D and E are associated with symptoms on apiaceous plants. To date, one complete genome of haplotype B and two high quality draft genomes of haplotype A have been obtained for these unculturable bacteria using metagenomics from the psyllid vector Bactericera cockerelli. Here, we present the first genomic sequences obtained for the carrot-associated CLso. These two genomic sequences of haplotype C, FIN114 (1.24 Mbp) and FIN111 (1.20 Mbp), were obtained from carrot psyllids (Trioza apicalis) harboring CLso. Genomic comparisons between the haplotypes A, B and C revealed that the genome organization differs between these haplotypes, due to large inversions and other recombinations. Comparison of protein-coding genes indicated that the core genome of CLso consists of 885 ortholog groups, with the pan-genome consisting of 1327 ortholog groups. Twenty-seven ortholog groups are unique to CLso haplotype C, whilst 11 ortholog groups shared by the haplotypes A and B, are not found in the haplotype C. Some of these ortholog groups that are not part of the core genome may encode functions related to interactions with the different host plant and psyllid species. PMID:28158295

  19. The S haplotype-specific F-box protein gene, SFB, is defective in self-compatible haplotypes of Prunus avium and P. mume.

    Science.gov (United States)

    Ushijima, Koichiro; Yamane, Hisayo; Watari, Akiko; Kakehi, Eiko; Ikeda, Kazuo; Hauck, Nathanael R; Iezzoni, Amy F; Tao, Ryutaro

    2004-08-01

    Many Prunus species, including sweet cherry and Japanese apricot, of the Rosaceae, display an S-RNase-based gametophytic self-incompatibility (GSI). The specificity of this outcrossing mechanism is determined by a minimum of two genes that are located in a multigene complex, termed the S locus, which controls the pistil and pollen specificities. SFB, a gene located in the S locus region, encodes an F-box protein that has appropriate S haplotype-specific variation to be the pollen determinant in the self-incompatibility reaction. This study characterizes SFBs of two self-compatible (SC) haplotypes, S(4') and S(f), of Prunus. S(4') of sweet cherry is a pollen-part mutant (PPM) that was produced by X-ray irradiation, while S(f) of Japanese apricot is a naturally occurring SC haplotype that is considered to be a PPM. DNA sequence analysis revealed defects in both SFB(4') and SFB(f). A 4 bp deletion upstream from the HVa coding region of SFB(4') causes a frame-shift that produces transcripts of a defective SFB lacking the two hypervariable regions, HVa and HVb. Similarly, the presence of a 6.8 kbp insertion in the middle of the SFB(f) coding region leads to transcripts for a defective SFB lacking the C-terminal half that contains HVa and HVb. As all reported SFBs of functional S haplotypes encode intact SFB, the fact that the partial loss-of-function mutations in SFB are present in SC mutant haplotypes of Prunus provides additional evidence that SFB is the pollen S gene in GSI in Prunus.

  20. Human leucocyte antigens class II allele and haplotype association with Type 1 Diabetes in Madeira Island (Portugal).

    Science.gov (United States)

    Spínola, H; Lemos, A; Couto, A R; Parreira, B; Soares, M; Dutra, I; Bruges-Armas, J; Brehm, A; Abreu, S

    2017-08-20

    This study confirms for Madeira Island (Portugal) population the Type 1 Diabetes (T1D) susceptible and protective Human leucocyte antigens (HLA) markers previously reported in other populations and adds some local specificities. Among the strongest T1D HLA associations, stands out, as susceptible, the alleles DRB1*04:05 (OR = 7.3), DQB1*03:02 (OR = 6.1) and DQA1*03:03 (OR = 4.5), as well as the haplotypes DRB1*04:05-DQA1*03:03-DQB1*03:02 (OR = 100.9) and DRB1*04:04-DQA1*03:01-DQB1*03:02 (OR = 22.1), and DQB1*06:02 (OR = 0.07) and DRB1*15:01-DQA1*01:02-DQB1*06:02 (OR = 0.04) as protective. HLA-DQA1 positive for Arginine at position 52 (Arg52) (OR = 15.2) and HLA-DQB1 negative for Aspartic acid at the position 57 (Asp57) (OR = 9.0) alleles appear to be important genetic markers for T1D susceptibility, with higher odds ratio values than any single allele and than most of the haplotypes. Genotypes generated by the association of markers Arg52 DQA1 positive and Asp57 DQB1 negative increase T1D susceptibility much more than one would expected by a simple additive effect of those markers separately (OR = 26.9). This study also confirms an increased risk for DRB1*04/DRB1*03 heterozygote genotypes (OR = 16.8) and also a DRB1*04-DQA1*03:01-DQB1*03:02 haplotype susceptibility dependent on the DRB1*04 allele (DRB1*04:01, OR = 7.9; DRB1*04:02, OR = 3.2; DRB1*04:04, OR = 22.1). © 2017 John Wiley & Sons Ltd.

  1. On the Minimum Error Correction Problem for Haplotype Assembly in Diploid and Polyploid Genomes.

    Science.gov (United States)

    Bonizzoni, Paola; Dondi, Riccardo; Klau, Gunnar W; Pirola, Yuri; Pisanti, Nadia; Zaccaria, Simone

    2016-09-01

    In diploid genomes, haplotype assembly is the computational problem of reconstructing the two parental copies, called haplotypes, of each chromosome starting from sequencing reads, called fragments, possibly affected by sequencing errors. Minimum error correction (MEC) is a prominent computational problem for haplotype assembly and, given a set of fragments, aims at reconstructing the two haplotypes by applying the minimum number of base corrections. MEC is computationally hard to solve, but some approximation-based or fixed-parameter approaches have been proved capable of obtaining accurate results on real data. In this work, we expand the current characterization of the computational complexity of MEC from the approximation and the fixed-parameter tractability point of view. In particular, we show that MEC is not approximable within a constant factor, whereas it is approximable within a logarithmic factor in the size of the input. Furthermore, we answer open questions on the fixed-parameter tractability for parameters of classical or practical interest: the total number of corrections and the fragment length. In addition, we present a direct 2-approximation algorithm for a variant of the problem that has also been applied in the framework of clustering data. Finally, since polyploid genomes, such as those of plants and fishes, are composed of more than two copies of the chromosomes, we introduce a novel formulation of MEC, namely the k-ploid MEC problem, that extends the traditional problem to deal with polyploid genomes. We show that the novel formulation is still both computationally hard and hard to approximate. Nonetheless, from the parameterized point of view, we prove that the problem is tractable for parameters of practical interest such as the number of haplotypes and the coverage, or the number of haplotypes and the fragment length.

  2. Chloride and other anions inhibit dichloroacetate-induced inactivation of human liver GSTZ1 in a haplotype-dependent manner.

    Science.gov (United States)

    Zhong, Guo; Li, Wenjun; Gu, Yuan; Langaee, Taimour; Stacpoole, Peter W; James, Margaret O

    2014-05-25

    The in vivo elimination rate of dichloroacetate (DCA), an investigational drug; is determined by the rate of its biotransformation to glyoxylate, catalyzed by glutathione transferase ζ1 (GSTZ1). DCA is a mechanism-based inactivator of GSTZ1, thus elimination of DCA is slowed with repeated dosing. We observed that chloride, a physiologically important anion, attenuated DCA-induced GSTZ1 inactivation in human liver cytosol in a concentration and GSTZ1 haplotype-dependent way. In the absence of chloride, incubation with 0.5mM DCA resulted in inactivation of GSTZ1 with a half-life of 0.4h (samples with the KRT haplotype) to 0.5h (EGT haplotype). At the hepatic physiological chloride concentration, 38mM, samples with the EGT haplotype retained more activity (80%) following a 2-h incubation with 0.5mM DCA than those possessing the KRT haplotype (55%). The chloride concentration that protected 50% of the GSTZ1 activity following 2-h incubation with 0.5mM DCA (EC50) was 15.0±3.1mM (mean±S.D., n=3) for EGT samples and 36.2±2.2mM for KRT samples. Bromide, iodide and sulfite also protected GSTZ1 from inactivation by DCA, however fluoride, sulfate, carbonate, acetate, cyanide did not. Protection by bromide varied by GSTZ1 haplotype: EC50 was 1.3±0.3mM for the EGT haplotype and 5.0±0.60mM for the KRT haplotype. The EC50 values for iodide and sulfite in liver cytosol samples with EGT haplotype were respectively 0.14±0.06mM and 9.6±1.1mM (mean±S.D., n=3). Because the in vivo half-life of DCA is determined by the fraction of active GSTZ1 in the liver, identifying factors that regulate GSTZ1 activity is important in determining appropriate DCA dosing in humans.

  3. Relaxin as an additional protective substance in preserving and reperfusion solution for liver transplantation, shown in a model of isolated perfused rat liver.

    Science.gov (United States)

    Boehnert, Markus U; Hilbig, Heidegard; Armbruster, Franz P

    2005-05-01

    Reperfusion injury is a problem in organ transplantation. Relaxin causes vessel dilation and inhibition of platelet and mast cell activation. The study investigates the protective effect of relaxin on liver tissue against cell damage during organ preservation and reperfusion. Liver transplantation was simulated in a model of isolated perfused rat liver. Relaxin was applicated during reperfusion and/or preservation. To quantify cell damage, we examined the perfusate for malonyldialdehyde (MDA) and myeloperoxidase activity (MPO), and liver tissue underwent immunohistochemical study. Relaxin as an additional substance in preserving/reperfusion solution decreases MPO and MDA levels in the perfusate and immunohistochemical study. Relaxin seems to have a protective effect against cell damage in ischemia and reperfusion injury.

  4. Divergence at the casein haplotypes in dairy and meat goat breeds.

    Science.gov (United States)

    Küpper, Julia; Chessa, Stefania; Rignanese, Daniela; Caroli, Anna; Erhardt, Georg

    2010-02-01

    Casein genes have been proved to have an influence on milk properties, and are in addition appropriate for phylogeny studies. A large number of casein polymorphisms exist in goats, making their analysis quite complex. The four casein loci were analyzed by molecular techniques for genetic polymorphism detection in the two dairy goat breeds Bunte Deutsche Edelziege (BDE; n=96), Weisse Deutsche Edelziege (WDE; n=91), and the meat goat breed Buren (n=75). Of the 35 analyzed alleles, 18 were found in BDE, and 17 in Buren goats and WDE. In addition, a new allele was identified at the CSN1S1 locus in the BDE, showing a frequency of 0.05. This variant, named CSN1S1*A', is characterized by a t-->c transversion in intron 9. Linkage disequilibrium was found at the casein haplotype in all three breeds. A total of 30 haplotypes showed frequencies higher than 0.01. In the Buren breed only one haplotype showed a frequency higher than 0.1. The ancestral haplotype B-A-A-B (in the order: CSN1S1-CSN2-CSN1S2-CSN3) occurred in all three breeds, showing a very high frequency (>0.8) in the Buren.

  5. Haplotype diversity of 13 RM Y-STRs in Chinese Han population and an update on the allele designation of DYF403S1.

    Science.gov (United States)

    Zhang, Wenqiong; Xiao, Chao; Wei, Tian; Pan, Chao; Yi, Shaohua; Huang, Daixin

    2016-07-01

    Rapidly mutating Y-STRs (RM Y-STRs) have been paid much attention in recent years. The 13 RM Y-STRs have been proved to have substantially higher haplotype diversity and discrimination capacity than conventionally used Y-STRs, indicating the considerable power in paternal lineage differentiation. To investigate the haplotype diversity in Chinese Han population, we collected 252 unrelated male samples and tested the genotype of the 13 RM Y-STRs. Among 252 male individuals, a total of 250 haplotypes were observed in which only 2 haplotypes were shared by 2 males respectively. The haplotype diversity reached 0.999937 and the discrimination capacity was 99.21%, showing a great discrimination power in Chinese Han population. In addition, an update on the allele designation of DYF403S1 was proposed.

  6. Associations of Haplotypes Upstream of IRS1 with Insulin Resistance, Type 2 Diabetes, Dyslipidemia, Preclinical Atherosclerosis, and Skeletal Muscle LOC646736 mRNA Levels

    Directory of Open Access Journals (Sweden)

    Selma M. Soyal

    2015-01-01

    Full Text Available The genomic region ~500 kb upstream of IRS1 has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible haplotypes, 6 haplotypes with frequencies >0.01 were observed. We identified one haplotype that was protective against insulin resistance (determined by HOMA-IR and fasting plasma insulin levels, type 2 diabetes, an adverse lipid profile, increased C-reactive protein, and asymptomatic atherosclerotic disease (assessed by intima media thickness of the common carotid arteries. BMI and total adipose tissue mass as well as visceral and subcutaneous adipose tissue mass did not differ between the reference and protective haplotypes. In 92 subjects, we observed an association of the protective haplotype with higher skeletal muscle mRNA levels of LOC646736, which is located in the same haplotype block as the informative SNPs and is mainly expressed in skeletal muscle, but only at very low levels in liver or adipose tissues. These data suggest a role for LOC646736 in human insulin resistance and warrant further studies on the functional effects of this locus.

  7. A fast and accurate algorithm for diploid individual haplotype reconstruction.

    Science.gov (United States)

    Wu, Jingli; Liang, Binbin

    2013-08-01

    Haplotypes can provide significant information in many research fields, including molecular biology and medical therapy. However, haplotyping is much more difficult than genotyping by using only biological techniques. With the development of sequencing technologies, it becomes possible to obtain haplotypes by combining sequence fragments. The haplotype reconstruction problem of diploid individual has received considerable attention in recent years. It assembles the two haplotypes for a chromosome given the collection of fragments coming from the two haplotypes. Fragment errors significantly increase the difficulty of the problem, and which has been shown to be NP-hard. In this paper, a fast and accurate algorithm, named FAHR, is proposed for haplotyping a single diploid individual. Algorithm FAHR reconstructs the SNP sites of a pair of haplotypes one after another. The SNP fragments that cover some SNP site are partitioned into two groups according to the alleles of the corresponding SNP site, and the SNP values of the pair of haplotypes are ascertained by using the fragments in the group that contains more SNP fragments. The experimental comparisons were conducted among the FAHR, the Fast Hare and the DGS algorithms by using the haplotypes on chromosome 1 of 60 individuals in CEPH samples, which were released by the International HapMap Project. Experimental results under different parameter settings indicate that the reconstruction rate of the FAHR algorithm is higher than those of the Fast Hare and the DGS algorithms, and the running time of the FAHR algorithm is shorter than those of the Fast Hare and the DGS algorithms. Moreover, the FAHR algorithm has high efficiency even for the reconstruction of long haplotypes and is very practical for realistic applications.

  8. COX-2 gene promoter haplotypes and prostate cancer risk.

    Science.gov (United States)

    Panguluri, Ramesh C K; Long, Layron O; Chen, Weidong; Wang, Songping; Coulibaly, Aoua; Ukoli, Flora; Jackson, Aaron; Weinrich, Sally; Ahaghotu, Chiledum; Isaacs, William; Kittles, Rick A

    2004-06-01

    Cyclooxygenase-2 (COX-2) is a key rate-limiting enzyme that converts arachidonic acid into pro-inflammatory prostaglandins. COX-2 expression is strongly correlated with increased tumor microvasculature density and plays an important role in inhibiting apoptosis, stimulating angiogenesis and promoting tumor cell metastasis and invasion. However, little is known about the role that sequence variation of the COX-2 gene contributes to prostate cancer. Thus, we searched for polymorphisms in the promoter region of the COX-2 gene using denaturing high-performance liquid chromatography. Four single nucleotide polymorphisms (SNPs), -1285A/G, -1265G/A, -899G/C and -297C/G, were detected and confirmed by direct sequencing. Three of the SNPs in the promoter region of COX-2 gene create at least three putative transcription factor binding sites and eliminate CCAAT/enhancer binding protein alpha (C/EBP alpha) and NF-kappa B binding sites. A case-control study of the four SNPs in African American (n = 288), Bini Nigerian (n = 264) and European American (n = 184) prostate cancer cases and age-matched controls revealed that SNP -297G was associated with a decreased risk for prostate cancer [odds ratio (OR) = 0.49; CI = 0.2-0.9; P = 0.01]. The effect on risk was observed in both African Americans (OR = 0.51; CI = 0.2-0.9; P = 0.01) and European Americans (OR = 0.33; CI = 0.1-0.9; P = 0.02). In addition, SNPs -1265A and -899C were associated with increased prostate cancer risk in African Americans (OR = 2.72; CI = 1.3-5.8; P = 0.007 and OR = 3.67; CI = 1.4-9.9; P = 0.007, respectively). Haplotype analyses revealed modest effects on susceptibility to prostate cancer across populations. Haplotype GGCC conferred increased risk in the African American and Nigerian populations. Conversely, haplotype AGGG exhibited a negative association with prostate cancer risk in African Americans (OR = 0.4; CI = 0.1-0.9; P = 0.02) and European Americans (OR = 0.2; CI = 0.1-0.9; P = 0.03). These data

  9. Occurrence of 15 Haplotypes of Linepithema micans (Hymenoptera: Formicidae) in Southern Brazil.

    Science.gov (United States)

    Ramalho, Manuela Oliveira; Martins, C; Campos, T; Nondillo, A; Botton, M; Bueno, O C

    2017-08-01

    The ant genus Linepithema is widely known, thanks to the pest species Linepithema humile (Mayr), which is easily mistaken for Linepithema micans (Forel) due to their morphological similarity. Like L. humile, L. micans is associated to the main grapevine pest in Brazil, Eurhizococcus brasiliensis (Wille), also known as ground pearl. Therefore, the present study uses mtDNA fragments to expand the knowledge of haplotype diversity and distribution of L. micans in the state of Rio Grande do Sul (Brazil), to understand the genetic differences of the populations identified in this study. We identified 15 haplotypes of L. micans spread across different localities. Twelve of these haplotypes were new for the species. The high haplotype diversity uncovered in Rio Grande do Sul (Brazil) for this species was predictable, as L. micans is in its native environment. Additional studies that take gene flow into account may reveal interesting aspects of diversity in these populations. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. An overview of the haplotype problems and algorithms

    Institute of Scientific and Technical Information of China (English)

    ZHAO Yuzhong; XU Yun; ZHANG Qiangfeng; CHEN Guoliang

    2007-01-01

    A single nucleotide polymorphism (SNP),as the most common form of genetic variation,has been widely studied to help analyze the possible association between diseases and genomes.To gain more information,SNPs on a single chromosome are usually studied together,which constitute a haplotype.Gaining haplotypes from biological experiments is usually very costly and time-consuming,which causes people to develop efficient methods to determine haplotypes from the computational angle.Many problems and algorithms about haplotypes have been proposed to reduce the cost of studies of disease association.In general,four categories of problems are widely researched:the haplotype assembly problem,the haplotype inference problem,the haplotype block partition problem,and the haplotype tagging SNP selection problem.The former two problems have been well reviewed by many researchers,whereas the latter two have not been comprehensively surveyed to our knowledge.In this paper,we try to make a detailed introduction to the four problems,especially the latter two.

  11. Reconstruction of N-acetyltransferase 2 haplotypes using PHASE.

    Science.gov (United States)

    Golka, Klaus; Blaszkewicz, Meinolf; Samimi, Mirabutaleb; Bolt, Hermann M; Selinski, Silvia

    2008-04-01

    The genotyping of N-acetyltransferase 2 (NAT2) by PCR/RFLP methods yields in a considerable percentage ambiguous results. To resolve this methodical problem a statistical approach was applied. PHASE v2.1.1, a statistical program for haplotype reconstruction was used to estimate haplotype pairs from NAT2 genotyping data, obtained by the analysis of seven single nucleotide polymorphisms relevant for Caucasians. In 1,011 out of 2,921 (35%) subjects the haplotype pairs were clearcut by the PCR/RFLP data only. For the majority of the data the applied method resulted in a multiplicity (2-4) of possible haplotype pairs. Haplotype reconstruction using PHASE v2.1.1 cleared this ambiguity in all cases but one, where an alternative haplotype pair was considered with a probability of 0.029. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles *12A, *12B, *12C or *13 to the rapid or slow NAT2 genotype has been discussed controversially. A clear assignment is indispensable in surveys of human bladder cancer caused by aromatic amine exposures. In conclusion, PHASE v2.1.1 software allowed an unambiguous haplotype reconstruction in 2,920 of 2,921 cases (>99.9%).

  12. A method for haplotype inference in general pedigrees without recombination

    Institute of Scientific and Technical Information of China (English)

    WANG ChunKao; WANG ZhiPeng; QIU XiaoTian; ZHANG Qin

    2007-01-01

    The abundance of single nucleotide polymorphisms (SNPs) makes the haplotype-based method instead of single-maker-oriented method the main approach to association studies on QTL mapping. The key problem in haploptype-based method is how to reconstruct haplotypes from genotype data. Directly assaying haplotypes in diploid individuals by experimental methods is too expensive, therefore the in silico haplotyping-determination methods are the major choice at the present. This paper presents a rapid and reliable algorithm for haplotype reconstruction for tightly linked SNPs in general pedigrees. It is based on six rules and consists of three steps. First, the parental origins of alleles in offspring are assigned conditional on genotypes in parent-offspring trios; second, the redundant haplotypes are eliminated based on the six rules; and finally, the most likely haplotype combinations are chosen via maximum likelihood method. Our method was verified and compared with PEDPHASE by simulated data with different pedigree sizes, numbers of loci, and proportions of missing genotypes. The result shows that our algorithm was superior to PEDPHASE in terms of computing time and accuracy of haplotype estimation. The computing time for 100 runs was 10-15 times less and the accuracy was 4%-10% higher than PEDPHASE. The result also indicates that our method was very robust and was hardly affected by pedigree size, number of loci, and proportion of missing genotypes.

  13. Restriction digestion method for haplotyping the potato psyllid, Bactericera cockerelli

    Science.gov (United States)

    A restriction digestion method has been developed for haplotyping the potato psyllid, Bactericera cockerelli Sulc., an economically important pest of solanaceous crops. This method differentiates the four known potato psyllid haplotypes by utilizing restriction enzyme digestion of a portion of the ...

  14. Interleukin-10 haplotypes in Celiac Disease in the Spanish population

    Directory of Open Access Journals (Sweden)

    Fernández-Arquero Miguel

    2006-03-01

    Full Text Available Abstract Background Celiac disease (CD is a chronic disorder characterized by a pathological inflammatory response after exposure to gluten in genetically susceptible individuals. The HLA complex accounts for less than half of the genetic component of the disease, and additional genes must be implicated. Interleukin-10 (IL-10 is an important regulator of mucosal immunity, and several reports have described alterations of IL-10 levels in celiac patients. The IL-10 gene is located on chromosome 1, and its promoter carries several single nucleotide polymorphisms (SNPs and microsatellites which have been associated to production levels. Our aim was to study the role of those polymorphisms in susceptibility to CD in our population. Methods A case-control and a familial study were performed. Positions -1082, -819 and -592 of the IL-10 promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm. Results No significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02 status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either. Conclusion The IL-10 polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease.

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

    Science.gov (United States)

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

    2015-03-01

    Recently introduced rapidly mutating Y-chromosomal short tandem repeat (RM Y-STR) loci, displaying a multiple-fold higher mutation rate relative to any other Y-STRs, including those conventionally used in forensic casework, have been demonstrated to improve the resolution of male lineage differentiation and to allow male relative separation usually impossible with standard Y-STRs. However, large and geographically-detailed frequency haplotype databases are required to estimate the statistical weight of RM Y-STR haplotype matches if observed in forensic casework. With this in mind, the Italian Working Group (GEFI) of the International Society for Forensic Genetics launched a collaborative exercise aimed at generating an Italian quality controlled forensic RM Y-STR haplotype database. Overall 1509 male individuals from 13 regional populations covering northern, central and southern areas of the Italian peninsula plus Sicily were collected, including both "rural" and "urban" samples classified according to population density in the sampling area. A subset of individuals was additionally genotyped for Y-STR loci included in the Yfiler and PowerPlex Y23 (PPY23) systems (75% and 62%, respectively), allowing the comparison of RM and conventional Y-STRs. Considering the whole set of 13 RM Y-STRs, 1501 unique haplotypes were observed among the 1509 sampled Italian men with a haplotype diversity of 0.999996, largely superior to Yfiler and PPY23 with 0.999914 and 0.999950, respectively. AMOVA indicated that 99.996% of the haplotype variation was within populations, confirming that genetic-geographic structure is almost undetected by RM Y-STRs. Haplotype sharing among regional Italian populations was not observed at all with the complete set of 13 RM Y-STRs. Haplotype sharing within Italian populations was very rare (0.27% non-unique haplotypes), and lower in urban (0.22%) than rural (0.29%) areas. Additionally, 422 father-son pairs were investigated, and 20.1% of them could

  16. CIDEB、CIDEC 基因单倍型及单倍型交互作用与肥胖的关系%The main effect and interaction between haplotypes of CIDEB and CIDEC to obesity

    Institute of Scientific and Technical Information of China (English)

    平智广; 刘莉; 詹芳芳; 戚敏杰; 乐晓萍

    2015-01-01

    选取528名无关研究对象,男性198人,女性330人,平均年龄(52.2±13.4)岁,依体重指数分为正常体重组253人和超重肥胖组275人。检测 CIDEB 和 CIDEC 基因的10个 SNPs,采用 SHEsis 分析基因的单倍型。按加性遗传模式对各位点与肥胖的关系进行 logistic 回归,分析两种基因的单倍型致肥胖的主效应与交互作用。 CIDEB 基因的 rs2144493位点可能与肥胖有关,C 为保护性等位基因,OR(95% CI)为0.722(0.525~0.992)。 CIDEB 基因 CCTT 单倍型携带者和 CIDEC 基因 GCG 单倍型携带者可能更易患超重肥胖。两个基因单倍型之间存在交互作用。 CIDEB、CIDEC 基因单倍型在致肥胖方面可能存在独立以及交互作用。%[Summary] A selection of 528 unrelated subjects were enrolled(198 males, 330 females) with the mean age of(52. 23 ± 13. 41) years old. According to body mass index, 253 persons belonged to the normal weight group and 275 persons overweight/ obesity group. A total of 10 SNPs in CIDEB and CIDEC genes were detected. SHEsis online were used to get the haplotypes of these two genes. The relationship between above SNPs and obesity were analyzed under additive inheritance pattern. The main effects and interaction on obesity induced by two genes’ haplotypes were analyzed by logistic regression. rs2144493 in CIDEB gene was associated with obesity, C was a protective alleles, OR (95% CI) equals 0. 722(0. 525-0. 992). CCTT haplotype of CIDEB gene carriers and GCG haplotype of CIDEC gene carriers were more prone to obesity or overweight, there was an interaction between the haplotypes of 2 genes. CIDEB, CIDEC haplotypes may play independent and interactive roles in causing obesity.

  17. Batrachochytrium dendrobatidis shows high genetic diversity and ecological niche specificity among haplotypes in the Maya Mountains of Belize.

    Directory of Open Access Journals (Sweden)

    Kristine Kaiser

    Full Text Available The amphibian pathogen Batrachochytrium dendrobatidis (Bd has been implicated in amphibian declines around the globe. Although it has been found in most countries in Central America, its presence has never been assessed in Belize. We set out to determine the range, prevalence, and diversity of Bd using quantitative PCR (qPCR and sequencing of a portion of the 5.8 s and ITS1-2 regions. Swabs were collected from 524 amphibians of at least 26 species in the protected areas of the Maya Mountains of Belize. We sequenced a subset of 72 samples that had tested positive for Bd by qPCR at least once; 30 samples were verified as Bd. Eight unique Bd haplotypes were identified in the Maya Mountains, five of which were previously undescribed. We identified unique ecological niches for the two most broadly distributed haplotypes. Combined with data showing differing virulence shown in different strains in other studies, the 5.8 s - ITS1-2 region diversity found in this study suggests that there may be substantial differences among populations or haplotypes. Future work should focus on whether specific haplotypes for other genomic regions and possibly pathogenicity can be associated with haplotypes at this locus, as well as the integration of molecular tools with other ecological tools to elucidate the ecology and pathogenicity of Bd.

  18. Haplotype-resolved genome sequencing of a Gujarati Indian individual.

    Science.gov (United States)

    Kitzman, Jacob O; Mackenzie, Alexandra P; Adey, Andrew; Hiatt, Joseph B; Patwardhan, Rupali P; Sudmant, Peter H; Ng, Sarah B; Alkan, Can; Qiu, Ruolan; Eichler, Evan E; Shendure, Jay

    2011-01-01

    Haplotype information is essential to the complete description and interpretation of genomes, genetic diversity and genetic ancestry. Although individual human genome sequencing is increasingly routine, nearly all such genomes are unresolved with respect to haplotype. Here we combine the throughput of massively parallel sequencing with the contiguity information provided by large-insert cloning to experimentally determine the haplotype-resolved genome of a South Asian individual. A single fosmid library was split into a modest number of pools, each providing ∼3% physical coverage of the diploid genome. Sequencing of each pool yielded reads overwhelmingly derived from only one homologous chromosome at any given location. These data were combined with whole-genome shotgun sequence to directly phase 94% of ascertained heterozygous single nucleotide polymorphisms (SNPs) into long haplotype blocks (N50 of 386 kilobases (kbp)). This method also facilitates the analysis of structural variation, for example, to anchor novel insertions to specific locations and haplotypes.

  19. Haplotype map of sickle cell anemia in Tunisia.

    Science.gov (United States)

    Moumni, Imen; Ben Mustapha, Maha; Sassi, Sarra; Zorai, Amine; Ben Mansour, Ikbel; Douzi, Kais; Chouachi, Dorra; Mellouli, Fethi; Bejaoui, Mohamed; Abbes, Salem

    2014-01-01

    β-Globin haplotypes are important to establish the ethnic origin and predict the clinical development of sickle cell disease patients (SCD). To determine the chromosomal background of β (S) Tunisian sickle cell patients, in this first study in Tunisia, we have explored four polymorphic regions of β-globin cluster on chromosome 11. It is the 5' region of β-LCR-HS2 site, the intervening sequence II (IVSII) region of two fetal ((G)γ and (A)γ) genes and the 5' region of β-globin gene. The results reveal a high molecular diversity of a microsatellite configuration describing the sequences haplotypes. The linkage disequilibrium analysis showed various haplotype combinations giving 22 "extended haplotypes". These results confirm the utility of the β-globin haplotypes for population studies and contribute to knowledge of the Tunisian gene pool, as well as establishing the role of genetic markers in physiopathology of SCD.

  20. General Framework for Meta-Analysis of Haplotype Association Tests.

    Science.gov (United States)

    Wang, Shuai; Zhao, Jing Hua; An, Ping; Guo, Xiuqing; Jensen, Richard A; Marten, Jonathan; Huffman, Jennifer E; Meidtner, Karina; Boeing, Heiner; Campbell, Archie; Rice, Kenneth M; Scott, Robert A; Yao, Jie; Schulze, Matthias B; Wareham, Nicholas J; Borecki, Ingrid B; Province, Michael A; Rotter, Jerome I; Hayward, Caroline; Goodarzi, Mark O; Meigs, James B; Dupuis, Josée

    2016-04-01

    For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

  1. Experimental generation of SNP haplotype signatures in patients with sickle cell anaemia.

    Directory of Open Access Journals (Sweden)

    Stephan Menzel

    Full Text Available BACKGROUND: Sickle cell anemia is caused by a single type of mutation, a homozygous A→T substitution in the ß globin gene. Clinical severity is diverse, partially due to additional, disease-modifying genetic factors. We are studying one such modifier locus, HMIP (HBS1L-MYB intergenic polymorphism, chromosome 6q23.3. Working with a genetically admixed patient population, we have encountered the necessity to generate haplotype signatures of genetic markers to label genomic fragments with distinct genealogical origin at this locus. With the goal to generate haplotype signatures from patients experimentally, we have investigated the suitability of an existing nanofluidic assay platform to perform phase alignment with single-nucleotide polymorphism alleles. METHODOLOGY/PRINCIPAL FINDINGS: Patient DNA samples were loaded onto Fluidigm Digital Arrays and individual DNA molecules were assayed with allele-specific probes for SNP markers. Here we present data showing the utility of the nanofluidic approach, yielding haplotype data identical to those obtained with a family-based method. We then determined haplotype composition in a group of patients with sickle cell disease, including in those where a mathematical inference approach gave ambiguous or misleading results. Experimental phasing of genotypes across 3.8 kb for rs9399137, rs9402685, and rs11759553 created unequivocal haplotype signatures for each of the patients. In 68 patients, we found 8 copies of a haplotype signature ('C-C-T', which is known to be prevalent in Europeans but to be absent in West African populations. We have confirmed the identity of our phased allele pairs by single-molecule sequencing and have demonstrated, in principle, that three-allele phasing (using three colors is a potential extension to this method. CONCLUSIONS/SIGNIFICANCE: Phased haplotypes yield more information than the individual marker genotypes. Procedures such as the one described here would therefore

  2. The IGF1 small dog haplotype is derived from Middle Eastern grey wolves

    Directory of Open Access Journals (Sweden)

    Ostrander Elaine A

    2010-02-01

    Full Text Available Abstract Background A selective sweep containing the insulin-like growth factor 1 (IGF1 gene is associated with size variation in domestic dogs. Intron 2 of IGF1 contains a SINE element and single nucleotide polymorphism (SNP found in all small dog breeds that is almost entirely absent from large breeds. In this study, we surveyed a large sample of grey wolf populations to better understand the ancestral pattern of variation at IGF1 with a particular focus on the distribution of the small dog haplotype and its relationship to the origin of the dog. Results We present DNA sequence data that confirms the absence of the derived small SNP allele in the intron 2 region of IGF1 in a large sample of grey wolves and further establishes the absence of a small dog associated SINE element in all wild canids and most large dog breeds. Grey wolf haplotypes from the Middle East have higher nucleotide diversity suggesting an origin there. Additionally, PCA and phylogenetic analyses suggests a closer kinship of the small domestic dog IGF1 haplotype with those from Middle Eastern grey wolves. Conclusions The absence of both the SINE element and SNP allele in grey wolves suggests that the mutation for small body size post-dates the domestication of dogs. However, because all small dogs possess these diagnostic mutations, the mutations likely arose early in the history of domestic dogs. Our results show that the small dog haplotype is closely related to those in Middle Eastern wolves and is consistent with an ancient origin of the small dog haplotype there. Thus, in concordance with past archeological studies, our molecular analysis is consistent with the early evolution of small size in dogs from the Middle East. See associated opinion by Driscoll and Macdonald: http://jbiol.com/content/9/2/10

  3. Phasing for medical sequencing using rare variants and large haplotype reference panels

    Science.gov (United States)

    Sharp, Kevin; Kretzschmar, Warren; Delaneau, Olivier; Marchini, Jonathan

    2016-01-01

    Motivation: There is growing recognition that estimating haplotypes from high coverage sequencing of single samples in clinical settings is an important problem. At the same time very large datasets consisting of tens and hundreds of thousands of high-coverage sequenced samples will soon be available. We describe a method that takes advantage of these huge human genetic variation resources and rare variant sharing patterns to estimate haplotypes on single sequenced samples. Sharing rare variants between two individuals is more likely to arise from a recent common ancestor and, hence, also more likely to indicate similar shared haplotypes over a substantial flanking region of sequence. Results: Our method exploits this idea to select a small set of highly informative copying states within a Hidden Markov Model (HMM) phasing algorithm. Using rare variants in this way allows us to avoid iterative MCMC methods to infer haplotypes. Compared to other approaches that do not explicitly use rare variants we obtain significant gains in phasing accuracy, less variation over phasing runs and improvements in speed. For example, using a reference panel of 7420 haplotypes from the UK10K project, we are able to reduce switch error rates by up to 50% when phasing samples sequenced at high-coverage. In addition, a single step rephasing of the UK10K panel, using rare variant information, has a downstream impact on phasing performance. These results represent a proof of concept that rare variant sharing patterns can be utilized to phase large high-coverage sequencing studies such as the 100 000 Genomes Project dataset. Availability and implementation: A webserver that includes an implementation of this new method and allows phasing of high-coverage clinical samples is available at https://phasingserver.stats.ox.ac.uk/. Contact: marchini@stats.ox.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153703

  4. A common haplotype in the G-protein-coupled receptor gene GPR74 is associated with leanness and increased lipolysis

    DEFF Research Database (Denmark)

    Dahlman, Ingrid; Dicker, Andrea; Jiao, Hong

    2007-01-01

    0.36; P=.036) among those selected for obese or lean phenotypes. The ATAG haplotype was associated with increased adipocyte lipid mobilization (lipolysis) in vivo and in vitro. In human fat cells, GPR74 receptor stimulation and inhibition caused a significant and marked decrease and increase......, respectively, of lipolysis, which could be linked to catecholamine stimulation of adipocytes through beta -adrenergic receptors. These findings suggest that a common haplotype in the GPR74 gene protects against obesity, which, at least in part, is caused by a relief of inhibition of lipid mobilization from...... with protection against obesity in two samples selected for obese and lean phenotypes (odds ratio for obesity 0.48 and 0.62; nominal P=.0014 and .014; n=1,013 and 1,423, respectively). In a population-based sample, it was associated with lower waist (P=.02) among 3,937 men and with obesity protection (odds ratio...

  5. Accounting for haplotype phase uncertainty in linkage disequilibrium estimation.

    Science.gov (United States)

    Kulle, B; Frigessi, A; Edvardsen, H; Kristensen, V; Wojnowski, L

    2008-02-01

    The characterization of linkage disequilibrium (LD) is applied in a variety of studies including the identification of molecular determinants of the local recombination rate, the migration and population history of populations, and the role of positive selection in adaptation. LD suffers from the phase uncertainty of the haplotypes used in its calculation, which reflects limitations of the algorithms used for haplotype estimation. We introduce a LD calculation method, which deals with phase uncertainty by weighting all possible haplotype pairs according to their estimated probabilities as evaluated by PHASE. In contrast to the expectation-maximization (EM) algorithm as implemented in the HAPLOVIEW and GENETICS packages, our method considers haplotypes based on the entire genetic information available for the candidate region. We tested the method using simulated and real genotyping data. The results show that, for all practical purposes, the new method is advantageous in comparison with algorithms that calculate LD using only the most probable haplotype or bilocus haplotypes based on the EM algorithm. The new method deals especially well with low LD regions, which contribute strongly to phase uncertainty. Altogether, the method is an attractive alternative to standard LD calculation procedures, including those based on the EM algorithm. We implemented the method in the software suite R, together with an interface to the popular haplotype calculation package PHASE.

  6. Sulfite Additives

    OpenAIRE

    1988-01-01

    The CMA recommends that sulfites be banned as food preservatives when satisfactory and safe alternatives are available. When there is no suitable substitute strict labelling requirements on foods should be imposed for sulfite additives. The association supports the efforts of the Health Protection Branch of the Department of National Health and Welfare to regulate sulfites in the food and drug industry to prevent adverse reactions in people sensitive to sulfites. The CMA recommends that the D...

  7. Nasopharyngeal Carcinoma (NPC Related Human Leukocyte Antigen (HLA Haplotype Sharing among Southern East Asian Population

    Directory of Open Access Journals (Sweden)

    Rika Yuliwulandari

    2017-02-01

    Full Text Available Abstract The human leukocyte antigens (HLAs play important roles in the immune systems to response to various pathogens and disease among individuals. The aim of this study was analyze the HLA allele and haplotype frequencies of Southern East Asian population that show high incidence of nasopharyngeal carcinoma (NPC to evaluate the shared HLA haplotype contribution to NPC susceptibility among the population and analyses the genetic affinities between the population. We collect information of HLA haplotype from our previous study, other published paper, and HLA database in 19 population during 2005 to 2015. Haplotype frequencies were estimated using the maximum likelihood method based on an expectation maximization algorithm with ARLEQUIN v.2.0 software. We also calculated the genetic distance among 19 Southern East Asians based on HLA allele frequency using modified Cavalli-Sforza (DA distance method. Then, a phylogenetic tree was constructed using DISPAN software and principal component analysis (PCA was performed using XLSTAT-PRO software. A33-B58-DR3 haplotype, tightly linked to NPC, was commonly observed in all populations, supporting the high incidence of NPC in the populations. In addition, A2-B46 haplotype also associated with NPC, was also commonly found in several population that may also have a role in the disease development. The conclusion is the HLA haplotype sharing has an important role than the HLA allele sharing. The A33-B58-DR3 haplotype and A2-B46-DR9 haplotype in this study could be related to NPC in the Southern East Asian populations. The observed haplotype needs to be tested in the real patients to confirm the assumption. Abstrak Human leukocyte antigens (HLAs berperan penting dalam sistem imun untuk merespons berbagai patogen dan penyakit di antara individu yang berbeda. Tujuan penelitian ini menganalisis frekuensi alel dan haplotipe HLA populasi Southern East Asia yang menunjukkan insidensi yang tinggi terhadap

  8. Multi-locus stepwise regression: a haplotype-based algorithm for finding genetic associations applied to atopic dermatitis

    Directory of Open Access Journals (Sweden)

    Knüppel Sven

    2012-01-01

    Full Text Available Abstract Background Genome-wide association studies (GWAS provide an increasing number of single nucleotide polymorphisms (SNPs associated with diseases. Our aim is to exploit those closely spaced SNPs in candidate regions for a deeper analysis of association beyond single SNP analysis, combining the classical stepwise regression approach with haplotype analysis to identify risk haplotypes for complex diseases. Methods Our proposed multi-locus stepwise regression starts with an evaluation of all pair-wise SNP combinations and then extends each SNP combination stepwise by one SNP from the region, carrying out haplotype regression in each step. The best associated haplotype patterns are kept for the next step and must be corrected for multiple testing at the end. These haplotypes should also be replicated in an independent data set. We applied the method to a region of 259 SNPs from the epidermal differentiation complex (EDC on chromosome 1q21 of a German GWAS using a case control set (1,914 individuals and to 268 families with at least two affected children as replication. Results A 4-SNP haplotype pattern with high statistical significance in the case control set (p = 4.13 × 10-7 after Bonferroni correction could be identified which remained significant in the family set after Bonferroni correction (p = 0.0398. Further analysis revealed that this pattern reflects mainly the effect of the well-known FLG gene; however, a FLG-independent haplotype in case control set (OR = 1.71, 95% CI: 1.32-2.23, p = 5.6 × 10-5 and family set (OR = 1.68, 95% CI: 1.18-2.38, p = 2.19 × 10-3 could be found in addition. Conclusion Our approach is a useful tool for finding allele combinations associated with diseases beyond single SNP analysis in chromosomal candidate regions.

  9. A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study.

    Science.gov (United States)

    Lupo, Philip J; Chapa, Claudia; Nousome, Darryl; Duhon, Cody; Canfield, Mark A; Shaw, Gary M; Finnell, Richard H; Zhu, Huiping

    2012-11-01

    Tetrahydrobiopterin (BH(4)) is an essential cofactor and an important cellular antioxidant. BH(4) deficiency has been associated with diseases whose etiologies stem from excessive oxidative stress. GTP cyclohydrolase I (GCH1) catalyzes the first and rate-limiting step of de novo BH(4) synthesis. A 3-SNP haplotype in GCH1 (rs8007267, rs3783641, and rs10483639) is known to modulate GCH1 gene expression levels and has been suggested as a major determinant of plasma BH(4) bioavailability. As plasma BH(4) bioavailability has been suggested as a mechanism of neural tube defect (NTD) teratogenesis, we evaluated the association between this GCH1 haplotype and the risk of NTDs. Samples were obtained from 760 NTD case-parent triads included in the National Birth Defects Prevention Study (NBDPS). The three SNPs were genotyped using TaqMan® SNP assays. An extension of the log-linear model was used to assess the association between NTDs and both offspring and maternal haplotypes. Offspring carrying two copies of haplotype C-T-C had a significantly increased NTD risk (risk ratio [RR]=3.40, 95% confidence interval [CI]: 1.02-11.50), after adjusting for the effect of the maternal haplotype. Additionally, mothers carrying two copies of haplotype C-T-C had a significantly increased risk of having an NTD-affected offspring (RR=3.46, 95% CI: 1.05-11.00), after adjusting for the effect of the offspring haplotype. These results suggest offspring and maternal variation in the GCH1 gene and altered BH(4) biosynthesis may contribute to NTD risk.

  10. A haplotype of human angiotensinogen gene containing -217A increases blood pressure in transgenic mice compared with -217G.

    Science.gov (United States)

    Jain, Sudhir; Vinukonda, Govindaiah; Fiering, Steven N; Kumar, Ashok

    2008-12-01

    The human angiotensinogen (hAGT) gene contains an A/G polymorphism at -217, and frequency of -217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb region of its promoter, and variant -217A almost always occurs with -532T, -793A, and -1074T, whereas variant -217G almost always occurs with -532C, -793G, and -1074G. Since allele -6A is the predominant allele in African-Americans, the AGT gene can be subdivided into two main haplotypes, -6A:-217A (AA) and -6A:-217G (AG). To understand the role of these haplotypes on hAGT gene expression and on blood pressure regulation in an in vivo situation, we have generated double transgenic mice containing human renin gene and either AA or AG haplotype of the hAGT gene using knock-in strategy at the hypoxanthine phosphoribosyltransferase locus. We show here that 1) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%; and 2) plasma AGT level is increased by approximately 40%, and plasma angiotensin II level is increased by approximately 50% in male double transgenic mice containing AA haplotype of the hAGT gene compared with the AG haplotype. In addition, systolic blood pressure is increased by 8 mmHg in transgenic mice containing the AA haplotype compared with the AG haplotype. This is the first report to show the effect of polymorphisms in the promoter of a human gene on its transcription in an in vivo situation that ultimately leads to an increase in blood pressure.

  11. Beta-globin haplotype analysis suggests that a major source of Malagasy ancestry is derived from Bantu-speaking Negroids.

    Science.gov (United States)

    Hewitt, R; Krause, A; Goldman, A; Campbell, G; Jenkins, T

    1996-06-01

    The origins of the inhabitants of Madagascar have not been fully resolved. Anthropological studies and preliminary genetic data point to two main sources of ancestry of the Malagasy, namely, Indonesian and African, with additional contributions from India and Arabia. The sickle-cell (beta s) mutation is found in populations of African and Indian origin. The frequency of the beta s-globin gene, derived from 1,425 Malagasy individuals, varies from 0 in some highland populations to .25 in some coastal populations. The beta s mutation is thought to have arisen at least five times, on the basis of the presence of five distinct beta s-associated haplotypes, each found in a separate geographic area. Twenty-five of the 35 Malagasy beta s haplotypes were of the typical "Bantu" type, 1 "Senegal" haplotype was found, and 2 rare or atypical haplotypes were observed; the remaining 7 haplotypes were consistent with the Bantu haplotype. The Bantu beta s mutation is thought to have been introduced into Madagascar by Bantu-speaking immigrants (colonists or slaves) from central or east Africa. The Senegal beta s mutation may have been introduced to the island via Portuguese naval explorers. This study provides the first definitive biological evidence that a major component of Malagasy ancestry is derived from African populations, in particular, Bantu-speaking Negroids. beta A haplotypes are also consistent with the claim for a significant African contribution to Malagasy ancestry but are also suggestive of Asian/Oceanic and Caucasoid admixture within the Malagasy population.

  12. Maximum-likelihood estimation of haplotype frequencies in nuclear families.

    Science.gov (United States)

    Becker, Tim; Knapp, Michael

    2004-07-01

    The importance of haplotype analysis in the context of association fine mapping of disease genes has grown steadily over the last years. Since experimental methods to determine haplotypes on a large scale are not available, phase has to be inferred statistically. For individual genotype data, several reconstruction techniques and many implementations of the expectation-maximization (EM) algorithm for haplotype frequency estimation exist. Recent research work has shown that incorporating available genotype information of related individuals largely increases the precision of haplotype frequency estimates. We, therefore, implemented a highly flexible program written in C, called FAMHAP, which calculates maximum likelihood estimates (MLEs) of haplotype frequencies from general nuclear families with an arbitrary number of children via the EM-algorithm for up to 20 SNPs. For more loci, we have implemented a locus-iterative mode of the EM-algorithm, which gives reliable approximations of the MLEs for up to 63 SNP loci, or less when multi-allelic markers are incorporated into the analysis. Missing genotypes can be handled as well. The program is able to distinguish cases (haplotypes transmitted to the first affected child of a family) from pseudo-controls (non-transmitted haplotypes with respect to the child). We tested the performance of FAMHAP and the accuracy of the obtained haplotype frequencies on a variety of simulated data sets. The implementation proved to work well when many markers were considered and no significant differences between the estimates obtained with the usual EM-algorithm and those obtained in its locus-iterative mode were observed. We conclude from the simulations that the accuracy of haplotype frequency estimation and reconstruction in nuclear families is very reliable in general and robust against missing genotypes.

  13. The Effect of Haplotype-Block Definitions on Inference of Haplotype-Block Structure and htSNPs Selection

    Institute of Scientific and Technical Information of China (English)

    KeyueDing; KaixinZhou; JingZhang; JoanneKnight; XuegongZhang; YanShen

    2005-01-01

    It has been recently suggested that the human genome is organized as a series of haplotype blocks, and efforts to create a genome-wide haplotype map are already underway. Several computational algorithms have been proposed to partition the genome. However, little is known about their behaviors in relation to the haplotype-block partitioning and haplotypetagging SNPs selection. Here, we present a systematic comparison of three classes of haplotype-block partition definitions, a diversity-based method, a linkage-disequilibrium (LD)-based method, and a recombination-based method.The data used were derived from a coalescent simulation under both a uniform recombination model and one that assumes recombination hotspots. There were considerable differences in haplotype information loss in the measure of entropy when the partition methods were compared under different population-genetics scenarios. Under both recombination models, the results from the LD-based definition and the recombination-based definition were more similar to each other than were the results from the diversity-based definition. This work demonstrates that when undertaking haplotype-based association mapping, the choice of haplotype-block definition and SNP selection requires careful consideration.

  14. High frequency of Plasmodium falciparum CICNI/SGEAA and CVIET haplotypes without association with resistance to sulfadoxine/pyrimethamine and chloroquine combination in the Daraweesh area, in Sudan

    DEFF Research Database (Denmark)

    A-Elbasit, I E; Khalil, I F; Elbashir, M I

    2008-01-01

    , 50%; TF 55%) were not associated with TF. In contrast to other studies in Africa, the triple 51I/59R/108N mutation was rare (0.6%). In addition, the pfcrt CVIET haplotype (93%) was found to be associated with the CICNI/SGEAA haplotype. Finally, these data represent a baseline for SP resistance...

  15. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects.

    Science.gov (United States)

    Hennah, William; Varilo, Teppo; Kestilä, Marjo; Paunio, Tiina; Arajärvi, Ritva; Haukka, Jari; Parker, Alex; Martin, Rory; Levitzky, Steve; Partonen, Timo; Meyer, Joanne; Lönnqvist, Jouko; Peltonen, Leena; Ekelund, Jesper

    2003-12-01

    We have previously reported a linkage peak on 1q42 in a Finnish schizophrenia sample. In this study we genotyped 28 single nucleotide polymorphisms (SNPs) from 1q42 covering the three candidate genes TRAX, DISC1 and DISC2, using a study sample of 458 Finnish families ascertained for schizophrenia. Two-point and haplotype association analysis revealed a significant region of interest within the DISC1 gene. A common haplotype (HEP3) was observed to be significantly under-transmitted to affected individuals (P=0.0031). HEP3 represents a two SNP haplotype spanning from intron 1 to exon 2 of DISC1. This haplotype also displayed sex differences in transmission distortion, the under-transmission being significant only to affected females (P=0.00024). Three other regions of interest were observed in the TRAX and DISC genes. However, analysis of only those families with complete genotype information specifically highlights the HEP3 haplotype as a true observation. The finding of a common under-transmitted SNP haplotype might imply that this particular allele offers some protection from the development of schizophrenia. Analysis of component-traits of schizophrenia, derived from the Operational Criteria Checklist of Psychotic Illness (OCCPI), displayed association of HEP3 to features of the general phenotype of schizophrenia, including traits representing delusions, hallucinations and negative symptoms. This study provides further evidence for the hypothesis that the DISC1 gene is involved in the aetiology of schizophrenia, and implies a putative sex difference for the effect of the gene. Our findings would also encourage more detailed analyses of the effect of DISC1 on the component-traits of schizophrenia.

  16. Mitochondrial DNA polymorphisms in Phytophthora infestans: new haplotypes are identified and re-defined by PCR.

    Science.gov (United States)

    Yang, Zhi-Hui; Qi, Ming-Xing; Qin, Yu-Xuan; Zhu, Jie-Hua; Gui, Xiu-Mei; Tao, Bu; Xu, Xiao-Hu; Zhang, Fu-Guang

    2013-11-01

    Polymorphisms of mitochondrial DNA (mt-DNA) are particularly useful for monitoring specific pathogen populations like Phytophthora infestans. Basically type I and II of P. infestans mt-DNA were categorized by means of polymorphism lengths caused by an ~2 kb insertion, which can be detected via restriction enzyme digestion. In addition genome sequencing of haplotype Ib has been used as a simple Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method to indirectly identify type I and II alterations through EcoR I restriction enzyme DNA fragment patterns of the genomic P4 area. However, with the common method, wrong mt-DNA typing occurs due to an EcoR I recognition site mutation in the P4 genomic area. Genome sequencing of the four haplotypes (Ia, Ib, IIa, and IIb) allowed us to thoroughly examine mt-DNA polymorphisms and we indentified two hypervariable regions (HVRs) named HVRi and HVRii. The HVRi length polymorphism caused by a 2 kb insertion/deletion was utilized to identify mt-DNA types I and II, while another length polymorphism in the HVRii region is caused by a variable number of tandem repeats (n = 1, 2, or 3) of a 36 bp sized DNA stretch and was further used to determine mt-DNA sub-types, which were described as R(n = 1, 2, or 3). Finally, the P. infestans mt-DNA haplotypes were re-defined as IR(1) or IIR(2) according to PCR derived HVRi and HVRii length polymorphisms. Twenty-three isolates were chosen to verify the feasibility of our new approach for identifying mt-DNA haplotypes and a total of five haplotypes (IR(1), IR(2), IR(3), IIR(2) and IIR(3)) were identified. Additionally, we found that six isolates determined as type I by our method were mistakenly identified as type II by the PCR-RFLP technique. In conclusion, we propose a simple and rapid PCR method for identification of mt-DNA haplotypes based on sequence analyses of the mitochondrial P. infestans genome.

  17. Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Nilsson Michael

    2010-03-01

    Full Text Available Abstract Background Oxidative stress is heavily implicated in the pathogenic process of Parkinson's disease. Varying capacity to detoxify radical oxygen species through induction of phase II antioxidant enzymes in substantia nigra may influence disease risk. Here, we hypothesize that variation in NFE2L2 and KEAP1, the genes encoding the two major regulators of the phase II response, may affect the risk of Parkinson's disease. Methods The study included a Swedish discovery case-control material (165 cases and 190 controls and a Polish replication case-control material (192 cases and 192 controls. Eight tag single nucleotide polymorphisms representing the variation in NFE2L2 and three representing the variation in KEAP1 were chosen using HapMap data and were genotyped using TaqMan Allelic Discrimination. Results We identified a protective NFE2L2 haplotype in both of our European case-control materials. Each haplotype allele was associated with five years later age at onset of the disease (p = 0.001 in the Swedish material, and decreased risk of PD (p = 2 × 10-6, with an odds ratio of 0.4 (95% CI 0.3-0.6 for heterozygous and 0.2 (95% CI 0.1-0.4 for homozygous carriers, in the Polish material. The identified haplotype includes a functional promoter haplotype previously associated with high transcriptional activity. Genetic variation in KEAP1 did not show any associations. Conclusion These data suggest that variation in NFE2L2 modifies the Parkinson's disease process and provide another link between oxidative stress and neurodegeneration.

  18. De novo assembly of a haplotype-resolved human genome.

    Science.gov (United States)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang; Huang, Shujia; Sun, Yuhui; Tong, Xin; Xie, Yinlong; Liu, Binghang; Yang, Hailong; Zheng, Hancheng; Li, Jian; Li, Bo; Wang, Yu; Yang, Fang; Sun, Peng; Liu, Siyang; Gao, Peng; Huang, Haodong; Sun, Jing; Chen, Dan; He, Guangzhu; Huang, Weihua; Huang, Zheng; Li, Yue; Tellier, Laurent C A M; Liu, Xiao; Feng, Qiang; Xu, Xun; Zhang, Xiuqing; Bolund, Lars; Krogh, Anders; Kristiansen, Karsten; Drmanac, Radoje; Drmanac, Snezana; Nielsen, Rasmus; Li, Songgang; Wang, Jian; Yang, Huanming; Li, Yingrui; Wong, Gane Ka-Shu; Wang, Jun

    2015-06-01

    The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should aid in translating genotypes to phenotypes for the development of personalized medicine.

  19. De novo assembly of a haplotype-resolved human genome

    DEFF Research Database (Denmark)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang

    2015-01-01

    The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome...... of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should...... shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb...

  20. Haplotype Map of Sickle Cell Anemia in Tunisia

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    Imen Moumni

    2014-01-01

    Full Text Available β-Globin haplotypes are important to establish the ethnic origin and predict the clinical development of sickle cell disease patients (SCD. To determine the chromosomal background of βS Tunisian sickle cell patients, in this first study in Tunisia, we have explored four polymorphic regions of β-globin cluster on chromosome 11. It is the 5′ region of β-LCR-HS2 site, the intervening sequence II (IVSII region of two fetal (γG and γA genes and the 5′ region of β-globin gene. The results reveal a high molecular diversity of a microsatellite configuration describing the sequences haplotypes. The linkage disequilibrium analysis showed various haplotype combinations giving 22 “extended haplotypes”. These results confirm the utility of the β-globin haplotypes for population studies and contribute to knowledge of the Tunisian gene pool, as well as establishing the role of genetic markers in physiopathology of SCD.

  1. Hematological observations on Arabian SS patients with a homozygosity or heterozygosity for a beta S chromosome with haplotype #31.

    Science.gov (United States)

    Kutlar, A; Hattori, Y; Bakioglu, I; Kutlar, F; Kamel, K; Huisman, T H

    1985-01-01

    Hematological and hemoglobin composition data are presented for seven Arabian SS patients with mild disease and with high Hb F levels varying between 21 and 34%. Four patients were homozygous for a beta S chromosome with a specific haplotype (#31). The data for these four patients were similar to those for three other SS patients (and for five patients reported earlier, Ref. 2) who were heterozygous for the same beta S chromosome (#31) and for a beta S chromosome with another haplotype (mainly #19). These data offer additional evidence indicating that the increased gamma chain production is specific for the beta S chromosome with haplotype #31. The similarities in hematological data and Hb F levels between these two groups of SS patients and the normal Hb F value in Hb S heterozygotes with beta S chromosome (#31) support the suggestion that the increased Hb F production mainly occurs in response to the anemia of the sickle cell disease.

  2. Y-chromosome STR haplotypes in males from Greenland

    DEFF Research Database (Denmark)

    Hallenberg, Charlotte; Tomas Mas, Carmen; Simonsen, Bo;

    2009-01-01

    A total of 272 males from Greenland were typed for 11 Y-chromosome STRs DYS19, DYS385a/b, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 with the PowerPlex Y System (Promega). A total of 146 different haplotypes were observed and the haplotype diversity was 0.9887....

  3. Haplotypes in tribal Indians bearing the sickle gene: evidence for the unicentric origin of the beta S mutation and the unicentric origin of the tribal populations of India.

    Science.gov (United States)

    Labie, D; Srinivas, R; Dunda, O; Dode, C; Lapoumeroulie, C; Devi, V; Devi, S; Ramasami, K; Elion, J; Ducrocq, R

    1989-08-01

    To determine the origin of sickle cell anemia (SS) in India, we analyzed haplotypes of the beta gene cluster in beta S-carrying individuals belonging to tribal populations living in the Nilgiris region of southern India and complemented the available data on tribes of east-central India. We found that in the Nilgiris tribes chromosomes bearing the beta S gene are linked in 91% of the cases to the "Asian" (Arab-Indian) haplotype (although 25% of the haplotypes had the epsilon polymorphic site negative, making the 5' portion of the haplotype identical with the African Senegal haplotype). These XmnI (+) chromosomes were associated with high G gamma expression (67.2 +/- 5.9%) and a high percentage of Hb F (15.5 +/- 7.9%; range, 6-25.3%). We have similar findings for tribal groups from west-central India (Gujarat). In east-central India we have confirmed the data of others, finding the same haplotype linked to beta S in tribes living in the east (Orissa, Andhra Pradesh). We conclude that the beta S gene in presently isolated and disperse tribal populations in India is associated with one predominant typical haplotype, suggesting a unicentric origin of the mutation in India. In addition, this finding implies a unicentric origin of the tribal populations themselves: The gene must have arisen and spread before tribal dispersion. Furthermore, we find extremely high frequencies of the (-alpha) haplotype in the Nilgiris (0.89) and in Gujarat (0.95). The beta S gene linkage to a high Hb F-expressing haplotype and the high incidence of alpha-thalassemia predict a mild phenotypical expression of sickle cell anemia in India.

  4. Conditional likelihood inference in a case- cohort design: an application to haplotype analysis.

    Science.gov (United States)

    Saarela, Olli; Kulathinal, Sangita

    2007-01-01

    Under the setting of a case-cohort design, covariate values are ascertained for a smaller subgroup of the original study cohort which typically is a representative sample from a population. Individuals with a specific event outcome are selected to the second stage study group as cases and an additional subsample is selected to act as a control group. We carry out analysis of such a design using conditional likelihood where the likelihood expression is conditioned on the ascertainment to the second stage study group. Such likelihood expression involves the probability of ascertainment which need to be expressed in terms of the model parameters. We present examples of conditional likelihoods for models for categorical response and time-to-event response. We show that the conditional likelihood inference leads to valid estimation of population parameters. Our application considers joint estimation of haplotype-event association parameters and population haplotype frequencies based on SNP genotype data collected under a case-cohort design.

  5. Short communication: casein haplotype variability in sicilian dairy goat breeds.

    Science.gov (United States)

    Gigli, I; Maizon, D O; Riggio, V; Sardina, M T; Portolano, B

    2008-09-01

    In the Mediterranean region, goat milk production is an important economic activity. In the present study, 4 casein genes were genotyped in 5 Sicilian goat breeds to 1) identify casein haplotypes present in the Argentata dell'Etna, Girgentana, Messinese, Derivata di Siria, and Maltese goat breeds; and 2) describe the structure of the Sicilian goat breeds based on casein haplotypes and allele frequencies. In a sample of 540 dairy goats, 67 different haplotypes with frequency >or=0.01 and 27 with frequency >or=0.03 were observed. The most common CSN1S1-CSN2-CSN1S2-CSN3 haplotype for Derivata di Siria and Maltese was FCFB (0.17 and 0.22, respectively), whereas for Argentata dell'Etna, Girgentana and Messinese was ACAB (0.06, 0.23, and 0.10, respectively). According to the haplotype reconstruction, Argentata dell'Etna, Girgentana, and Messinese breeds presented the most favorable haplotype for cheese production, because the casein concentration in milk of these breeds might be greater than that in Derivata di Siria and Maltese breeds. Based on a cluster analysis, the breeds formed 2 main groups: Derivata di Siria, and Maltese in one group, and Argentata dell'Etna and Messinese in the other; the Girgentana breed was between these groups but closer to the latter.

  6. Haplotype allelic classes for detecting ongoing positive selection.

    Science.gov (United States)

    Hussin, Julie; Nadeau, Philippe; Lefebvre, Jean-François; Labuda, Damian

    2010-01-28

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

  7. Haplotype allelic classes for detecting ongoing positive selection

    Directory of Open Access Journals (Sweden)

    Lefebvre Jean-François

    2010-01-01

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

  8. MHC Class II haplotypes of Colombian Amerindian tribes.

    Science.gov (United States)

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

    2013-07-01

    We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America.

  9. MHC Class II haplotypes of Colombian Amerindian tribes

    Directory of Open Access Journals (Sweden)

    Juan J. Yunis

    2013-01-01

    Full Text Available We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family, Embera, Waunana (Choco linguistic family, Puinave and Nukak (Maku-Puinave linguistic families, Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family, Guahibo and Guayabero (Guayabero Linguistic Family, Curripaco and Piapoco (Arawak linguistic family and Yucpa (Karib linguistic family. for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1. Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America.

  10. Allelic variation of the inducible costimulator (ICOS) gene: detection of polymorphisms, analysis of the promoter region, and extended haplotype estimation

    DEFF Research Database (Denmark)

    Andersen, A.D.H.; Lange, Marianne; Lillevang, S.T.

    2003-01-01

    , consistent with the [T](n) and the [GT](n) regions reported in a Japanese study. Putative haplotypes for the established SNP and repeat polymorphisms have been estimated by computational analysis. Sequencing of similar to3500 by of the upstream region of ICOS revealed an additional eight SNP of which two...

  11. "HOOF-Print" Genotyping and Haplotype Inference Discriminates among Brucella spp Isolates From a Small Spatial Scale

    Science.gov (United States)

    We demonstrate that the “HOOF-Print” assay provides high power to discriminate among Brucella isolates collected on a small spatial scale (within Portugal). Additionally, we illustrate how haplotype identification using non-random association among markers allows resolution of B. melitensis biovars ...

  12. Association testing by haplotype-sharing methods applicable to whole-genome analysis

    NARCIS (Netherlands)

    Nolte, Ilja M.; Vries, André R. de; Spijker, Geert T.; Jansen, Ritsert C.; Brinza, Dumitru; Zelikovsky, Alexander; Meerman, Gerard J. te

    2007-01-01

    We propose two new haplotype-sharing methods for identifying disease loci: the haplotype sharing statistic (HSS), which compares length of shared haplotypes between cases and controls, and the CROSS test, which tests whether a case and a control haplotype show less sharing than two random

  13. Excap: maximization of haplotypic diversity of linked markers.

    Directory of Open Access Journals (Sweden)

    André Kahles

    Full Text Available Genetic markers, defined as variable regions of DNA, can be utilized for distinguishing individuals or populations. As long as markers are independent, it is easy to combine the information they provide. For nonrecombinant sequences like mtDNA, choosing the right set of markers for forensic applications can be difficult and requires careful consideration. In particular, one wants to maximize the utility of the markers. Until now, this has mainly been done by hand. We propose an algorithm that finds the most informative subset of a set of markers. The algorithm uses a depth first search combined with a branch-and-bound approach. Since the worst case complexity is exponential, we also propose some data-reduction techniques and a heuristic. We implemented the algorithm and applied it to two forensic caseworks using mitochondrial DNA, which resulted in marker sets with significantly improved haplotypic diversity compared to previous suggestions. Additionally, we evaluated the quality of the estimation with an artificial dataset of mtDNA. The heuristic is shown to provide extensive speedup at little cost in accuracy.

  14. Association with Spontaneous Hepatitis C Viral Clearance and Genetic Differentiation of IL28B/IFNL4 Haplotypes in Populations from Mexico

    Science.gov (United States)

    Gonzalez-Aldaco, Karina; Rebello Pinho, João R.; Roman, Sonia; Gleyzer, Ketti; Fierro, Nora A.; Oyakawa, Leticia; Ramos-Lopez, Omar; Ferraz Santana, Rubia A.; Sitnik, Roberta; Panduro, Arturo

    2016-01-01

    Aim To analyze the genetic heterogeneity of the Amerindian and admixed population (Mestizos) based on the IL28B (rs12979860, rs8099917) and IFNL4 (rs368234815) haplotypes, and their association with spontaneous clearance (SC) and liver damage in patients with hepatitis C infection from West Mexico. Methods A total of 711 subjects from West Mexico (181 Amerindians and 530 Mestizos) were studied for the prevalence of IL28B (rs12979860C/T, rs8099917G/T) and IFNL4 (rs368234815∆G/TT) genotypes. A case-control study was performed in 234 treatment-naïve HCV Mestizos (149 chronic hepatitis C and 85 with SC) for the association of haplotypes with SC and liver damage. A real-time PCR assay was used for genotyping, and transitional elastography staged liver damage. Results Significant Fst-values indicated differentiation between the studied populations. The frequencies of the protective C, T, TT alleles were significantly lower in the Amerindians than in Mestizos (p<0.05). The r2 measure of linkage disequilibrium was significant for all variants and the T/G/ΔG risk haplotype predominated in Amerindians and secondly in Mestizos. The protective C/T/TT haplotype was associated with SC (OR = 0.46, 95% IC 0.22–0.95, p = 0.03) and less liver damage (OR = 0.32, 95% IC 0.10–0.97, p = 0.04) in chronic patients. The Structure software analysis demonstrated no significant differences in ancestry among SC and chronic patients. Conclusions West Mexico´s population is genetically heterogeneous at the IL28B/IFNL4 polymorphisms. The T/G/ΔG high-risk haplotype predominated in Amerindians and the beneficial alternative haplotype in Mestizos. The C/T/TT haplotype was associated with SC and less liver damage in chronically infected Mestizo patients. PMID:26741362

  15. Inducible Nitric Oxide Synthase Promoter Haplotypes and Residential Traffic-Related Air Pollution Jointly Influence Exhaled Nitric Oxide Level in Children.

    Directory of Open Access Journals (Sweden)

    Muhammad T Salam

    road lengths within 200m buffer on FeNO were also observed.Higher exposure from residential traffic nullifies the protective effect of one common NOS2 promoter haplotype on FeNO level. Regulation of traffic-related pollution may protect children's respiratory health.

  16. DNA analysis of ancient dogs of the Americas: identifying possible founding haplotypes and reconstructing population histories.

    Science.gov (United States)

    Witt, Kelsey E; Judd, Kathleen; Kitchen, Andrew; Grier, Colin; Kohler, Timothy A; Ortman, Scott G; Kemp, Brian M; Malhi, Ripan S

    2015-02-01

    As dogs have traveled with humans to every continent, they can potentially serve as an excellent proxy when studying human migration history. Past genetic studies into the origins of Native American dogs have used portions of the hypervariable region (HVR) of mitochondrial DNA (mtDNA) to indicate that prior to European contact the dogs of Native Americans originated in Eurasia. In this study, we summarize past DNA studies of both humans and dogs to discuss their population histories in the Americas. We then sequenced a portion of the mtDNA HVR of 42 pre-Columbian dogs from three sites located in Illinois, coastal British Columbia, and Colorado, and identify four novel dog mtDNA haplotypes. Next, we analyzed a dataset comprised of all available ancient dog sequences from the Americas to infer the pre-Columbian population history of dogs in the Americas. Interestingly, we found low levels of genetic diversity for some populations consistent with the possibility of deliberate breeding practices. Furthermore, we identified multiple putative founding haplotypes in addition to dog haplotypes that closely resemble those of wolves, suggesting admixture with North American wolves or perhaps a second domestication of canids in the Americas. Notably, initial effective population size estimates suggest at least 1000 female dogs likely existed in the Americas at the time of the first known canid burial, and that population size increased gradually over time before stabilizing roughly 1200 years before present.

  17. Analysis of Case-Control Association Studies: SNPs, Imputation and Haplotypes

    KAUST Repository

    Chatterjee, Nilanjan

    2009-11-01

    Although prospective logistic regression is the standard method of analysis for case-control data, it has been recently noted that in genetic epidemiologic studies one can use the "retrospective" likelihood to gain major power by incorporating various population genetics model assumptions such as Hardy-Weinberg-Equilibrium (HWE), gene-gene and gene-environment independence. In this article we review these modern methods and contrast them with the more classical approaches through two types of applications (i) association tests for typed and untyped single nucleotide polymorphisms (SNPs) and (ii) estimation of haplotype effects and haplotype-environment interactions in the presence of haplotype-phase ambiguity. We provide novel insights to existing methods by construction of various score-tests and pseudo-likelihoods. In addition, we describe a novel two-stage method for analysis of untyped SNPs that can use any flexible external algorithm for genotype imputation followed by a powerful association test based on the retrospective likelihood. We illustrate applications of the methods using simulated and real data. © Institute of Mathematical Statistics, 2009.

  18. Genotype variability and haplotype profile of ABCB1 (MDR1) gene polymorphisms in Macedonian population.

    Science.gov (United States)

    Naumovska, Zorica; Nestorovska, Aleksandra K; Sterjev, Zoran; Filipce, Ana; Dimovski, Aleksandar; Suturkova, Ljubica

    2014-01-01

    The aim of this study was to evaluate the most common ABCB1 (MDR1, P-glycoprotein) polymorphisms in the population of R. Macedonia and compare the allele and haplotype frequencies with the global geographic data reported from different ethnic populations. The total of 107 healthy Macedonian individuals from the general population was included. Genotypes for the ABCB1 for three polymorphisms C1236T [rs1128503], G2677A/T [rs2032582] and C3435T [rs1045642] were analyzed by Real-Time PCR. Obtained allele frequencies for these three SNPs were similar to those observed in other European Caucasians. The detected genotype frequencies were 33.6% for 1236CC, 44.9% for 1236CT and 21.5% for 1236TT in exon 12; 32.7%, 44.9% and 22.4% for 2677GG, 2677GT and 2677GT consecutively in exon 21; and 25.2% for 3435CC, 52.3% for 3435CT and 22.5% for 3435TT in exon 26.Strong LD was observed in our study among all three SNPs with the highest association confirmed for C1236T and G2677T ((D'=0.859, r2=0.711). Eight different haplotypes were identified and the most prominent was the CGC haplotype (45.3%). Our study was the first to have documented the distribution of ABCB1 alleles, genotypes and haplotypes in the population of R. Macedonia. The obtained results can help in the prediction of different response to the drugs that are P-glycoprotein substrates. Additionally, in the era of individualized medicine the determination of the P-glycoprotein genotype might be a good predictive marker for determination of the subpopulations with higher risk to certain diseases.

  19. Insights into HLA-G genetics provided by worldwide haplotype diversity

    Directory of Open Access Journals (Sweden)

    Erick C Castelli

    2014-10-01

    Full Text Available Human Leucocyte Antigen G (HLA-G belongs to the family of nonclassical HLA class I genes, located within the major histocompatibility complex (MHC. HLA-G has been the target of most recent research regarding the function of class I nonclassical genes. The main features that distinguish HLA-G from classical class I genes are: a limited protein variability; b alternative splicing generating several membrane bound and soluble isoforms; c short cytoplasmic tail; d modulation of immune response (immune tolerance; e restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments (promoter, coding and 3’untranslated regions. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding and 3’ untranslated regions are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.

  20. Remarkable variation in maize genome structure inferred from haplotype diversity at the bz locus.

    Science.gov (United States)

    Wang, Qinghua; Dooner, Hugo K

    2006-11-21

    Maize is probably the most diverse of all crop species. Unexpectedly large differences among haplotypes were first revealed in a comparison of the bz genomic regions of two different inbred lines, McC and B73. Retrotransposon clusters, which comprise most of the repetitive DNA in maize, varied markedly in makeup, and location relative to the genes in the region and genic sequences, later shown to be carried by two helitron transposons, also differed between the inbreds. Thus, the allelic bz regions of these Corn Belt inbreds shared only a minority of the total sequence. To investigate further the variation caused by retrotransposons, helitrons, and other insertions, we have analyzed the organization of the bz genomic region in five additional cultivars selected because of their geographic and genetic diversity: the inbreds A188, CML258, and I137TN, and the land races Coroico and NalTel. This vertical comparison has revealed the existence of several new helitrons, new retrotransposons, members of every superfamily of DNA transposons, numerous miniature elements, and novel insertions flanked at either end by TA repeats, which we call TAFTs (TA-flanked transposons). The extent of variation in the region is remarkable. In pairwise comparisons of eight bz haplotypes, the percentage of shared sequences ranges from 25% to 84%. Chimeric haplotypes were identified that combine retrotransposon clusters found in different haplotypes. We propose that recombination in the common gene space greatly amplifies the variability produced by the retrotransposition explosion in the maize ancestry, creating the heterogeneity in genome organization found in modern maize.

  1. Effects of the number of markers per haplotype and clustering of haplotypes on the accuracy of QTL mapping and prediction of genomic breeding values

    NARCIS (Netherlands)

    Calus, M.P.L.; Meuwissen, T.H.E.; Windig, J.J.; Knol, E.F.; Schrooten, C.; Vereijken, A.L.J.; Veerkamp, R.F.

    2009-01-01

    The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD) probabilities between haplotypes, various haplotype definitions were tested i.e. i

  2. GPIIb/IIIa Receptor Antagonism Using Small Molecules Provides no Additive Long-Term Protection after Percutaneous Coronary Intervention as Compared to Clopidogrel Plus Aspirin

    Science.gov (United States)

    Schiariti, Michele; Saladini, Angela; Papalia, Francesco; Grillo, Placido; Nesta, Cristina; Cuturello, Domenico; Missiroli, Bindo; Puddu, Paolo Emilio

    2010-01-01

    ) provided no additive long-term protection against the occurrence of composite ischemic events whereas thrombolysis by tenecteplase did. PMID:20922049

  3. Evolution of the CCR5 Delta32 mutation based on haplotype variation in Jewish and Northern European population samples.

    Science.gov (United States)

    Klitz, W; Brautbar, C; Schito, A M; Barcellos, L F; Oksenberg, J R

    2001-05-01

    The chemokine receptor 5 (CCR5) serves as a fusion cofactor for macrophage-tropic strains of HIV-1. In addition, CCR5 has been shown to mediate the entry of poxviruses into target cells. Individuals homozygous for the Delta32 deletion-mutation have no surface expression of CCR5 and are highly protected against HIV-1 infection. To gain insights into the evolution of the mutation in modern populations, the relatively high frequency of the Delta32-ccr5 allele in some European and Jewish populations is explored here by examining haplotypes of 3p21.3 constructed of five polymorphic marker loci surrounding CCR5. By sampling Ashkenazi, non-Ashkenazi and non-Jewish populations, we utilize the natural experiment that occurred as a consequence of the Jewish Diaspora, and demonstrate that a single mutation was responsible for all copies of Delta32. This mutation must have moved from Northern European populations to the Ashkenazi Jews where evidence suggests that Delta32 carriers of both groups were favored by repeated occurrence of epidemic small pox beginning in the 8th century AD.

  4. High-resolution haplotype block structure in the cattle genome

    Directory of Open Access Journals (Sweden)

    Choi Jungwoo

    2009-04-01

    Full Text Available Abstract Background The Bovine HapMap Consortium has generated assay panels to genotype ~30,000 single nucleotide polymorphisms (SNPs from 501 animals sampled from 19 worldwide taurine and indicine breeds, plus two outgroup species (Anoa and Water Buffalo. Within the larger set of SNPs we targeted 101 high density regions spanning up to 7.6 Mb with an average density of approximately one SNP per 4 kb, and characterized the linkage disequilibrium (LD and haplotype block structure within individual breeds and groups of breeds in relation to their geographic origin and use. Results From the 101 targeted high-density regions on bovine chromosomes 6, 14, and 25, between 57 and 95% of the SNPs were informative in the individual breeds. The regions of high LD extend up to ~100 kb and the size of haplotype blocks ranges between 30 bases and 75 kb (10.3 kb average. On the scale from 1–100 kb the extent of LD and haplotype block structure in cattle has high similarity to humans. The estimation of effective population sizes over the previous 10,000 generations conforms to two main events in cattle history: the initiation of cattle domestication (~12,000 years ago, and the intensification of population isolation and current population bottleneck that breeds have experienced worldwide within the last ~700 years. Haplotype block density correlation, block boundary discordances, and haplotype sharing analyses were consistent in revealing unexpected similarities between some beef and dairy breeds, making them non-differentiable. Clustering techniques permitted grouping of breeds into different clades given their similarities and dissimilarities in genetic structure. Conclusion This work presents the first high-resolution analysis of haplotype block structure in worldwide cattle samples. Several novel results were obtained. First, cattle and human share a high similarity in LD and haplotype block structure on the scale of 1–100 kb. Second, unexpected

  5. Geographic distribution of haplotype diversity at the bovine casein locus

    Directory of Open Access Journals (Sweden)

    Moazami-Goudarzi Katy

    2004-03-01

    Full Text Available Abstract The genetic diversity of the casein locus in cattle was studied on the basis of haplotype analysis. Consideration of recently described genetic variants of the casein genes which to date have not been the subject of diversity studies, allowed the identification of new haplotypes. Genotyping of 30 cattle breeds from four continents revealed a geographically associated distribution of haplotypes, mainly defined by frequencies of alleles at CSN1S1 and CSN3. The genetic diversity within taurine breeds in Europe was found to decrease significantly from the south to the north and from the east to the west. Such geographic patterns of cattle genetic variation at the casein locus may be a result of the domestication process of modern cattle as well as geographically differentiated natural or artificial selection. The comparison of African Bos taurus and Bos indicus breeds allowed the identification of several Bos indicus specific haplotypes (CSN1S1*C-CSN2*A2-CSN3*AI/CSN3*H that are not found in pure taurine breeds. The occurrence of such haplotypes in southern European breeds also suggests that an introgression of indicine genes into taurine breeds could have contributed to the distribution of the genetic variation observed.

  6. [Hemoglobin beta S haplotype in the Kebili region (southern Tunisia)].

    Science.gov (United States)

    Frikha, M; Fakhfakh, F; Mseddi, S; Gargouri, J; Ghali, L; Labiadh, Z; Harrabi, M; Souissi, T; Ayadi, H

    1998-04-01

    Sickle cell anemia is a monogenic hereditary disease characterized by a mutation in the beta globin gene. Five major haplotypes associated with the beta S mutation have been defined: Benin, Bantu, Senegalian, Camerounian, and Arabo-Indian. Previous studies in northern Tunisia showed that sickle cell anemia was of Benin origin in this region. Patients from the south of Tunisia, mainly from the Kebili region, were not previously concerned. In this study, we have determined the beta S haplotype and evaluated phenotypical expression of the disease in 14 patients from this latter region. The use of four restriction endonucleases having polymorphic sites in the beta globin gene showed that all patients had the Benin haplotype, confirming the Benin origin of sickle cell anemia in Tunisia. This haplotype is associated with an heterogeneous expression of fetal hemoglobin (HbF) with extremes varying from 2.4 to 16.3% and a mean expression rate of 8.16%, which is in accordance with literature data. In spite of the haplotype homogeneity in our patients, clinical heterogeneity was noted. A unique case of alpha-thalassemia could not explain this heterogeneity. In contrast, we found a certain correlation between fetal hemoglobin expression and clinical severity.

  7. In Vivo Characterization of Human APOA5 Haplotypes

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Akiyama, Jennifer; Chapman-Helleboid, Audrey; Fruchart, Jamila; Pennacchio, Len A.

    2006-10-01

    Increased plasma triglycerides concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effect of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy intact APOA5 haplotypes at a targeted location in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 and minor APOA5*2 haplotype, the introduction of the single APOA5*3 defining allele (19W) resulted in 3-fold lower ApoAV plasma levels consistent with existing genetic association studies. These results indicate that S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.

  8. Visualization of haplotype sharing patterns in pedigree samples.

    Science.gov (United States)

    Kim, Sulgi; Saad, Mohamad; Tsuang, Debby W; Wijsman, Ellen M

    2014-01-01

    A particular approach to the visualization of descent of founder DNA copies in a pedigree has been suggested, which helps to understand haplotype sharing patterns among subjects of interest. However, the approach does not provide the information in an ideal format to show haplotype sharing patterns. Therefore, we aimed to find an efficient way to visualize such sharing patterns and to demonstrate that our tool provides useful information for finding an informative subset of subjects for a sequence study. The visualization package, SharedHap, computes and visualizes a novel metric, the SharedHap proportion, which quantifies haplotype sharing among a set of subjects of interest. We applied SharedHap to simulated and real pedigree datasets to illustrate the approach. SharedHap successfully represents haplotype sharing patterns that contribute to linkage signals in both simulated and real datasets. Using the visualizations we were also able to find ideal sets of subjects for sequencing studies. Our novel metric that can be computed using the SharedHap package provides useful information about haplotype sharing patterns among subjects of interest. The visualization of the SharedHap proportion provides useful information in pedigree studies, allowing for a better selection of candidate subjects for use in further sequencing studies. © 2014 S. Karger AG, Basel.

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

    Science.gov (United States)

    Chen, Chunxian; Gmitter, Fred G

    2013-11-01

    Single nucleotide polymorphisms (SNPs), the most abundant variations in a genome, have been widely used in various studies. Detection and characterization of citrus haplotype-based expressed sequence tag (EST) SNPs will greatly facilitate further utilization of these gene-based resources. In this paper, haplotype-based SNPs were mined out of publicly available citrus expressed sequence tags (ESTs) from different citrus cultivars (genotypes) individually and collectively for comparison. There were a total of 567,297 ESTs belonging to 27 cultivars in varying numbers and consequentially yielding different numbers of haplotype-based quality SNPs. Sweet orange (SO) had the most (213,830) ESTs, generating 11,182 quality SNPs in 3,327 out of 4,228 usable contigs. Summed from all the individually mining results, a total of 25,417 quality SNPs were discovered - 15,010 (59.1%) were transitions (AG and CT), 9,114 (35.9%) were transversions (AC, GT, CG, and AT), and 1,293 (5.0%) were insertion/deletions (indels). A vast majority of SNP-containing contigs consisted of only 2 haplotypes, as expected, but the percentages of 2 haplotype contigs varied widely in these citrus cultivars. BLAST of the 25,417 25-mer SNP oligos to the Clementine reference genome scaffolds revealed 2,947 SNPs had "no hits found", 19,943 had 1 unique hit / alignment, 1,571 had one hit and 2+ alignments per hit, and 956 had 2+ hits and 1+ alignment per hit. Of the total 24,293 scaffold hits, 23,955 (98.6%) were on the main scaffolds 1 to 9, and only 338 were on 87 minor scaffolds. Most alignments had 100% (25/25) or 96% (24/25) nucleotide identities, accounting for 93% of all the alignments. Considering almost all the nucleotide discrepancies in the 24/25 alignments were at the SNP sites, it served well as in silico validation of these SNPs, in addition to and consistent with the rate (81%) validated by sequencing and SNaPshot assay. High-quality EST-SNPs from different citrus genotypes were detected, and

  10. Different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease.

    Science.gov (United States)

    Alshiekh, S; Zhao, L P; Lernmark, Å; Geraghty, D E; Naluai, Å T; Agardh, D

    2017-08-01

    Celiac disease is associated with the HLA-DR3-DQA1*05:01-DQB1*02:01 and DR4-DQA1*03:01-DQB1*03:02 haplotypes. In addition, there are currently over 40 non-HLA loci associated with celiac disease. This study extends previous analyses on different HLA haplotypes in celiac disease using next generation targeted sequencing. Included were 143 patients with celiac disease and 135 non-celiac disease controls investigated at median 9.8 years (1.4-18.3 years). PCR-based amplification of HLA and sequencing with Illumina MiSeq technology were used for extended sequencing of the HLA class II haplotypes HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1, respectively. Odds ratios were computed marginally for every allele and haplotype as the ratio of allelic frequency in patients and controls as ratio of exposure rates (RR), when comparing a null reference with equal exposure rates in cases and controls. Among the extended HLA haplotypes, the strongest risk haplotype for celiac disease was shown for DRB3*01:01:02 in linkage with DQA1*05:01-DQB1*02:01 (RR = 6.34; P-value celiac disease among non-Scandinavians (RR = 7.94; P = .011). The data also revealed 2 distinct celiac disease risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either the DRB3*01:01:02 or DRB3*02:02:01 alleles, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. The associated risk of celiac disease for DR3-DRB3*01:01:02-DQA1*05:01-DQB1*02:01 is predominant among patients of Scandinavian ethnicity. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Haplotyping a single triploid individual based on genetic algorithm.

    Science.gov (United States)

    Wu, Jingli; Chen, Xixi; Li, Xianchen

    2014-01-01

    The minimum error correction model is an important combinatorial model for haplotyping a single individual. In this article, triploid individual haplotype reconstruction problem is studied by using the model. A genetic algorithm based method GTIHR is presented for reconstructing the triploid individual haplotype. A novel coding method and an effectual hill-climbing operator are introduced for the GTIHR algorithm. This relatively short chromosome code can lead to a smaller solution space, which plays a positive role in speeding up the convergence process. The hill-climbing operator ensures algorithm GTIHR converge at a good solution quickly, and prevents premature convergence simultaneously. The experimental results prove that algorithm GTIHR can be implemented efficiently, and can get higher reconstruction rate than previous algorithms.

  12. JAK2 GGCC haplotype in MPL mutated myeloproliferative neoplasms.

    Science.gov (United States)

    Pietra, Daniela; Casetti, Ilaria; Da Vià, Matteo C; Elena, Chiara; Milanesi, Chiara; Rumi, Elisa

    2012-07-01

    JAK2 (V617F) is associated with a genetic predisposition to its acquisition,as it is preferentially found in subjects with a common constitutional JAK2 haplotype known as 46/1 or GGCC. A recent study suggests that a genetic predisposition to acquisition of MPL mutation may exist in sporadic patients, since an association was found with the JAK2 46/1 haplotype. We genotyped 509 patients with myeloproliferative neoplasms (MPN), 7% of which carrying a somatic mutation of MPL Exon 10. We found that the JAK2 GGCC haplotype was closely associated with JAK2 (V617F) (OR 1.84, P < 0.001) but not with MPL mutations (OR 0.98), suggesting a different genetic background for these molecular lesions.

  13. Beta-globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon.

    Science.gov (United States)

    Inati, A; Taher, A; Bou Alawi, W; Koussa, S; Kaspar, H; Shbaklo, H; Zalloua, P A

    2003-02-01

    Sickle cell disease (SCD) is an inherited autosomal recessive disorder of the beta-globin chain. Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of the clinical and hematological manifestations is extremely variable. This study examined for the first time in Lebanon the correlation between the clinical manifestation of SCD and the beta-globin gene haplotypes. The haplotypes of 50 patients diagnosed with SCD were determined using polymerase chain reaction amplification of fragments containing nine polymorphic restriction sites around and within the epsilon-Ggamma-Agamma-psibeta-delta-beta-globin gene complex. Most reported haplotypes were found in our population with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels into three groups (Group A: HbF 15%), surprisingly, the highest levels of HbF were associated with the most severe clinical cases. Our findings suggest that fetal hemoglobin levels are important but not the only parameters that affect the severity of the disease. In addition, the high levels of HbF in patients with CAR haplotypes did not seem to ameliorate the severity of symptoms, suggesting that genetic factors other than haplotypes are the major determinants of increased HbF levels in Lebanon.

  14. Prion gene haplotypes of U.S. cattle

    Directory of Open Access Journals (Sweden)

    Harhay Gregory P

    2006-11-01

    Full Text Available Abstract Background Bovine spongiform encephalopathy (BSE is a fatal neurological disorder characterized by abnormal deposits of a protease-resistant isoform of the prion protein. Characterizing linkage disequilibrium (LD and haplotype networks within the bovine prion gene (PRNP is important for 1 testing rare or common PRNP variation for an association with BSE and 2 interpreting any association of PRNP alleles with BSE susceptibility. The objective of this study was to identify polymorphisms and haplotypes within PRNP from the promoter region through the 3'UTR in a diverse sample of U.S. cattle genomes. Results A 25.2-kb genomic region containing PRNP was sequenced from 192 diverse U.S. beef and dairy cattle. Sequence analyses identified 388 total polymorphisms, of which 287 have not previously been reported. The polymorphism alleles define PRNP by regions of high and low LD. High LD is present between alleles in the promoter region through exon 2 (6.7 kb. PRNP alleles within the majority of intron 2, the entire coding sequence and the untranslated region of exon 3 are in low LD (18.0 kb. Two haplotype networks, one representing the region of high LD and the other the region of low LD yielded nineteen different combinations that represent haplotypes spanning PRNP. The haplotype combinations are tagged by 19 polymorphisms (htSNPS which characterize variation within and across PRNP. Conclusion The number of polymorphisms in the prion gene region of U.S. cattle is nearly four times greater than previously described. These polymorphisms define PRNP haplotypes that may influence BSE susceptibility in cattle.

  15. SNP haplotype mapping in a small ALS family.

    Directory of Open Access Journals (Sweden)

    Katherine A Dick Krueger

    Full Text Available The identification of genes for monogenic disorders has proven to be highly effective for understanding disease mechanisms, pathways and gene function in humans. Nevertheless, while thousands of Mendelian disorders have not yet been mapped there has been a trend away from studying single-gene disorders. In part, this is due to the fact that many of the remaining single-gene families are not large enough to map the disease locus to a single site in the genome. New tools and approaches are needed to allow researchers to effectively tap into this genetic gold-mine. Towards this goal, we have used haploid cell lines to experimentally validate the use of high-density single nucleotide polymorphism (SNP arrays to define genome-wide haplotypes and candidate regions, using a small amyotrophic lateral sclerosis (ALS family as a prototype. Specifically, we used haploid-cell lines to determine if high-density SNP arrays accurately predict haplotypes across entire chromosomes and show that haplotype information significantly enhances the genetic information in small families. Panels of haploid-cell lines were generated and a 5 centimorgan (cM short tandem repeat polymorphism (STRP genome scan was performed. Experimentally derived haplotypes for entire chromosomes were used to directly identify regions of the genome identical-by-descent in 5 affected individuals. Comparisons between experimentally determined and in silico haplotypes predicted from SNP arrays demonstrate that SNP analysis of diploid DNA accurately predicted chromosomal haplotypes. These methods precisely identified 12 candidate intervals, which are shared by all 5 affected individuals. Our study illustrates how genetic information can be maximized using readily available tools as a first step in mapping single-gene disorders in small families.

  16. HLA-A-B-C-DRB1-DQB1 phased haplotypes in 124 Nigerian families indicate extreme HLA diversity and low linkage disequilibrium in Central-West Africa.

    Science.gov (United States)

    Testi, M; Battarra, M; Lucarelli, G; Isgro, A; Morrone, A; Akinyanju, O; Wakama, T; Nunes, J M; Andreani, M; Sanchez-Mazas, A

    2015-10-01

    The simultaneous typing of five-HLA loci at high resolution and the availability of pedigree data allowed us to characterize extended five-locus phased haplotypes in 124 Nigerian families and to compare the observed frequencies with those expected by an expectation-maximization algorithm for unphased data. Despite the occurrence of some frequent alleles at each locus (e.g. B*53:01, which is assumed to protect against Plasmodium falciparum), as many as 82% of the sampled individuals carry two unique five-locus haplotypes and only three extended haplotypes with frequency above 1% exhibit significant linkage disequilibrium. Although preliminary, these results reveal an extreme level of HLA diversity in the Nigerian population, which reflects both its multi-ethnic composition and the very ancient demographic history of African populations.

  17. Linkage Disequilibrium Decay and Haplotype Block Structure in the Pig

    NARCIS (Netherlands)

    Amaral, A.J.; Megens, H.J.W.C.; Crooijmans, R.P.M.A.; Heuven, H.C.M.; Groenen, M.A.M.

    2008-01-01

    Linkage disequilibrium (LD) may reveal much about domestication and breed history. Ail investigation was conducted, to analyze the extent of LD, haploblock partitioning, and haplotype diversity within haploblocks across several pig breeds from China and Europe and in European wild boar. In total, 37

  18. Rapid haplotype reconstruction in predigrees with dense marker maps

    NARCIS (Netherlands)

    Windig, J.J.; Meuwissen, T.H.E.

    2004-01-01

    Reconstruction of marker phases is not straightforward when parents are untyped. In these cases information from other relatives has to be used. In dense marker maps, however, the space of possible haplotype configurations tends to be too large for procedures such as Monte Carlo Markov chains (MCMC)

  19. Genetics of chloroquine-resistant malaria: a haplotypic view

    Directory of Open Access Journals (Sweden)

    Gauri Awasthi

    2013-12-01

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

  20. Accuracy of genomic selection using different methods to define haplotypes

    NARCIS (Netherlands)

    Calus, M.P.L.; Meuwissen, T.H.E.; Roos, de S.; Veerkamp, R.F.

    2008-01-01

    Genomic selection uses total breeding values for juvenile animals, predicted from a large number of estimated marker haplotype effects across the whole genome. In this study the accuracy of predicting breeding values is compared for four different models including a large number of markers, at diffe

  1. Geographical distribution of a specific mitochondrial haplotype of Zymoseptoria tritici

    Directory of Open Access Journals (Sweden)

    Sameh BOUKEF

    2014-01-01

    Full Text Available Severity of disease caused by the fungus Zymoseptoria tritici throughout world cereal growing regions has elicited much debate on the potential evolutionary mechanism conferring high adaptability of the pathogen to diverse climate conditions and different wheat hosts (Triticum durum and T. aestivum. Specific mitochondrial DNA sequence was used to investigate geographic distribution of the type 4 haplotype (mtRFLP4 within 1363 isolates of Z. tritici originating from 21 countries. The mtRFLP4 haplotype was detected from both durum and bread wheat hosts with greater frequency on durum wheat. The distribution of mtRFLP4 was limited to populations sampled from the Mediterranean and the Red Sea region. Greater frequencies of mtRFLP4 were found in Tunisia (87% and Algeria (60%. The haplotype was absent within European, Australian, North and South American populations except Argentina. While alternative hypotheses such as climatic adaptation could not be ruled out, it is postulated that mtRFLP4 originated in North Africa (e.g. Tunisia or Algeria as an adaptation to durum wheat as the prevailing cereal crop. The specialized haplotype has subsequently spread as indicated by lower frequency of occurrence in the surrounding Mediterranean countries and on bread wheat hosts.

  2. Bayesian genomic selection: the effect of haplotype lenghts and priors

    DEFF Research Database (Denmark)

    Villumsen, Trine Michelle; Janss, Luc

    2009-01-01

    Breeding values for animals with marker data are estimated using a genomic selection approach where data is analyzed using Bayesian multi-marker association models. Fourteen model scenarios with varying haplotype lengths, hyper parameter and prior distributions were compared to find the scenario ...

  3. ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Barratt DT

    2012-04-01

    Full Text Available Daniel T Barratt1, Janet K Coller1, Richard Hallinan2, Andrew Byrne2, Jason M White1, David JR Foster3, Andrew A Somogyi1,41Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia; 2The Byrne Surgery, Specialist Drug and Alcohol Practice, Redfern, New South Wales; 3Division of Health Sciences, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia; 4Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaBackground: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment.Methods: Opioid-dependent subjects (n = 119 maintained on methadone (15–300 mg/day were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T, as well as for the OPRM1 18A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R-methadone concentrations (Ctrough were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype, and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype.Results: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype had significantly lower doses (median ± standard

  4. Serpin peptidase inhibitor (SERPINB5) haplotypes are associated with susceptibility to hepatocellular carcinoma

    Science.gov (United States)

    Yang, Shun-Fa; Yeh, Chao-Bin; Chou, Ying-Erh; Lee, Hsiang-Lin; Liu, Yu-Fan

    2016-05-01

    Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related death worldwide. The serpin peptidase inhibitor SERPINB5 is a tumour-suppressor gene that promotes the development of various cancers in humans. However, whether SERPINB5 gene variants play a role in HCC susceptibility remains unknown. In this study, we genotyped 6 SNPs of the SERPINB5 gene in an independent cohort from a replicate population comprising 302 cases and 590 controls. Additionally, patients who had at least one rs2289520 C allele in SERPINB5 tended to exhibit better liver function than patients with genotype GG (Child-Pugh grade A vs. B or C; P = 0.047). Next, haplotype blocks were reconstructed according to the linkage disequilibrium structure of the SERPINB5 gene. A haplotype “C-C-C” (rs17071138 + rs3744941 + rs8089204) in SERPINB5-correlated promoter showed a significant association with an increased HCC risk (AOR = 1.450 P = 0.031). Haplotypes “T-C-A” and “C-C-C” (rs2289519 + rs2289520 + rs1455555) located in the SERPINB5 coding region had a decreased (AOR = 0.744 P = 0.031) and increased (AOR = 1.981 P = 0.001) HCC risk, respectively. Finally, an additional integrated in silico analysis confirmed that these SNPs affected SERPINB5 expression and protein stability, which significantly correlated with tumour expression and subsequently with tumour development and aggressiveness. Taken together, our findings regarding these biomarkers provide a prediction model for risk assessment.

  5. MHC class I and class II phenotype, gene, and haplotype frequencies in Greeks using molecular typing data.

    Science.gov (United States)

    Papassavas, E C; Spyropoulou-Vlachou, M; Papassavas, A C; Schipper, R F; Doxiadis, I N; Stavropoulos-Giokas, C

    2000-06-01

    In the present study, DNA typing for HLA-A, C, B, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, and DPB1 was performed for 246 healthy, unrelated Greek volunteers of 20-59 years of age. Phenotype, genotype frequencies, Hardy-Weinberg equilibrium fit, and 3-locus haplotype frequencies for HLA-A, C, B, HLA-A, B, DRB1, HLA-DRB1, DQA1, DQB1, and HLA-DRB1, DQB1, DPB1 were calculated. Furthermore, linkage disequilibrium, deltas, relative deltas and p-values for significance of the deltas were defined. The population studied is in Hardy-Weinberg equilibrium, and many MHC haplotypes are in linkage disequilibrium. The most frequent specificities were HLA-A*02 (phenotype frequency = 44.3%) followed by HLA-A*24 (27.2%), HLA-B*51 (28.5%), HLA-B*18 (26.8%) and HLA-B*35 (26.4%) and HLA-Cw*04 (30.1%) and HLA-Cw*12 (26.8%). The most frequent MHC class II alleles were HLA-DRB1*1104 (34.1%), HLA-DQB1*0301 (54.5%) and HLA-DPB1*0401 with a phenotype frequency of 59.8%. The most prominent HLA-A, C, B haplotypes were HLA-A*24, Cw*04, B*35, and HLA-A*02, Cw*04, B*35, each of them observed in 21/246 individuals. The most frequent HLA-A, B, DRB1 haplotype was HLA-A*02, B*18, DRB1*1104 seen in 20/246 individuals, while the haplotype HLA-DRB1*1104, DQB1*0301, DPB1*0401 was found in 49/246 individuals. Finally, the haplotype DRB1*1104, DQA1*0501, DQB1*0301 was observed in 83/246 individuals. These results can be used for the estimation of the probability of finding a suitable haplotypically identical related or unrelated stem cell donor for patients of Greek ancestry. In addition, they can be used for HLA and disease association studies, genetic distance studies in the Balkan and Mediterranean area, paternity cases, and matching probability calculations for the optimal allocation of kidneys in Greece.

  6. A substantially lower frequency of uninformative matches between 23 versus 17 Y-STR haplotypes in north Western Europe.

    Science.gov (United States)

    Larmuseau, Maarten H D; Vanderheyden, Nancy; Van Geystelen, Anneleen; Decorte, Ronny

    2014-07-01

    The analysis of human short tandem repeats of the Y-chromosome (Y-STRs) provides a powerful tool in forensic cases for male sex identification, male lineage identification and identification of the geographical origin of male lineages. As the commonly used 12 and 17 Y-STR multiplexes do not discriminate between some unrelated males, additional Y-STRs were implemented in the PowerPlex(®) Y23 System to supplement the existing commercial Y-STR kits. Until today, the forensic value of a (near) 23 versus 17 Y-STR haplotype match between an unknown DNA donor and a certain biological sample in a database is not yet well studied. This will be of huge interest for cases where an autosomal DNA profile yields no match to a DNA database and the database is used for familial searching (male relative(s) of the offender) or for the estimation of the geographical origin of the offender. In order to value (near) 23 Y-STR haplotype matches in a local sample from Western Europe, we selected the region of Flanders (Belgium) due to the already present knowledge on its Y-chromosomal variants. Many Y-chromosomes of this region were previously genotyped with Y-SNPs at a high resolution of the most recently updated Y-chromosomal tree and the deep-rooted genealogy of each DNA donor was already established. By comparing (near) matches of 23 versus 17 Y-STR haplotypes between patrilineal-unrelated males, a substantial lower number of uninformative (near) 23 Y-STR haplotype matches has been observed compared to 17 Y-STR haplotypes. Furthermore, the use of SNP data was informative to discriminate >60% of unrelated males with an (near) identical 17 Y-STR match while SNP data was only necessary to discriminate about 10% of unrelated males with a 23 Y-STR haplotype that differed at only two Y-STRs. This shows the higher value of the Y23 haplotype within familial DNA searching and the estimation of the geographical origin of a DNA donor. Therefore, the use of the PowerPlex(®) Y23 System instead

  7. Evaluation of TcpF-A2-CTB chimera and evidence of additive protective efficacy of immunizing with TcpF and CTB in the suckling mouse model of cholera.

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    Gregory A Price

    Full Text Available The secreted colonization factor, TcpF, which is produced by Vibrio cholerae 01 and 0139, has generated interest as a potential protective antigen in the development of a subunit vaccine against cholera. This study evaluated immunogenicity/protective efficacy of a TcpF holotoxin-like chimera (TcpF-A2-CTB following intraperitoneal immunization compared to TcpF alone, a TcpF+CTB mixture, or CTB alone. Immunization with the TcpF-A2-CTB chimera elicited significantly greater amounts of anti-TcpF IgG than immunization with the other antigens (P<0.05. Protective efficacy was measured using 6-day-old pups reared from immunized dams and orogastrically challenged with a lethal dose of El Tor V. cholerae 01 Inaba strain N16961. Protection from death, and weight loss analysis at 24 and 48 hours post-infection demonstrated that immunization with TcpF alone was poorly protective. However, immunization with TcpF+CTB was highly protective and showed a trend toward greater protection than immunization with CTB alone (82% vs 64% survival. Immunization with the TcpF-A2-CTB chimera demonstrated less protection (50% survival than immunization with the TcpF+CTB mixture. The TcpF-A2-CTB chimera used for this study contained the heterologous classical CTB variant whereas the El Tor CTB variant (expressed by the challenge strain was used in the other immunization groups. For all immunization groups that received CTB, quantitative ELISA data demonstrated that the amounts of serum IgG directed against the homologous immunizing CTB antigen was statistically greater than the amount to the heterologous CTB antigen (P≤0.003. This finding provides a likely explanation for the poorer protection observed following immunization with the TcpF-A2-CTB chimera and the relatively high level of protection seen after immunization with homologous CTB alone. Though immunization with TcpF alone provided no protection, the additive protective effect when TcpF was combined with CTB

  8. Risk of Pediatric Celiac Disease According to HLA Haplotype and Country

    Science.gov (United States)

    Liu, Edwin; Lee, Hye-Seung; Aronsson, Carin A.; Hagopian, William A.; Koletzko, Sibylle; Rewers, Marian J.; Eisenbarth, George S.; Bingley, Polly J.; Bonifacio, Ezio; Simell, Ville; Agardh, Daniel

    2014-01-01

    BACKGROUND The presence of HLA haplotype DR3–DQ2 or DR4–DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS We studied 6403 children with HLA haplotype DR3–DQ2 or DR4–DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3–DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3–DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4–DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS Children with the HLA haplotype DR3–DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries

  9. Performance of Unequal Error Protection Using Maximum A- posteriori Probability Algorithm and Modified MAP in Additive White Gaussian Noise and Fading Channel

    Directory of Open Access Journals (Sweden)

    T. Gnanasekaran

    2008-01-01

    Full Text Available Problem statement: In this study we propose a method to improve the performance of Maximum A-Posteriori Probability Algorithm, which is used in turbo decoder. Previously the performance of turbo decoder is improved by means of scaling the channel reliability value. Approach: A modification in MAP algorithm proposed in this study, which achieves further improvement in forward error correction by means of scaling the extrinsic information in both decoders without introducing any complexity. The encoder is modified with a new puncturing matrix, which yields Unequal Error Protection (UEP. This modified MAP algorithm is analyzed with the traditional turbo code system Equal Error Protection (EEP and also with Unequal Error Protection (UEP both in AWGN channel and fading channel. Result: MAP and modified MAP achieve coding gain of 0.6 dB over EEP in AWGN channel. The MAP and modified MAP achieve coding gain of 0.4 dB and 0.9dB over EEP respectively in Rayleigh fading channel. Modified MAP in UEP class 1 and class 2 gained 0.8 dB and 0.6 dB respectively in AWGN channel where as in fading channel class 1 and 2 gained 0.4 dB and 0.6 dB respectively. Conclusion/Recommendations: The modified MAP algorithm improves the Bit Error Rate (BER performance in EEP as well as UEP both in AWGN and fading channels. We propose modified MAP error correction algorithm with UEP for broad band communication.

  10. Absence of atypical haplotype and presence of Senegal haplotype sickle cell disease in African-descent population in the northern Brazil

    OpenAIRE

    Nascimento,Rafael E.; Castelo,Natália M.; Bueno,Adriana C.; Larissa Mescouto; Artemis S. N. Rodrigues

    2015-01-01

    Introduction: Sickle cell anemia (SCA) is the most severe form of sickle cell disease; it presents variants that are called haplotypes βS. There are five major haplotypes βS gene: Arab-Indian/Saudi, Senegal, Benin, Bantu, and Camaroon. Objective: Characterize the presence of haplotypes in patients with SCA in Amapá. Methods: 46 sample were studied, all samples were amplified and analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Resul...

  11. A haplotype of human angiotensinogen gene containing −217A increases blood pressure in transgenic mice compared with −217G

    Science.gov (United States)

    Jain, Sudhir; Vinukonda, Govindaiah; Fiering, Steven N.; Kumar, Ashok

    2008-01-01

    The human angiotensinogen (hAGT) gene contains an A/G polymorphism at −217, and frequency of −217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb region of its promoter, and variant −217A almost always occurs with −532T, −793A, and −1074T, whereas variant −217G almost always occurs with −532C, −793G, and −1074G. Since allele −6A is the predominant allele in African-Americans, the AGT gene can be subdivided into two main haplotypes, −6A:−217A (AA) and −6A:−217G (AG). To understand the role of these haplotypes on hAGT gene expression and on blood pressure regulation in an in vivo situation, we have generated double transgenic mice containing human renin gene and either AA or AG haplotype of the hAGT gene using knock-in strategy at the hypoxanthine phosphoribosyltransferase locus. We show here that 1) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%; and 2) plasma AGT level is increased by ∼40%, and plasma angiotensin II level is increased by ∼50% in male double transgenic mice containing AA haplotype of the hAGT gene compared with the AG haplotype. In addition, systolic blood pressure is increased by 8 mmHg in transgenic mice containing the AA haplotype compared with the AG haplotype. This is the first report to show the effect of polymorphisms in the promoter of a human gene on its transcription in an in vivo situation that ultimately leads to an increase in blood pressure. PMID:18945948

  12. Principles guiding embryo selection following genome-wide haplotyping of preimplantation embryos.

    Science.gov (United States)

    Dimitriadou, Eftychia; Melotte, Cindy; Debrock, Sophie; Esteki, Masoud Zamani; Dierickx, Kris; Voet, Thierry; Devriendt, Koen; de Ravel, Thomy; Legius, Eric; Peeraer, Karen; Meuleman, Christel; Vermeesch, Joris Robert

    2017-03-01

    How to select and prioritize embryos during PGD following genome-wide haplotyping? In addition to genetic disease-specific information, the embryo selected for transfer is based on ranking criteria including the existence of mitotic and/or meiotic aneuploidies, but not carriership of mutations causing recessive disorders. Embryo selection for monogenic diseases has been mainly performed using targeted disease-specific assays. Recently, these targeted approaches are being complemented by generic genome-wide genetic analysis methods such as karyomapping or haplarithmisis, which are based on genomic haplotype reconstruction of cell(s) biopsied from embryos. This provides not only information about the inheritance of Mendelian disease alleles but also about numerical and structural chromosome anomalies and haplotypes genome-wide. Reflections on how to use this information in the diagnostic laboratory are lacking. We present the results of the first 101 PGD cycles (373 embryos) using haplarithmisis, performed in the Centre for Human Genetics, UZ Leuven. The questions raised were addressed by a multidisciplinary team of clinical geneticist, fertility specialists and ethicists. Sixty-three couples enrolled in the genome-wide haplotyping-based PGD program. Families presented with either inherited genetic variants causing known disorders and/or chromosomal rearrangements that could lead to unbalanced translocations in the offspring. Embryos were selected based on the absence or presence of the disease allele, a trisomy or other chromosomal abnormality leading to known developmental disorders. In addition, morphologically normal Day 5 embryos were prioritized for transfer based on the presence of other chromosomal imbalances and/or carrier information. Some of the choices made and principles put forward are specific for cleavage-stage-based genetic testing. The proposed guidelines are subject to continuous update based on the accumulating knowledge from the implementation of

  13. Haplotype analyses of haemoglobin C and haemoglobin S and the dynamics of the evolutionary response to malaria in Kassena-Nankana District of Ghana.

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    Anita Ghansah

    Full Text Available BACKGROUND: Haemoglobin S (HbS and C (HbC are variants of the HBB gene which both protect against malaria. It is not clear, however, how these two alleles have evolved in the West African countries where they co-exist at high frequencies. Here we use haplotypic signatures of selection to investigate the evolutionary history of the malaria-protective alleles HbS and HbC in the Kassena-Nankana District (KND of Ghana. METHODOLOGY/PRINCIPAL FINDINGS: The haplotypic structure of HbS and HbC alleles was investigated, by genotyping 56 SNPs around the HBB locus. We found that, in the KND population, both alleles reside on extended haplotypes (approximately 1.5 Mb for HbS and 650 Kb for HbC that are significantly less diverse than those of the ancestral HbA allele. The extended haplotypes span a recombination hotspot that is known to exist in this region of the genome SIGNIFICANCE: Our findings show strong support for recent positive selection of both the HbS and HbC alleles and provide insights into how these two alleles have both evolved in the population of northern Ghana.

  14. Beta-globin gene cluster haplotypes in sickle cell patients from southwest Iran.

    Science.gov (United States)

    Rahimi, Z; Karimi, M; Haghshenass, M; Merat, A

    2003-11-01

    Sickle cell anemia in Iran is accompanied by a high level of HbF and mild clinical presentation. Here we report haplotypes of the beta gene cluster found in 81 randomly selected sickle cell patients, including 47 sickle cell anemia (SS), 17 sickle cell trait (AS), and 17 sickle/thalassemia (S/thal) from southwest Iran. We found all five common typical haplotypes as well as five atypical haplotypes in our patients. Except for four patients with homozygous Benin haplotype, none of the other African typical haplotypes were found in a homozygous state. Arab-Indian was found to be the most prevalent haplotype in the study population. This haplotype accounted for 51.1% as the homozygous form in SS patients, where 69.1% of chromosomes in these patients had the Arab-Indian haplotype. Bantu A2 was the second most prevalent haplotype among all patients. The mean %HbF in SS patients was 27.83 and in the homozygous Arab-Indian haplotype it was still higher (30.40%), while in AS patients the %HbF was only 1.20. The high %Ggamma chain (71.81) in the Arab-Indian homozygous haplotype was concomitant with the presence of an Xmn I site in both chromosomes. The presence of the Arab-Indian haplotype as the predominant haplotype might be suggestive of a gene flow to/from Saudi Arabia or India. More haplotype investigations of a normal population can clarify the high incidence of Bantu A2 haplotype in our population.

  15. HLA-DRB1 and -DRB3 allele frequencies and haplotypic associations in Koreans.

    Science.gov (United States)

    Song, Eun Young; Park, Hyejin; Roh, Eun Youn; Park, Myoung Hee

    2004-03-01

    We have investigated the frequencies of human leukocyte antigen-DRB1 (HLA-DRB1) and -DRB3 alleles and DRB1-DRB3 haplotypic associations in 800 Koreans. DRB1 genotyping was done using polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) and PCR-single strand conformation polymorphism (SSCP) methods. DRB3 genotyping was done on 447 samples carrying DRB3-associated DRB1 alleles (DRB1*03, *11, *12, *13, and *14) using PCR-SSCP method. The allele frequencies of DRB3*0101, DRB3*0202, and DRB3*0301 were 0.073, 0.136, and 0.120, respectively, and we found one case of a probable new allele (DRB3*01new, 0.001). DRB1-DRB3 haplotypes with frequency (HF) > 0.005 exhibited strong associations between DRB3*0101 and DRB1*1201, *1301, and *1403; between DRB3*0301 and DRB1*1202 and *1302; between DRB3*0202 and DRB1*0301, *1101, *1401, *1405, and *1406 alleles. Most of the DRB1 alleles with frequency > 0.005 were exclusively associated with particular DRB3 alleles with relative linkage disequilibrium values of 1.0, except for DRB1*1201, *1202 and *1301; the rare presence (HF DRB3*0202 associations were observed for these DRB1 alleles. We also investigated and presented rare DRB1-DRB3 associations in additional 6000 Koreans. Comparison with other ethnic groups revealed that DRB1*0301 and *1301 related DRB1-DRB3 haplotypes vary among different populations, in that Koreans and other Asian populations show less diversity compared with Caucasoids or African Americans.

  16. Association of an MHC class II haplotype with increased risk of polymyositis in Hungarian Vizsla dogs.

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    Jonathan Massey

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

  17. 4G/5G polymorphism and haplotypes of SERPINE1 in atherosclerotic diseases of coronary arteries.

    Science.gov (United States)

    Koch, Werner; Schrempf, Matthias; Erl, Anna; Mueller, Jakob C; Hoppmann, Petra; Schömig, Albert; Kastrati, Adnan

    2010-06-01

    We assessed the association between common variation at the SERPINE1 (PAI1) locus and myocardial infarction (MI). Haplotype-tagging polymorphisms, including the 4G/5G deletion/insertion polymorphism and seven single nucleotide polymorphisms, were analysed in a German sample containing 3,657 cases with MI and 1,211 controls. The association between the 4G/5G polymorphism and MI was examined in a meta-analysis of data extracted from 32 studies (13,267 cases/14,716 controls). In addition, the relation between the 4G/5G polymorphism and coronary diseases, comprising MI, coronary artery disease, coronary heart disease, or the acute coronary syndrome, was assessed in a combined analysis enclosing 43 studies (17,278 cases/18,039 controls). None of the tagging polymorphisms was associated with MI in the present sample (p 4G allele carriers was 1.02 (95% confidence interval [CI] 0.87-1.19) compared to the 5G5G genotype. None of 13 common (frequency >1.0%) 8-marker haplotypes was related to the risk of MI. In a meta-analysis specifically addressing the association with MI, no elevated risk was found in the carriers of the 4G allele (OR 1.07, 95% CI 0.99-1.16; p = 0.11). A more general combined analysis of coronary diseases showed a marginally increased risk in 4G allele carriers (OR 1.08, 95% CI 1.00-1.16; p = 0.044). In essence, tagging polymorphisms, including the 4G/5G polymorphism, and common haplotypes of the SERPINE1 gene region were not associated with MI in a German sample, and no compelling evidence was obtained for a relationship of the 4G/5G polymorphism to MI and coronary atherosclerosis in a meta-analysis.

  18. Beta-globin gene cluster haplotypes in Venezuelan sickle cell patients from the State of Aragua

    OpenAIRE

    Nancy Moreno; Martínez, José A.; Zorella Blanco; Leidys Osorio; Patrick Hackshaw

    2002-01-01

    Seven polymorphic sites in the beta-globin gene cluster were analyzed on a sample of 96 chromosomes of Venezuelan sickle cell patients from the State of Aragua. The Benin haplotype was predominant with a frequency of 0.479, followed by the Bantu haplotype (0.406); a minority of cases with other haplotypes was also identified: atypical Bantu A2 (0.042), Senegal (0.031), atypical Bantu A7 (0.021) and Saudi Arabia/Indian (0.021) haplotypes; however, the Cameroon haplotype was not identified in t...

  19. Fetal Hemoglobin in Sickle Cell Anemia: Genetic Studies of the Arab-Indian Haplotype

    OpenAIRE

    Ngo, Duyen; Bae, Harold; Steinberg, Martin H.; Sebastiani, Paola; Solovieff, Nadia; Baldwin, Clinton T.; Melista, Efthymia; Safaya, Surinder; Farrar, Lindsay A.; Suliman, Ahmed M.; Albuali, Waleed H; Al Bagshi, Muneer H.; Akinsheye, Idowu; Gallagher, Patrick; Luo, Hong-yuan

    2013-01-01

    Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefor studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, ...

  20. Origin of celiac disease: How old are predisposing haplotypes?

    Institute of Scientific and Technical Information of China (English)

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

    2012-01-01

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

  1. PRIMUS: improving pedigree reconstruction using mitochondrial and Y haplotypes.

    Science.gov (United States)

    Staples, Jeffrey; Ekunwe, Lynette; Lange, Ethan; Wilson, James G; Nickerson, Deborah A; Below, Jennifer E

    2016-02-15

    PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data. However, when genetic data for individuals within a pedigree are missing, often multiple pedigrees can be reconstructed that fit the data. We report a major expansion of PRIMUS that uses mitochondrial (mtDNA) and non-recombining Y chromosome (NRY) haplotypes to eliminate many pedigree structures that are inconsistent with the genetic data. We demonstrate that discordances in mtDNA and NRY haplotypes substantially reduce the number of potential pedigrees, and often lead to the identification of the correct pedigree. We have implemented PRIMUS updates in PERL and it is available at primus.gs.washington.edu. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. The RooPfs study to assess whether improved housing provides additional protection against clinical malaria over current best practice in The Gambia

    DEFF Research Database (Denmark)

    Pinder, Margeret; Conteh, Lesong; Jeffries, David

    2016-01-01

    economic and social science studies will undertake a cost-effectiveness analysis and use qualitative and participatory methods to explore the acceptability of the housing modifications and to design strategies for scaling-up housing interventions. Discussion The study is the first of its kind to measure......Background In malaria-endemic areas, residents of modern houses have less malaria than those living in traditional houses. This study will determine if modern housing provides incremental protection against clinical malaria over the current best practice of long-lasting insecticidal nets (LLINs......) and prompt treatment in The Gambia, determine the incremental cost-effectiveness of the interventions, and analyze the housing market in The Gambia. Methods/design A two-armed, household, cluster-randomized, controlled study will be conducted to assess whether improved housing and LLINs combine to provide...

  3. Haplotype reconstruction error as a classical misclassification problem: introducing sensitivity and specificity as error measures.

    Directory of Open Access Journals (Sweden)

    Claudia Lamina

    Full Text Available BACKGROUND: Statistically reconstructing haplotypes from single nucleotide polymorphism (SNP genotypes, can lead to falsely classified haplotypes. This can be an issue when interpreting haplotype association results or when selecting subjects with certain haplotypes for subsequent functional studies. It was our aim to quantify haplotype reconstruction error and to provide tools for it. METHODS AND RESULTS: By numerous simulation scenarios, we systematically investigated several error measures, including discrepancy, error rate, and R(2, and introduced the sensitivity and specificity to this context. We exemplified several measures in the KORA study, a large population-based study from Southern Germany. We find that the specificity is slightly reduced only for common haplotypes, while the sensitivity was decreased for some, but not all rare haplotypes. The overall error rate was generally increasing with increasing number of loci, increasing minor allele frequency of SNPs, decreasing correlation between the alleles and increasing ambiguity. CONCLUSIONS: We conclude that, with the analytical approach presented here, haplotype-specific error measures can be computed to gain insight into the haplotype uncertainty. This method provides the information, if a specific risk haplotype can be expected to be reconstructed with rather no or high misclassification and thus on the magnitude of expected bias in association estimates. We also illustrate that sensitivity and specificity separate two dimensions of the haplotype reconstruction error, which completely describe the misclassification matrix and thus provide the prerequisite for methods accounting for misclassification.

  4. A Dynamic Programming Algorithm for the k-Haplotyping Problem

    Institute of Scientific and Technical Information of China (English)

    Zhen-ping Li; Ling-yun Wu; Yu-ying Zhao; Xiang-sun Zhang

    2006-01-01

    The Minimum Fragments Removal (MFR) problem is one of the haplotyping problems: given a set of fragments, remove the minimum number of fragments so that the resulting fragments can be partitioned into k classes of non-conflicting subsets. In this paper, we formulate the k-MFR problem as an integer linear programming problem, and develop a dynamic programming approach to solve the k-MFR problem for both the gapless and gap cases.

  5. Extended HLA-D region haplotype associated with celiac disease

    Energy Technology Data Exchange (ETDEWEB)

    Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

    1988-01-01

    Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II ..beta..-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this ..beta..-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP ..beta..-chain. This celiac disease-associated HLA-DP ..beta..-chain gene was flanked by HLA-DP ..cap alpha..-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP..cap alpha..-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP ..cap alpha..- and ..beta..-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion.

  6. Whole-genome molecular haplotyping of single cells

    OpenAIRE

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

    2010-01-01

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

  7. Global haplotype partitioning for maximal associated SNP pairs

    Directory of Open Access Journals (Sweden)

    Pezeshk Hamid

    2009-08-01

    Full Text Available Abstract Background Global partitioning based on pairwise associations of SNPs has not previously been used to define haplotype blocks within genomes. Here, we define an association index based on LD between SNP pairs. We use the Fisher's exact test to assess the statistical significance of the LD estimator. By this test, each SNP pair is characterized as associated, independent, or not-statistically-significant. We set limits on the maximum acceptable proportion of independent pairs within all blocks and search for the partitioning with maximal proportion of associated SNP pairs. Essentially, this model is reduced to a constrained optimization problem, the solution of which is obtained by iterating a dynamic programming algorithm. Results In comparison with other methods, our algorithm reports blocks of larger average size. Nevertheless, the haplotype diversity within the blocks is captured by a small number of tagSNPs. Resampling HapMap haplotypes under a block-based model of recombination showed that our algorithm is robust in reproducing the same partitioning for recombinant samples. Our algorithm performed better than previously reported models in a case-control association study aimed at mapping a single locus trait, based on simulation results that were evaluated by a block-based statistical test. Compared to methods of haplotype block partitioning, we performed best on detection of recombination hotspots. Conclusion Our proposed method divides chromosomes into the regions within which allelic associations of SNP pairs are maximized. This approach presents a native design for dimension reduction in genome-wide association studies. Our results show that the pairwise allelic association of SNPs can describe various features of genomic variation, in particular recombination hotspots.

  8. A prospective study of XRCC1 haplotypes and their interaction with plasma carotenoids on breast cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Mohrenweiser, H W; Han, J; Hankinson, S E; De Vivo, I; Spiegelman, D; Tamimi, R M; Colditz, G A; Hunter, D J

    2004-01-15

    The XRCC1 protein is involved in the base excision repair pathway through interactions with other proteins. Polymorphisms in the XRCC1 gene may lead to variation in repair proficiency and confer inherited predisposition to cancer. We prospectively assessed the associations between polymorphisms and haplotypes in XRCC1 and breast cancer risk in a nested case-control study within the Nurses' Health Study (incident cases, n 1004; controls, n 1385). We further investigated gene-environment interactions between the XRCC1 variations and plasma carotenoids on breast cancer risk. We genotyped four haplotype-tagging single nucleotide polymorphisms Arg {sup 194}Trp, C26602T, Arg{sup 399}Gln, and Gln{sup 632}Gln in the XRCC1 gene. Five common haplotypes accounted for 99% of the chromosomes in the present study population of mostly Caucasian women. We observed a marginally significant reduction in the risk of breast cancer among {sup 194}Trp carriers. As compared with no-carriers, women with at least one {sup 194}Trp allele had a multivariate odds ratio of 0.79 (95% of the confidence interval, 0.60 -1.04). The inferred haplotype harboring the {sup 194}Trp allele was more common in controls than in cases (6.6 versus 5.3%, P 0.07). We observed that the Arg {sup 194}Trp modified the inverse associations of plasma -carotene level (P, ordinal test for interaction 0.02) and plasma -carotene level (P, ordinal test for interaction 0.003) with breast cancer risk. No suggestion of an interaction was observed between the Arg {sup 194}Trp and cigarette smoking. Our results suggest an inverse association between XRCC1 {sup 194}Trp allele and breast cancer risk. The findings of the effect modification of the Arg {sup 194}Trp on the relations of plasma -and -carotene levels with breast cancer risk suggest a potential protective effect of carotenoids in breast carcinogenesis by preventing oxidative DNA damage.

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

    Science.gov (United States)

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

    2009-01-01

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

  10. Population differentiation and phylogeographic pattern of a relict species, Conandron ramondioides (Gesneriaceae), revealed from sequence polymorphism and haplotypes of the CYCLOIDEA gene

    Institute of Scientific and Technical Information of China (English)

    Li-Hong XIAO; Zhi LI; Rui WANG; yin-Zheng WANG

    2012-01-01

    Historical events are expected to affect population genetic differentiation and DNA molecular evolution,but the impact of these effects remains a matter of debate.Here,for Conandron ramondioides (Gesneriaceae),we analyzed the genetic structure and phylogeographical pattern of 248 individuals from 13 populations,distributed in mainland China and Taiwan Island,based on the nucleotide sequence and haplotype of the coding sequence of CYCLOIDEA1 (GCYC1).Among the populations,we found a high level of haplotype diversity (h =0.831) and a relatively low level of nucleotide diversity (Dij =0.004).Both the haplotype network and the neighbor-joining tree constructed from GCYC1 haplotypes suggest two major geographical groupings,one on the mainland and the other on Taiwan.Consistently,AMOVA analysis revealed high genetic differentiation between these groupings,with 84.65% variation partitioning the two regions,and the two groupings shared no haplotype.On the mainland,population genetic differentiation was correlated with more recent events,presumably Pleistocene glaciations and human activities since the Neolithic.In addition,C.ramondioides GCYC1 rapidly accumulated neutral mutations,consistent with this gene being silenced or down-regulated in actinomorphic lineages of the Lamiales,such as Conandron.

  11. Genetic diversity and haplotype structure of 24 Y-chromosomal STR in Chinese Hui ethnic group and its genetic relationships with other populations.

    Science.gov (United States)

    Zhu, Bo-Feng; Zhang, Yu-Dang; Liu, Wen-Juan; Meng, Hao-Tian; Yuan, Guo-Lian; Lv, Zhe; Dong, Nan; Li, Qiong; Yang, Chun-Hua; Zhang, Yu-Hong; Hou, Yin-Ling; Qian, Li; Fan, Shuan-Liang; Xu, Peng

    2014-07-01

    In the present study, 24 Y-chromosomal short tandem repeat (Y-STR) loci were analyzed in 115 unrelated Hui male individuals from Haiyuan county or Tongxin county, Ningxia Hui Autonomous Region, China, to evaluate the forensic application of the 24 STR loci and to analyze interpopulation differentiations by making comparisons between the Hui group data and previously published data of other 13 populations. A total of 115 different haplotypes were observed on these 24 Y-STR loci. The gene diversities ranged from 0.4049 (DYS437) to 0.9729 (DYS385a, b). The overall haplotype diversity was 1 at AGCU 24 Y-STR loci level, while the values were reduced to 0.999237, 0.996949, and 0.996644 at the Y-filer 17 loci, 11 Y-STR loci of extended haplotype and 9 Y-STR loci of minimal haplotype levels, respectively; whereas, haplotype diversity for additional 7 loci (not included in Y-filer 17 loci) was 0.995271. The pairwise FST , multidimensional scaling plot and neighbor-joining tree indicated the Hui group had the closest genetic relationship with Sala in the paternal lineage in the present study. In summary, the results in our study indicated the 24 Y-STRs had a high level of polymorphism in Hui group and hence could be a powerful tool for forensic application and population genetic study.

  12. A unified framework for haplotype inference in nuclear families.

    Science.gov (United States)

    Iliadis, Alexandros; Anastassiou, Dimitris; Wang, Xiaodong

    2012-07-01

    Many large genome-wide association studies include nuclear families with more than one child (trio families), allowing for analysis of differences between siblings (sib pair analysis). Statistical power can be increased when haplotypes are used instead of genotypes. Currently, haplotype inference in families with more than one child can be performed either using the familial information or statistical information derived from the population samples but not both. Building on our recently proposed tree-based deterministic framework (TDS) for trio families, we augment its applicability to general nuclear families. We impose a minimum recombinant approach locally and independently on each multiple children family, while resorting to the population-derived information to solve the remaining ambiguities. Thus our framework incorporates all available information (familial and population) in a given study. We demonstrate that using all the constraints in our approach we can have gains in the accuracy as opposed to breaking the multiple children families to separate trios and resorting to a trio inference algorithm or phasing each family in isolation. We believe that our proposed framework could be the method of choice for haplotype inference in studies that include nuclear families with multiple children. Our software (tds2.0) is downloadable from www.ee.columbia.edu/∼anastas/tds.

  13. The Haplotyping Problem: An Overview of Computational Models and Solutions

    Institute of Scientific and Technical Information of China (English)

    Paola Bonizzoni; Gianluca Della Vedova; Riccardo Dondi; Jing Li

    2003-01-01

    The investigation of genetic differences among humans has given evidence that mutations in DNA sequences are responsible for some genetic diseases. The most common mutation is the one that involves only a single nucleotide of the DNA sequence, which is called a single nucleotide polymorphism (SNP). As a consequence, computing a complete map of all SNPs occurring in the human populations is one of the primary goals of recent studies in human genomics. The construction of such a map requires to determine the DNA sequences that from all chromosomes. In diploid organisms like humans, each chromosome consists of two sequences called haplotypes. Distinguishing the information contained in both haplotypes when analyzing chromosome sequences poses several new computational issues which collectively form a new emerging topic of Computational Biology known as Haplotyping.This paper is a comprehensive study of some new combinatorial approaches proposed in this research area and it mainly focuses on the formulations and algorithmic solutions of some basic biological problems. Three statistical approaches are briefly discussed at the end of the paper.

  14. The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis.

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    F David Carmona

    Full Text Available Systemic sclerosis (SSc is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA region corresponds to interferon (IFN regulatory factor 5 (IRF5, a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP of each block (rs10488631, rs2004640, and rs4728142 in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10(-8, OR  = 1.22, CI 95%  = 1.14-1.30; rs2004640: P  = 4.60×10(-7, OR  = 0.84, CI 95%  = 0.78-0.90; rs10488631: P  = 7.53×10(-20, OR  = 1.63, CI 95%  = 1.47-1.81. However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598. The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10(-22, OR  = 1.75, CI 95%  = 1.56-1.97 better explained the observed association (likelihood P-value  = 1.48×10(-4, suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this

  15. HLA class II DR-DQ amino acids and insulin-dependent diabetes mellitus: Application of the haplotype method

    Energy Technology Data Exchange (ETDEWEB)

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

    1997-03-01

    Insulin-dependent diabetes mellitus (IDDM) HLA class III DRB1-DQA1-DQB1 data from four populations (Norwegian, Sardinian, Mexican American, and Taiwanese) have been analyzed to detect the amino acids involved in the disease process. The combination of sites DRB1 No. 67 and 86; DQA1 No. 47; and DQB1 No. 9, 26, 57, and 70 predicts the IDDM component in these four populations, when the results and criteria of the haplotype method for amino acids, developed in the companion paper in this issue of the journal, are used. The following sites, either individually, or in various combinations, previously have been suggested as IDDM components: DRB1 No. 57, 70, 71, and 86; DQA1 No. 52; and DQB1 No. 13, 45, and 57 (DQB1 No. 13 and 45 correlates 100% with DQB1 No. 9 and 26). We propose that DQA1 No. 47 is a better predictor of IDDM than is the previously suggested DQA1 No. 52, and we add DRB1 No. 67 and DQB1 No. 70 to the HLA DR-DQ IDDM amino acids. We do not claim to have identified all HLA DR-DQ amino acids - or highly correlated sites - involved in IDDM. The frequencies and predisposing/protective effects of the haplotypes defined by these seven sites have been compared, and the effects on IDDM are consistent across the populations. The strongest susceptible effects came from haplotypes DRB1*0301/DQA1*0501/ DQB1*0201 and DRB1*0401-5-7-8/DQA1*0301/DQB1*0302. The number of strong protective haplotypes observed was larger than the number of susceptible ones; some of the predisposing haplotypes were present in only one or two populations. Although the sites under consideration do not necessarily have a functional involvement in IDDM, they should be highly associated with such sites and should prove to be useful in risk assessment. 48 refs., 2 figs., 4 tabs.

  16. Definition of gene content for nine common group B haplotypes of the Caucasoid population: KIR haplotypes contain between seven and eleven KIR genes.

    Science.gov (United States)

    Uhrberg, Markus; Parham, Peter; Wernet, Peter

    2002-07-01

    The segregation of killer cell immunoglobulin-like receptor ( KIR) genes was determined for a panel of 21 Caucasoid families: 23 different KIR gene patterns were found and could be assigned to combinations of 16 different haplotypes. Four loci were held in common by all haplotypes: KIR2DL4, KIR3DL2, the putative pseudogene KIR3DL3 and KIR2DL2/KIR2DL3, the latter likely being alleles of one gene. Group A haplotypes, which have a unique combination of seven KIR genes, were found at 80% frequency in the family panel, the polygenic group B haplotypes at 65% frequency. KIR gene segregation was fully determined for the nine group B haplotypes, which occurred at highest frequencies in both the family panel and a panel of unrelated individuals. The group B haplotypes carried between seven and 11 KIR genes and encoded inhibitory KIR for one, two, or all three major HLA class I epitopes. Analysis of human leucocyte antigen (HLA) class I genotypes revealed that most, but not all, individuals possess an inhibitory KIR for a self HLA class I epitope. The number of stimulatory KIR genes in group B haplotypes varied considerably between one and five. The data show that group B haplotypes possess a broad spectrum of KIR gene patterns, which is largely complementary to the KIR gene set of group A haplotypes. The results suggest that rapid diversification of group B haplotypes is the result of pathogen-mediated selection for KIR genotypes that have more than the set of KIR genes provided by the group A haplotype.

  17. Combining an Evolution-guided Clustering Algorithm and Haplotype-based LRT in Family Association Studies

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    Huang Su-Yun

    2011-05-01

    Full Text Available Abstract Background With the completion of the international HapMap project, many studies have been conducted to investigate the association between complex diseases and haplotype variants. Such haplotype-based association studies, however, often face two difficulties; one is the large number of haplotype configurations in the chromosome region under study, and the other is the ambiguity in haplotype phase when only genotype data are observed. The latter complexity may be handled based on an EM algorithm with family data incorporated, whereas the former can be more problematic, especially when haplotypes of rare frequencies are involved. Here based on family data we propose to cluster long haplotypes of linked SNPs in a biological sense, so that the number of haplotypes can be reduced and the power of statistical tests of association can be increased. Results In this paper we employ family genotype data and combine a clustering scheme with a likelihood ratio statistic to test the association between quantitative phenotypes and haplotype variants. Haplotypes are first grouped based on their evolutionary closeness to establish a set containing core haplotypes. Then, we construct for each family the transmission and non-transmission phase in terms of these core haplotypes, taking into account simultaneously the phase ambiguity as weights. The likelihood ratio test (LRT is next conducted with these weighted and clustered haplotypes to test for association with disease. This combination of evolution-guided haplotype clustering and weighted assignment in LRT is able, via its core-coding system, to incorporate into analysis both haplotype phase ambiguity and transmission uncertainty. Simulation studies show that this proposed procedure is more informative and powerful than three family-based association tests, FAMHAP, FBAT, and an LRT with a group consisting exclusively of rare haplotypes. Conclusions The proposed procedure takes into account the

  18. Sequence variations in the 5' flanking and IVS-II regions of the G gamma- and A gamma-globin genes of beta S chromosomes with five different haplotypes.

    Science.gov (United States)

    Lanclos, K D; Oner, C; Dimovski, A J; Gu, Y C; Huisman, T H

    1991-06-01

    We have amplified and sequenced the 5' flanking and the second intervening sequence (IVS-II) regions of both the G gamma- and A gamma-globin genes of the beta S chromosomes from sickle cell anemia (SS) patients with homozygosities for five different haplotypes. The sequencing data, compared with previously published sequences for the normal chromosomes A and B, show many similarities to chromosome B for haplotypes 19, 20, and 17, while haplotypes 3 and 31 are remarkably similar to chromosome A and also similar to each other. Several unique mutations were found in the 5' flanking regions (G gamma and A gamma) of haplotypes 19 and 20 and in the IVS-II segments of the same genes of haplotypes 19, 20, and 17; the IVS-II of haplotypes 3 and 31 were identical to those of chromosome A. Dot-blot analyses of amplified DNA from additional SS patients with specific probes have confirmed that these mutations are unique for each haplotype. The two general patterns that have been observed among the five haplotypes have most probably arisen by gene conversion events between the A and B type chromosomes in the African population. These patterns correlate with high and low fetal hemoglobin expression, and it is speculated that these and other yet unknown gene conversions may contribute to the variations in hemoglobin F and G gamma levels observed among SS patients. In vitro expression experiments involving the approximately 1.3-kb 5' flanking regions of the G gamma- and A gamma-globin genes of the beta S chromosomes with the five different haplotypes failed to detect differences between the levels of expression, suggesting that the sequence variations observed between these segments of DNA are not the primary cause of the differences in hemoglobin F levels among the SS patients.

  19. Comparison of haplotype frequencies differentiate fall armyworm (Lepidoptera: Noctuidae) corn-strain populations from Florida and Brazil.

    Science.gov (United States)

    Nagoshi, Rod N; Silvie, Pierre; Meagher, Robert L

    2007-06-01

    Fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a major economic pest throughout the Western Hemisphere. Populations can be subdivided into two morphologically identical but genetically distinct strains (corn-strain and rice-strain) that differ in their host plant preferences. These strains can be distinguished by using polymorphisms in the mitochondrial cytochrome oxidase 1 gene. Additional sequence analysis of this locus identified two sites that were highly polymorphic in the corn-strain population and that produced four different haplotype subgroups. Comparisons of the frequency distribution of these haplotypes found no seasonal or plant host specificities, but they did demonstrate that the Brazil corn-strain population is different from corn-strain fall armyworm found in Florida. The development of a rapid means of distinguishing fall armyworm populations originating from Brazil versus Florida provides an opportunity for investigating and comparing the genetic complexity and long-range movements of this important agricultural pest.

  20. Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect.

    Science.gov (United States)

    Ghosh, Priyanka; Bhaumik, Pranami; Ghosh, Sujoy; Ozbek, Umut; Feingold, Eleanor; Maslen, Cheryl; Sarkar, Biswanath; Pramanik, Vishmadeb; Biswas, Priyanka; Bandyopadhyay, Biswajit; Dey, Subrata Kumar

    2012-11-01

    To explore the role of CRELD1 variants on congenital heart defects, we sequenced the entire reading frame of CRELD1 in the samples from Kolkata and adjoining areas. Nearly, 400 participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD, and euploid without AVSD. A significant association was found between AVSD and three polymorphisms, namely rs9878047 (c.1049-129T > C), rs3774207 (c.1119C > T), and rs73118372 (c.1136T > C) among the Down syndrome and euploid individuals. The polymorphism rs73118372, involves a transition (c.1136T > C) that leads to change in amino acid methionine to threonine which alters protein secondary structure as confirmed by the bioinformatics software SOPMA. In addition, two haplotypes, C-T-C and C-T-T, in the order of loci rs9878047-rs3774207-rs73118372 were associated with incidence of AVSD among euploid and Down syndrome, with a slightly higher odds ratio in the later group. We hypothesize that these haplotypes increase the risk of AVSD, and the susceptibility is exacerbated in DS, possibly due to the trisomy 21 genetic background. Moreover, we report for the first time on an interaction between the mutant alleles of rs3774207 and rs73118372 which could disrupt the delicate balance between different CRELD1 isoforms.

  1. [The distribution of Y-chromosome haplotypes of Shui ethnic in Sandu,Guizhou].

    Science.gov (United States)

    He, Yan; Wen, Bo; Shan, Ke-Ren; Huang, Wei; Xie, Yuan; Wu, Chang-Xue; Xiong, Xiao-Yan; Xiu, Jin; Zhang, Jing; Zhang, Xiao-Lei; Ren, Xi-Lin; Jin, Li

    2003-05-01

    Non-recombination region of Y-chromosome is a useful marker in tracing evolutionary history of paternal lineage. In the present study, total 92 individuals from Shui ethnic group in Sandu Shui Ethnic Group Autonomous County of Guizhou Province were inspected with 11 SNP sites including M7, M9, M15, M45, M89, M95, M119,M122, M130, M134 and YAP on Y-chromosome.All the subjects were required to be unrelated and without intermarriage with other ethnic groups within three generations. The haplotypes were analyzed by PCR-RFLP method. Four haplotypes H5,H8,H9 and H11 were detected with frequencies of 0.054, 0.044, 0.315 and 0.587, respectively.Principle component indicated that the paternal lineage of Shui ethnic group is much closer to Li ethnic group of Hainan Province and Bouyei ethnic group of Guizhou Province,which belong to the group of Zhuang-Dong branch of Sino-Tibetan language family. In addition genetic study of Shui coincides with its linguistic distribution.

  2. Haplotype variation of Green Revolution gene Rht-D1 during wheat domestication and improvement

    Institute of Scientific and Technical Information of China (English)

    Chihong Zhang; Lifeng Gao; Jiaqiang Sun; Jizeng Jia; Zhenglong Ren

    2014-01-01

    Green Revolution made a substantial contribution to wheat yields worldwide in the 1960s and 1970s. It is of great importance to analyze the haplotype variation of Rht-D1, the Green Revolution gene, during wheat (Triticum aestivum L.) domestication and breeding to understand its evolution and function in wheat breeding history. In this study, the Rht-D1 and its flanking regions were sequenced and single nucleotide polymorphisms were detected based on a panel of 45 accessions of Aegilops tauschi , 51 accessions of landraces and 80 accessions of commercial varieties. Genetic diversity in the wild accessions was much higher than that in the varieties and higher than that reported previously. Seven haplotypes (Hapl I to Hapl VII) of Rht-D1 were identified and their evolutionary relationships were proposed. In addition to the wel-known Green Revolution al ele Rht-D1b, Hapl VII (an al ele Rht-D1k) was identified in early breeding varieties, which reduced plant height by 16%. The results suggested that Rht-D1k had been used in breeding before the Green Revolution and made a great contribution to wheat production worldwide. Based on the breeding history and molecular evidence, we proposed that the wheat Green Revolution in China and International Maize and Wheat Improvement Center (CIMMYT) occurred independently.

  3. ParaHaplo 2.0: a program package for haplotype-estimation and haplotype-based whole-genome association study using parallel computing

    Directory of Open Access Journals (Sweden)

    Kamatani Naoyuki

    2010-06-01

    Full Text Available Abstract Background The use of haplotype-based association tests can improve the power of genome-wide association studies. Since the observed genotypes are unordered pairs of alleles, haplotype phase must be inferred. However, estimating haplotype phase is time consuming. When millions of single-nucleotide polymorphisms (SNPs are analyzed in genome-wide association study, faster methods for haplotype estimation are required. Methods We developed a program package for parallel computation of haplotype estimation. Our program package, ParaHaplo 2.0, is intended for use in workstation clusters using the Intel Message Passing Interface (MPI. We compared the performance of our algorithm to that of the regular permutation test on both Japanese in Tokyo, Japan and Han Chinese in Beijing, China of the HapMap dataset. Results Parallel version of ParaHaplo 2.0 can estimate haplotypes 100 times faster than a non-parallel version of the ParaHaplo. Conclusion ParaHaplo 2.0 is an invaluable tool for conducting haplotype-based genome-wide association studies (GWAS. The need for fast haplotype estimation using parallel computing will become increasingly important as the data sizes of such projects continue to increase. The executable binaries and program sources of ParaHaplo are available at the following address: http://en.sourceforge.jp/projects/parallelgwas/releases/

  4. Absence of atypical haplotype and presence of Senegal haplotype sickle cell disease in African-descent population in the northern Brazil

    Directory of Open Access Journals (Sweden)

    Rafael E. Nascimento

    2015-04-01

    Full Text Available Introduction: Sickle cell anemia (SCA is the most severe form of sickle cell disease; it presents variants that are called haplotypes βS. There are five major haplotypes βS gene: Arab-Indian/Saudi, Senegal, Benin, Bantu, and Camaroon. Objective: Characterize the presence of haplotypes in patients with SCA in Amapá. Methods: 46 sample were studied, all samples were amplified and analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP. Results: Bantu (61.2%, followed by Benin (26.5% and Senegal (12.2%. Conclusion: We identified three haplotypes characteristic of African ethnicity, with the presence of Senegal. In our study we found the presence of atypical haplotype, suggesting concentration and semi-isolation of the founding groups with little mixing.

  5. MalHaploFreq: A computer programme for estimating malaria haplotype frequencies from blood samples

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    Smith Thomas A

    2008-07-01

    Full Text Available Abstract Background Molecular markers, particularly those associated with drug resistance, are important surveillance tools that can inform policy choice. People infected with falciparum malaria often contain several genetically-distinct clones of the parasite; genotyping the patients' blood reveals whether or not the marker is present (i.e. its prevalence, but does not reveal its frequency. For example a person with four malaria clones may contain both mutant and wildtype forms of a marker but it is not possible to distinguish the relative frequencies of the mutant and wildtypes i.e. 1:3, 2:2 or 3:1. Methods An appropriate method for obtaining frequencies from prevalence data is by Maximum Likelihood analysis. A computer programme has been developed that allows the frequency of markers, and haplotypes defined by up to three codons, to be estimated from blood phenotype data. Results The programme has been fully documented [see Additional File 1] and provided with a user-friendly interface suitable for large scale analyses. It returns accurate frequencies and 95% confidence intervals from simulated dataset sets and has been extensively tested on field data sets. Additional File 1 User manual for MalHaploFreq. Click here for file Conclusion The programme is included [see Additional File 2] and/or may be freely downloaded from 1. It can then be used to extract molecular marker and haplotype frequencies from their prevalence in human blood samples. This should enhance the use of frequency data to inform antimalarial drug policy choice. Additional File 2 executable programme compiled for use on DOS or windows Click here for file

  6. Microsatellite diversity and crossover regions within homozygous and heterozygous SLA haplotypes of different pig breeds.

    Science.gov (United States)

    Ando, Asako; Uenishi, Hirohide; Kawata, Hisako; Tanaka-Matsuda, Maiko; Shigenari, Atsuko; Flori, Laurence; Chardon, Patrick; Lunney, Joan K; Kulski, Jerzy K; Inoko, Hidetoshi

    2008-07-01

    Our aim was to investigate microsatellite (MS) diversity and find crossover regions at 42 polymorphic MS loci in the swine leukocyte antigen (SLA) genomic region of 72 pigs with different well-defined homozygous and heterozygous SLA haplotypes. We analyzed the genetic polymorphisms of 42 MS markers in 23 SLA homozygous-heterozygous, common pig breeds with 12 SLA serological haplotypes and 49 National Institutes of Health (NIH) and Clawn homozygous-heterozygous miniature pigs with nine SLA serological or genotyped haplotypes including four recombinant haplotypes. In comparing the same and different haplotypes, both haplospecific patterns and allelic variations were observed at the MS loci. Some of the shared haplotype blocks extended over 2 Mb suggesting the existence of strong linkage disequilibrium (LD) in the entire SLA region. Crossover regions were easily defined by the MS markers within the class I and/or III region in the NIH and Clawn recombinant haplotypes. The present haplotype comparison shows that our set of MS markers provides a fast and cost-efficient alternative, or complementary, method to the serological or sequence-based determination of the SLA alleles for the characterization of SLA haplotypes and/or the crossover regions between different haplotypes.

  7. HLA-A, HLA-B, HLA-DRB1 allele and haplotype frequencies in 6384 umbilical cord blood units and transplantation matching and engraftment statistics in the Zhejiang cord blood bank of China.

    Science.gov (United States)

    Wang, F; He, J; Chen, S; Qin, F; Dai, B; Zhang, W; Zhu, F M; Lv, H J

    2014-02-01

    Umbilical cord blood (UCB) is a widely accepted source of progenitor cells, and now, many cord blood banks were established. Here, we analysed the HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies, HLA matching possibilities for searching potential donors and outcome of UCB transplantations in Zhejiang cord blood bank of China. A total of 6384 UCB units were characterized for 17 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles at the first field resolution level. Additionally, B*14, B*15 and B*40 were typed to the second field level. A total of 1372 distinct A-B-DRB1 haplotypes were identified. The frequencies of 7 haplotypes were more than 1%, and 439 haplotypes were blood bank of Zhejiang province. These data can help to select potential UCB donors for transplantation and used to assess the scale of new cord blood banking endeavours.

  8. Mechanistic Insight in the Function of Phosphite Additives for Protection of LiNi0.5Co0.2Mn0.3O2 Cathode in High Voltage Li-Ion Cells.

    Science.gov (United States)

    He, Meinan; Su, Chi-Cheung; Peebles, Cameron; Feng, Zhenxing; Connell, Justin G; Liao, Chen; Wang, Yan; Shkrob, Ilya A; Zhang, Zhengcheng

    2016-05-11

    Triethlylphosphite (TEP) and tris(2,2,2-trifluoroethyl) phosphite (TTFP) have been evaluated as electrolyte additives for high-voltage Li-ion battery cells using a Ni-rich layered cathode material LiNi0.5Co0.2Mn0.3O2 (NCM523) and the conventional carbonate electrolyte. The repeated charge/discharge cycling for cells containing 1 wt % of these additives was performed using an NCM523/graphite full cell operated at the voltage window from 3.0-4.6 V. During the initial charge process, these additives decompose on the cathode surface at a lower oxidation potential than the baseline electrolyte. Impedance spectroscopy and post-test analyses indicate the formation of protective coatings by both additives on the cathode surface that prevent oxidative breakdown of the electrolyte. However, only TTFP containing cells demonstrate the improved capacity retention and Coulombic efficiency. For TEP, the protective coating is also formed, but low Li(+) ion mobility through the interphase layer results in inferior performance. These observations are rationalized through the inhibition of electrocatalytic centers present on the cathode surface and the formation of organophosphate deposits isolating the cathode surface from the electrolyte. The difference between the two phosphites clearly originates in the different properties of the resulting phosphate coatings, which may be in Li(+) ion conductivity through such materials.

  9. Globally dispersed Y chromosomal haplotypes in wild and domestic sheep.

    Science.gov (United States)

    Meadows, J R S; Hanotte, O; Drögemüller, C; Calvo, J; Godfrey, R; Coltman, D; Maddox, J F; Marzanov, N; Kantanen, J; Kijas, J W

    2006-10-01

    To date, investigations of genetic diversity and the origins of domestication in sheep have utilised autosomal microsatellites and variation in the mitochondrial genome. We present the first analysis of both domestic and wild sheep using genetic markers residing on the ovine Y chromosome. Analysis of a single nucleotide polymorphism (oY1) in the SRY promoter region revealed that allele A-oY1 was present in all wild bighorn sheep (Ovis canadensis), two subspecies of thinhorn sheep (Ovis dalli), European Mouflon (Ovis musimon) and the Barbary (Ammontragis lervia). A-oY1 also had the highest frequency (71.4%) within 458 domestic sheep drawn from 65 breeds sampled from Africa, Asia, Australia, the Caribbean, Europe, the Middle East and Central Asia. Sequence analysis of a second locus, microsatellite SRYM18, revealed a compound repeat array displaying fixed differences, which identified bighorn and thinhorn sheep as distinct from the European Mouflon and domestic animals. Combined genotypic data identified 11 male-specific haplotypes that represented at least two separate lineages. Investigation of the geographical distribution of each haplotype revealed that one (H6) was both very common and widespread in the global sample of domestic breeds. The remaining haplotypes each displayed more restricted and informative distributions. For example, H5 was likely founded following the domestication of European breeds and was used to trace the recent transportation of animals to both the Caribbean and Australia. A high rate of Y chromosomal dispersal appears to have taken place during the development of domestic sheep as only 12.9% of the total observed variation was partitioned between major geographical regions.

  10. Inducible nitric oxide synthase haplotype associated with migraine and aura.

    Science.gov (United States)

    de O S Mansur, Thiago; Gonçalves, Flavia M; Martins-Oliveira, Alisson; Speciali, Jose G; Dach, Fabiola; Lacchini, Riccardo; Tanus-Santos, Jose E

    2012-05-01

    Migraine is a complex neurological disorder with a clear neurogenic inflammatory component apparently including enhanced nitric oxide (NO) formation. Excessive NO amounts possibly contributing to migraine are derived from increased expression and activity of inducible NO synthase (iNOS). We tested the hypothesis that two functional, clinically relevant iNOS genetic polymorphisms (C(-1026)A-rs2779249 and G2087A-rs2297518) are associated with migraine with or without aura. We studied 142 healthy women without migraine (control group) and 200 women with migraine divided into two groups: 148 with migraine without aura (MWA) and 52 with aura (MA). Genotypes were determined by real-time polymerase chain reaction using the Taqman(®) allele discrimination assays. The PHASE 2.1 software was used to estimate the haplotypes. The A allele for the G2087A polymorphism was more commonly found in the MA group than in the MWA group (28 vs. 18%; P 0.05). The haplotype combining both A alleles for the two polymorphisms was more commonly found in the MA group than in the control group or in the MWA group (19 vs. 10 or 8%; P = 0.0245 or 0.0027, respectively). Our findings indicate that the G2087A and the C(-1026)A polymorphism in the iNOS gene affect the susceptibility to migraine with aura when their effects are combined within haplotypes, whereas the G2087A affects the susceptibility to aura in migraine patients. These finding may have therapeutic implications when examining the effects of selective iNOS inhibitors.

  11. Genetic diversity and haplotype structure of 21 Y-STRs, including nine noncore loci, in South Tunisian Population: Forensic relevance.

    Science.gov (United States)

    Makki-Rmida, Faten; Kammoun, Arwa; Mahfoudh, Nadia; Ayadi, Adnene; Gibriel, Abdullah Ahmed; Mallek, Bakhta; Maalej, Leila; Hammami, Zouheir; Maatoug, Samir; Makni, Hafedh; Masmoudi, Saber

    2015-12-01

    Y chromosome STRs (Y-STRs) are being used frequently in forensic laboratories. Previous studies of Y-STR polymorphisms in different groups of the Tunisian population identified low levels of diversity and discrimination capacity (DC) using various commercial marker sets. This definitely limits the use of such systems for Y-STRs genotyping in Tunisia. In our investigation on South Tunisia, 200 unrelated males were typed for the 12 conventional Y-STRs included in the PowerPlex® Y System. Additional set of nine noncore Y-STRs including DYS446, DYS456, DYS458, DYS388, DYS444, DYS445, DYS449, DYS710, and DYS464 markers were genotyped and evaluated for their potential in improving DC. Allele frequency, gene diversity, haplotype diversity (HD), and DC calculation revealed that DYS464 was the most diverse marker followed by DYS710 and DYS449 markers. The standard panel of 12 Y-STRs (DC = 80.5%) and the nine markers were combined to obtain DC of 99%. Among the 198 different haplotypes observed, 196 haplotypes were unique (HD = 99.999). Out of the nine noncore set, six Y-STRs (DYS458, DYS456, DYS449, DYS710, DYS444, and DYS464) had the greatest impact on enhancing DC. Our data provided putative Y-STRs combination to be used for genetic and forensic applications.

  12. An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy.

    Science.gov (United States)

    Luo, Minjie; Liu, Liu; Peter, Inga; Zhu, Jun; Scott, Stuart A; Zhao, Geping; Eversley, Chevonne; Kornreich, Ruth; Desnick, Robert J; Edelmann, Lisa

    2014-02-01

    Spinal muscular atrophy is a common autosomal-recessive disorder caused by mutations of the SMN1 gene. Spinal muscular atrophy carrier screening uses dosage-sensitive methods that determine SMN1 copy number, and the frequency of carriers varies by ethnicity, with detection rates ranging from 71 to 94% due to the inability to identify silent (2 + 0) carriers with two copies of SMN1 on one chromosome 5 and deletion on the other. We hypothesized that identification of deletion and/or duplication founder alleles might provide an approach to identify silent carriers in various ethnic groups. SMN1 founder alleles were investigated in the Ashkenazi Jewish population by microsatellite analysis and next-generation sequencing. An extended haplotype block, specific to Ashkenazi Jewish SMN1 duplications, was identified by microsatellite analysis, and next-generation sequencing of SMN1 further defined a more localized haplotype. Of note, six novel SMN1 sequence variants were identified that were specific to duplications and not present on single-copy alleles. The haplotype was also identified on SMN1 duplication alleles in additional ethnic groups. Identification of these novel variants in an individual with two copies of SMN1 significantly improves the accuracy of residual risk estimates and has important implications for spinal muscular atrophy carrier screening.

  13. Haplotypes associated with resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum in two malaria endemic locations in Colombia.

    Science.gov (United States)

    Hernández, Diana Carolina; Guerra, Angela Patricia; Cucunubá, Zulma Milena; Nicholls, Ruben Santiago; Barrera, Sandra Milena

    2013-08-01

    Colombia has four main malaria transmission zones. In vivo efficacy studies carried out in these areas showed big differences in the response of Plasmodium falciparum to treatment with sulphadoxine-pyrimethamine. In addition, there is still insufficient information about the genetics of P. falciparum populations. The objective of this study was to determine the haplotypes in dhfr and dhps genes of P. falciparum circulating in two distinct endemic zones. Samples from patients with non-complicated P. falciparum malaria were collected: 135 from Tumaco and 206 from Tierralta. Alleles 108 and 51 of the dhfr gene, and 437 and 540 of the dhps gene were analyzed by PCR/enzymatic restriction, while alleles 59 and 164 (dhfr), and 581(dhps) by PCR/dot blot/hybridization. Five different haplotypes were found, of which the triple mutant 51I/C59/108N/I164/437G/K540/A581 was the most frequent (54.6%). In Tumaco, the parasites with wild haplotype predominated, while mutant parasites predominated in Tierralta. Another interesting finding is the presence of the C59R mutation in the dhfr gene in two samples, a mutation rarely found in South America. These data provide information about parasite population genetics and highlight the importance of starting a long term molecular surveillance program.

  14. 24 Y-chromosomal STR haplotypic polymorphisms for Chinese Uygur ethnic group and its phylogenic analysis with other Chinese groups.

    Science.gov (United States)

    Liu, Wen-Juan; Pu, Hong-Wei; Yang, Chun-Hua; Meng, Hao-Tian; Zhang, Yu-Dang; Zhang, Li-Ping; Yan, Jiang-Wei; Wang, Hong-Dan; Ren, Jian-Wen; Sun, Jun-Yi; Liu, Chao; Wang, Hui; Zhu, Bo-Feng

    2015-02-01

    The Uygur ethnic minority is the largest ethnic group in the Xinjiang Uygur Autonomous Region of China, and is a precious resource for the study of ethnogeny and forensic biology. Previous studies have focused on the genetic background of the Uygur group, however, the patrilineal descent of the group is still unclear. In this study, we investigated the genetic diversity of 24 Y-STR loci in the Uygur group and analyzed the population differentiations as well as the genetic relationships between the Uygur group and other previously reported populations using 17 Y-filer loci. According to haplotypic analysis of the 24 Y-STR loci in 109 Uygur individuals, 104 different haplotypes were obtained, 99 of which were unique. The haplotypic diversity and discrimination capacity of these 24 Y-STR loci in Uygur group were 0.9992 and 0.9541, respectively. An additional 7 loci (DYS388, DYS444, DYS447, DYS449, DYS522, and DYS527a,b) showed high genetic diversity and improved the overall discrimination capacity of the 24 Y-STR system. Pairwise Fst and neighbor-joining analysis showed that the Uygur group was genetically close to the Han populations from different regions. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. CCR5 haplotypes and mother-to-child HIV transmission in Malawi.

    Directory of Open Access Journals (Sweden)

    Bonnie R Pedersen

    Full Text Available BACKGROUND: CCR5 and CCR2 gene polymorphisms (SNPs have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT in Malawi. Blood samples from infants (n = 552 of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12, and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13. No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91, and -2135T (RR, 0.51; CI, 0.28-0.92. Statistically significant protection was not found at high MVL. CONCLUSIONS/SIGNIFICANCE: Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability.

  16. Association of CAPN10 SNPs and haplotypes with polycystic ovary syndrome among South Indian Women.

    Directory of Open Access Journals (Sweden)

    Shilpi Dasgupta

    Full Text Available Polycystic Ovary Syndrome (PCOS is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM, and calpain 10 gene (CAPN10 being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63 with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p = 0.007 with highly significant odds ratio when compared to TC (OR = 2.51, p = 0.003, 95% CI = 1.37-4.61 as well as TT (OR = 1.94, p = 0.016, 95% CI = 1.13-3.34. While the haplotype carrying the SNP-44 and SNP-19 variants (21121 exhibited a 2 fold increase in the risk for PCOS (OR = 2.37, p = 0.03, the haplotype containing SNP-56 and SNP-19 variants (11221 seems to have a protective role against PCOS (OR = 0.20, p = 0.004. Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS.

  17. Association of ORAI1 haplotypes with the risk of HLA-B27 positive ankylosing spondylitis.

    Directory of Open Access Journals (Sweden)

    James Cheng-Chung Wei

    Full Text Available Ankylosing spondylitis (AS is a chronic inflammation of the sacroiliac joints, spine and peripheral joints. The aetiology of ankylosing spondylitis is still unclear. Previous studies have indicated that genetics factors such as human leukocyte antigen HLA-B27 associates to AS susceptibility. We carried out a case-control study to determine whether the genetic polymorphisms of ORAI1 gene, a major component of store-operated calcium channels that involved the regulation of immune system, is a susceptibility factor to AS in a Taiwanese population. We enrolled 361 AS patients fulfilled the modified New York criteria and 379 controls from community. Five tagging single nucleotides polymorphisms (tSNPs at ORAI1 were selected from the data of Han Chinese population in HapMap project. Clinical statuses of AS were assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI, and Bath Ankylosing Spondylitis Global Index (BAS-G. Our results indicated that subjects carrying the minor allele homozygote (CC of the promoter SNP rs12313273 or TT homozygote of the SNP rs7135617 had an increased risk of HLA-B27 positive AS. The minor allele C of 3'UTR SNP rs712853 exerted a protective effect to HLA-B27 positive AS. Furthermore, the rs12313273/rs7135617 pairwise allele analysis found that C-G (OR 1.69, 95% CI 1.27, 2.25; p = 0.0003 and T-T (OR 1.75, 95% CI 1.36, 2.27; p<0.0001 haplotypes had a significantly association with the risk of HLA-B27-positive AS in comparison with the T-G carriers. This is the first study that indicate haplotypes of ORAI1 (rs12313273 and rs7135617 are associated with the risk of HLA-B27 positive AS.

  18. Haplotype Map of Sickle Cell Anemia in Tunisia

    OpenAIRE

    Imen Moumni; Maha Ben Mustapha; Sarra Sassi; Amine Zorai; Ikbel Ben Mansour; Kais Douzi; Dorra Chouachi; Fethi Mellouli; Mohamed Bejaoui; Salem Abbes

    2014-01-01

    International audience; β-Globin haplotypes are important to establish the ethnic origin and predict the clinical development of sickle cell disease patients (SCD). To determine the chromosomal background of β (S) Tunisian sickle cell patients, in this first study in Tunisia, we have explored four polymorphic regions of β-globin cluster on chromosome 11. It is the 5' region of β-LCR-HS2 site, the intervening sequence II (IVSII) region of two fetal ((G)γ and (A)γ) genes and the 5' region of β-...

  19. Haplotype diversity of 17 Y-chromosomal STRs in three native Sarawak populations (Iban, Bidayuh and Melanau) in East Malaysia.

    Science.gov (United States)

    Chang, Yuet Meng; Swaran, Yuvaneswari; Phoon, Yoong Keat; Sothirasan, Kavin; Sim, Hang Thiew; Lim, Kong Boon; Kuehn, Daniel

    2009-06-01

    17 Y-STRs (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385a/b, DYS393, DYS391, DYS439, DYS635 or Y-GATA C4, DYS392, Y-GATA H4, DYS437, DYS438 and DYS448) have been analyzed in 320 male individuals from Sarawak, an eastern state of Malaysia on the Borneo island using the AmpFlSTR Y-filer (Applied Biosystems, Foster City, CA). These individuals were from three indigenous ethnic groups in Sarawak comprising of 103 Ibans, 113 Bidayuhs and 104 Melanaus. The observed 17-loci haplotypes and the individual allele frequencies for each locus were estimated, whilst the locus diversity, haplotype diversity and discrimination capacity were calculated in the three groups. Analysis of molecular variance (AMOVA) indicated that 87.6% of the haplotypic variation was found within population and 12.4% between populations (fixation index F(ST)=0.124, p=0.000). This study has revealed that the indigenous populations in Sarawak are distinctly different to each other, and to the three major ethnic groups in Malaysia (Malays, Chinese and Indians), with the Melanaus having a strikingly high degree of shared haplotypes within. There are rare unusual variants and microvariants that were not present in Malaysian Malay, Chinese or Indian groups. In addition, occurrences of DYS385 duplications which were only noticeably present in Chinese group previously was also observed in the Iban group whilst null alleles were detected at several Y-loci (namely DYS19, DYS392, DYS389II and DYS448) in the Iban and Melanau groups.

  20. Analysis of polymorphisms and haplotype structure of the human thymidylate synthase genetic region: a tool for pharmacogenetic studies.

    Directory of Open Access Journals (Sweden)

    Soma Ghosh

    Full Text Available 5-Fluorouracil (5FU, a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms. Prior studies implicated a VNTR (variable numbers of tandem repeats polymorphism in the 5'-untranslated region (5'-UTR of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T repeats and novel single nucleotide polymorphisms (SNPs flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt, polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing.

  1. The likelihood ratio and frequency of DQ2/DQ8 haplotypes in Iranian patients with celiac disease

    Science.gov (United States)

    Khosravi, Asghar; Mansouri, Masoume; Rostami-Nejad, Mohammad; Shahbazkhani, Bijan; Ekhlasi, Golnaz; Kalantari, Ebrahim

    2016-01-01

    Aim: The aim of this study was to evaluate the likelihood ratio and frequency of DQ2 and DQ8 in Iranian patients with celiac disease (CD). Background: The HLA DQ2 and HLA DQ8 are the important mediators in the development of celiac disease. A few studies evaluated the frequency of HLA DQ2 and HLA DQ8 haplotypes among the Iranian population with low sample size. Patients and methods: In this cross-sectional study, to predict HLA–DQ2 and DQ8 haplotypes, 141(73 male, 78 female) confirmed CD patients compared to 151 healthy controls were enrolled into this study during 2013-2014. HLA DQ2/ DQ8 haplotypes was determined in cases and controls using PCR-SSP technique. Results: DQ2 and DQ8 were positive in 80% (n=111) and 49% (n= 69) of CD patients and 36% (n=61) and 13% (n=21) of control group respectively. Moreover, 32% (n=45) of CD patients and 5.3% (n=8) of the control group were carrier of both haplotypes. In the case group about one-third of patients (32.2%) were positive for carrying both DQ2 and DQ8 heterodimers while only 5.3% (n=8) of the control group were carrier. In addition, the positive likelihood ratio of DQ2 and DQ8 were 1.74 (CI: 1.4- 2.1), and 2.6 (CI: 1.8– 2.7), respectively. Conclusion: The result of this study showed that the frequency of DQ8 among our population is higher than those reported by European countries, but it is close to those founded in South America and Middle East. This result suggests that the higher prevalence of HLA DQ8 pattern in Iranian CD patients is similar to non-European patients. PMID:26744610

  2. The dopamine transporter haplotype and reward-related striatal responses in adult ADHD

    OpenAIRE

    Hoogman, M.; Onnink, M.; Coolen, R.; Aarts, E.; van Kan, C; Arias Vasquez, A.; Buitelaar, J; Franke, B

    2013-01-01

    Attention deficit/hyperactivity disorder (ADHD) is a highly heritable disorder and several genes increasing disease risk have been identified. The dopamine transporter gene, SLC6A3/DAT1, has been studied most extensively in ADHD research. Interestingly, a different haplotype of this gene (formed by genetic variants in the 3' untranslated region and intron 8) is associated with childhood ADHD (haplotype 10-6) and adult ADHD (haplotype 9-6). The expression of DAT1 is highest in striatal regions...

  3. Novel strategies to mine alcoholism-related haplotypes and genes by combining existing knowledge framework.

    Science.gov (United States)

    Zhang, RuiJie; Li, Xia; Jiang, YongShuai; Liu, GuiYou; Li, ChuanXing; Zhang, Fan; Xiao, Yun; Gong, BinSheng

    2009-02-01

    High-throughout single nucleotide polymorphism detection technology and the existing knowledge provide strong support for mining the disease-related haplotypes and genes. In this study, first, we apply four kinds of haplotype identification methods (Confidence Intervals, Four Gamete Tests, Solid Spine of LD and fusing method of haplotype block) into high-throughout SNP genotype data to identify blocks, then use cluster analysis to verify the effectiveness of the four methods, and select the alcoholism-related SNP haplotypes through risk analysis. Second, we establish a mapping from haplotypes to alcoholism-related genes. Third, we inquire NCBI SNP and gene databases to locate the blocks and identify the candidate genes. In the end, we make gene function annotation by KEGG, Biocarta, and GO database. We find 159 haplotype blocks, which relate to the alcoholism most possibly on chromosome 1 approximately 22, including 227 haplotypes, of which 102 SNP haplotypes may increase the risk of alcoholism. We get 121 alcoholism-related genes and verify their reliability by the functional annotation of biology. In a word, we not only can handle the SNP data easily, but also can locate the disease-related genes precisely by combining our novel strategies of mining alcoholism-related haplotypes and genes with existing knowledge framework.

  4. Novel strategies to mine alcoholism-related haplotypes and genes by combining existing knowledge framework

    Institute of Scientific and Technical Information of China (English)

    ZHANG RuiJie; LI Xia; JIANG YongShuai; LIU GuiYou; LI ChuanXing; ZHANG Fan; XIAO Yun; GONG BinSheng

    2009-01-01

    High-throughout single nucleotide polymorphism detection technology and the existing knowledge provide strong support for mining the disease-related haplotypes and genes. In this study, first, we apply four kinds of haplotype identification methods (Confidence Intervals, Four Gamete Testa, Solid Spine of LD and fusing method of haplotype block) into high-throughout SNP genotype data to identify blocks, then use cluster analysis to verify the effectiveness of the four methods, and select the alcoholism-related SNP haplotypes through risk analysis. Second, we establish a mapping from haplotypes to alcoholism-related genes. Third, we inquire NCBI SNP and gene databases to locate the blocks and identify the candidate genes. In the end, we make gene function annotation by KEGG, Biocarta, and GO database. We find 159 haplotype blocks, which relate to the alcoholism most possibly on chromosome 1-22, including 227 haplotypes, of which 102 SNP haplotypes may increase the risk of alcoholism. We get 121 alcoholism-related genes and verify their reliability by the functional annotation of biology. In a word, we not only can handle the SNP data easily, but also can locate the disease-related genes precisely by combining our novel strategies of mining alcoholism-related haplotypes and genes with existing knowledge framework.

  5. Novel strategies to mine alcoholism-related haplotypes and genes by combining existing knowledge framework

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    High-throughout single nucleotide polymorphism detection technology and the existing knowledge provide strong support for mining the disease-related haplotypes and genes. In this study, first, we apply four kinds of haplotype identification methods (Confidence Intervals, Four Gamete Tests, Solid Spine of LD and fusing method of haplotype block) into high-throughout SNP genotype data to identify blocks, then use cluster analysis to verify the effectiveness of the four methods, and select the alco- holism-related SNP haplotypes through risk analysis. Second, we establish a mapping from haplotypes to alcoholism-related genes. Third, we inquire NCBI SNP and gene databases to locate the blocks and identify the candidate genes. In the end, we make gene function annotation by KEGG, Biocarta, and GO database. We find 159 haplotype blocks, which relate to the alcoholism most possibly on chromosome 1~22, including 227 haplotypes, of which 102 SNP haplotypes may increase the risk of alcoholism. We get 121 alcoholism-related genes and verify their reliability by the functional annotation of biology. In a word, we not only can handle the SNP data easily, but also can locate the disease-related genes pre- cisely by combining our novel strategies of mining alcoholism-related haplotypes and genes with ex- isting knowledge framework.

  6. Updated listing of haplotypes at the human phenylalanine hydroxylase (PAH) locus

    Energy Technology Data Exchange (ETDEWEB)

    Eisensmith, R.C.; Woo, S.L.C. (Baylor College of Medicine, Houston, TX (United States))

    1992-12-01

    Analysis of mutant PAH chromosomes has identified approximately 60 different single-base substitutions and deletions within the PAH locus. Nearly all of these molecular lesions are in strong linkage disequilibrium with specific RFLP haplotypes in different ethnic populations. Thus, haplotype analysis is not only useful for diagnostic purposes but is proving to be a valuable tool in population genetic studies of the origin and spread of phenylketonuria alleles in human populations. PCR-based methods have been developed to detect six of the eight polymorphic restriction sites used for determination of RFLP haplotypes at the PAH locus. A table of the proposed expanded haplotypes is given.

  7. On detecting incomplete soft or hard selective sweeps using haplotype structure

    DEFF Research Database (Denmark)

    Ferrer-Admetlla, Anna; Liang, Mason; Korneliussen, Thorfinn Sand

    2014-01-01

    We present a new haplotype-based statistic (nSL) for detecting both soft and hard sweeps in population genomic data from a single population. We compare our new method with classic single-population haplotype and site frequency spectrum (SFS)-based methods and show that it is more robust, particu......We present a new haplotype-based statistic (nSL) for detecting both soft and hard sweeps in population genomic data from a single population. We compare our new method with classic single-population haplotype and site frequency spectrum (SFS)-based methods and show that it is more robust...

  8. Effects of TMEM154 haplotypes 1 and 3 on susceptibility to ovine progressive pneumonia virus following natural exposure in sheep.

    Science.gov (United States)

    Leymaster, K A; Chitko-McKown, C G; Clawson, M L; Harhay, G P; Heaton, M P

    2013-11-01

    Small ruminant lentiviruses (SRLV) adversely affect production and well-being of sheep and goats throughout much of the world. The SRLV, including ovine progressive pneumonia virus (OPPV) in North America, cause lifetime infections, and management procedures to eradicate or reduce disease prevalence are costly. Variants of ovine transmembrane protein 154 gene (TMEM154) affect susceptibility to OPPV. The primary experimental objective was to estimate additive and dominance effects of TMEM154 haplotypes 1 and 3 on susceptibility to OPPV infection following natural exposure. A group of 187 trial lambs was born and raised by mature, infected ewes to ensure natural exposure to OPPV. Parents of trial lambs were heterozygous for haplotypes 1 and 3, producing lambs with diplotypes "1 1," "1 3," and "3 3." A group of 20 sentinel lambs was born and raised by mature, uninfected ewes that were diplotype "1 1." Sentinel lambs had diplotypes "1 1" and "1 3," being sired by the same set of rams as trial lambs. Trial and sentinel lambs were comingled during the experiment. Lambs were weaned at 60 d of age, bled 1 wk after weaning, and thereafter at intervals of 4 or 5 wk until 9 mo of age when OPPV infection status was determined by use of a competitive enzyme-linked immunosorbent assay. Only 1 sentinel lamb became infected. Infection status of trial lambs was analyzed using logistic regression procedures to account for the binary nature of infection status and random effects of sires. Effects of sex, type of birth, type of rearing, age of dam, breed type of dam, and sires were not detected (P>0.20). Infection status was affected by diplotype of lamb (P=0.005), with additive (P=0.002) and dominance (P=0.052) effects identified. Predicted probabilities of infection for lambs with diplotypes "1 1," "1 3," and "3 3" were 0.094, 0.323, and 0.346, respectively. Confidence intervals for probabilities of infection for diplotypes "1 3" and "3 3" were similar, but distinct from diplotype

  9. A Method for Calling Copy Number Polymorphism Using Haplotypes

    Directory of Open Access Journals (Sweden)

    Gun Ho eJang

    2013-09-01

    Full Text Available Single nucleotide polymorphism (SNP and copy number variation (CNV are both widespread characteristic of the human genome, but are often called separately on common genotyping platforms. To capture integrated SNP and CNV information, methods have been developed for calling allelic specific copy numbers or so called copy number polymorphism (CNP, using limited inter-marker correlation. In this paper, we proposed a haplotype-based maximum likelihood method to call CNP, which takes advantage of the valuable multi-locus linkage disequilibrium (LD information in the population. We also developed a computationally efficient EM algorithm to estimate haplotype frequencies and optimize individual CNP calls simultaneously, even at presence of missing data. Through simulations, we demonstrated our model is more sensitive and accurate in detecting various CNV regions, compared with commonly-used CNV calling methods including PennCNV, another hidden Markov model using CNP, a scan statistic, segCNV, and cnvHap. Our method often performs better in the regions with higher LD, in longer CNV regions, and in common CNV than the opposite. We implemented our method on the genotypes of 90 HapMap CEU samples and 23 patients with acute lung injury (ALI. For each ALI patient the genotyping was performed twice. The CNPs from our method show good consistency and accuracy comparable to others.

  10. HIV-1 Vif adaptation to human APOBEC3H haplotypes.

    Science.gov (United States)

    Ooms, Marcel; Brayton, Bonnie; Letko, Michael; Maio, Susan M; Pilcher, Christopher D; Hecht, Frederick M; Barbour, Jason D; Simon, Viviana

    2013-10-16

    Several human APOBEC3 deaminases can inhibit HIV-1 replication in vitro. HIV-1 Vif counteracts this restriction by targeting APOBEC3 for proteasomal degradation. Human APOBEC3H (A3H) is highly polymorphic, with natural variants differing considerably in anti-HIV-1 activity in vitro. To examine HIV-1 adaptation to variation in A3H activity in a natural infection context, we determined the A3H haplotypes and Vif sequences from 76 recently infected HIV-1 patients. We detected A3H-specific Vif changes suggesting viral adaptation. The patient-derived Vif sequences were used to engineer viruses that specifically differed in their ability to counteract A3H. Replication of these Vif-variant viruses in primary T cells naturally expressing active or inactive A3H haplotypes showed that endogenously expressed A3H restricts HIV-1 replication. Proviral DNA from A3H-restricted viruses showed high levels of G-to-A mutations in an A3H-specific GA dinucleotide context. Taken together, our data validate A3H expressed at endogenous levels as a bona fide HIV-1 restriction factor.

  11. Haplotypes and Sequence Variation in the Ovine Adiponectin Gene (ADIPOQ

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    Qing-Ming An

    2015-11-01

    Full Text Available The adiponectin gene (ADIPOQ plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5 of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A1-D1, A2-D2 were detected in region-1 and region-2, respectively, with seven and six SNPs being revealed. In region-3, three different patterns (A3-C3 and three SNPs were observed. Two patterns (A4-B4, A5-B5 and two and one SNPs were observed in region-4 and region-5, respectively. In total, nineteen SNPs were detected, with five of them in the coding region and two (c.46T/C and c.515G/A putatively resulting in amino acid changes (p.Tyr16His and p.Lys172Arg. In region-1, -2 and -3 of 316 sheep from eight New Zealand breeds, variants A1, A2 and A3 were the most common, although variant frequencies differed in the eight breeds. Across region-1 and region-3, nine haplotypes were identified and haplotypes A1-A3, A1-C3, B1-A3 and B1-C3 were most common. These results indicate that the ADIPOQ gene is polymorphic and suggest that further analysis is required to see if the variation in the gene is associated with animal production traits.

  12. Haplotype Diversity at Sub1 Locus and Allelic Distribution Among Rice Varieties of Tide and Flood Prone Areas of South-East Asia

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    A.S.M. Masuduzzaman

    2017-07-01

    Full Text Available Single nucleotide polymorphisms and restriction digestion-based haplotype variations among 160 flood prone rice varieties were analyzed with enzymes Alu I and Cac8 I to generate polymorphisms at Sub1A and Sub1C loci (conferring submergence tolerance, respectively. Haplotype associated with phenotype was used to study the haplotype variations at Sub1A and Sub1C loci and to determine their functional influence on submergence tolerance and stem elongation. Three patterns at Sub1A locus, Sub1A0 (null allele, Sub1A1 (does not cut and Sub1A2 (one SNP, and four patterns at Sub1C locus, Sub1C1, Sub1C2, Sub1C3 and Sub1C4, were generated. Both tolerant Sub1A1 and intolerant Sub1A2 had the same length, but the difference was presence of a restriction site in the Sub1A2, but absent at the Sub1A1. Further, two types of polymorphism were detected at the Sub1C, one included major length polymorphisms (165, 170 and 175 bp and the other was a single restriction site at different position. Eight haplotypes (different combinations of the two loci, A1C1, A1C2, A1C4, A2C2, A2C4, A0C2, A0C3 and A0C4, were detected among 160 varieties. Haplotype A1C1 was comparatively more related to haplotypes A1C2 and A1C4, having the same Sub1A allele, and these haplotypes were found only in Bangladeshi, Sri Lankan and Indian varieties. Most tolerant varieties in A1C1 haplotype showed slow elongation, having tolerant specific Sub1A1 and Sub1C1 alleles. Further, the varieties Madabaru and Kottamali (A2C2 also showed moderate level of tolerance without Sub1A1 allele. These varieties were different with FR13A and also suspected to carry different novel tolerant genes at other loci. These materials could be used for hybridization with Sub1 varieties for pyramiding additional tolerant specific alleles into a single genotype for improving submergence tolerance in rice.

  13. Multisite haplotype on cattle chromosome 3 is associated with quantitative trait locus effects on lactation traits.

    Science.gov (United States)

    Cohen-Zinder, Miri; Donthu, Ravikiran; Larkin, Denis M; Kumar, Charu Gupta; Rodriguez-Zas, Sandra L; Andropolis, Kalista E; Oliveira, Rosane; Lewin, Harris A

    2011-11-07

    The goal of this study was to identify candidate genes and DNA polymorphisms for quantitative trait loci (QTL) affecting milk yield (MY), fat yield (FY), and protein yield (PY) previously mapped to bovine chromosome 3 (BTA3). To accomplish this, 373 half-siblings sired by three bulls previously shown to be segregating for lactation trait QTL, and 263 additional sires in the U.S. Dairy Bull DNA Repository (DBDR) were genotyped for 2,500 SNPs within a 16.3 Mbp QTL critical region on BTA3. Targeted resequencing of ∼1.8 Mbp within the QTL critical region of one of the QTL heterozygous sires identified additional polymorphisms useful for association studies. Twenty-three single nucleotide polymorphisms (SNPs) within a fine-mapped region were associated with effects on breeding values for MY, FY, or PY in DBDR sires, of which five SNPs were in strong linkage disequilibrium in the population. This multisite haplotype included SNPs located within exons or promoters of four tightly linked genes: RAP1A, ADORA3, OVGP1, and C3H1orf88. An SNP within RAP1A showed strong evidence of a recent selective sweep based on integrated haplotype score and was also associated with breeding value for PY. Because of its known function in alveolar lumen formation in the mammary gland, RAP1A is thus a strong candidate gene for QTL effects on lactation traits. Our results provide a detailed assessment of a QTL region that will be a useful guide for complex traits analysis in humans and other noninbred species.

  14. The insulin gene region and susceptibility to insulin-dependent diabetes mellitus in four races; new insights from Afro-Caribbean race-specific haplotypes.

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    Mijovic, C H; Penny, M A; Jenkins, D; Jacobs, K; Heward, J; Knight, S W; Lucassen, A; Morrison, E; Barnett, A H

    1997-01-01

    The IDDM2 component of the genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) has been mapped to chromosome 11p15.5. The exact identity of IDDM2 remains uncertain. It has been suggested that IDDM2 maps within the 5' VNTR (variable number tandem repeat) polymorphism upstream of the insulin gene (INS). This has not been confirmed and a contribution from other INS gene region polymorphisms cannot be excluded. We present INS region genotype data from four racial groups: the Japanese, Hong Kong Chinese, North Indian Asians and Afro-Caribbeans (two groups; one born and resident in the UK, one in Jamaica). These races have not been previously studied with the range of INS region polymorphisms included here. No INS polymorphism was associated with IDDM across all races. These data from this study thus do not identify any INS polymorphism as IDDM2. The Afro-Caribbean race showed a very different distribution of INS genotypes from the other races and novel race-specific INS haplotypes were identified. Analysis of these excluded a contribution to susceptibility to IDDM from the- 23HphI INS polymorphism. An Afro-Caribbean INS haplotype which differed only at the VNTR from the very protective INS haplotype (VPH) identified in white Caucasians was detected. Population analysis of this haplotype will allow direct assessment of the role of the VNTR in susceptibility to IDDM. In conclusion, the diverse Afro-Caribbean TH/INS/IGF2 haplotypes identified in this study will be valuable in mapping IDDM2 more precisely.

  15. Development of a Mo-Si-B coating for Nb-based Alloys and the Effects of Zr Additions to Mo-Si-B Coatings for Enhanced Oxidation Protection in Ultra-High Temperature Applications

    Science.gov (United States)

    Lu-Steffes, Otto John

    Higher efficiencies and reduced emissions performance of fossil fuel energy systems are achieved with increasing operation temperatures. This increase in operating temperature requires the use of materials with higher melting points such as refractory metal alloys. However, refractory metals suffer from catastrophic oxidation in this type of environment. Thus, oxidation protection for refractory metal alloys is a crucial step in developing next generation ultra-high temperature materials. To meet this challenge, an oxidation resistant coating for Nb based alloys has been designed as well as the incorporation of zirconium into the Mo-Si-B coating to provide further corrosion protection and a reduction in temperature for the underlying multi-layered structure. Niobium samples coated with a Mo-Si-B coating demonstrate enhanced oxidation protection compared to samples only coated with Si-B. Thermogravimetric analysis testing at 1300°C for 24 hours for both the Mo-Si-B coated Nb and Nb-based alloys show enhanced oxidation protection with mass changes of 0.44 mg/cm2 and 0.55 mg/cm2, respectively, compared to the uncoated alloy that had a mass change of 87.6 mg/cm2. To demonstrate the design concept for a coating with thermal barrier behavior, Zr is added to the Mo-Si-B coating through the pack cementation technique. The resulting coating shows that the Zr reacts with the aluminosilica top layer to form Zr silicides and ZrO2. Upon oxidation, the coating forms a mixed top layer composed of borosilica, ZrO2 and ZrSiO 4. Oxidation testing of the Zr modified Mo-Si-B coating exhibits low mass change indicating that the coating provides oxidation protection and that the Zr additions do not interfere with the oxidation protection of the Mo-Si-B coating. Finite element modeling using object oriented finite element analysis of the coating structures yielded an evaluation of the mechanical and thermal properties of the coatings, providing insight into the thermal performance and

  16. Chronic inflammatory state in sickle cell anemia patients is associated with HBB(*)S haplotype.

    Science.gov (United States)

    Bandeira, Izabel C J; Rocha, Lillianne B S; Barbosa, Maritza C; Elias, Darcielle B D; Querioz, José A N; Freitas, Max Vitor Carioca; Gonçalves, Romélia P

    2014-02-01

    The chronic inflammatory state in sickle cell anemia (SCA) is associated with several factors such as the following: endothelial damage; increased production of reactive oxygen species; hemolysis; increased expression of adhesion molecules by leukocytes, erythrocytes, and platelets; and increased production of proinflammatory cytokines. Genetic characteristics affecting the clinical severity of SCA include variations in the hemoglobin F (HbF) level, coexistence of alpha-thalassemia, and the haplotype associated with the HbS gene. The different haplotypes of SCA are Bantu, Benin, Senegal, Cameroon, and Arab-Indian. These haplotypes are associated with ethnic groups and also based on the geographical origin. Studies have shown that the Bantu haplotype is associated with higher incidence of clinical complications than the other haplotypes and is therefore considered to have the worst prognosis. This study aimed to evaluate the profile of the proinflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-17 in patients with SCA and also to assess the haplotypes associated with beta globin cluster S (HBB(*)S). We analyzed a total of 62 patients who had SCA and had been treated with hydroxyurea; they had received a dose ranging between 15 and 25 (20.0±0.6)mg/kg/day for 6-60 (18±3.4)months; their data were compared with those for 30 normal individuals. The presence of HbS was detected and the haplotypes of the beta S gene cluster were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our study demonstrated that SCA patients have increased inflammatory profile when compared to the healthy individuals. Further, analysis of the association between the haplotypes and inflammatory profile showed that the levels of IL-6 and TNF-α were greater in subjects with the Bantu/Bantu haplotype than in subjects with the Benin/Benin haplotype. The Bantu/Benin haplotype individuals had lower levels of cytokines than those with

  17. Study of the optimum haplotype length to build genomic relationship matrices.

    Science.gov (United States)

    Ferdosi, Mohammad H; Henshall, John; Tier, Bruce

    2016-09-29

    As genomic data becomes more abundant, genomic prediction is more routinely used to estimate breeding values. In genomic prediction, the relationship matrix ([Formula: see text]), which is traditionally used in genetic evaluations is replaced by the genomic relationship matrix ([Formula: see text]). This paper considers alternative ways of building relationship matrices either using single markers or haplotypes of different lengths. We compared the prediction accuracies and log-likelihoods when using these alternative relationship matrices and the traditional [Formula: see text] matrix, for real and simulated data. For real data, we built relationship matrices using 50k genotype data for a population of Brahman cattle to analyze three traits: scrotal circumference (SC), age at puberty (AGECL) and weight at first corpus luteum (WTCL). Haplotypes were phased with hsphase and imputed with BEAGLE. The relationship matrices were built using three methods based on haplotypes of different lengths. The log-likelihood was considered to define the optimum haplotype lengths for each trait and each haplotype-based relationship matrix. Based on simulated data, we showed that the inverse of [Formula: see text] matrix and the inverse of the haplotype relationship matrices for methods using one-single nucleotide polymorphism (SNP) phased haplotypes provided coefficients of determination (R(2)) close to 1, although the estimated genetic variances differed across methods. Using real data and multiple SNPs in the haplotype segments to build the relationship matrices provided better results than the [Formula: see text] matrix based on one-SNP haplotypes. However, the optimal haplotype length to achieve the highest log-likelihood depended on the method used and the trait. The optimal haplotype length (7 to 8 SNPs) was similar for SC and AGECL. One of the haplotype-based methods achieved the largest increase in log-likelihood for SC, i.e. from -1330 when using [Formula: see text] to

  18. Gardasil 9 Protects against Additional HPV Types

    Science.gov (United States)

    A summary of results from a large randomized clinical trial that shows a new human papillomavirus (HPV) vaccine effectively prevented infection and disease caused by seven HPV types that cause cancer and two HPV types that cause genital warts.

  19. Genetic relationships among native americans based on beta-globin gene cluster haplotype frequencies

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    Rita de Cassia Mousinho-Ribeiro

    2003-01-01

    Full Text Available The distribution of b-globin gene haplotypes was studied in 209 Amerindians from eight tribes of the Brazilian Amazon: Asurini from Xingú, Awá-Guajá, Parakanã, Urubú-Kaapór, Zoé, Kayapó (Xikrin from the Bacajá village, Katuena, and Tiriyó. Nine different haplotypes were found, two of which (n. 11 and 13 had not been previously identified in Brazilian indigenous populations. Haplotype 2 (+ - - - - was the most common in all groups studied, with frequencies varying from 70% to 100%, followed by haplotype 6 (- + + - +, with frequencies between 7% and 18%. The frequency distribution of the b-globin gene haplotypes in the eighteen Brazilian Amerindian populations studied to date is characterized by a reduced number of haplotypes (average of 3.5 and low levels of heterozygosity and intrapopulational differentiation, with a single clearly predominant haplotype in most tribes (haplotype 2. The Parakanã, Urubú-Kaapór, Tiriyó and Xavante tribes constitute exceptions, presenting at least four haplotypes with relatively high frequencies. The closest genetic relationships were observed between the Brazilian and the Colombian Amerindians (Wayuu, Kamsa and Inga, and, to a lesser extent, with the Huichol of Mexico. North-American Amerindians are more differentiated and clearly separated from all other tribes, except the Xavante, from Brazil, and the Mapuche, from Argentina. A restricted pool of ancestral haplotypes may explain the low diversity observed among most present-day Brazilian and Colombian Amerindian groups, while interethnic admixture could be the most important factor to explain the high number of haplotypes and high levels of diversity observed in some South-American and most North-American tribes.

  20. Musical Aptitude Is Associated with AVPR1A-Haplotypes

    Science.gov (United States)

    Ukkola, Liisa T.; Onkamo, Päivi; Raijas, Pirre; Karma, Kai; Järvelä, Irma

    2009-01-01

    Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h2 = .84; composing h2 = .40; arranging h2 = .46; improvising h2 = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (p<.0001). We discovered an overall haplotype association with AVPR1A gene (markers RS1 and RS3) and KMT (p = 0.0008; corrected p = 0.00002), SP (p = 0.0261; corrected p = 0.0072) and combined music test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be

  1. Glucose-6-phosphate dehydrogenase mutations and haplotypes in Mexican Mestizos.

    Science.gov (United States)

    Arámbula, E; Aguilar L, J C; Vaca, G

    2000-08-01

    In a screening for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in 1985 unrelated male subjects from the general population (Groups A and B) belonging to four states of the Pacific coast, 21 G-6-PD-deficient subjects were detected. Screening for mutations at the G-6-PD gene by PCR-restriction enzyme in these 21 G-6-PD-deficient subjects as well as in 14 G-6-PD-deficient patients with hemolytic anemia belonging to several states of Mexico showed two common G-6-PD variants: G-6-PD A-(202A/376G) (19 cases) and G-6-PD A-(376G/968C) (9 cases). In 7 individuals the mutations responsible for the enzyme deficiency remain to be determined. Furthermore, four silent polymorphic sites at the G-6-PD gene (PvuII, PstI, 1311, and NlaIII) were investigated in the 28 individuals with G-6-PD A- variants and in 137 G-6-PD normal subjects. As expected, only 10 different haplotypes were observed. To date, in our project aiming to determine the molecular basis of G-6-PD deficiency in Mexico, 60 unrelated G-6-PD-deficient Mexican males-25 in previous studies and 35 in the present work-have been studied. More than 75% of these individuals are from states of the Pacific coast (Sinaloa, Nayarit, Jalisco, Michoacán, Guerrero, Oaxaca, and Chiapas). The results show that although G-6-PD deficiency is heterogeneous at the DNA level in Mexico, only three polymorphic variants have been observed: G-6-PD A-(202A/376G) (36 cases), G-6-PD A-(376G/968C) (13 cases), and G-6-PD Seattle(844C) (2 cases). G-6-PD A- variants are relatively distributed homogeneously and both variants explain 82% of the overall prevalence of G-6-PD deficiency. The variant G-6-PD A-(202A/376G) represents 73% of the G-6-PD A- alleles. Our data also show that the variant G-6-PD A-(376G/968C)-which has been observed in Mexico in the context of two different haplotypes-is more common than previously supposed. The three polymorphic variants that we observed in Mexico are on the same haplotypes as found in subjects from

  2. Musical aptitude is associated with AVPR1A-haplotypes.

    Directory of Open Access Journals (Sweden)

    Liisa T Ukkola

    Full Text Available Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A, serotonin transporter (SLC6A4, catecol-O-methyltranferase (COMT, dopamin receptor D2 (DRD2 and tyrosine hydroxylase 1 (TPH1, genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT and Carl Seashores tests for pitch (SP and for time (ST. Data on creativity in music (composing, improvising and/or arranging music was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2 = .84; composing h(2 = .40; arranging h(2 = .46; improvising h(2 = .62 in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (p<.0001. We discovered an overall haplotype association with AVPR1A gene (markers RS1 and RS3 and KMT (p = 0.0008; corrected p = 0.00002, SP (p = 0.0261; corrected p = 0.0072 and combined music test scores (COMB (p = 0.0056; corrected p = 0.0006. AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184 and COMB (p = 0.0083; corrected p = 0.0040 using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment

  3. Haplotypes of NOS3 Gene Polymorphisms in Dilated Cardiomyopathy

    Science.gov (United States)

    Matsa, Lova Satyanarayana; Rangaraju, Advithi; Vengaldas, Viswamitra; Latifi, Mona; Jahromi, Hossein Mehraban; Ananthapur, Venkateshwari; Nallari, Pratibha

    2013-01-01

    Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO), a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3) gene viz., T-786C of the 5′ flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C) with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p = 0.01) was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34–3.27, p = 0.0011), with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p = 0.003). The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM

  4. Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy.

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    Lova Satyanarayana Matsa

    Full Text Available Dilated Cardiomyopathy (DCM is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO, a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3 gene viz., T-786C of the 5' flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p = 0.01 was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34-3.27, p = 0.0011, with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p = 0.003. The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM

  5. Role of TGF-β1 haplotypes in the occurrence of myocardial infarction in young Italian patients

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    Frea Simone

    2008-02-01

    Full Text Available Abstract Background Transforming growth factor beta 1 (TGF-β1 gene play an important role in the acute myocardial infarction (AMI, however no investigation has been conducted so far in young AMI patients. In this study, we evaluated the influence of TGF-β1 polymorphisms/haplotypes on the onset and progression of AMI in young Italian population. Methods 201 cases and 201 controls were genotyped for three TGF-β1 polymorphisms (G-800A, C-509T and Leu10Pro. The main follow-up end-points (mean follow-up, 107 ± 49 months were death, myocardial infarction or revascularization procedures. Results Significant risk factors were smoking (p -4, family history for coronary artery disease (p -4, hypercholesterolemia (p = 0.001 and hypertension (p = 0.002. The C-509T and Leu10Pro polymorphisms showed significant differences (p = 0.026 and p = 0.004 between cases and controls. The most common haplotypes revealed a possible protective effect (GCT, OR 0.75, 95% CI 0.57–0.99, p = 0.042 and an increased risk of AMI (GTC, OR 1.51, 95% CI 1.13–2.02, p = 0.005, respectively. No statistical differences were observed in genotype distribution in the follow-up study between the two groups: 61 patients with subsequent events (13 deaths and 108 without events. Conclusion Even though our results need to be further confirmed in larger studies, this is the first study reporting on a possible role of TGFβ1 common haplotypes in the onset of AMI in young patients.

  6. Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients.

    Science.gov (United States)

    Žavbi, Mateja; Korošec, Peter; Fležar, Matjaž; Škrgat Kristan, Sabina; Marc Malovrh, Mateja; Rijavec, Matija

    2016-06-01

    One of the major asthma susceptibility loci is 17q12-17q21.1, but the relationship between this locus and adult asthma is unclear. Association analysis of 13 single nucleotide polymorphisms (SNPs) and haplotypes from 17q12-17q21.1 was performed in 418 adult patients with asthma and 288 controls from Slovenia. Single SNP analysis revealed only marginal associations with adult asthma for SNPs located in GSDMA, GSDMB, ORMDL3 and ZPBP2 genes, and rs7219080 was the most highly associated. Analyses of asthma phenotypes found no association with atopy or lung function, but rs2305480 and rs8066582 were associated with childhood asthma and rs9916279 was associated with asthma in smokers. Notably, haplotypes consisting of rs9916279, rs8066582, rs1042658, and rs2302777 harbouring PSMD3, CSF3 and MED24 genes were highly associated with asthma. The four most common haplotypes, TCCG, TTTA, CCCA and TTCA, were more frequent in patients with asthma, whereas TTCG, TCCA, TCTA and TTTG were more frequent in controls. Only 3% of asthma patients belonged to haplotypes TTCG, TCCA, TCTA and TTTG compared with nearly one-third (31%) of controls. Associations confirmed that the 17q12-17q21.1 locus harbours a genetic determinant for asthma risk in adults and suggest that in addition to the previously known ORMDL3-GSDM locus, CSF3-PSMD3-MED24 also plays a role in asthma pathogenesis.

  7. Effects of the number of markers per haplotype and clustering of haplotypes on the accuracy of QTL mapping and prediction of genomic breeding values

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    Schrooten Chris

    2009-01-01

    Full Text Available Abstract The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD probabilities between haplotypes, various haplotype definitions were tested i.e. including 2, 6, 12 or 20 marker alleles and clustering base haplotypes related with an IBD probability of > 0.55, 0.75 or 0.95. Simulated data contained 1100 animals with known genotypes and phenotypes and 1000 animals with known genotypes and unknown phenotypes. Genomes comprising 3 Morgan were simulated and contained 74 polymorphic QTL and 383 polymorphic SNP markers with an average r2 value of 0.14 between adjacent markers. The total number of haplotypes decreased up to 50% when the window size was increased from two to 20 markers and decreased by at least 50% when haplotypes related with an IBD probability of > 0.55 instead of > 0.95 were clustered. An intermediate window size led to more precise QTL mapping. Window size and clustering had a limited effect on the accuracy of predicted total breeding values, ranging from 0.79 to 0.81. Our conclusion is that different optimal window sizes should be used in QTL-mapping versus genome-wide breeding value prediction.

  8. Effects of the number of markers per haplotype and clustering of haplotypes on the accuracy of QTL mapping and prediction of genomic breeding values.

    Science.gov (United States)

    Calus, Mario P L; Meuwissen, Theo H E; Windig, Jack J; Knol, Egbert F; Schrooten, Chris; Vereijken, Addie L J; Veerkamp, Roel F

    2009-01-15

    The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD) probabilities between haplotypes, various haplotype definitions were tested i.e. including 2, 6, 12 or 20 marker alleles and clustering base haplotypes related with an IBD probability of > 0.55, 0.75 or 0.95. Simulated data contained 1100 animals with known genotypes and phenotypes and 1000 animals with known genotypes and unknown phenotypes. Genomes comprising 3 Morgan were simulated and contained 74 polymorphic QTL and 383 polymorphic SNP markers with an average r2 value of 0.14 between adjacent markers. The total number of haplotypes decreased up to 50% when the window size was increased from two to 20 markers and decreased by at least 50% when haplotypes related with an IBD probability of > 0.55 instead of > 0.95 were clustered. An intermediate window size led to more precise QTL mapping. Window size and clustering had a limited effect on the accuracy of predicted total breeding values, ranging from 0.79 to 0.81. Our conclusion is that different optimal window sizes should be used in QTL-mapping versus genome-wide breeding value prediction.

  9. Association between Gene Haplotypes and Growth Traits in Japanese Hinai-dori Crossbred Chickens

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    Hideaki Takahashi

    2014-03-01

    Full Text Available We previously identified quantitative trait loci (QTL for body weight and average daily gain in a common region between ADL0198 (chr 1: 171.7 Mb and ABR0287 (chr 1: 173.4 Mb on chicken chromosome 1 in an F2 resource population produced by crossing low- and high-growth lines of the Hinai-dori breed. Motilin receptor (MLNR is a candidate gene affecting growth traits in the region. In this study, we genotyped polymorphisms of the MLNR gene and investigated its association with growth traits in a Hinai-dori F2 intercross population. All the exons of the MLNR gene in the parental population were subjected to PCR amplification, nucleotide sequenced and haplotypes identified. To distinguish resultant diplotype individuals in the F2 population, a mismatch amplification mutation assay was performed. Three haplotypes (Haplotypes 1–3 were accordingly identified. Six genotypes produced by the combination of three haplotypes (Haplotype 1, 2, and 3 were examined in order to identify associations between MLNR haplotypes and growth traits. The data showed that Haplotype 1 was superior to Haplotype 2 and 3 in body weight at 10 and 14 weeks of age, average daily gain between 4 and 10 weeks, 10 and 14 weeks, and 0 and 14 weeks of age in female in F2 females. It was concluded that MLNR is a useful marker of growth traits and could be used to develop strategies for improving growth traits in the Hinai-dori breed.

  10. Clarifying haplotype ambiguity of NAT2 in multi-national cohorts.

    Science.gov (United States)

    Selinski, Silvia; Blaszkewicz, Meinolf; Agundez, Jose A G; Martinez, Carmen; Garcia-Martin, Elena; Hengstler, Jan G; Golka, Klaus

    2013-01-01

    N-Acetyltransferase 2 (NAT2) is the key enzyme in aromatic amine metabolism. NAT2 genotyping requires a subsequent determination of the haplotype pairs (formerly: alleles) to derive the acetylation status. The chromosomal phase of the single nucleotide polymorphisms (SNPs) is unclear for about 2/3 of the genotypes. We investigated NAT2 genotypes of 1,234 bladder cancer cases and 2,207 controls from Germany, Hungary, Pakistan and Venezuela plus 696 further German cancer cases. We reconstructed NAT2 haplotypes using PHASE v2.1.1. We analysed if the variability of the NAT2 haplotypes affected the haplotype reconstruction. Furthermore, we compared population haplotype frequencies in three Caucasian control cohorts (German, Hungarian, Spanish), in Pakistanis and Venezuelans and the impact on bladder cancer. We conclude that a common haplotype reconstruction is feasible, enhances precision and reliability. Hungarian controls showed the largest intra-ethnic variability whereas the Pakistanis showed a haplotype distribution typical for Caucasians. The main differences could be observed for the slow haplotypes *5B, *6A and *7B. The association of slow NAT2 genotypes with bladder cancer risk was most prominent in the Venezuelan study group.

  11. Class I gene regulation of haplotype preference may influence antiviral immunity in vivo

    DEFF Research Database (Denmark)

    Thomsen, Allan Randrup; Marker, O

    1989-01-01

    The lymphocytic choriomeningitis virus (LCMV)-specific Tc response in (C3 X D2) F1 hybrids (k X d) is markedly biased in favor of the H-2d haplotype. Adoptive transfer experiments established that this haplotype preference also applied to T cell function in vivo. Using different mouse strain...

  12. Inheritance of the 8.1 ancestral haplotype in recurrent pregnancy loss

    DEFF Research Database (Denmark)

    Kolte, Astrid M; Nielsen, Henriette S; Steffensen, Rudi;

    2015-01-01

    BACKGROUND AND OBJECTIVES: The 8.1 ancestral haplotype (AH) (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2) is a remarkably long and conserved haplotype in the human major histocompatibility complex. It has been associated with both beneficial and detrimental effects, consistent with antagonistic pleiotr...

  13. The putative oncogene Pim-1 in the mouse: its linkage and variation among t haplotypes.

    Science.gov (United States)

    Nadeau, J H; Phillips, S J

    1987-11-01

    Pim-1, a putative oncogene involved in T-cell lymphomagenesis, was mapped between the pseudo-alpha globin gene Hba-4ps and the alpha-crystallin gene Crya-1 on mouse chromosome 17 and therefore within the t complex. Pim-1 restriction fragment variants were identified among t haplotypes. Analysis of restriction fragment sizes obtained with 12 endonucleases demonstrated that the Pim-1 genes in some t haplotypes were indistinguishable from the sizes for the Pim-1b allele in BALB/c inbred mice. There are now three genes, Pim-1, Crya-1 and H-2 I-E, that vary among independently derived t haplotypes and that have indistinguishable alleles in t haplotypes and inbred strains. These genes are closely linked within the distal inversion of the t complex. Because it is unlikely that these variants arose independently in t haplotypes and their wild-type homologues, we propose that an exchange of chromosomal segments, probably through double crossingover, was responsible for indistinguishable Pim-1 genes shared by certain t haplotypes and their wild-type homologues. There was, however, no apparent association between variant alleles of these three genes among t haplotypes as would be expected if a single exchange introduced these alleles into t haplotypes. If these variant alleles can be shown to be identical to the wild-type allele, then lack of association suggests that multiple exchanges have occurred during the evolution of the t complex.

  14. Mapping of HLA- DQ haplotypes in a group of Danish patients with celiac disease

    DEFF Research Database (Denmark)

    Lund, Flemming; Hermansen, Mette N; Pedersen, Merete F

    2015-01-01

    BACKGROUND: A cost-effective identification of HLA- DQ risk haplotypes using the single nucleotide polymorphism (SNP) technique has recently been applied in the diagnosis of celiac disease (CD) in four European populations. The objective of the study was to map risk HLA- DQ haplotypes in a group...

  15. Haplotype sharing analysis with SNPs in candidate genes : The genetic analysis workshop 12 example

    NARCIS (Netherlands)

    Fischer, C; Beckmann, L; Majoram, P; Meerman, GT; Chang-Claude, J

    2003-01-01

    Haplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct

  16. Wolbachia infection differs among divergent mitochondrial haplotypes of Bactericera cockerelli (Hemiptera: Triozidae)

    Science.gov (United States)

    Four mitochondrial (cytrochrome oxidase I) haplotypes of the potato psyllid, Bactericera cockerelli (S'ulc) (Hemiptera: Triozidae), have been identified in North America: western, central, northwestern,and southwestern. A recent study found that females of the northwestern haplotype mated by males o...

  17. Haplotypes of beta S chromosomes among patients with sickle cell anemia from Georgia.

    Science.gov (United States)

    Hattori, Y; Kutlar, F; Kutlar, A; McKie, V C; Huisman, T H

    1986-01-01

    Fetal hemoglobin and G gamma levels have been correlated with the presence or absence of eight restriction sites within the beta globin gene cluster (haplotypes) for numerous sickle cell anemia patients from Georgia. The most common haplotypes were #19 (Benin) and #20 (CAR); all patients with haplotype combinations 19/19, 20/20, and 19/20 were severely affected with low Hb F and low G gamma levels. A modified #19 beta S chromosome with a -G gamma-G gamma- globin gene arrangement, instead of -G gamma-A gamma-, was present in SS and SC newborn babies with G gamma values above 80%. Haplotype #3 (Senegal) was present among 15% of the beta S chromosomes; the two adult patients with the 3/3 combination were mildly affected with high Hb F and G gamma values. The haplotype AT with the variant A gamma T chain was a rarity. A new haplotype was found in one 17-year-old SS patient and five of his Hb S heterozygous relatives. This haplotype is associated with an increased production of Hb F in heterozygous and homozygous Hb S individuals; this Hb F contained primarily A gamma chains. A comparison was made between the different haplotypes among SS patients and normal Black individuals, and a remarkable similarity was noted in the fetal hemoglobin data for subjects with these different chromosomes.

  18. Haplotyping and copy number estimation of the highly polymorphic human beta-defensin locus on 8p23 by 454 amplicon sequencing

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    Rosenstiel Philip

    2010-04-01

    Full Text Available Abstract Background The beta-defensin gene cluster (DEFB at chromosome 8p23.1 is one of the most copy number (CN variable regions of the human genome. Whereas individual DEFB CNs have been suggested as independent genetic risk factors for several diseases (e.g. psoriasis and Crohn's disease, the role of multisite sequence variations (MSV is less well understood and to date has only been reported for prostate cancer. Simultaneous assessment of MSVs and CNs can be achieved by PCR, cloning and Sanger sequencing, however, these methods are labour and cost intensive as well as prone to methodological bias introduced by bacterial cloning. Here, we demonstrate that amplicon sequencing of pooled individual PCR products by the 454 technology allows in-depth determination of MSV haplotypes and estimation of DEFB CNs in parallel. Results Six PCR products spread over ~87 kb of DEFB and harbouring 24 known MSVs were amplified from 11 DNA samples, pooled and sequenced on a Roche 454 GS FLX sequencer. From ~142,000 reads, ~120,000 haplotype calls (HC were inferred that identified 22 haplotypes ranging from 2 to 7 per amplicon. In addition to the 24 known MSVs, two additional sequence variations were detected. Minimal CNs were estimated from the ratio of HCs and compared to absolute CNs determined by alternative methods. Concordance in CNs was found for 7 samples, the CNs differed by one in 2 samples and the estimated minimal CN was half of the absolute in one sample. For 7 samples and 2 amplicons, the 454 haplotyping results were compared to those by cloning/Sanger sequencing. Intrinsic problems related to chimera formation during PCR and differences between haplotyping by 454 and cloning/Sanger sequencing are discussed. Conclusion Deep amplicon sequencing using the 454 technology yield thousands of HCs per amplicon for an affordable price and may represent an effective method for parallel haplotyping and CN estimation in small to medium-sized cohorts. The

  19. Y-chromosome-Specific STR haplotype data on the Rapanui population (Easter Island).

    Science.gov (United States)

    Ghiani, Maria Elena; Moral, Pedro; Mitchell, Robert John; Hernández, Miguel; García-Moro, Clara; Vona, Giuseppe

    2006-10-01

    Located in the south Pacific Ocean, Rapanui is one of the most isolated inhabited islands in the world. Cultural and biological data suggest that the initial Rapanui population originated from central Polynesia, although the presence of foreign or exotic genes in the contemporary population, as a result of admixture with Europeans and/or South Americans during the last two centuries, also has to be considered. To estimate the genetic affinities of the Rapanui population with neighboring populations, we analyzed seven microsatellite polymorphisms of the Y chromosome that recently have been indicated as useful in the study of local population structure and recent demographic history. Phylogenetic analysis of Rapanui Y-chromosome haplotypes identified two clusters. The largest cluster contained 60% of all haplotypes and is characterized, in particular, by the presence of the DYS19*16, DYS390*20, and DYS393*14 alleles, a combination found frequently in Western Samoa. The second cluster is characterized by the presence of the DYS19*14, DYS390*24, and DYS393*13 alleles, and these have a relatively high frequency in European and European-derived populations but are either infrequent or absent in native Pacific populations. In addition to the two clusters, one male is of haplogroup Q*, which is indicative of native American ancestry. The genetic structure of the current male population of Rapanui is most likely a product of some genetic contribution from European and South American invaders who mated with the indigenous Polynesian women. However, analysis of Rapanui's relationships with other Pacific and Asian populations indicates that, as in Western Samoa and Samoa, the population has experienced extreme drift and founder events.

  20. An Efficient Trio-Based Mini-Haplotyping Method for Genetic Diagnosis of Phenylketonuria

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    Saeed Talebi

    2016-07-01

    Full Text Available Objective The phenylalanine hydroxylase (PAH locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficient method for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explain how to resolve the dye shift challenge in multiplex short tandem repeat (STR genotyping. Materials and Methods One hundred family trios were included in this descriptive study. The forward primer of a tetra-nucleotide STR and the reverse primer of a variable number tandem repeat (VNTR were labeled with three different non-overlapping dyes 5-carboxyfluorescein (FAM, 6-carboxy-N,N,N’,N’-tetramethylrhodamine (HEX and 6-carboxy-N,N,N’,N’-tetramethylrhodamine (TAMRA. The polymerase chain reaction (PCR products from each family trio were multiplexed for capillary electrophoresis and results were analyzed using Peak Scanner software. Results Multiplexing trio products decreased the cost significantly. The TAMRA labeled products had a significant predictable shift (migrated at a slower electrophoretic rate relative to the HEX and FAM labeled products. Through our methodology we achieve, the less inter-dye shift than intra-dye shift variance. Correcting the dye shift in the labeled products, according to the reference allele size, significantly decreased the inter-dye variability (P<0.001. Conclusion Multiplexing trio products helps to detect and resolve the dye shift accurately in each family, which otherwise would result in diagnostic error. The dye system of FAM, HEX and TAMRA is more feasible and cheaper than other dye systems.

  1. A haplotype inference algorithm for trios based on deterministic sampling

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    Iliadis Alexandros

    2010-08-01

    Full Text Available Abstract Background In genome-wide association studies, thousands of individuals are genotyped in hundreds of thousands of single nucleotide polymorphisms (SNPs. Statistical power can be increased when haplotypes, rather than three-valued genotypes, are used in analysis, so the problem of haplotype phase inference (phasing is particularly relevant. Several phasing algorithms have been developed for data from unrelated individuals, based on different models, some of which have been extended to father-mother-child "trio" data. Results We introduce a technique for phasing trio datasets using a tree-based deterministic sampling scheme. We have compared our method with publicly available algorithms PHASE v2.1, BEAGLE v3.0.2 and 2SNP v1.7 on datasets of varying number of markers and trios. We have found that the computational complexity of PHASE makes it prohibitive for routine use; on the other hand 2SNP, though the fastest method for small datasets, was significantly inaccurate. We have shown that our method outperforms BEAGLE in terms of speed and accuracy for small to intermediate dataset sizes in terms of number of trios for all marker sizes examined. Our method is implemented in the "Tree-Based Deterministic Sampling" (TDS package, available for download at http://www.ee.columbia.edu/~anastas/tds Conclusions Using a Tree-Based Deterministic sampling technique, we present an intuitive and conceptually simple phasing algorithm for trio data. The trade off between speed and accuracy achieved by our algorithm makes it a strong candidate for routine use on trio datasets.

  2. Susceptibility of biallelic haplotype and genotype frequencies to genotyping error.

    Science.gov (United States)

    Moskvina, Valentina; Schmidt, Karl Michael

    2006-12-01

    With the availability of fast genotyping methods and genomic databases, the search for statistical association of single nucleotide polymorphisms with a complex trait has become an important methodology in medical genetics. However, even fairly rare errors occurring during the genotyping process can lead to spurious association results and decrease in statistical power. We develop a systematic approach to study how genotyping errors change the genotype distribution in a sample. The general M-marker case is reduced to that of a single-marker locus by recognizing the underlying tensor-product structure of the error matrix. Both method and general conclusions apply to the general error model; we give detailed results for allele-based errors of size depending both on the marker locus and the allele present. Multiple errors are treated in terms of the associated diffusion process on the space of genotype distributions. We find that certain genotype and haplotype distributions remain unchanged under genotyping errors, and that genotyping errors generally render the distribution more similar to the stable one. In case-control association studies, this will lead to loss of statistical power for nondifferential genotyping errors and increase in type I error for differential genotyping errors. Moreover, we show that allele-based genotyping errors do not disturb Hardy-Weinberg equilibrium in the genotype distribution. In this setting we also identify maximally affected distributions. As they correspond to situations with rare alleles and marker loci in high linkage disequilibrium, careful checking for genotyping errors is advisable when significant association based on such alleles/haplotypes is observed in association studies.

  3. Musical aptitude is associated with AVPR1A-haplotypes.

    Science.gov (United States)

    Ukkola, Liisa T; Onkamo, Päivi; Raijas, Pirre; Karma, Kai; Järvelä, Irma

    2009-05-20

    Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2) = .84; composing h(2) = .40; arranging h(2) = .46; improvising h(2) = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (pmusic test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment behavior.

  4. Inference of population structure using dense haplotype data.

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    Daniel John Lawson

    2012-01-01

    Full Text Available The advent of genome-wide dense variation data provides an opportunity to investigate ancestry in unprecedented detail, but presents new statistical challenges. We propose a novel inference framework that aims to efficiently capture information on population structure provided by patterns of haplotype similarity. Each individual in a sample is considered in turn as a recipient, whose chromosomes are reconstructed using chunks of DNA donated by the other individuals. Results of this "chromosome painting" can be summarized as a "coancestry matrix," which directly reveals key information about ancestral relationships among individuals. If markers are viewed as independent, we show that this matrix almost completely captures the information used by both standard Principal Components Analysis (PCA and model-based approaches such as STRUCTURE in a unified manner. Furthermore, when markers are in linkage disequilibrium, the matrix combines information across successive markers to increase the ability to discern fine-scale population structure using PCA. In parallel, we have developed an efficient model-based approach to identify discrete populations using this matrix, which offers advantages over PCA in terms of interpretability and over existing clustering algorithms in terms of speed, number of separable populations, and sensitivity to subtle population structure. We analyse Human Genome Diversity Panel data for 938 individuals and 641,000 markers, and we identify 226 populations reflecting differences on continental, regional, local, and family scales. We present multiple lines of evidence that, while many methods capture similar information among strongly differentiated groups, more subtle population structure in human populations is consistently present at a much finer level than currently available geographic labels and is only captured by the haplotype-based approach. The software used for this article, ChromoPainter and fineSTRUCTURE, is

  5. Improved haplotype analysis of human myelin basic protein short tandem repeat loci.

    Science.gov (United States)

    Watanabe, G; Umetsu, K; Yuasa, I; Suzuki, T

    2000-06-01

    We report an improved haplotype analysis of the human myelin basic protein gene (MBP) short tandem repeat (STR) polymorphism. The polymorphic G-->A transition and 2 conventional STR polymorphisms, MBPA and MBPB, were simultaneously determined by an amplified product length polymorphism technique. After the MBPC fragments containing MBPA and MBPB were amplified, the linkage of these 2 STR loci was determined by a second amplification, using polymerase chain reaction (PCR) technique, of the isolated MBPC fragments. The present haplotype analysis dispensed with family studies for the haplotyping of MBPA and MBPB. Polymorphisms of the MBP loci studied in German and Japanese populations showed a high genomic variation. Haplotype analysis of the MBP loci showed distinct differences between the German and the Japanese populations. Consequently, haplotype analysis of the MBP loci promises to be useful in forensic identification and paternity testing.

  6. Beta-globin gene cluster haplotypes in Venezuelan sickle cell patients from the State of Aragua

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    Nancy Moreno

    2002-01-01

    Full Text Available Seven polymorphic sites in the beta-globin gene cluster were analyzed on a sample of 96 chromosomes of Venezuelan sickle cell patients from the State of Aragua. The Benin haplotype was predominant with a frequency of 0.479, followed by the Bantu haplotype (0.406; a minority of cases with other haplotypes was also identified: atypical Bantu A2 (0.042, Senegal (0.031, atypical Bantu A7 (0.021 and Saudi Arabia/Indian (0.021 haplotypes; however, the Cameroon haplotype was not identified in this study. Our results are in agreement with the historical records that establish Sudanese and Bantu origins for the African slaves brought into Venezuela.

  7. Polymorphism at expressed DQ and DR loci in five common equine MHC haplotypes.

    Science.gov (United States)

    Miller, Donald; Tallmadge, Rebecca L; Binns, Matthew; Zhu, Baoli; Mohamoud, Yasmin Ali; Ahmed, Ayeda; Brooks, Samantha A; Antczak, Douglas F

    2017-03-01

    The polymorphism of major histocompatibility complex (MHC) class II DQ and DR genes in five common equine leukocyte antigen (ELA) haplotypes was determined through sequencing of mRNA transcripts isolated from lymphocytes of eight ELA homozygous horses. Ten expressed MHC class II genes were detected in horses of the ELA-A3 haplotype carried by the donor horses of the equine bacterial artificial chromosome (BAC) library and the reference genome sequence: four DR genes and six DQ genes. The other four ELA haplotypes contained at least eight expressed polymorphic MHC class II loci. Next generation sequencing (NGS) of genomic DNA of these four MHC haplotypes revealed stop codons in the DQA3 gene in the ELA-A2, ELA-A5, and ELA-A9 haplotypes. Few NGS reads were obtained for the other MHC class II genes that were not amplified in these horses. The amino acid sequences across haplotypes contained locus-specific residues, and the locus clusters produced by phylogenetic analysis were well supported. The MHC class II alleles within the five tested haplotypes were largely non-overlapping between haplotypes. The complement of equine MHC class II DQ and DR genes appears to be well conserved between haplotypes, in contrast to the recently described variation in class I gene loci between equine MHC haplotypes. The identification of allelic series of equine MHC class II loci will aid comparative studies of mammalian MHC conservation and evolution and may also help to interpret associations between the equine MHC class II region and diseases of the horse.

  8. Characterisation of TNF block haplotypes affecting the production of TNF and LTA.

    Science.gov (United States)

    Tan, J H; Temple, S E L; Kee, C; Waterer, G W; Tan, C R T; Gut, I; Price, P

    2011-02-01

    Polymorphisms in the central major histocompatibility complex (MHC) (particularly TNF and adjacent genes) associate with several immunopathological diseases and with susceptibility to pneumonia. The MHC is characterised by strong linkage disequilibrium (LD), so identification of loci affecting disease must be based on haplotypes. We have defined 31 tumour necrosis factor (TNF) block haplotypes (denoted FV1-31) in Caucasians, Asians and Australian Aboriginals. This study correlates the carriage of TNF block haplotypes with TNF and lymphotoxin alpha (LTA) protein production by peripheral blood mononuclear cells from 205 healthy Caucasian subjects, following in vitro stimulation with Streptococcus pneumoniae (S. pneumoniae; gram-positive bacteria), Escherichia coli (E. coli; gram-negative bacteria) or TNF over 4, 8 and 24 h. Fifteen haplotypes were present at >1%, accounting for 94.5% of the cohort. The haplotypes were grouped into five families based on common alleles. Following stimulation, cells from carriers of the FV10 haplotype (family 2) produced less LTA compared with non-FV10 carriers. Carriers of the FV18 haplotype (family 4) produced more LTA than other donors. Induction of TNF by S. pneumoniae following 24 h stimulation was also greater in donors with FV18. The FV18 haplotype associated with the 44.1 MHC ancestral haplotype (HLA-A2, -C5, -B44, -DRB1*0401 and -DQB1*0301) that has few disease associations. FV16 occurred in the 8.1 MHC haplotype (HLA-A2, B8, DR3) that is associated with multiple immunopathological diseases. FV16 did not affect TNF or LTA levels. The findings suggest that many genetic variations critical in vivo are not effectively modelled by short-term cultures.

  9. β3 Integrin Haplotype Influences Gene Regulation and Plasma von Willebrand Factor Activity

    Science.gov (United States)

    Payne, Katie E; Bray, Paul F; Grant, Peter J; Carter, Angela M

    2008-01-01

    The Leu33Pro polymorphism of the gene encoding β3 integrin (ITGB3) is associated with acute coronary syndromes and influences platelet aggregation. Three common promoter polymorphisms have also been identified. The aims of this study were to (1) investigate the influence of the ITGB3 −400C/A, −425A/C and −468G/A promoter polymorphisms on reporter gene expression and nuclear protein binding and (2) determine genotype and haplotype associations with platelet αIIbβ3 receptor density. Promoter haplotypes were introduced into an ITGB3 promoter-pGL3 construct by site directed mutagenesis and luciferase reporter gene expression analysed in HEL and HMEC-1 cells. Binding of nuclear proteins was assessed by electrophoretic mobility shift assay. The association of ITGB3 haplotype with platelet αIIbβ3 receptor density was determined in 223 subjects. Species conserved motifs were identified in the ITGB3 promoter in the vicinity of the 3 polymorphisms. The GAA, GCC, AAC, AAA and ACC constructs induced ~50% increased luciferase expression relative to the GAC construct in both cell types. Haplotype analysis including Leu33Pro indicated 5 common haplotypes; no associations between ITGB3 haplotypes and receptor density were found. However, the GCC-Pro33 haplotype was associated with significantly higher vWF activity (128.6 [112.1–145.1]%) compared with all other haplotypes (107.1 [101.2–113.0]%, p=0.02). In conclusion, the GCC-Pro33 haplotype was associated with increased vWF activity but not with platelet αIIbβ3 receptor density, which may indicate ITGB3 haplotype influences endothelial function. PMID:18045606

  10. Additivity dominance

    Directory of Open Access Journals (Sweden)

    Paul Rozin

    2009-10-01

    Full Text Available Judgments of naturalness of foods tend to be more influenced by the process history of a food, rather than its actual constituents. Two types of processing of a ``natural'' food are to add something or to remove something. We report in this study, based on a large random sample of individuals from six countries (France, Germany, Italy, Switzerland, UK and USA that additives are considered defining features of what makes a food not natural, whereas ``subtractives'' are almost never mentioned. In support of this, skim milk (with major subtraction of fat is rated as more natural than whole milk with a small amount of natural vitamin D added. It is also noted that ``additives'' is a common word, with a synonym reported by a native speaker in 17 of 18 languages, whereas ``subtractive'' is lexicalized in only 1 of the 18 languages. We consider reasons for additivity dominance, relating it to omission bias, feature positive bias, and notions of purity.

  11. Human PIV-2 recombinant Sendai virus (rSeV) elicits durable immunity and combines with two additional rSeVs to protect against hPIV-1, hPIV-2, hPIV-3, and RSV.

    Science.gov (United States)

    Jones, Bart; Zhan, Xiaoyan; Mishin, Vasiliy; Slobod, Karen S; Surman, Sherri; Russell, Charles J; Portner, Allen; Hurwitz, Julia L

    2009-03-13

    The human parainfluenza viruses (hPIVs) and respiratory syncytial viruses (RSVs) are the leading causes of hospitalizations due to respiratory viral disease in infants and young children, but no vaccines are yet available. Here we describe the use of recombinant Sendai viruses (rSeVs) as candidate vaccine vectors for these respiratory viruses in a cotton rat model. Two new Sendai virus (SeV)-based hPIV-2 vaccine constructs were generated by inserting the fusion (F) gene or the hemagglutinin-neuraminidase (HN) gene from hPIV-2 into the rSeV genome. The inoculation of either vaccine into cotton rats elicited neutralizing antibodies toward both homologous and heterologous hPIV-2 virus isolates. The vaccines elicited robust and durable antibodies toward hPIV-2, and cotton rats immunized with individual or mixed vaccines were fully protected against hPIV-2 infections of the lower respiratory tract. The immune responses toward a single inoculation with rSeV vaccines were long-lasting and cotton rats were protected against viral challenge for as long as 11 months after vaccination. One inoculation with a mixture of the hPIV-2-HN-expressing construct and two additional rSeVs (expressing the F protein of RSV and the HN protein of hPIV-3) resulted in protection against challenge viruses hPIV-1, hPIV-2, hPIV-3, and RSV. Results identify SeV vectors as promising vaccine candidates for four different paramyxoviruses, each responsible for serious respiratory infections in children.

  12. Haplotype identity between individuals who share a CFTR mutation allele ''identical by descent'' : Demonstration of the usefulness of the haplotype-sharing concept for gene mapping in real populations

    NARCIS (Netherlands)

    deVries, HG; vanderMeulen, MA; Rozen, R; Halley, DJJ; Scheffer, H; tenKate, LP; Buys, CHCM; teMeerman, GJ

    1996-01-01

    Cystic fibrosis (CF) patients with the A455E mutation, in both the French Canadian and the Dutch population, share a common haplotype over distances of up to 25 cM. French Canadian patients with the 621+1G-->T mutation share a common haplotype of more than 14 cM. In contrast, haplotypes containing t

  13. To assess whether indoor residual spraying can provide additional protection against clinical malaria over current best practice of long-lasting insecticidal mosquito nets in The Gambia: study protocol for a two-armed cluster-randomised trial

    Directory of Open Access Journals (Sweden)

    Parker David

    2011-06-01

    Full Text Available Abstract Background Recently, there has been mounting interest in scaling-up vector control against malaria in Africa. It needs to be determined if indoor residual spraying (IRS with DDT will provide significant marginal protection against malaria over current best practice of long-lasting insecticidal nets (LLINs and prompt treatment in a controlled trial, given that DDT is currently the most persistent insecticide for IRS. Methods A 2 armed cluster-randomised controlled trial will be conducted to assess whether DDT IRS and LLINs combined provide better protection against clinical malaria in children than LLINs alone in rural Gambia. Each cluster will be a village, or a group of small adjacent villages; all clusters will receive LLINs and half will receive IRS in addition. Study children, aged 6 months to 13 years, will be enrolled from all clusters and followed for clinical malaria using passive case detection to estimate malaria incidence for 2 malaria transmission seasons in 2010 and 2011. This will be the primary endpoint. Exposure to malaria parasites will be assessed using light and exit traps followed by detection of Anopheles gambiae species and sporozoite infection. Study children will be surveyed at the end of each transmission season to estimate the prevalence of Plasmodium falciparum infection and the prevalence of anaemia. Discussion Practical issues concerning intervention implementation, as well as the potential benefits and risks of the study, are discussed. Trial Registration ISRCTN01738840 - Spraying And Nets Towards malaria Elimination (SANTE

  14. Interleukin-1 Gene Cluster Polymorphisms and its Haplotypes may Predict the Risk to Develop Cervical Cancer in Tunisia.

    Science.gov (United States)

    Zidi, Sabrina; Sghaier, Ikram; Zouidi, Ferjeni; Benahmed, Amira; Stayoussef, Mouna; Kochkar, Radhia; Gazouani, Ezzedine; Mezlini, Amel; Yacoubi-Loueslati, Besma

    2015-09-01

    Our study aimed to evaluate the association between IL-1α (4845 G/T), IL-1β (-511C/T) and IL-1RN (VNTR) polymorphisms and risk of cervical cancer. This case-control study investigates three polymorphisms in 130 patients and 260 controls by PCR-restriction fragment length polymorphism (RFLP). The IL-1RN (VNTR) A1/A3 genotype appear as a cervical cancer risk factor (p = 0.048; OR = 2.92; 95 % CI = 1.00-8.74), moreover, the L/2* decreased the risk (p = 0.011; OR = 0.47; 95 % CI = 0.25-0.88) and may be a protective factor against this pathology. Stratified analysis according to the FIGO stage subgroup revealed that the IL-1β-511 T/T genotype and T allele may be a protective factors against cervical cancer development for patients with early stage (p = 0.030; OR = 0.46; 95 % CI = 0.22-0.96) (p = 0.020; OR = 0.68; 95 % CI = 0.48-0.97). However, for the patients with advanced FIGO stage, IL-1RN-VNTR L/2* genotype appear as a protective factor for this pathology (p = 0.023; OR = 0.29; 95 % CI = 0.08-0.99). The (G-T-L) haplotype showed a significant decreased frequency in cervical cancer patients as compared to controls (p = 0.032; OR = 0.53; 95 % CI = 0.29-0.95). In contrast, the (T-T-2*) combination appear a risk factor for the development of cervical cancer (p = 0.018; OR = 1.57; 95 % CI = 1.07-2.30). Our study suggested that IL1 cluster polymorphisms and haplotypes may be a genetic risk factor for cervical cancer.

  15. 氨基酸硒对桃设施栽培环境适应性的影响%Effects of selenoamino acids addition on the adaptability of peach ( Prunus persica) to the condition of protected culti-vation

    Institute of Scientific and Technical Information of China (English)

    王孝娣; 刘凤之; 史祥宾; 王宝亮; 郑晓翠; 王海波

    2015-01-01

    探讨了硒提高桃适应设施栽培环境的效果, 为提高设施桃的环境适应能力和改善果实品质调控技术提供依据. 以4年生桃设施栽培的主栽品种中油4号油桃和春雪毛桃为试验材料, 研究氨基酸硒对桃光合作用光响应曲线、二氧化碳响应曲线、 温度响应曲线和蒸腾速率的影响. 喷施氨基酸硒使设施桃的光补偿点和二氧化碳补偿点显著降低, 表观量子效率和羧化效率显著提高, 使设施桃净光合速率在高温条件下保持较高数值且呈平稳状态, 显著促进了设施桃的蒸腾作用. 喷施氨基酸硒显著增强了桃对设施弱光、 二氧化碳浓度低、 高温和高湿环境的适应能力, 为设施桃品质的改善奠定了良好基础, 因此, 喷施氨基酸硒是一项切实可行的提高桃对设施环境适应能力的重要农艺措施.%To study the effects of application of selenoamino acids ( Se-aa) on the physiological parameters of peach tree and its adaptability to the protected cultivation condition, an experiment was carried using two 4-year-old peach ( Prunus persica) cultivars ('No. 4 Zhongyou' nectarine and'Springsnow' peach) which were cultivated in greenhouse as experimental materi-als. The results showed that Se-aa addition significantly decreased light compensation point and CO2 compensation point of peach plant, but significantly increased apparent quantum efficiency and carboxylation efficiency. Meanwhile, Se-aa addition improved net photosynthetic rate of protected peach plant under the condition of high temperature, and significantly improved the peach transpiration. These results fully showed that Se-aa addition significantly enhanced the adaptability of peach to the weak light condition with low concentration of CO2 , high temperature and high humidity under protected cultivation, which could be helpful for improveing the quality of peach fruits. It could be concluded that Se-aa addition could be taken as a

  16. HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies of 10 918 Koreans from bone marrow donor registry in Korea.

    Science.gov (United States)

    Park, H; Lee, Y-J; Song, E Y; Park, M H

    2016-10-01

    The human leucocyte antigen (HLA) system is the most polymorphic genetic system in humans, and HLA matching is crucial in organ transplantation, especially in hematopoietic stem cell transplantation. We investigated HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies at allelic level in 10 918 Koreans from bone marrow donor registry in Korea. Intermediate resolution HLA typing was performed using Luminex technology (Wakunaga, Japan), and additional allelic level typing was performed using PCR-single-strand conformation polymorphism method and/or sequence-based typing (Abbott Molecular, USA). Allele and haplotype frequencies were calculated by direct counting and maximum likelihood methods, respectively. A total of 39 HLA-A, 66 HLA-B and 47 HLA-DRB1 alleles were identified. High-frequency alleles found at a frequency of ≥5% were 6 HLA-A (A*02:01, *02:06, *11:01, *24:02, *31:01 and *33:03), 6 HLA-B (B*15:01, *35:01, *44:03, *51:01, 54:01 and *58:01) and 8 HLA-DRB1 (DRB1*01:01, *04:05, *04:06, *07:01, *08:03, *09:01, *13:02 and *15:01) alleles. At each locus, A*02, B*15 and DRB1*14 generic groups were most diverse at allelic level, consisting of 9, 12 and 11 different alleles, respectively. A total of 366, 197 and 21 different HLA-A-B-DRB1 haplotypes were estimated with frequencies of ≥0.05%, ≥0.1% and ≥0.5%, respectively. The five most common haplotypes with frequencies of ≥2.0% were A*33:03-B*44:03-DRB1*13:02 (4.97%), A*33:03-B*58:01-DRB1*13:02, A*33:03-B*44:03-DRB1*07:01, A*24:02-B*07:02-DRB1*01:01 and A*24:02-B*52:01-DRB1*15:02. Among 34 serologic HLA-A-B-DR haplotypes with frequencies of ≥0.5%, 17 haplotypes revealed allele-level diversity and majority of the allelic variation was arising from A2, A26, B61, B62, DR4 and DR14 specificities. Haplotype diversity obtained in this study is the most comprehensive data thus far reported in Koreans, and the information will be useful for unrelated stem cell transplantation as well as for disease

  17. Mitochondrial genomic analysis of late onset Alzheimer's disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging.

    Directory of Open Access Journals (Sweden)

    Perry G Ridge

    Full Text Available BACKGROUND: Alzheimer's disease (AD is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA variants and haplogroups in AD risk is uncertain. METHODOLOGY/PRINCIPAL FINDINGS: We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p=0.017, corrected for multiple comparisons. The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. CONCLUSIONS/SIGNIFICANCE: Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.

  18. Potlining Additives

    Energy Technology Data Exchange (ETDEWEB)

    Rudolf Keller

    2004-08-10

    In this project, a concept to improve the performance of aluminum production cells by introducing potlining additives was examined and tested. Boron oxide was added to cathode blocks, and titanium was dissolved in the metal pool; this resulted in the formation of titanium diboride and caused the molten aluminum to wet the carbonaceous cathode surface. Such wetting reportedly leads to operational improvements and extended cell life. In addition, boron oxide suppresses cyanide formation. This final report presents and discusses the results of this project. Substantial economic benefits for the practical implementation of the technology are projected, especially for modern cells with graphitized blocks. For example, with an energy savings of about 5% and an increase in pot life from 1500 to 2500 days, a cost savings of $ 0.023 per pound of aluminum produced is projected for a 200 kA pot.

  19. Additivity dominance

    OpenAIRE

    2009-01-01

    Judgments of naturalness of foods tend to be more influenced by the process history of a food, rather than its actual constituents. Two types of processing of a ``natural'' food are to add something or to remove something. We report in this study, based on a large random sample of individuals from six countries (France, Germany, Italy, Switzerland, UK and USA) that additives are considered defining features of what makes a food not natural, whereas ``subtractives'' are almost never mentioned....

  20. A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females

    NARCIS (Netherlands)

    Klok, M.D.; Giltay, E.J.; Does, van der A.J.W.; Geleijnse, J.M.; Antypa, N.; Penninx, B.W.J.H.; Geus, de E.J.C.; Willemsen, G.; Boomsma, D.; Leeuwen, van N.; Zitman, F.G.; Kloet, de E.R.

    2011-01-01

    Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant

  1. Practical interpretation of CYP2D6 haplotypes: Comparison and integration of automated and expert calling.

    Science.gov (United States)

    Ruaño, Gualberto; Kocherla, Mohan; Graydon, James S; Holford, Theodore R; Makowski, Gregory S; Goethe, John W

    2016-05-01

    We describe a population genetic approach to compare samples interpreted with expert calling (EC) versus automated calling (AC) for CYP2D6 haplotyping. The analysis represents 4812 haplotype calls based on signal data generated by the Luminex xMap analyzers from 2406 patients referred to a high-complexity molecular diagnostics laboratory for CYP450 testing. DNA was extracted from buccal swabs. We compared the results of expert calls (EC) and automated calls (AC) with regard to haplotype number and frequency. The ratio of EC to AC was 1:3. Haplotype frequencies from EC and AC samples were convergent across haplotypes, and their distribution was not statistically different between the groups. Most duplications required EC, as only expansions with homozygous or hemizygous haplotypes could be automatedly called. High-complexity laboratories can offer equivalent interpretation to automated calling for non-expanded CYP2D6 loci, and superior interpretation for duplications. We have validated scientific expert calling specified by scoring rules as standard operating procedure integrated with an automated calling algorithm. The integration of EC with AC is a practical strategy for CYP2D6 clinical haplotyping.

  2. HLA-G regulatory haplotypes and implantation outcome in couples who underwent assisted reproduction treatment.

    Science.gov (United States)

    Costa, Cynthia Hernandes; Gelmini, Georgia Fernanda; Wowk, Pryscilla Fanini; Mattar, Sibelle Botogosque; Vargas, Rafael Gustavo; Roxo, Valéria Maria Munhoz Sperandio; Schuffner, Alessandro; Bicalho, Maria da Graça

    2012-09-01

    The role of HLA-G in several clinical conditions related to reproduction has been investigated. Important polymorphisms have been found within the 5'URR and 3'UTR regions of the HLA-G promoter. The aim of the present study was to investigate 16 SNPs in the 5'URR and 14-bp insertion/deletion (ins/del) polymorphism located in the 3'UTR region of the HLA-G gene and its possible association with the implantation outcome in couples who underwent assisted reproduction treatments (ART). The case group was composed of 25 ART couples. Ninety-four couples with two or more term pregnancies composed the control group. Polymorphism haplotype frequencies of the HLA-G were determined for both groups. The Haplotype 5, Haplotype 8 and Haplotype 11 were absolute absence in ART couples. The HLA-G*01:01:02a, HLA-G*01:01:02b alleles and the 14-bp ins polymorphism, Haplotype 2, showed an increased frequency in case women and similar distribution between case and control men. However, this susceptibility haplotype is significantly presented in case women and in couple with failure implantation after treatment, which led us to suggest a maternal effect, associated with this haplotype, once their presence in women is related to a higher number of couples who underwent ART.

  3. Casein haplotypes and their association with milk production traits in the Finnish Ayrshire cattle.

    Science.gov (United States)

    Velmala, R; Vilkki, J; Elo, K; Mäki-Tanila, A

    1995-12-01

    Polymorphism of casein genes was studied in half-sib families of artificial insemination bulls of the Finnish Ayrshire dairy breed. Ten grandsires and 300 of their sons were genotyped for the following polymorphisms: alpha s1-casein (B, C), beta-casein (A1, A2), the microsatellite within the kappa-casein gene (ms5, ms4) and kappa-casein (A, B, E). Nine different combinations of these alleles, casein haplotypes, were found. Associations between casein haplotypes and milk production traits (milk and protein yield, fat and protein percentage and milking speed) were studied with ordinary least-squares analysis to find a direct effect of the haplotypes or an association within individual grandsire families using the granddaughter design. Estimated breeding values of sons were obtained from cow evaluation by animal model. No direct effect of the casein haplotypes on the traits was found. Within grandsire families, in one out of four families the chromosomal segment characterized by haplotype 3 (B-A2-ms4-A) was associated with an increase in milk yield (P < 0.01) and a decrease in fat percentage (P < 0.01) when contrasted with haplotype 8 (B-A1-ms4-E). The results provide evidence that in the Finnish Ayrshire breed at least one quantitative trait locus affecting the genetic variation in yields traits is segregating linked to either haplotype 3 (B-A2-ms4-A) or 8 (B-A1-ms4-E).

  4. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

    Science.gov (United States)

    Song, Chi; Chen, Gary K.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Ingles, Sue A.; Press, Michael F.; Deming, Sandra L.; Rodriguez-Gil, Jorge L.; Chanock, Stephen J.; Wan, Peggy; Sheng, Xin; Pooler, Loreall C.; Van Den Berg, David J.; Le Marchand, Loic; Kolonel, Laurence N.; Henderson, Brian E.; Haiman, Chris A.; Stram, Daniel O.

    2013-01-01

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density. PMID:23468962

  5. β-globin gene cluster haplotypes in ethnic minority populations of southwest China

    Science.gov (United States)

    Sun, Hao; Liu, Hongxian; Huang, Kai; Lin, Keqin; Huang, Xiaoqin; Chu, Jiayou; Ma, Shaohui; Yang, Zhaoqing

    2017-01-01

    The genetic diversity and relationships among ethnic minority populations of southwest China were investigated using seven polymorphic restriction enzyme sites in the β-globin gene cluster. The haplotypes of 1392 chromosomes from ten ethnic populations living in southwest China were determined. Linkage equilibrium and recombination hotspot were found between the 5′ sites and 3′ sites of the β-globin gene cluster. 5′ haplotypes 2 (+−−−), 6 (−++−+), 9 (−++++) and 3′ haplotype FW3 (−+) were the predominant haplotypes. Notably, haplotype 9 frequency was significantly high in the southwest populations, indicating their difference with other Chinese. The interpopulation differentiation of southwest Chinese minority populations is less than those in populations of northern China and other continents. Phylogenetic analysis shows that populations sharing same ethnic origin or language clustered to each other, indicating current β-globin cluster diversity in the Chinese populations reflects their ethnic origin and linguistic affiliations to a great extent. This study characterizes β-globin gene cluster haplotypes in southwest Chinese minorities for the first time, and reveals the genetic variability and affinity of these populations using β-globin cluster haplotype frequencies. The results suggest that ethnic origin plays an important role in shaping variations of the β-globin gene cluster in the southwestern ethnic populations of China. PMID:28205625

  6. Study on sickle cell disease haplotypes reveals the African origin of Amapá's population

    Directory of Open Access Journals (Sweden)

    Natália de Morais Castelo

    2014-04-01

    Full Text Available Introduction:Sickle cell disease (SCD is a hereditary, hematologic, multifactorial disease, with high prevalence worldwide; its cause is a mutation in the sixth codon of the beta globin gene (βs.Objective:To identify the haplotypes present in people with SCD in Amapá, and relate them to African descent.Methods:We analyzed, by molecular techniques, 46 blood samples from people with SCD in Macapá, the capital of Amapá, with the purpose of obtaining information about haplotype frequency distribution, which helps understand the ethnic background of Amapá's population.Results:Our study revealed that the most frequent haplotype is Bantu (61.2%, followed by Benin (26.6% and Senegal (12.2%. Results showed statistical differences from studies conducted in other regions. A high frequency of the Senegal haplotype stands out, in comparison with some Brazilian studies.Conclusion:Amapá's results exhibit unique characteristics when compared to haplotypes in other regions, with high frequency of Senegal and Benin haplotypes, absence of atypical, Cameroon and Saudi, confirming that Brazil shows ethnic background diversity, as well as different haplotype frequencies.

  7. An Extensive Analysis of Y-Chromosomal Microsatellite Haplotypes in Globally Dispersed Human Populations

    Science.gov (United States)

    Kayser, Manfred; Krawczak, Michael; Excoffier, Laurent; Dieltjes, Patrick; Corach, Daniel; Pascali, Vincente; Gehrig, Christian; Bernini, Luigi F.; Jespersen, Jørgen; Bakker, Egbert; Roewer, Lutz; de Knijff, Peter

    2001-01-01

    The genetic variance at seven Y-chromosomal microsatellite loci (or short tandem repeats [STRs]) was studied among 986 male individuals from 20 globally dispersed human populations. A total of 598 different haplotypes were observed, of which 437 (73.1%) were each found in a single male only. Population-specific haplotype-diversity values were .86–.99. Analyses of haplotype diversity and population-specific haplotypes revealed marked population-structure differences between more-isolated indigenous populations (e.g., Central African Pygmies or Greenland Inuit) and more-admixed populations (e.g., Europeans or Surinamese). Furthermore, male individuals from isolated indigenous populations shared haplotypes mainly with male individuals from their own population. By analysis of molecular variance, we found that 76.8% of the total genetic variance present among these male individuals could be attributed to genetic differences between male individuals who were members of the same population. Haplotype sharing between populations, ΦST statistics, and phylogenetic analysis identified close genetic affinities among European populations and among New Guinean populations. Our data illustrate that Y-chromosomal STR haplotypes are an ideal tool for the study of the genetic affinities between groups of male subjects and for detection of population structure. PMID:11254455

  8. Evaluation of logistic Bayesian LASSO for identifying association with rare haplotypes.

    Science.gov (United States)

    Biswas, Swati; Papachristou, Charalampos

    2014-01-01

    It has been hypothesized that rare variants may hold the key to unraveling the genetic transmission mechanism of many common complex traits. Currently, there is a dearth of statistical methods that are powerful enough to detect association with rare haplotypes. One of the recently proposed methods is logistic Bayesian LASSO for case-control data. By penalizing the regression coefficients through appropriate priors, logistic Bayesian LASSO weeds out the unassociated haplotypes, making it possible for the associated rare haplotypes to be detected with higher powers. We used the Genetic Analysis Workshop 18 simulated data to evaluate the behavior of logistic Bayesian LASSO in terms of its power and type I error under a complex disease model. We obtained knowledge of the simulation model, including the locations of the functional variants, and we chose to focus on two genomic regions in the MAP4 gene on chromosome 3. The sample size was 142 individuals and there were 200 replicates. Despite the small sample size, logistic Bayesian LASSO showed high power to detect two haplotypes containing functional variants in these regions while maintaining low type I errors. At the same time, a commonly used approach for haplotype association implemented in the software hapassoc failed to converge because of the presence of rare haplotypes. Thus, we conclude that logistic Bayesian LASSO can play an important role in the search for rare haplotypes.

  9. Predicting childhood effortful control from interactions between early parenting quality and children's dopamine transporter gene haplotypes.

    Science.gov (United States)

    Li, Yi; Sulik, Michael J; Eisenberg, Nancy; Spinrad, Tracy L; Lemery-Chalfant, Kathryn; Stover, Daryn A; Verrelli, Brian C

    2016-02-01

    Children's observed effortful control (EC) at 30, 42, and 54 months (n = 145) was predicted from the interaction between mothers' observed parenting with their 30-month-olds and three variants of the solute carrier family C6, member 3 (SLC6A3) dopamine transporter gene (single nucleotide polymorphisms in intron8 and intron13, and a 40 base pair variable number tandem repeat [VNTR] in the 3'-untranslated region [UTR]), as well as haplotypes of these variants. Significant moderating effects were found. Children without the intron8-A/intron13-G, intron8-A/3'-UTR VNTR-10, or intron13-G/3'-UTR VNTR-10 haplotypes (i.e., haplotypes associated with the reduced SLC6A3 gene expression and thus lower dopamine functioning) appeared to demonstrate altered levels of EC as a function of maternal parenting quality, whereas children with these haplotypes demonstrated a similar EC level regardless of the parenting quality. Children with these haplotypes demonstrated a trade-off, such that they showed higher EC, relative to their counterparts without these haplotypes, when exposed to less supportive maternal parenting. The findings revealed a diathesis-stress pattern and suggested that different SLC6A3 haplotypes, but not single variants, might represent different levels of young children's sensitivity/responsivity to early parenting.

  10. Association of USP26 haplotypes in men in Taiwan, China with severe spermatogenic defect

    Institute of Scientific and Technical Information of China (English)

    I-Wen Lee; Long-Ching Kuan; Chien-Hung Lin; Hsien-An Pan; Chao-Chin Hsu; Yung-Chieh Tsai; Pao-Lin Kuo; Yen-Ni Teng

    2008-01-01

    Aim: To complete comprehensive haplotype analysis of USP26 for both fertile and infertile men. Methods: Two hundred infertile men with severe oligospermia or non-obstructive azoospermia were subjected to sequence analysis for the entire coding sequences of the USP26 gene. Two hundred men with proven fertility were genotyped by primer extension methods. Allele/genotype frequencies, linkage disequilibrium (LD) characteristics and haplotypes of fertile men were compared with infertile men. Results: The allele frequencies of five single nucleotide polymor-phisms (370-371 insACA, 494T>C, 576G>A, ss6202791C>T, 1737G>A) were significantly higher in infertile patients than control subjects. The major haplotypes in infertile men were TACCGA (28% of the population), TGCCGA (15%), TACCAA (8%), TGCCAA (6%), TATCAA (5%) and CATCAA (5%). The major haplotypes for the control subjects were TACCGA (58% of the population), CACCGA (7%), CATCGA (6%) and TGCCGA (5%). Haplotypes TGCCGA, TATCAA, CATCAA, CATCGC, TACCAA and TGCCAA were over-transmitted in patients with spermato-genic defect, whereas haplotypes TACCGA, CACCGA, and CATCGA were under-transmitted in these patients.Conclusion: Some USP26 alleles and haplotypes are associated with spermatogenic defect in the Han nationality in Taiwan, China.

  11. Haplotype diversity in the equine myostatin gene with focus on variants associated with race distance propensity and muscle fiber type proportions

    OpenAIRE

    Petersen, Jessica L.; Valberg, Stephanie J; Mickelson, James R.; McCue, Molly E

    2014-01-01

    Two variants in the equine myostatin gene (MSTN), including a T/C SNP substitution in the first intron and a 227-bp SINE insertion in the promoter, are associated with muscle fiber type proportions in the Quarter Horse (QH) and with the prediction of race distance propensity in the Thoroughbred (TB). Genotypes from these loci, along with 18 additional variants surrounding MSTN, were examined in 301 horses of 14 breeds to evaluate haplotype relationships and diversity. The C allele of intron 1...

  12. Haplotype analysis in Huntington desease provides insights into mechanisms of CAG repeat expansion

    Energy Technology Data Exchange (ETDEWEB)

    Andrew, S.E.; Goldberg, Y.P.; Squitieri, F. [Univ. of British Columbia, Vancouver (Canada)] [and others

    1994-09-01

    Huntington disease (HD) is one of 7 disorders now known to be caused by expansion of a trinucleotide repeat. The HD mutation is a polymorphic trinucleotide (CAG) repeat in the 5{prime} region of a novel gene that expands beyond the normal range of 10-35 repeats in persons destined to develop the disease. Haplotype analysis of other dynamic mutation disorders such as myotonic dystrophy and Fragil X have suggested that a rare ancestral expansion event on a normal chromosome is followed by subsequent expansion events, resulting in a pool of chromosomes in the premutation range, which is inherently unstable and prone to further multiple expansion events leading to disease range chromosomes. Haplotype analysis of 67 HD and 84 control chromosomes using 5 polymorphic markers, both intragenic and 5{prime} to the disease mutation, demonstrate that multiple haplotypes underlie HD. However, 94% of the chromosomes can be grouped under two major haplotypes. These two haplotypes are also present in the normal population. A third major haplotype is seen on 38% of normal chromosomes but rarely on HD chromosomes (6%). CAG lengths on the normal chromosomes with the two haplotypes seen in the HD population are higher than those seen on the normal chromosomes with the haplotype rarely seen on HD chromosomes. Furthermore, in populations with a diminished frequency of HD, CAG length on normal chromosomes is significantly less than other populations with higher prevalence rates for HD. These data suggest that CAG length on normal chromosomes may be a significant factor contributing to repeat instability that eventually leads to chromosomes with CAG repeat lengths in the HD range. Haplotypes on the HD chromosomes are identical to those normal chromosomes which have CAG lengths in the high range of normal, suggesting that further expansions of this pool of chromosomes leads to chromosomes with CAG repeat sizes within the disease range, consistent with a multistep model.

  13. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype.

    Science.gov (United States)

    Ngo, Duyen; Bae, Harold; Steinberg, Martin H; Sebastiani, Paola; Solovieff, Nadia; Baldwin, Clinton T; Melista, Efthymia; Safaya, Surinder; Farrer, Lindsay A; Al-Suliman, Ahmed M; Albuali, Waleed H; Al Bagshi, Muneer H; Naserullah, Zaki; Akinsheye, Idowu; Gallagher, Patrick; Luo, Hong-yuan; Chui, David H K; Farrell, John J; Al-Ali, Amein K; Alsultan, Abdulrahman

    2013-06-01

    Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefore studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and employed targeted genotyping of polymorphic sites to explore cis- and trans- acting elements associated with high HbF expression. We also described sequences which appear to be unique to the AI haplotype for which future functional studies are needed to further define their role in HbF modulation. All cases, regardless of HbF concentration, were homozygous for AI haplotype-specific elements cis to HBB. SNPs in BCL11A and HBS1L-MYB that were associated with HbF in other populations explained only 8.8% of the variation in HbF. KLF1 polymorphisms associated previously with high HbF were not present in the 44 patients tested. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remains unexplained by the genetic loci that we studied. The dispersion of HbF levels among AI haplotype patients suggests that other genetic elements modulate the effects of the known cis- and trans-acting regulators. These regulatory elements, which remain to be discovered, might be specific in the Saudi and some other populations where HbF levels are especially high.

  14. β-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil

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    Wellington dos Santos Silva

    2010-01-01

    Full Text Available Five restriction site polymorphisms in the β-globin gene cluster (HincII-5'ε, HindIII-Gγ, HindIII-ªγ, HincII-'ψβ1 and HincII-3''ψβ1 were analyzed in three populations (n = 114 from Reconcavo Baiano, State of Bahia, Brazil. The groups included two urban populations from the towns of Cachoeira and Maragojipe and one rural Afro-descendant population, known as the "quilombo community", from Cachoeira municipality. The number of haplotypes found in the populations ranged from 10 to 13, which indicated higher diversity than in the parental populations. The haplotypes 2 (+----,3(----+,4(-+--+and6(-++-+onthe βA chromosomes were the most common, and two haplotypes, 9 (-++++and 14 (++--+, were found exclusively in the Maragojipe population. The other haplotypes (1, 5, 9, 11, 12, 13, 14 and 16 had lower frequencies. Restriction site analysis and the derived haplotypes indicated homogeneity among the populations. Thirty-two individuals with hemoglobinopathies (17 sickle cell disease, 12 HbSC disease and 3 HbCC disease were also analyzed. The haplotype frequencies of these patients differed significantly from those of the general population. In the sickle cell disease subgroup, the predominant haplotypes were BEN (Benin and CAR (Central African Republic, with frequencies of 52.9% and 32.4%, respectively. The high frequency of the BEN haplotype agreed with the historical origin of the afro-descendant population in the state of Bahia. However, this frequency differed from that of Salvador, the state capital, where the CAR and BEN haplotypes have similar frequencies, probably as a consequence of domestic slave trade and subsequent internal migrations to other regions of Brazil.

  15. Genetic and molecular characterization of three novel S-haplotypes in sour cherry (Prunus cerasus L.).

    Science.gov (United States)

    Tsukamoto, Tatsuya; Potter, Daniel; Tao, Ryutaro; Vieira, Cristina P; Vieira, Jorge; Iezzoni, Amy F

    2008-01-01

    Tetraploid sour cherry (Prunus cerasus L.) exhibits gametophytic self-incompatibility (GSI) whereby the specificity of self-pollen rejection is controlled by alleles of the stylar and pollen specificity genes, S-RNase and SFB (S haplotype-specific F-box protein gene), respectively. As sour cherry selections can be either self-compatible (SC) or self-incompatible (SI), polyploidy per se does not result in SC. Instead the genotype-dependent loss of SI in sour cherry is due to the accumulation of non-functional S-haplotypes. The presence of two or more non-functional S-haplotypes within sour cherry 2x pollen renders that pollen SC. Two new S-haplotypes from sour cherry, S(33) and S(34), that are presumed to be contributed by the P. fruticosa species parent, the complete S-RNase and SFB sequences of a third S-haplotype, S(35), plus the presence of two previously identified sweet cherry S-haplotypes, S(14) and S(16) are described here. Genetic segregation data demonstrated that the S(16)-, S(33)-, S(34)-, and S(35)-haplotypes present in sour cherry are fully functional. This result is consistent with our previous finding that 'hetero-allelic' pollen is incompatible in sour cherry. Phylogenetic analyses of the SFB and S-RNase sequences from available Prunus species reveal that the relationships among S-haplotypes show no correspondence to known organismal relationships at any taxonomic level within Prunus, indicating that polymorphisms at the S-locus have been maintained throughout the evolution of the genus. Furthermore, the phylogenetic relationships among SFB sequences are generally incongruent with those among S-RNase sequences for the same S-haplotypes. Hypotheses compatible with these results are discussed.

  16. Analysis of SNPs and haplotypes in vitamin D pathway genes and renal cancer risk.

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    Sara Karami

    Full Text Available In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR, most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC etiology. RCC cases (N = 777 and controls (N = 1,035 were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02 and retinoid-X-receptor-alpha (RXRA (p-value = 0.10 were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991 across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09-1.57 haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3' of the coding sequence (rs748964, rs3118523, increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings.

  17. The Investigation of Haplotype Phasing Efficiency at the PAH Gene Region in Iranian Family Trios

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    Z Fazeli

    2009-12-01

    Full Text Available "nBackground: The haplotype phasing is more useful than genotyping markers independently at carrier detection and prena­tal diagnosis of diseases. The PAH gene region contains several markers used in detection of PKU disease. In the present study, the efficiency of BglII-EcoRI-VNTR haplotype phasing in Iranian family trios was investigated. Then, this informa­tion was compared with those obtained for unrelated individuals."nMethods: Blood samples were collected from 20 healthy family trios and 60 unrelated individuals. The genomic DNA was ex­tracted by use of salting-out procedure. The two markers BglII and EcoRI were genotyped by use of PCR-RFLP. The geno­type of VNTR marker was identified by use of PCR and electrophoresis. The genotyping data obtained from family trios was used to infer haplotype phase. We also compared this data with results obtained from a widely used method for hap­lotype frequency inference from unrelated individuals, the PHASE program."nResults: The haplotype phase of all members was only ascertained at eight family trios.  The comparison of this data with the results obtained by use of PHASE program showed that eight haplotypes [211, 221, 215, 216, 214, 121, 225 and 111] were in­formative haplotypes in Iranian population."nConclusion: Since diversity of BglII-EcoRI-VNTR haplotypes was high in Iranian population, haplotype phasing at family trios was difficult. The results of this study showed that the genotyping data obtained from family trios could not provide enough information for BglII-EcoRI-VNTR haplotype phasing at Iranian PKU families and the genotyping of other family mem­bers was necessary at most cases.

  18. β-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    Wellington dos Santos Silva

    2010-01-01

    Full Text Available Five restriction site polymorphisms in the β-globin gene cluster (HincII-5'ε, HindIII-Gγ, HindIII-ªγ, HincII-'ψβ1 and HincII-3''ψβ1 were analyzed in three populations (n = 114 from Reconcavo Baiano, State of Bahia, Brazil. The groups included two urban populations from the towns of Cachoeira and Maragojipe and one rural Afro-descendant population, known as the "quilombo community", from Cachoeira municipality. The number of haplotypes found in the populations ranged from 10 to 13, which indicated higher diversity than in the parental populations. The haplotypes 2 (+----,3(----+,4(-+--+and6(-++-+onthe βA chromosomes were the most common, and two haplotypes, 9 (-++++and 14 (++--+, were found exclusively in the Maragojipe population. The other haplotypes (1, 5, 9, 11, 12, 13, 14 and 16 had lower frequencies. Restriction site analysis and the derived haplotypes indicated homogeneity among the populations. Thirty-two individuals with hemoglobinopathies (17 sickle cell disease, 12 HbSC disease and 3 HbCC disease were also analyzed. The haplotype frequencies of these patients differed significantly from those of the general population. In the sickle cell disease subgroup, the predominant haplotypes were BEN (Benin and CAR (Central African Republic, with frequencies of 52.9% and 32.4%, respectively. The high frequency of the BEN haplotype agreed with the historical origin of the afro-descendant population in the state of Bahia. However, this frequency differed from that of Salvador, the state capital, where the CAR and BEN haplotypes have similar frequencies, probably as a consequence of domestic slave trade and subsequent internal migrations to other regions of Brazil.

  19. IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn's disease location

    Institute of Scientific and Technical Information of China (English)

    Rocio Sanchez; Emile Levy; Florin Costea; Daniel Sinnett

    2009-01-01

    AIM: To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-α and the interleukin (IL)-10 in childhood Crohn's disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes. METHODS: Ten variants in GR, TNF-α and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin. RESULTS: For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5'flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-α gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-α, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively. CONCLUSION: This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.

  20. β-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil.

    Science.gov (United States)

    Dos Santos Silva, Wellington; de Nazaré Klautau-Guimarães, Maria; Grisolia, Cesar Koppe

    2010-07-01

    Five restriction site polymorphisms in the β-globin gene cluster (HincII-5' ε, HindIII-(G) γ, HindIII-(A) γ, HincII- ψβ1 and HincII-3' ψβ1) were analyzed in three populations (n = 114) from Reconcavo Baiano, State of Bahia, Brazil. The groups included two urban populations from the towns of Cachoeira and Maragojipe and one rural Afro-descendant population, known as the "quilombo community", from Cachoeira municipality. The number of haplotypes found in the populations ranged from 10 to 13, which indicated higher diversity than in the parental populations. The haplotypes 2 (+ - - - -), 3 (- - - - +), 4 (- + - - +) and 6 (- + + - +) on the β(A) chromosomes were the most common, and two haplotypes, 9 (- + + + +) and 14 (+ + - - +), were found exclusively in the Maragojipe population. The other haplotypes (1, 5, 9, 11, 12, 13, 14 and 16) had lower frequencies. Restriction site analysis and the derived haplotypes indicated homogeneity among the populations. Thirty-two individuals with hemoglobinopathies (17 sickle cell disease, 12 HbSC disease and 3 HbCC disease) were also analyzed. The haplotype frequencies of these patients differed significantly from those of the general population. In the sickle cell disease subgroup, the predominant haplotypes were BEN (Benin) and CAR (Central African Republic), with frequencies of 52.9% and 32.4%, respectively. The high frequency of the BEN haplotype agreed with the historical origin of the afro-descendant population in the state of Bahia. However, this frequency differed from that of Salvador, the state capital, where the CAR and BEN haplotypes have similar frequencies, probably as a consequence of domestic slave trade and subsequent internal migrations to other regions of Brazil.

  1. Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients

    Institute of Scientific and Technical Information of China (English)

    Jessica; Mwinyi; Christa; Wenger; Jyrki; J; Eloranta; Gerd; A; Kullak-Ublick

    2010-01-01

    AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, whi...

  2. The role of antigens and HLA class I haplotypes in indigenous women in Tashkent with hysteromyoma

    Directory of Open Access Journals (Sweden)

    Landish Isanbaeva

    2011-05-01

    Full Text Available Immunogenetic analysis on HLA I class in 177 indigenous women with uterine myoma showed the positive association in the risk of uterine fibroids with antigens HLA-B8/B22 and haplotype A28/B22; antigens HLA-A28, Cw5 and haplotype B17-Sw5 played role of auxiliary markers. HLA-antigens A2, B35, Cw4 and haplotypes A2-B35, B5-Cw4 showed the negative association. Carrying immunogenetic studies may be useful to search for individual genes involved in the determination of the disease - uterine fibroids, especially among patients with hereditary anamnesis.

  3. γA gene repeats polymorphism for the analysis of haplotypes of abnormal hemoglobins

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    Nejat Akar

    2014-09-01

    Full Text Available Aim of this study was to analyze γ A gene repeat polymorphism for the analysis of haplotypes of hemoglobin (Hb variants such as Hb S, Hb D-Punjab, Hb O-Arab. Sickle cell cases had mainly Benin and Arab/Indian haplotype. We found three different haplotypes among Hb S, Hb O Arab and Hb D-Punjab cases. We named these three variants as Anatolian-1 and Anatolian-2 and Asian. Our data revealed that Hb O Arab may arise twice one from Asia and the other from Europe.

  4. G6PD haplotypes spanning Xq28 from F8C to red/green color vision

    Energy Technology Data Exchange (ETDEWEB)

    Filosa, S.; Lania, G.; Martini, G. (Instituto Internazionale di Genetica e Biofisica, Naples (Italy)); Brancati, C.; Tagarelli, A. (Instituto per lo Studio delle Malattie Ereditarie e Carenziali, Cosenza (Italy)); Calabro, V. (Instituto per lo Studio delle Malattie Ereditarie e Carenziali, Cosenza (Italy) Hammersmith Hospital, London (United Kingdom)); Vulliamy, T.J.; Luzzatto, L. (Hammersmith Hospital, London (United Kingdom))

    1993-07-01

    The most telomeric region of the human X chromosome within band Xq28 consists of a gene-rich region of about 3 Mb which contains the genes for coagulation factor VIIIc, glucose-6-phosphate dehydrogenase (G6PD), and red/green color vision. The authors have studied five polymorphic sites from this region, in a sample of normal people from the Cosenza province of Southern Italy. These sites, which span a distance of some 350 kb, are in strong linkage disequilibrium. Of the 32 possible haplotypes only 10 were found, and 4 of these account for 80% of all X chromosomes analyzed. In addition, they found that all G6PD-deficient people with the G6PD Mediterranean mutation belong to only two haplotypes. One of these (Med 1) is found only within a small subregion of the area investigated, west of the Appennine mountain range. Most remarkably, all Med 1 G6PD-deficient individuals also had red/green color blindness. The more frequent haplotype (Med 2) is the same in Calabria and in Sardinia, where it accounts for about 90% of the G6PD Mediterranean mutations, despite the fact that gene flow between the populations of Sardinia and Southern Italy must have been limited. These data do not enable determination of whether the two types of G6PD Mediterranean have arisen through two separate identical mutational events or through a single mutational event followed by recombination. However, the data indicate relatively little recombination over an extended region of the X chromosome and they suggest that the G6PD Mediterranean mutation is recent by comparison to the other polymorphisms investigated. 44 refs., 4 figs., 5 tabs.

  5. Salt tolerance underlies the cryptic invasion of North American salt marshes by an introduced haplotype of the common reed Phragmites australis (Poaceae)

    Science.gov (United States)

    Vasquez, Edward A.; Glenn, Edward P.; Brown, J. Jed; Guntenspergen, Glenn R.; Nelson, Stephen G.

    2005-01-01

    A distinct, non-native haplotype of the common reed Phragmites australis has become invasive in Atlantic coastal Spartina marshes. We compared the salt tolerance and other growth characteristics of the invasive M haplotype with 2 native haplotypes (F and AC) in greenhouse experiments. The M haplotype retained 50% of its growth potential up to 0.4 M NaCl, whereas the F and AC haplotypes did not grow above 0.1 M NaCl. The M haplotype produced more shoots per gram of rhizome tissue and had higher relative growth rates than the native haplotypes on both freshwater and saline water treatments. The M haplotype also differed from the native haplotypes in shoot water content and the biometrics of shoots and rhizomes. The results offer an explanation for how the M haplotype is able to spread in coastal salt marshes and support the conclusion of DNA analyses that the M haplotype is a distinct ecotype of P. australis.

  6. Slam haplotype 2 promotes NKT but suppresses Vγ4+ T-cell activation in coxsackievirus B3 infection leading to increased liver damage but reduced myocarditis.

    Science.gov (United States)

    Huber, Sally Ann; Roberts, Brian; Moussawi, Mohamad; Boyson, Jonathan E

    2013-02-01

    There are two major haplotypes of signal lymphocytic activation molecule (Slam) in inbred mouse strains, with the Slam haplotype 1 expressed in C57Bl/6 mice and the Slam haplotype 2 expressed in most other commonly used inbred strains, including 129 mice. Because signaling through Slam family receptors can affect innate immunity [natural killer T cell (NKT) and γ-δ T-cell receptor], and innate immunity can determine susceptibility to coxsackievirus B3 (CVB3) infection, the present study evaluated the response of C57Bl/6 and congenic B6.129c1 mice (expressing the 129-derived Slam locus) to CVB3. CVB3-infected C57Bl/6 male mice developed increased myocarditis but reduced hepatic injury compared with infected B6.129c1 mice. C57Bl/6 mice also had increased γδ(+) and CD8(+)interferon-γ(+) cells but decreased numbers of NKT (T-cell receptor β chain + mCD1d tetramer(+)) and CD4(+)FoxP3(+) cells compared with B6.129c1 mice. C57Bl/6 mice were infected with CVB3 and treated with either α-galactosylceramide, an NKT cell-specific ligand, or vehicle (dimethyl sulfoxide/PBS). Mice treated with α-galactosylceramide showed significantly reduced myocarditis. Liver injuries, as determined by alanine aminotransferase levels in plasma, were increased significantly, confirming that NKT cells are protective for myocarditis but pathogenic in the liver.

  7. Haplotype structure of the beta2-adrenergic receptor gene in 814 Danish Caucasian subjects and association with body mass index

    DEFF Research Database (Denmark)

    Jensen, Mette Kamp; Nielsen, Morten; Koefoed, Pernille

    2009-01-01

    with body mass index (BMI). The SNPs showed organization into 13 distinct haplotypes and 41 haplotype pairs. The study identified four common haplotypes: ACCCC (10.1 +/- 0.3 %), ACCCG (27.9 +/- 0.3 %), GCCAC (10.8 +/- 0.1 %) and GGCCG (41.0 +/- 0.2 %) (frequencies (SD), seen in 91 % of the population....... In the total population (mean age +/- SD: 50 +/- 16 years), BMI was not related to haplotype pairs, individual SNPs or allelic haplotypes. However, in subjects ... to individual SNPs. In subjects subjects (BMI

  8. Haplotype and missing data inference in nuclear families.

    Science.gov (United States)

    Lin, Shin; Chakravarti, Aravinda; Cutler, David J

    2004-08-01

    Determining linkage phase from population samples with statistical methods is accurate only within regions of high linkage disequilibrium (LD). Yet, affected individuals in a genetic mapping study, including those involving cases and controls, may share sequences identical-by-descent stretching on the order of 10s to 100s of kilobases, quite possibly over regions of low LD in the population. At the same time, inferring phase from nuclear families may be hampered by missing family members, missing genotypes, and the noninformativity of certain genotype patterns. In this study, we reformulate our previous haplotype reconstruction algorithm, and its associated computer program, to phase parents with information derived from population samples as well as from their offspring. In applications of our algorithm to 100-kb stretches, simulated in accordance to a Wright-Fisher model with typical levels of LD in humans, we find that phase reconstruction for 160 trios with 10% missing data is highly accurate (>90%) over the entire length. Furthermore, our algorithm can estimate allelic status for missing data at high accuracy (>95%). Finally, the input capacity of the program is vast, easily handling thousands of segregating sites in > or = 1000 chromosomes.

  9. [International regulation of ethics committees on biomedical research as protection mechanisms for people: analysis of the Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research of the Council of Europe].

    Science.gov (United States)

    de Lecuona, Itziar

    2013-01-01

    The article explores and analyses the content of the Council of Europe's Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research regarding the standard legal instrument in biomedical research, issued by an international organization with leadership in bioethics. This implies ethics committees are mechanisms of protection of humans in biomedical research and not mere bureaucratic agencies and that a sound inescapable international regulatory framework exists for States to regulate biomedical research. The methodology used focuses on the analysis of the background, the context in which it is made and the nature and scope of the Protocol. It also identifies and analyses the characteristics and functions of ethics committees in biomedical research and, in particular, the information that should be provided to this bodies to develop their functions previously, during and at the end of research projects. This analysis will provide guidelines, suggestions and conclusions for the awareness and training of members of these committees in order to influence the daily practice. This paper may also be of interest to legal practitioners who work in different areas of biomedical research. From this practical perspective, the article examines the legal treatment of the Protocol to meet new challenges and classic issues in research: the treatment of human biological samples, the use of placebos, avoiding double standards, human vulnerability, undue influence and conflicts of interest, among others. Also, from a critical view, this work links the legal responses to develop work procedures that are required for an effective performance of the functions assigned of ethics committees in biomedical research. An existing international legal response that lacks doctrinal standards and provides little support should, however, serve as a guide and standard to develop actions that allow ethics committees -as key bodies for States- to advance in

  10. Sudden Bilateral Sensorineural Hearing Loss Associated with HLA A1-B8-DR3 Haplotype

    Directory of Open Access Journals (Sweden)

    G. Psillas

    2013-01-01

    Full Text Available Sudden sensorineural hearing loss may be present as a symptom in systemic autoimmune diseases or may occur as a primary disorder without another organ involvement (autoimmune inner ear disease. The diagnosis of autoimmune inner ear disease is still predicated on clinical features, and to date specific diagnostic tests are not available. We report a case of bilateral sudden hearing loss, tinnitus, intense rotatory vertigo, and nausea in a female patient in which the clinical manifestations, in addition to raised levels of circulating immune complexes, antithyroglobulin antibodies, and the presence of the HLA A1-B8-DR3 haplotype, allowed us to hypothesize an autoimmune inner ear disease. Cyclosporine-A immunosuppressive treatment in addition to steroids helped in hearing recovery that occurred progressively with normalization of the hearing function after a five-month treatment. Cyclosporine-A could be proposed as a therapeutic option in case of autoimmune inner ear disease allowing the suspension of corticosteroids that, at high dose, expose patients to potentially serious adverse events.

  11. The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR A haplotype in patients with advanced-stage classic Hodgkin lymphoma

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    Giorgio La Nasa

    2016-03-01

    Full Text Available Abstract Background Interim positron emission tomography after 2 cycles of ABVD (iPET-2 is a good predictor of outcome in advanced-stage classic Hodgkin lymphoma. So far, there are no other prognostic biomarkers capable of identifying chemotherapy refractory patients with comparable accuracy. Despite the considerable amount of evidence suggesting that antitumor immune surveillance is downregulated in classic Hodgkin lymphoma (cHL, few data exist on the impairment of natural killer cell function and the role of their killer immunoglobulin-like receptors (KIRs. Methods We investigated KIR gene frequencies, KIR haplotypes, and KIR-ligand combinations in a cohort of 135 patients with advanced-stage classic Hodgkin lymphoma and 221 healthy controls. We furthermore evaluated the correlation of KIR genes and KIR haplotypes with the achievement of negative iPET-2. Results In the cohort of patients, the 5-year overall survival and progression-free survival were 93.6 and 79 %, respectively. Homozygosity for KIR A haplotype and the HLA-C1 KIR ligand (KIR-AA/C1C1 was significantly higher in healthy controls (15.7 vs. 4.8 %, p = 0.001. The KIR-AA genotype resulted to have a significant predictive power for achieving iPET-2 negativity (p = 0.039. Conclusions Homozygosity for KIR A haplotype offers protection against classic Hodgkin lymphoma. The association found for the KIR-AA genotype and achievement of negative iPET-2 suggests that KIR-AA could be used in clinical practice to enhance the chemosensitivity predictive power of iPET-2. Our results point to the possibility of adapting treatment strategies based on the combination of KIR biomarkers and PET scan.

  12. Paraoxonase 1 (PON1 polymorphisms, haplotypes and activity in predicting cad risk in North-West Indian Punjabis.

    Directory of Open Access Journals (Sweden)

    Nidhi Gupta

    Full Text Available Human serum paraoxonase-1 (PON1 prevents oxidation of low density lipoprotein cholesterol (LDL-C and hydrolyzes the oxidized form, therefore preventing the development of atherosclerosis. The polymorphisms of PON1 gene are known to affect the PON1 activity and thereby coronary artery disease (CAD risk. As studies are lacking in North-West Indian Punjabi's, a distinct ethnic group with high incidence of CAD, we determined PON1 activity, genotypes and haplotypes in this population and correlated them with the risk of CAD.350 angiographically proven (≥ 70% stenosis CAD patients and 300 healthy controls were investigated. PON1 activity was determined towards paraoxon (Paraoxonase; PONase and phenylacetate (Arylesterase; AREase substrates. In addition, genotyping was carried out by using multiplex PCR, allele specific oligonucleotide -PCR and PCR-RFLP methods and haplotyping was determined by PHASE software. The serum PONase and AREase activities were significantly lower in CAD patients as compared to the controls. All studied polymorphisms except L55M had significant effect on PONase activity. However AREase activity was not affected by them. In a logistic regression model, after adjustment for the conventional risk factors for CAD, QR (OR: 2.73 (1.57-4.72 and RR (OR, 16.24 (6.41-41.14 genotypes of Q192R polymorphism and GG (OR: 2.07 (1.02-4.21 genotype of -162A/G polymorphism had significantly higher CAD risk. Haplotypes L-T-G-Q-C (OR: 3.25 (1.72-6.16 and L-T-G-R-G (OR: 2.82 (1.01-7.80 were also significantly associated with CAD.In conclusion this study shows that CAD patients had lower PONase and AREase activities as compared to the controls. The coding Q192R polymorphism, promoter -162A/G polymorphism and L-T-G-Q-C and L-T-G-R-G haplotypes are all independently associated with CAD.

  13. Mitochondrial DNA haplotyping of Testudo graeca on both continental sides of the Straits of Gibraltar.

    Science.gov (United States)

    Alvarez, Y; Mateo, J A; Andreu, A C; Díaz-Paniagua, C; Diez, A; Bautista, J M

    2000-01-01

    Testudo graeca is an endangered species of tortoise that inhabits Mediterranean areas of Africa, Asia, and Europe. Western populations are found on both sides of the Straits of Gibraltar. The effects of geographical isolation on genetic divergence were assessed by the sequence analysis of two mitochondrial DNA regions of the 12S rRNA and cytochrome b genes. Four different haplotypes were identified. A single haplotype was shared by all Spanish and some east Moroccan specimens. Two haplotypes were unique to the west Moroccan T. graeca populations and allowed the clear discrimination between individual specimens found west of the Moulouya River. Phylogenetic analysis based on the estimation of nucleotide sequence distances of the haplotypes suggests an African origin for the Spanish populations and a subspecies status for the west Moroccan pool.

  14. Haplotypes on pig chromosome 3 distinguish metabolically healthy from unhealthy obese individuals

    DEFF Research Database (Denmark)

    Frederiksen, Simona Denise; Karlskov-Mortensen, Peter; Pant, Sameer D.

    2017-01-01

    association (GWA) to identify loci with effect on blood lipid levels. The most significantly associated single nucleotide polymorphisms (SNPs) were used for linkage disequilibrium (LD) and haplotype analyses. Three separate haploblocks which influence the ratio between high density lipoprotein cholesterol...

  15. Analysis of 24 Y-STR haplotype data in a Chinese Han population from Guangdong Province.

    Science.gov (United States)

    Wang, Ying; Liu, Chao; Zhang, Chu-chu; Li, Ran; Liu, Hong; Ou, Xue-ling; Li, Hai-xia; Sun, Hong-yu

    2016-05-01

    In this study, we investigated the genetic polymorphisms of 24 Y-chromosomal short tandem repeat (Y-STR) loci in 885 unrelated Chinese Han male individuals from Guangdong Province, using a domestic AGCU Y24 STR kit. A total of 878 different haplotypes were observed at the 24 Y-STR loci; among them, 871 haplotypes were unique and 7 haplotypes occurred twice. The overall haplotype diversity was 0.99998 and the discrimination capacity was 99.2%. The gene diversity values ranged from 0.4354 at DYS438 to 0.9606 at DYS385a/b. Population relationships between the Guangdong Han population and seven other published Chinese populations were evaluated by Rst values and visualized in a two multi-dimensional scaling plot. The results showed the 24 Y-STR loci are highly polymorphic in Guangdong Han population and of great value in forensic application.

  16. Atypical beta(s) haplotypes are generated by diverse genetic mechanisms.

    Science.gov (United States)

    Zago, M A; Silva, W A; Dalle, B; Gualandro, S; Hutz, M H; Lapoumeroulie, C; Tavella, M H; Araujo, A G; Krieger, J E; Elion, J; Krishnamoorthy, R

    2000-02-01

    The majority of the chromosomes with the beta(S) gene have one of the five common haplotypes, designated as Benin, Bantu, Senegal, Cameroon, and Arab-Indian haplotypes. However, in every large series of sickle cell patients, 5-10% of the chromosomes have less common haplotypes, usually referred to as "atypical" haplotypes. In order to explore the genetic mechanisms that could generate these atypical haplotypes, we extended our analysis to other rarely studied polymorphic markers of the beta(S)-gene cluster, in a total of 40 chromosomes with uncommon haplotypes from Brazil and Cameroon. The following polymorphisms were examined: seven restriction site polymorphisms of the epsilongammadeltabeta-cluster, the pre-(G)gamma framework sequence including the 6-bp deletion/insertion pattern, HS-2 LCR (AT)xR(AT)y and pre-beta (AT)xTy repeat motifs, the GC/TT polymorphism at -1105-1106 of (G)gamma-globin gene, the C/T polymorphism at -551 of the beta-globin gene, and the intragenic beta-globin gene framework. Among the Brazilian subjects, the most common atypical structure (7/16) was a Bantu 3'-subhaplotype associated with different 5'-sequences, while in two chromosomes a Benin 3'-subhaplotype was associated with two different 5'-subhaplotypes. A hybrid Benin/Bantu configuration was also observed. In three chromosomes, the atypical haplotype differed from the typical one by the change of a single restriction site. In 2/134 chromosomes identified as having a typical Bantu RFLP-haplotype, a discrepant LCR repeat sequence was observed, probably owing to a crossover 5' to the epsilon-gene. Among 80 beta(S) chromosomes from Cameroon, 22 were associated with an atypical haplotype. The most common structure was represented by a Benin haplotype (from the LCR to the beta-gene) with a non-Benin segment 3' to the beta-globin gene. In two cases a Bantu LCR was associated with a Benin haplotype and a non-Benin segment 3' to the beta-globin gene. In three other cases, a more complex

  17. Beta-thalassemia and beta[A] globin gene haplotypes in Mexican mestizos.

    Science.gov (United States)

    Villalobos-Arámbula, A R; Bustos, R; Casas-Castañeda, M; Gutiérrez, E; Perea, F J; Thein, S L; Ibarra, B

    1997-04-01

    B-globin haplotypes of 20 beta-thalassemia (beta-thal) and 87 beta(A) Mexican mestizo chromosomes were analyzed to ascertain the origin of the beta-thal alleles and the frequencies and distribution of the beta(A) haplotypes among northwestern Mexican mestizos. Sixteen beta-thal chromosomes carried six Mediterranean alleles [five codon 39 C-->T; two IVS1:1 G-->A; two IVS1:5 G-->A; three IVS1:110 G(A; one codon 11 (-T) and three (deltabeta)zero-thal]; the remaining four were linked to three rare alleles (two -28 A-->C and one each: -87 C-->T and initiation codon ATG-->GTG). Among the 87 beta(A) chromosomes, 17 different 5' haplotypes with frequencies for 1, 3, 2 and 5 of 39.0%, 17. 2%, 9.2% and 6.9%, respectively, were observed. The beta-haplotype analysis showed that 13 out of 16 Mediterranean chromosomes could easily be explained by gene migration; however, one codon 39 associated with haplotype 4 (----+ +-), one IVS1:1 with haplotype 1(+----++) and one IVS1:5 G-->A, may represent separate mutational events. Analysis of the rare alleles showed that the -28 A-->C mutation was associated with the commonest beta(A) haplotype in Mexican mestizos, Mediterraneans and the total world population; therefore an independent origin cannot be ruled out. The -87 C-->T and initiation codon ATG-->GTG were found with beta-haplotypes different from the reported ones, suggesting an indigenous origin.

  18. Prognostic importance of VEGF-A haplotype combinations in a stage II colon cancer population

    DEFF Research Database (Denmark)

    Kjaer-Frifeldt, Sanne; Fredslund, Rikke; Lindebjerg, Jan;

    2012-01-01

    To investigate the prognostic effect of three VEGF-A SNPs, -2578, -460 and 405, as well as the corresponding haplotype combinations, in a unique population of stage II colon cancer patients.......To investigate the prognostic effect of three VEGF-A SNPs, -2578, -460 and 405, as well as the corresponding haplotype combinations, in a unique population of stage II colon cancer patients....

  19. Fetal Haemoglobin and β-globin Gene Cluster Haplotypes among Sickle Cell Patients in Chhattisgarh

    OpenAIRE

    Bhagat, Sanjana; Patra, Pradeep Kumar; Thakur, Amar Singh

    2013-01-01

    Background: Foetal Haemoglobin (HbF) is the best-known genetic modulator of sickle cell anaemia, which varies dramatically in concentration in the blood of these patients. The patients with SCA display a remarkable variability in the disease severity. High HbF levels and the β-globin gene cluster haplotypes influence the clinical presentation of sickle cell disease. To identify the genetic modifiers which influence the disease severity, we conducted a β-globin haplotype analysis in the sickle...

  20. Interleukin-6 (IL-6) haplotypes and the response to therapy of chronic hepatitis C virus infection

    OpenAIRE

    2009-01-01

    Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-α-2a is successful in eradicating virus from only 30%–80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained vir...

  1. Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness

    Directory of Open Access Journals (Sweden)

    Blöcker Helmut

    2009-11-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics. Results Screening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa × Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa × Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-δ mRNA levels. Haplotype 4 significantly increases PPAR-δ mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-δ. Conclusion This study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.

  2. The association between paired basic amino acid cleaving enzyme 4 gene haplotype and diastolic blood pressure

    Institute of Scientific and Technical Information of China (English)

    李建平; 王晓滨; 陈常忠; 徐新; 洪雪梅; 徐希平; 高炜; 霍勇

    2004-01-01

    Background In a previously identified locus linked to hypertension on chromosome 15q, we identified three blood pressure candidate genes: insulin-like growth factor 1 receptor gene (IGF1R), myocyte specific enhancer factor 2A gene (MEF2A), and paired basic amino acid cleaving enzyme 4 gene (PACE4). In this study, we tested their associations with hypertension using haplotype analysis.Methods A total of 288 unrelated individuals, including 163 high diastolic blood pressure (DBP) subjects and 125 normal DBP subjects were enrolled in this case-control study. Twenty single nucleotide polymorphisms (SNPs) in the three genes were genotyped using polymerase chain reaction followed by restriction enzyme digestion. Haplotype analysis was accomplished in the following stages: (1) pair-wise linkage disequilibrium test among SNPs on the same gene was performed to explore blocks in which recombination is very unlikely to happen; (2) Estimation-Maximization algorithm was applied to estimate haplotype frequencies in each block; (3) the chi-square test was used to examine the specific haplotype difference, and a permutation test was used to examine the overall haplotype profile difference between cases and controls in each block.Results An estimated haplotype "CCCCG" frequency in the haplotype block on the PACE4 gene was significantly higher in high DBP cases than in controls (P<0.01). The overall estimated haplotype profile in this block was also significantly different between the cases and the controls (P<0.001). This association indicates. Conclusions This study for the first time demonstrated that PACE4 gene may play an important role in the regulation of DBP. This association indicates that variations influencing DBP resides in or near this genomic region.

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

    OpenAIRE

    Chen, Chunxian; Gmitter Jr, Fred G

    2013-01-01

    Background Single nucleotide polymorphisms (SNPs), the most abundant variations in a genome, have been widely used in various studies. Detection and characterization of citrus haplotype-based expressed sequence tag (EST) SNPs will greatly facilitate further utilization of these gene-based resources. Results In this paper, haplotype-based SNPs were mined out of publicly available citrus expressed sequence tags (ESTs) from different citrus cultivars (genotypes) individually and collectively for...

  4. 基于加乘同态与组合函数技术的MA保护研究%Research of MA Protection Based on Addition-multiplication Homomorphism and Composite Function Technology

    Institute of Scientific and Technical Information of China (English)

    吴杰宏; 张坡; 石祥滨

    2012-01-01

    Addition-multiplication homomoiphism and composite function encryption protecting scheme is put forward, aiming to solve the security problems of Mobile agents (MA) migrating across heterogeneous network execution environments. Homomorphism idea is applied to mobile cryptography, and encrypted mobile codes can be executed directly on different platforms without decryption. Addition-multiplication homomorphism (AMH) and composite function encryption strategies are introduced here, and encrypting steps are used as follows: first three address operands are encrypted by Addition-multiplication homomorphism method, then three address operating codes are encrypted by composite function method, double encryption problems are considered at last, and eliminating the statements that are encrypted by both AMH and composite function methods. Correctness and security are verified in this scheme. Experimental results show: By contrast to homomorphism encryption method, nearly 5.12s executing time will be saved using this addition-multiplication homomorphism and composite function encryption scheme, and malicious hosts are detected timely.%针对移动代理在异质网络环境中的安全问题,提出一种基于加乘同态与组合函数加密策略的MA保护方案,同态思想应用于移动密码学中,不用解密即可使加密任务代理在其它网络平台上运行.该方案在同态的基础上引入了加乘同态加密策略,采用了加乘同态加密三地址码操作数,组合函数加密三地址码操作码的加密步骤,并在加密后排除了由加乘同态与组合函数引起的双重加密问题.最后给出了该方案的正确性及安全性验证.实验结果表明:对比同态加密方法,该方案节省执行时间5.12秒,并能及时侦测出恶意主机.

  5. A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype.

    Science.gov (United States)

    Leal, Alejandro; Berghoff, Corinna; Berghoff, Martin; Rojas-Araya, Melissa; Carolina, Ortiz; Heuss, Dieter; Del Valle, Gerardo; Rautenstrauss, Bernd

    2014-12-01

    The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers' sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive.

  6. A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ p.Thr124Met mutation shares the Belgian haplotype

    Directory of Open Access Journals (Sweden)

    Alejandro Leal

    2014-12-01

    Full Text Available The p.Thr124Met mutation in the myelin protein zero (MPZ causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers´ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch, the founder effect hypothesis for this allele migration is suggestive. Rev. Biol. Trop. 62 (4: 1285-1293. Epub 2014 December 01.

  7. Rare missense variants within a single gene form yin yang haplotypes.

    Science.gov (United States)

    Curtis, David

    2016-01-01

    Yin yang haplotype pairs differ at every SNP. They would not be accounted for by population models that incorporate sequential mutation, with or without recombination. Previous reports have claimed that there is a tendency for common SNPs to form yin yang haplotypes more often than would be expected by sequential mutation or by a random sample of all possible haplotypic arrangements of alleles. In the course of analysing next-generation sequencing data, instances of yin yang haplotypes being formed by very rare variants within a single gene were observed. As an example, this report describes a completely yin yang haplotype formed by eight rare missense variants in the ABCA13 gene. Of 1000 genome subjects, 21 have a copy of the alternate allele at all eight of these positions and a single subject is homozygous for all of them. None of the other 1070 subjects possesses any of the altetrnates. Thus, the eight alternate alleles are always found together and never occur separately. The existence of such yin yang haplotypes has important implications for statistical methods for analysing rare variants. Also, they may be of use for gaining a better understanding of the history of human populations.

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

    Directory of Open Access Journals (Sweden)

    Levente Bodoki

    2015-01-01

    Full Text Available Idiopathic inflammatory myopathies are autoimmune diseases characterized by symmetrical proximal muscle weakness. Our aim was to identify a correlation between VDR polymorphisms or haplotypes and myositis. We studied VDR-BsmI, VDR-ApaI, VDR-TaqI, and VDR-FokI polymorphisms and haplotypes in 89 Hungarian poly-/dermatomyositis patients (69 females and 93 controls (52 females. We did not obtain any significant differences for VDR-FokI, BsmI, ApaI, and TaqI genotypes and allele frequencies between patients with myositis and healthy individuals. There was no association of VDR polymorphisms with clinical manifestations and laboratory profiles in myositis patients. Men with myositis had a significantly different distribution of BB, Bb, and bb genotypes than female patients, control male individuals, and the entire control group. Distribution of TT, Tt, and tt genotypes was significantly different in males than in females in patient group. According to four-marker haplotype prevalence, frequencies of sixteen possible haplotypes showed significant differences between patient and control groups. The three most frequent haplotypes in patients were the fbAt, FBaT, and fbAT. Our findings may reveal that there is a significant association: Bb and Tt genotypes can be associated with myositis in the Hungarian population we studied. We underline the importance of our result in the estimated prevalence of four-marker haplotypes.

  9. Mitochondrial haplotypes reveal a strong genetic structure for three Indian sheep breeds.

    Science.gov (United States)

    Pardeshi, V C; Kadoo, N Y; Sainani, M N; Meadows, J R S; Kijas, J W; Gupta, V S

    2007-10-01

    This survey represents the first characterization of mitochondrial DNA diversity within three breeds of Indian sheep (two strains of the Deccani breed, as well as the Bannur and Garole breeds) from different geographic regions and with divergent phenotypic characteristics. A 1061-bp fragment of the mitochondrial genome spanning the control region, a portion of the 12S rRNA gene and the complete phenyl tRNA gene, was sequenced from 73 animals and compared with the corresponding published sequence from European and Asian breeds and the European Mouflon (Ovis musimon). Analysis of all 156 sequences revealed 73 haplotypes, 52 of which belonged to the Indian breeds. The three Indian breeds had no haplotypes in common, but one Indian haplotype was shared with European and other Asian breeds. The highest nucleotide and haplotype diversity was observed in the Bannur breed (0.00355 and 0.981 respectively), while the minimum was in the Sangamneri strain of the Deccani breed (0.00167 and 0.882 respectively). All 52 Indian haplotypes belonged to mitochondrial lineage A. Therefore, these Indian sheep are distinct from other Asian and European breeds studied so far. The relationships among the haplotypes showed strong breed structure and almost no introgression among these Indian breeds, consistent with Indian sheep husbandry, which discourages genetic exchange between breeds. These results have implications for the conservation of India's ovine biodiversity and suggest a common origin for the breeds investigated.

  10. Extended haplotypes in rheumatoid arthritis and preliminary evidence for an interaction with immunoglobulin genes.

    Science.gov (United States)

    Puttick, A; Briggs, D; Welsh, K; Jacoby, R; Williamson, E; Jones, V

    1986-06-01

    The incidence of extended haplotypes of the Major Histocompatibility Complex was compared between 20 probands with RA, their unaffected family members, and 42 controls. One haplotype only, HLA-Bw62 BfS C4A*3 C4B*3 DR4 GLO2, was significantly increased in the patient group, whereas HLA-B7 BfS C4A*3 C4B*1 DR2 GLO1, which was the most common haplotype in the control groups, was absent. The immunoglobulin allotype Glm(2) was significantly increased in frequency in the RA patients, and analysis showed that of the seven patients carrying Bw62-DR4, five were G1m(2) positive. Further, the increase in frequency of the phenotype Gm(1,2,17,21,3,5,23) was also significant and was carried by two of four probands with the extended haplotype HLA-Bw62 BfS C4A*3 C4B*3 DR4 GLO2 and by one proband also bearing this haplotype but with a null allele at the C4A locus. The striking association of G1m(2) and Bw62 with DR4 in our patients suggests that in interaction of immunoglobulin genes with DR4 is stronger when DR4 is associated with particular haplotypes rather than with DR4 in general.

  11. Triad of Risk for Late Onset Alzheimer’s: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex

    Science.gov (United States)

    Wang, Yiwei; Brinton, Roberta D.

    2016-01-01

    Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function, e.g., Alzheimer’s, Parkinson’s, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer’s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer’s disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases.

  12. Minor differences in haplotype frequency estimates can produce very large differences in heterogeneity test statistics

    Directory of Open Access Journals (Sweden)

    Xu Ke

    2007-06-01

    Full Text Available Abstract Background Tests for association between a haplotype and disease are commonly performed using a likelihood ratio test for heterogeneity between case and control haplotype frequencies. Using data from a study of association between heroin dependence and the DRD2 gene, we obtained estimated haplotype frequencies and the associated likelihood ratio statistic using two different computer programs, MLOCUS and GENECOUNTING. We also carried out permutation testing to assess the empirical significance of the results obtained. Results Both programs yielded similar, though not identical, estimates for the haplotype frequencies. MLOCUS produced a p value of 1.8*10-15 and GENECOUNTING produced a p value of 5.4*10-4. Permutation testing produced a p value 2.8*10-4. Conclusion The fact that very large differences occur between the likelihood ratio statistics from the two programs may reflect the fact that the haplotype frequencies for the combined group are not constrained to be equal to the weighted averages of the frequencies for the cases and controls, as they would be if they were directly observed rather than being estimated. Minor differences in haplotype frequency estimates can result in very large differences in the likelihood ratio statistic and associated p value.

  13. Unique haplotypes of cacao trees as revealed by trnH-psbA chloroplast DNA.

    Science.gov (United States)

    Gutiérrez-López, Nidia; Ovando-Medina, Isidro; Salvador-Figueroa, Miguel; Molina-Freaner, Francisco; Avendaño-Arrazate, Carlos H; Vázquez-Ovando, Alfredo

    2016-01-01

    Cacao trees have been cultivated in Mesoamerica for at least 4,000 years. In this study, we analyzed sequence variation in the chloroplast DNA trnH-psbA intergenic spacer from 28 cacao trees from different farms in the Soconusco region in southern Mexico. Genetic relationships were established by two analysis approaches based on geographic origin (five populations) and genetic origin (based on a previous study). We identified six polymorphic sites, including five insertion/deletion (indels) types and one transversion. The overall nucleotide diversity was low for both approaches (geographic = 0.0032 and genetic = 0.0038). Conversely, we obtained moderate to high haplotype diversity (0.66 and 0.80) with 10 and 12 haplotypes, respectively. The common haplotype (H1) for both networks included cacao trees from all geographic locations (geographic approach) and four genetic groups (genetic approach). This common haplotype (ancient) derived a set of intermediate haplotypes and singletons interconnected by one or two mutational steps, which suggested directional selection and event purification from the expansion of narrow populations. Cacao trees from Soconusco region were grouped into one cluster without any evidence of subclustering based on AMOVA (F ST = 0) and SAMOVA (F ST = 0.04393) results. One population (Mazatán) showed a high haplotype frequency; thus, this population could be considered an important reservoir of genetic material. The indels located in the trnH-psbA intergenic spacer of cacao trees could be useful as markers for the development of DNA barcoding.

  14. Unique haplotypes of cacao trees as revealed by trnH-psbA chloroplast DNA

    Directory of Open Access Journals (Sweden)

    Nidia Gutiérrez-López

    2016-04-01

    Full Text Available Cacao trees have been cultivated in Mesoamerica for at least 4,000 years. In this study, we analyzed sequence variation in the chloroplast DNA trnH-psbA intergenic spacer from 28 cacao trees from different farms in the Soconusco region in southern Mexico. Genetic relationships were established by two analysis approaches based on geographic origin (five populations and genetic origin (based on a previous study. We identified six polymorphic sites, including five insertion/deletion (indels types and one transversion. The overall nucleotide diversity was low for both approaches (geographic = 0.0032 and genetic = 0.0038. Conversely, we obtained moderate to high haplotype diversity (0.66 and 0.80 with 10 and 12 haplotypes, respectively. The common haplotype (H1 for both networks included cacao trees from all geographic locations (geographic approach and four genetic groups (genetic approach. This common haplotype (ancient derived a set of intermediate haplotypes and singletons interconnected by one or two mutational steps, which suggested directional selection and event purification from the expansion of narrow populations. Cacao trees from Soconusco region were grouped into one cluster without any evidence of subclustering based on AMOVA (FST = 0 and SAMOVA (FST = 0.04393 results. One population (Mazatán showed a high haplotype frequency; thus, this population could be considered an important reservoir of genetic material. The indels located in the trnH-psbA intergenic spacer of cacao trees could be useful as markers for the development of DNA barcoding.

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

    Directory of Open Access Journals (Sweden)

    Feng Qi-Sheng

    2007-07-01

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

  16. Haplotype Analysis Discriminates Genetic Risk for DR3-Associated Endocrine Autoimmunity and Helps Define Extreme Risk for Addison’s Disease

    Science.gov (United States)

    Baker, Peter R.; Baschal, Erin E.; Fain, Pam R.; Triolo, Taylor M.; Nanduri, Priyaanka; Siebert, Janet C.; Armstrong, Taylor K.; Babu, Sunanda R.; Rewers, Marian J.; Gottlieb, Peter A.; Barker, Jennifer M.; Eisenbarth, George S.

    2010-01-01

    Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD). Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. Main Outcome Measures: AD and genotype were measured. Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10−4) and 13% of general population controls (P = 3.00 × 10−19). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10−191). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10−5) and type 1 diabetes patients (73%, P = 1.93 × 10−3). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype. PMID:20631027

  17. Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus. SLE Study Group members.

    Science.gov (United States)

    Yao, Z; Kimura, A; Hartung, K; Haas, P J; Volgger, A; Brünnler, G; Bönisch, J; Albert, E D

    1993-01-01

    We have investigated the DNA polymorphism for the DQA1 promoter region (QAP) and HLA-class II DRB1, DQA1, and DQB1 genes in 178 central European patients with Systemic lupus erythematosus (SLE) using polymerase chain reaction and Dig-ddUTP labeled oligonucleotides. Increased frequencies of DRB1*02 and *03 are confirmed by DNA typing. In addition, the frequencies of DQA1*0501, *0102 and DQB1*0201, *0602 alleles are increased in the patients as compared to controls. The strongest association to SLE is found with DRB1*03 and DOB1*0201 alleles (p QAP variants. Increased frequencies of QAP1.2 and QAP4.1 are observed in patients as compared to controls (p QAP variants and DQA1, DRB1 alleles. Certain QAP variants are completely associated with DQA1 and DRB1 alleles, whereas others can combine with different DQA1 and DRB1 alleles. All DRB1*02-positive patients and controls carry QAP1.2, and all DRB1*03-positive patients and controls carry QAP4.1. Conversely, the QAP1.2 variant appears only in DRB1*02 haplotypes, while the QAP4.1 variant can be observed in DRB1*03, *11, and *1303 haplotypes. Based on the strong linkage disequilibria between DRB1-DQA1-DQB1 genes and between DRB1-QAP-DQA1, we have deduced the four-point haplotypes for DRB1-QAP-DQA1-DQB1 in patients and controls. Two haplotypes DRB1*02-QAP1.2-DQA1*0102-DQB1*0602 and DRB1*03-QAP4.1-DQA1*0501-DQB1*0201 are significantly increased in patients as compared to controls (p QAP, DQA1, and DQB1 as well as the investigation of the deduced DRB1-QAP-DQA1-DQB1 haplotypes leads to the conclusion that QAP4.1 and DQA1*0501 on the DR3 haplotypes are probably not involved in SLE susceptibility.(ABSTRACT TRUNCATED AT 400 WORDS)

  18. A haplotype of polymorphisms in ASE-1, RAI and ERCC1 and the effects of tobacco smoking and alcohol consumption on risk of colorectal cancer: a danish prospective case-cohort study

    Directory of Open Access Journals (Sweden)

    Wallin Håkan

    2008-02-01

    Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs are the most frequent type of genetic variation in the human genome, and are of interest for the study of susceptibility to and protection from diseases. The haplotype at chromosome 19q13.2-3 encompassing the three SNPs ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn have been associated with risk of breast cancer and lung cancer. Haplotype carriers are defined as the homozygous carriers of RAI IVS1 A4364GA, ERCC1 Asn118AsnT and ASE-1 G-21AG. We aimed to evaluate whether the three polymorphisms and the haplotype are associated to risk of colorectal cancer, and investigated gene-environment associations between the polymorphisms and the haplotype and smoking status at enrolment, smoking duration, average smoking intensity and alcohol consumption, respectively, in relation to risk of colorectal cancer. Methods Associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were examined, as well as gene-environment interaction, in a Danish case-cohort study including 405 cases and a comparison group of 810 persons. Incidence rate ratio (IRR were estimated by the Cox proportional hazards model stratified according to gender, and two-sided 95% confidence intervals (CI and p-values were calculated based on robust estimates of the variance-covariance matrix and Wald's test of the Cox regression parameter. Results No consistent associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were found. No statistically significant interactions between the genotypes and the lifestyle exposures smoking or alcohol consumption were observed. Conclusion Our results suggest that the ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn polymorphisms and the previously identified haplotype are not associated with risk of colorectal cancer. We found no evidence of gene-environment interaction between the three polymorphisms and the

  19. SNP-specific extraction of haplotype-resolved targeted genomic regions.

    Science.gov (United States)

    Dapprich, Johannes; Ferriola, Deborah; Magira, Eleni E; Kunkel, Mark; Monos, Dimitri

    2008-09-01

    The availability of genotyping platforms for comprehensive genetic analysis of complex traits has resulted in a plethora of studies reporting the association of specific single-nucleotide polymorphisms (SNPs) with common diseases or drug responses. However, detailed genetic analysis of these associated regions that would correlate particular polymorphisms to phenotypes has lagged. This is primarily due to the lack of technologies that provide additional sequence information about genomic regions surrounding specific SNPs, preferably in haploid form. Enrichment methods for resequencing should have the specificity to provide DNA linked to SNPs of interest with sufficient quality to be used in a cost-effective and high-throughput manner. We describe a simple, automated method of targeting specific sequences of genomic DNA that can directly be used in downstream applications. The method isolates haploid chromosomal regions flanking targeted SNPs by hybridizing and enzymatically elongating oligonucleotides with biotinylated nucleotides based on their selective binding to unique sequence elements that differentiate one allele from any other differing sequence. The targeted genomic region is captured by streptavidin-coated magnetic particles and analyzed by standard genotyping, sequencing or microarray analysis. We applied this technology to determine contiguous molecular haplotypes across a approximately 150 kb genomic region of the major histocompatibility complex.

  20. Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations.

    Science.gov (United States)

    Teo, Yik-Ying; Sim, Xueling; Ong, Rick T H; Tan, Adrian K S; Chen, Jieming; Tantoso, Erwin; Small, Kerrin S; Ku, Chee-Seng; Lee, Edmund J D; Seielstad, Mark; Chia, Kee-Seng

    2009-11-01

    The Singapore Genome Variation Project (SGVP) provides a publicly available resource of 1.6 million single nucleotide polymorphisms (SNPs) genotyped in 268 individuals from the Chinese, Malay, and Indian population groups in Southeast Asia. This online database catalogs information and summaries on genotype and phased haplotype data, including allele frequencies, assessment of linkage disequilibrium (LD), and recombination rates in a format similar to the International HapMap Project. Here, we introduce this resource and describe the analysis of human genomic variation upon agglomerating data from the HapMap and the Human Genome Diversity Project, providing useful insights into the population structure of the three major population groups in Asia. In addition, this resource also surveyed across the genome for variation in regional patterns of LD between the HapMap and SGVP populations, and for signatures of positive natural selection using two well-established metrics: iHS and XP-EHH. The raw and processed genetic data, together with all population genetic summaries, are publicly available for download and browsing through a web browser modeled with the Generic Genome Browser.

  1. Phylogeographic analyses of Phragmites australis in China: Native distribution and habitat preference of the haplotype that invaded North America

    Institute of Scientific and Technical Information of China (English)

    Jia-Xing AN; Qian WANG; Ji YANG; Jian-Quan LIU

    2012-01-01

    Phragmites australis is a cosmopolitan clonal species,but one haplotype from Eurasia has become highly invasive in North America.This article describes an investigation of the phylogeographic composition of 77 populations from China,based on the sequencing of two chloroplast non-coding DNA regions.A total of 11 haplotypes were detected,based on the sequence alignments of two chloroplast DNA fragments from 421 sampled individuals.Six of these haplotypes were completely new,and did not correspond to any of this species' 27 previously known haplotypes.The invasive haplotype M and haplotypes O and P were shown to occur frequently.Haplotype O is widely distributed across all regions and probably represents the primitive haplotype of this species.In contrast,P is mainly distributed in the humid eastern and northeastern regions of China,whereas M is more frequent in western and northwestern China— arid habitats with low precipitation.Between eastern and northeastern and western and northwestern regions,there was distinct genetic differentiation; the former region has a higher genetic diversity than the latter.The high occurrence of haplotype M in western China suggests that it prefers more arid habitats.These findings shed new light on the native distribution,adaptation,and habitat preference of haplotype M,which invaded North America.

  2. Fetal male lineage determination by analysis of Y-chromosome STR haplotype in maternal plasma.

    Science.gov (United States)

    Barra, Gustavo Barcelos; Santa Rita, Ticiane Henriques; Chianca, Camilla Figueiredo; Velasco, Lara Francielle Ribeiro; de Sousa, Claudia Ferreira; Nery, Lídia Freire Abdalla; Costa, Sandra Santana Soares

    2015-03-01

    The aim of this study is to determine the fetus Y-STR haplotype in maternal plasma during pregnancy and estimate, non-invasively, if the alleged father and fetus belong to the same male lineage. The study enrolled couples with singleton pregnancies and known paternity. All participants signed informed consent and the local ethics committee approved the study. Peripheral blood was collected in EDTA tubes (mother) and in FTA paper (father). Maternal plasma DNA was extracted by using NucliSens EasyMAG. Fetal gender was determined by qPCR targeting DYS-14 in maternal plasma and it was also confirmed after the delivery. From all included volunteers, the first consecutive 20 mothers bearing male fetuses and 10 mothers bearing female fetuses were selected for the Y-STR analysis. The median gestational age was 12 weeks (range 12-36). All DNA samples were subjected to PCR amplification by PowerPlex Y23, ampFLSTR Yfiler, and two in-house multiplexes, which together accounts for 27 different Y-STR. The PCR products were detected with 3500 Genetic Analyzer and they were analyzed using GeneMapper-IDX. Fetuses' haplotypes (Yfiler format) were compared to other 5328 Brazilian haplotypes available on Y-chromosome haplotypes reference database (YHRD). As a result, between 22 and 27 loci were successfully amplified from maternal plasma in all 20 cases of male fetuses. None of the women bearing female fetuses had a falsely amplified Y-STR haplotype. The haplotype detected in maternal plasma completely matched the alleged father haplotype in 16 out of the 20 cases. Four cases showed single mismatches and they did not configure exclusions; 1 case showed a mutation in the DYS 458 locus due to the loss of one repeat unit and 3 cases showed one DYS 385I/II locus dropout. All mismatches were confirmed after the delivery. Seventeen fetuses' haplotypes were not found in YHRD and one of them had a mutation, which corresponded to the paternity probability of 99.9812% and 95.7028%, respectively

  3. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients.

    OpenAIRE

    Labie, D; Pagnier, J.; Lapoumeroulie, C; Rouabhi, F; Dunda-Belkhodja, O; Chardin, P; Beldjord, C; Wajcman, H; Fabry, M E; Nagel, R L

    1985-01-01

    We have studied 42 homozygous beta-thalassemia patients from Algeria and 34 sickle cell anemia patients from Senegal and Benin, determining the relationship between haplotypes, Hb F, and G gamma-globin/A gamma-globin ratios. Populations selected have a high frequency of haplotype homozygotes because of consanguinity (Algeria) and geographic homogeneity (West Africa). We find in beta-thalassemia patients, that haplotype IX in haplotypic homozygotes and heterozygotes, haplotype III in heterozyg...

  4. Loss of pollen-S function in two self-compatible selections of Prunus avium is associated with deletion/mutation of an S haplotype-specific F-box gene.

    Science.gov (United States)

    Sonneveld, Tineke; Tobutt, Kenneth R; Vaughan, Simon P; Robbins, Timothy P

    2005-01-01

    Recently, an S haplotype-specific F-box (SFB) gene has been proposed as a candidate for the pollen-S specificity gene of RNase-mediated gametophytic self-incompatibility in Prunus (Rosaceae). We have examined two pollen-part mutant haplotypes of sweet cherry (Prunus avium). Both were found to retain the S-RNase, which determines stylar specificity, but one (S3' in JI 2434) has a deletion including the haplotype-specific SFB gene, and the other (S4' in JI 2420) has a frame-shift mutation of the haplotype-specific SFB gene, causing amino acid substitutions and premature termination of the protein. The loss or significant alteration of this highly polymorphic gene and the concomitant loss of pollen self-incompatibility function provides compelling evidence that the SFB gene encodes the pollen specificity component of self-incompatibility in Prunus. These loss-of-function mutations are inconsistent with SFB being the inactivator of non-self S-RNases and indicate the presence of a general inactivation mechanism, with SFB conferring specificity by protecting self S-RNases from inactivation.

  5. Powerful haplotype-based Hardy-Weinberg equilibrium tests for tightly linked loci.

    Directory of Open Access Journals (Sweden)

    Wei-Gao Mao

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

  6. Haplotype association analyses in resources of mixed structure using Monte Carlo testing

    Directory of Open Access Journals (Sweden)

    Thomas Alun

    2010-12-01

    Full Text Available Abstract Background Genomewide association studies have resulted in a great many genomic regions that are likely to harbor disease genes. Thorough interrogation of these specific regions is the logical next step, including regional haplotype studies to identify risk haplotypes upon which the underlying critical variants lie. Pedigrees ascertained for disease can be powerful for genetic analysis due to the cases being enriched for genetic disease. Here we present a Monte Carlo based method to perform haplotype association analysis. Our method, hapMC, allows for the analysis of full-length and sub-haplotypes, including imputation of missing data, in resources of nuclear families, general pedigrees, case-control data or mixtures thereof. Both traditional association statistics and transmission/disequilibrium statistics can be performed. The method includes a phasing algorithm that can be used in large pedigrees and optional use of pseudocontrols. Results Our new phasing algorithm substantially outperformed the standard expectation-maximization algorithm that is ignorant of pedigree structure, and hence is preferable for resources that include pedigree structure. Through simulation we show that our Monte Carlo procedure maintains the correct type 1 error rates for all resource types. Power comparisons suggest that transmission-disequilibrium statistics are superior for performing association in resources of only nuclear families. For mixed structure resources, however, the newly implemented pseudocontrol approach appears to be the best choice. Results also indicated the value of large high-risk pedigrees for association analysis, which, in the simulations considered, were comparable in power to case-control resources of the same sample size. Conclusions We propose hapMC as a valuable new tool to perform haplotype association analyses, particularly for resources of mixed structure. The availability of meta-association and haplotype-mining modules in

  7. Identification of the Mislabeled Breast Cancer Samples by Mitochondrial DNA Haplotyping

    Directory of Open Access Journals (Sweden)

    Xiaogang Chen

    2015-01-01

    Full Text Available The task to identify whether an archival malignant tumor specimen had been mislabeled or interchanged is a challenging one for forensic genetics. The nuclear DNA (nDNA markers were affected by the aberration of tumor cells, so they were not suitable for personal identification when the tumor tissues were tested. In this study, we focused on a new solution - mitochondrial single nucleotide polymorphism (mtSNP haplotyping by a multiplex SNaPshot assay. To validate our strategy of haplotyping with 25 mtSNPs, we analyzed 15 pairs of cancerous/healthy tissues taken from patients with ductal breast carcinoma. The haplotypes of all the fifteen breast cancer tissues were matched with their paired breast tissues. The heteroplasmy at 2 sites, 14783A/G and 16519C/T was observed in one breast tissue, which indicated a mixture of related mitochondrial haplotypes. However, only one haplotype was retained in the paired breast cancer tissue, which could be considered the result of proliferation of tumor subclone. The allele drop-out and allele drop-in were observed when 39 STRs and 20 tri-allelic SNPs of nDNA were applied. Compared to nDNA markers applied, 25 mtSNPs were more stable without interference from aberrance of breast cancer. Also, two cases were presented where the investigation of haplotype with 25 mtSNPs was used to prove the origin of biopsy specimen with breast cancer. The mislabeling of biopsy specimen with breast cancer could be certified in one case but could not be supported in the other case. We highlight the importance of stability of mtSNP haplotype in breast cancer. It was implied that our multiplex SNaPshot assay with 25 mtSNPs was a useful strategy to identify mislabeled breast cancer specimen.

  8. Role of CYP1A1 haplotypes in modulating susceptibility to coronary artery disease.

    Science.gov (United States)

    Lakshmi, Sana Venkata Vijaya; Naushad, Shaik Mohammad; Saumya, Kankanala; Rao, Damera Seshagiri; Kutala, Vijay Kumar

    2012-10-01

    To investigate the role of cytochrome P450 1A1 (CYP1A1) haplotypes in modulating susceptibility to coronary artery disease (CAD), a case-control study was conducted by enrolling 352 CAD cases and 282 healthy controls. PCR-RFLP, multiplex PCR, competitive ELISA techniques were employed for the analysis of CYP1A1 [ml (T-->C), m2 (A-->G) and m4 (C-->A)] haplotypes, glutathione-S-transferase (GST)T1/GSTM1 null variants and plasma 8-oxo-2'deoxyguanosine (8-oxodG) respectively. Two CYP1A1 haplotypes, i.e. CAC and TGC showed independent association with CAD risk, while all-wild CYP1A1 haplotype i.e. TAC showed reduced risk for CAD. All the three variants showed mild linkage disequilibrium (D': 0.05 to 0.17). GSTT1 null variant also exerted independent association with CAD risk (OR: 2.53, 95% CI 1.55-4.12). Among the conventional risk factors, smoking showed synergetic interaction with CAC haplotype of CYP1A1 and GSTT1 null genotype in inflating CAD risk. High risk alleles of this pathway showed dose-dependent association with percentage of stenosis and number of vessels affected. Elevated 8-oxodG levels were observed in subjects with CYP1A1 CAC haplotype and GSTT1 null variant. Multiple linear regression model of these xenobiotic variants explained 36% variability in 8-oxodG levels. This study demonstrated the association of CYP1A1 haplotypes and GSTT1 null variant with CAD risk and this association was attributed to increased oxidative DNA damage.

  9. Three Novel Haplotypes of Theileria bicornis in Black and White Rhinoceros in Kenya.

    Science.gov (United States)

    Otiende, M Y; Kivata, M W; Jowers, M J; Makumi, J N; Runo, S; Obanda, V; Gakuya, F; Mutinda, M; Kariuki, L; Alasaad, S

    2016-02-01

    Piroplasms, especially those in the genera Babesia and Theileria, have been found to naturally infect rhinoceros. Due to natural or human-induced stress factors such as capture and translocations, animals often develop fatal clinical piroplasmosis, which causes death if not treated. This study examines the genetic diversity and occurrence of novel Theileria species infecting both black and white rhinoceros in Kenya. Samples collected opportunistically during routine translocations and clinical interventions from 15 rhinoceros were analysed by polymerase chain reaction (PCR) using a nested amplification of the small subunit ribosomal RNA (18S rRNA) gene fragments of Babesia and Theileria. Our study revealed for the first time in Kenya the presence of Theileria bicornis in white (Ceratotherium simum simum) and black (Diceros bicornis michaeli) rhinoceros and the existence of three new haplotypes: haplotypes H1 and H3 were present in white rhinoceros, while H2 was present in black rhinoceros. No specific haplotype was correlated to any specific geographical location. The Bayesian inference 50% consensus phylogram recovered the three haplotypes monophyleticly, and Theileria bicornis had very high support (BPP: 0.98). Furthermore, the genetic p-uncorrected distances and substitutions between T. bicornis and the three haplotypes were the same in all three haplotypes, indicating a very close genetic affinity. This is the first report of the occurrence of Theileria species in white and black rhinoceros from Kenya. The three new haplotypes reported here for the first time have important ecological and conservational implications, especially for population management and translocation programs and as a means of avoiding the transport of infected animals into non-affected areas.

  10. Identification of a 10/10 matched donor for patients with an uncommon haplotype is unlikely.

    Science.gov (United States)

    Olson, J A; Gibbens, Y; Tram, K; Kempenich, J; Novakovich, J; Buck, K; Dehn, J

    2017-02-01

    Despite over 6 million subjects contributing to the National Marrow Donor Program human leukocyte antigen (HLA) haplotype frequency reference data (HFD), haplotypes cannot be predicted from the HLA assignments of some patients searching for an unrelated donor (URD) in the Be The Match Registry®. We aimed to determine the incidence of these patient searches and whether haplotypes lacking from the HFD can be found among the low-resolution typed URD pool. New NMDP searches with uncommon patient haplotypes (UPH), defined as a lack of haplotype pairs in any single ethnic group in the HFD based upon HLA-A˜C˜B˜DRB1˜DQB1, were identified. Each search had up to 20 potential 10/10 or 8/8 URDs typed to determine the likelihood of an allele match. The incidence of patient searches without haplotype pairs in a single ethnic group in the HFD was 1.2% (N=144 out of 12,172) and a majority of these patients (117; 81%) had one uncommon haplotype previously uncharacterized in the HFD. Non-White patients had the highest incidence of UPH. Importantly, no patients with UPH had a 10/10 URD identified. The transplant rate among UPH patients was 15%, and a majority of these patients utilized cord blood units as their transplant stem cell source. Therefore, the HLA HFD that informs the HapLogic matching algorithm is thorough as UPH patient searches were infrequent. Since such patients are highly unlikely to have a fully 10/10 matched URD identified, this study supports the identification of alternative stem cell sources including cord blood or a mismatched URD early in the search process. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Empirical vs Bayesian approach for estimating haplotypes from genotypes of unrelated individuals

    Directory of Open Access Journals (Sweden)

    Cheng Jacob

    2007-01-01

    Full Text Available Abstract Background The completion of the HapMap project has stimulated further development of haplotype-based methodologies for disease associations. A key aspect of such development is the statistical inference of individual diplotypes from unphased genotypes. Several methodologies for inferring haplotypes have been developed, but they have not been evaluated extensively to determine which method not only performs well, but also can be easily incorporated in downstream haplotype-based association analyses. In this paper, we attempt to do so. Our evaluation was carried out by comparing the two leading Bayesian methods, implemented in PHASE and HAPLOTYPER, and the two leading empirical methods, implemented in PL-EM and HPlus. We used these methods to analyze real data, namely the dense genotypes on X-chromosome of 30 European and 30 African trios provided by the International HapMap Project, and simulated genotype data. Our conclusions are based on these analyses. Results All programs performed very well on X-chromosome data, with an average similarity index of 0.99 and an average prediction rate of 0.99 for both European and African trios. On simulated data with approximation of coalescence, PHASE implementing the Bayesian method based on the coalescence approximation outperformed other programs on small sample sizes. When the sample size increased, other programs performed as well as PHASE. PL-EM and HPlus implementing empirical methods required much less running time than the programs implementing the Bayesian methods. They required only one hundredth or thousandth of the running time required by PHASE, particularly when analyzing large sample sizes and large umber of SNPs. Conclusion For large sample sizes (hundreds or more, which most association studies require, the two empirical methods might be used since they infer the haplotypes as accurately as any Bayesian methods and can be incorporated easily into downstream haplotype

  12. Characterisation of SNP haplotype structure in chemokine and chemokine receptor genes using CEPH pedigrees and statistical estimation

    Directory of Open Access Journals (Sweden)

    Clark Vanessa J

    2004-03-01

    Full Text Available Abstract Chemokine signals and their cell-surface receptors are important modulators of HIV-1 disease and cancer. To aid future case/control association studies, aim to further characterise the haplotype structure of variation in chemokine and chemokine receptor genes. To perform haplotype analysis in a population-based association study, haplotypes must be determined by estimation, in the absence of family information or laboratory methods to establish phase. Here, test the accuracy of estimates of haplotype frequency and linkage disequilibrium by comparing estimated haplotypes generated with the expectation maximisation (EM algorithm to haplotypes determined from Centre d'Etude Polymorphisme Humain (CEPH pedigree data. To do this, they have characterised haplotypes comprising alleles at 11 biallelic loci in four chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2, which span 150 kb on chromosome 3p21, and haplotyes of nine biallelic loci in six chemokine genes [MCP-1(CCL2, Eotaxin(CCL11, RANTES(CCL5, MPIF-1(CCL23, PARC(CCL18 and MIP-1α(CCL3 ] on chromosome 17q11-12. Forty multi-generation CEPH families, totalling 489 individuals, were genotyped by the TaqMan 5'-nuclease assay. Phased haplotypes and haplotypes estimated from unphased genotypes were compared in 103 grandparents who were assumed to have mated at random. For the 3p21 single nucleotide polymorphism (SNP data, haplotypes determined by pedigree analysis and haplotypes generated by the EM algorithm were nearly identical. Linkage disequilibrium, measured by the D' statistic, was nearly maximal across the 150 kb region, with complete disequilibrium maintained at the extremes between CCR3-Y17Y and CCRL2-1243V. D'-values calculated from estimated haplotypes on 3p21 had high concordance with pairwise comparisons between pedigree-phased chromosomes. Conversely, there was less agreement between analyses of haplotype frequencies and linkage disequilibrium using estimated haplotypes when

  13. Evaluate the action of polymeric additives in protect and recover water and bentonite clay based drilling fluids contaminated by degradation agents; Analise da acao de aditivos polimericos na protecao e recuperacao de fluidos de perfuracao base agua e bentonita contaminados por sais

    Energy Technology Data Exchange (ETDEWEB)

    Campos, L.F.A.; Ferreira, H.S.; Amorim, L.V.; Franca, K.B.; Ferreira, H.C. [Universidade Federal de Campina Grande (UFCG), PB (Brazil)

    2008-07-01

    The aim of this paper is study influences of electrolytes and cellulose polymers on rheological and water loss properties of dispersions of bentonite compositions. Evaluate the action of degradation additives CaSO{sub 4}, MgCl{sub 2} and CaCl{sub 2} and polymeric additives to protect and recover water and clay based. The results show a negative effect of degradation additives the rheological and water loss properties of drilling fluids. The cellulose polymers can be successfully applied to protect and recover of the rheological properties and water loss of the dispersions contaminated. (author)

  14. Analysis of single nucleotide polymorphisms and haplotypes in the neuropeptide Y gene: no evidence for association with alcoholism in a German population sample.

    Science.gov (United States)

    Zill, Peter; Preuss, Ulrich W; Koller, Gabrielle; Bondy, Brigitta; Soyka, Michael

    2008-03-01

    Several lines of evidence from animal and electrophysiological studies indicate that the neuropeptide Y (NPY) gene is involved in the pathophysiology of alcohol dependence. Recent studies have provided evidence for an association between a Leu7Pro polymorphism, as well as 2 promoter single nucleotide polymorphisms (SNPs) in the NPY gene (G-602T, T-399C) and alcohol dependence. The aim of the present study was to analyze these variants in a large sample of the Munich Gene Bank of Alcoholism. We performed single SNP and haplotype studies in 465 alcohol dependent patients and 448 healthy controls with 3 SNPs in the promoter region (-883ins/del, G-602T, T-399C) and the Leu7Pro polymorphism in exon 2 of the NPY gene. Neither single SNP-, nor haplotype analysis could detect significant associations with alcohol dependence. Additionally we could not detect any relation to Cloninger's Type 1/2 or Babor's Type A/B classification, to withdrawal symptoms, to the age of onset or to the amount of alcohol intake. In conclusion, our results suggest that the analyzed SNPs, as well as the corresponding haplotypes of the NPY gene are unlikely to play a major role in the pathophysiology of alcohol dependence in the investigated sample from the German population. Further analyses are needed to confirm the present results.

  15. A novel approach to rapid determination of betaS-globin haplotypes: sequencing of the Agamma-IVS-II region.

    Science.gov (United States)

    Vinson, Amy E; Walker, Aisha; Elam, Dedrey; Glendenning, Michele; Kutlar, Ferdane; Clair, Betsy; Harbin, Jeanette; Kutlar, Abdullah

    2004-01-01

    beta-Globin gene cluster haplotypes were originally determined by restriction endonuclease mapping with Southern blots of polymorphic sites around the gene cluster. Over the years, haplotyping has been found to be useful, not only in population genetics but also in predicting the severity of hemoglobinopathies such as sickle cell disease. The sickle mutation occurs on five distinct haplotypes. The hitherto used methods are cumbersome and time-consuming, making haplotype determination a tedious procedure. We report our experience with a novel, rapid approach to haplotyping based on sequence polymorphisms in the Agamma-IVS-II region. We provide an algorithm that allows rapid assignment of the four African haplotypes carrying the sickle mutation.

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

    Directory of Open Access Journals (Sweden)

    Koepke Tyson

    2012-01-01

    Full Text Available Abstract Background Sweet cherry (Prunus avium L., a non-model crop with narrow genetic diversity, is an important member of sub-family Amygdoloideae within Rosaceae. Compared to other important members like peach and apple, sweet cherry lacks in genetic and genomic information, impeding understanding of important biological processes and development of efficient breeding approaches. Availability of single nucleotide polymorphism (SNP-based molecular markers can greatly benefit breeding efforts in such non-model species. RNA-seq approaches employing second generation sequencing platforms offer a unique avenue to rapidly identify gene-based SNPs. Additionally, haplotype markers can be rapidly generated from transcript-based SNPs since they have been found to be extremely utile in identification of genetic variants related to health, disease and response to environment as highlighted by the human HapMap project. Results RNA-seq was performed on two sweet cherry cultivars, Bing and Rainier using a 3' untranslated region (UTR sequencing method yielding 43,396 assembled contigs. In order to test our approach of rapid identification of SNPs without any reference genome information, over 25% (10,100 of the contigs were screened for the SNPs. A total of 207 contigs from this set were identified to contain high quality SNPs. A set of 223 primer pairs were designed to amplify SNP containing regions from these contigs and high resolution melting (HRM analysis was performed with eight important parental sweet cherry cultivars. Six of the parent cultivars were distantly related to Bing and Rainier, the cultivars used for initial SNP discovery. Further, HRM analysis was also performed on 13 seedlings derived from a cross between two of the parents. Our analysis resulted in the identification of 84 (38.7% primer sets that demonstrated variation among the tested germplasm. Reassembly of the raw 3'UTR sequences using upgraded transcriptome assembly software

  17. Comparison of linkage disequilibrium and haplotype diversity on macro- and microchromosomes in chicken

    Directory of Open Access Journals (Sweden)

    Muir William M

    2009-12-01

    Full Text Available Abstract Background The chicken (Gallus gallus, like most avian species, has a very distinct karyotype consisting of many micro- and a few macrochromosomes. While it is known that recombination frequencies are much higher for micro- as compared to macrochromosomes, there is limited information on differences in linkage disequilibrium (LD and haplotype diversity between these two classes of chromosomes. In this study, LD and haplotype diversity were systematically characterized in 371 birds from eight chicken populations (commercial lines, fancy breeds, and red jungle fowl across macro- and microchromosomes. To this end we sampled four regions of ~1 cM each on macrochromosomes (GGA1 and GGA2, and four 1.5 -2 cM regions on microchromosomes (GGA26 and GGA27 at a high density of 1 SNP every 2 kb (total of 889 SNPs. Results At a similar physical distance, LD, haplotype homozygosity, haploblock structure, and haplotype sharing were all lower for the micro- as compared to the macrochromosomes. These differences were consistent across populations. Heterozygosity, genetic differentiation, and derived allele frequencies were also higher for the microchromosomes. Differences in LD, haplotype variation, and haplotype sharing between populations were largely in line with known demographic history of the commercial chicken. Despite very low levels of LD, as measured by r2 for most populations, some haploblock structure was observed, particularly in the macrochromosomes, but the haploblock sizes were typically less than 10 kb. Conclusion Differences in LD between micro- and macrochromosomes were almost completely explained by differences in recombination rate. Differences in haplotype diversity and haplotype sharing between micro- and macrochromosomes were explained by differences in recombination rate and genotype variation. Haploblock structure was consistent with demography of the chicken populations, and differences in recombination rates between micro

  18. A comprehensive literature review of haplotyping software and methods for use with unrelated individuals

    Directory of Open Access Journals (Sweden)

    Salem Rany M

    2005-03-01

    Full Text Available Abstract Interest in the assignment and frequency analysis of haplotypes in samples of unrelated individuals has increased immeasurably as a result of the emphasis placed on haplotype analyses by, for example, the International HapMap Project and related initiatives. Although there are many available computer programs for haplotype analysis applicable to samples of unrelated individuals, many of these programs have limitations and/or very specific uses. In this paper, the key features of available haplotype analysis software for use with unrelated individuals, as well as pooled DNA samples from unrelated individuals, are summarised. Programs for haplotype analysis were identified through keyword searches on PUBMED and various internet search engines, a review of citations from retrieved papers and personal communications, up to June 2004. Priority was given to functioning computer programs, rather than theoretical models and methods. The available software was considered in light of a number of factors: the algorithm(s used, algorithm accuracy, assumptions, the accommodation of genotyping error, implementation of hypothesis testing, handling of missing data, software characteristics and web-based implementations. Review papers comparing specific methods and programs are also summarised. Forty-six haplotyping programs were identified and reviewed. The programs were divided into two groups: those designed for individual genotype data (a total of 43 programs and those designed for use with pooled DNA samples (a total of three programs. The accuracy of programs using various criteria are assessed and the programs are categorised and discussed in light of: algorithm and method, accuracy, assumptions, genotyping error, hypothesis testing, missing data, software characteristics and web implementation. Many available programs have limitations (eg some cannot accommodate missing data and/or are designed with specific tasks in mind (eg estimating

  19. Familial Mediterranean Fever (FMF) in Moroccan Jews: Demonstration of a founder effect by extened haplotype analysis

    Energy Technology Data Exchange (ETDEWEB)

    Aksentijevich, I.; Pras, E.; Helling, S.; Prosen, L.; Kastner, D.L.; Gruberg, L.; Pras, M. (Heller Institute for Medical Research, Tel-Hashomer (Israel))

    1993-09-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disease causing attacks of fever and serositis. The FMF gene (designated MEF') is on 16p, with the gene order 16 cen-D16S80-MEF-D16S94-D16S283-D16S291-16pter. Here the authors report the association of FMF susceptibility with alleles at D16S94, D16S283, and D16S291 among 31 non-Ashkenazi Jewish families 14 Moroccan families. For the non-Moroccans, only the allelic association at D16S94 approached statistical significance. Haplotype analysis showed that 18/25 Moroccan FMF chromosomes, versus 0/21 noncarrier chromosomes, bore a specific haplotype for D16S94-D16S283-D16S291. Among non-Moroccans this haplotype was present in 6/26 FMF chromosomes versus 1/28 controls. Both groups of families are largely descended from Jews who fled the Spanish Inquisition. The strong haplotype association seen among the Moroccans is most likely a founder effect, given the recent origin and genetic isolation of the Moroccan Jewish community. The lowest haplotype frequency among non-Moroccan carriers may reflect differences both in history and in population genetics. 28 refs., 1 fig., 3 tabs.

  20. Phylogeography of Japanese horse chestnut (Aesculus turbinata) in the Japanese Archipelago based on chloroplast DNA haplotypes.

    Science.gov (United States)

    Sugahara, Kanako; Kaneko, Yuko; Ito, Satoshi; Yamanaka, Keisuke; Sakio, Hitoshi; Hoshizaki, Kazuhiko; Suzuki, Wajiro; Yamanaka, Norikazu; Setoguchi, Hiroaki

    2011-01-01

    Japanese horse chestnut (Aesculus turbinata: Hippocastanaceae) is one of the typical woody plants that grow in temperate riparian forests in the Japanese Archipelago. To analyze the phylogeography of this plant in the Japanese Archipelago, we determined cpDNA haplotypes for 337 samples from 55 populations covering the entire distribution range. Based on 1,313 bp of two spacers, we determined ten haplotypes that are distinguished from adjacent haplotypes by one or two steps. Most of the populations had a single haplotype, suggesting low diversity. Spatial analysis of molecular variance suggested three obvious phylogeographic structures in western Japan, where Japanese horse chestnut is scattered and isolated in mountainous areas. Conversely, no clear phylogeographic structure was observed from the northern to the southern limit of this species, including eastern Japan, where this plant is more common. Rare and private haplotypes were also found in southwestern Japan, where Japanese horse chestnuts are distributed sparsely. These findings imply that western Japan might have maintained a relatively large habitat for A. turbinata during the Quaternary climatic oscillations, while northerly regions could not.

  1. Conditional likelihood methods for haplotype-based association analysis using matched case-control data.

    Science.gov (United States)

    Chen, Jinbo; Rodriguez, Carmen

    2007-12-01

    Genetic epidemiologists routinely assess disease susceptibility in relation to haplotypes, that is, combinations of alleles on a single chromosome. We study statistical methods for inferring haplotype-related disease risk using single nucleotide polymorphism (SNP) genotype data from matched case-control studies, where controls are individually matched to cases on some selected factors. Assuming a logistic regression model for haplotype-disease association, we propose two conditional likelihood approaches that address the issue that haplotypes cannot be inferred with certainty from SNP genotype data (phase ambiguity). One approach is based on the likelihood of disease status conditioned on the total number of cases, genotypes, and other covariates within each matching stratum, and the other is based on the joint likelihood of disease status and genotypes conditioned only on the total number of cases and other covariates. The joint-likelihood approach is generally more efficient, particularly for assessing haplotype-environment interactions. Simulation studies demonstrated that the first approach was more robust to model assumptions on the diplotype distribution conditioned on environmental risk variables and matching factors in the control population. We applied the two methods to analyze a matched case-control study of prostate cancer.

  2. Patterns of mitochondrial haplotype diversity in the invasive pest Epiphyas postvittana (Lepidoptera: Tortricidae).

    Science.gov (United States)

    Tooman, Leah K; Rose, Caroline J; Carraher, Colm; Suckling, D Max; Paquette, Sébastien Rioux; Ledezma, Lisa A; Gilligan, Todd M; Epstein, Marc; Barr, Norman B; Newcomb, Richard D

    2011-06-01

    The light brown apple moth, Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae), is a horticultural pest of Australia and New Zealand that has more recently invaded Hawaii, Europe, and California. A 2,216-bp region of the mitochondrial genome containing the cytochrome oxidase I and II genes was sequenced from 752 individuals. Haplotype network analyses revealed a major split between a predominantly Western Australian clade and all other samples, suggestive of either a deep genetic divergence or a cryptic species. Nucleotide and haplotype diversity were highest in the country of origin, Australia, and in New Zealand populations, with evidence of haplotype sharing between New Zealand and Tasmania. Nucleotide and haplotype diversity were higher in California than within the British Isles or Hawaii. From the total of 96 haplotypes, seven were found in California, of which four were private. Within California, there have been at least two introductions; based on genetic diversity we were unable to assign a likely source for a single moth found and eradicated in Los Angeles in 2007; however, our data suggest it is unlikely that Hawaii and the British Isles are sources of the major E. postvittana population found throughout the rest of the state since 2006.

  3. PADI4 Haplotypes in Association with RA Mexican Patients, a New Prospect for Antigen Modulation

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    Maria Guadalupe Zavala-Cerna

    2013-01-01

    Full Text Available Peptidyl arginine deiminase IV (PAD 4 is the responsible enzyme for a posttranslational modification called citrullination, originating the antigenic determinant recognized by anti-cyclic citrullinated peptide antibodies (ACPA. Four SNPs (single nucleotide polymorphisms have been described in PADI4 gene to form a susceptibility haplotype for rheumatoid arthritis (RA; nevertheless, results in association studies appear contradictory in different populations. The aim of the study was to analyze if the presence of three SNPs in PADI4 gene susceptibility haplotype (GTG is associated with ACPA positivity in patients with RA. This was a cross-sectional study that included 86 RA patients and 98 healthy controls. Polymorphisms PADI4_89, PADI4_90, and PADI4_92 in the PADI4 gene were genotyped. The susceptibility haplotype (GTG was more frequent in RA patients; interestingly, we found a new haplotype associated with RA with a higher frequency (GTC. There were no associations between polymorphisms and high scores in Spanish HAQ-DI and DAS-28, but we did find an association between RARBIS index and PADI4_89, PADI4_90 polymorphisms. We could not confirm an association between susceptibility haplotype presence and ACPA positivity. Further evidence about proteomic expression of this gene will determine its participation in antigenic generation and autoimmunity.

  4. Mitochondrial control region haplotypes of the South American sea lion Otaria flavescens (Shaw, 1800

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    L.O. Artico

    2010-09-01

    Full Text Available The South American sea lion, Otaria flavescens, is widely distributed along the Pacific and Atlantic coasts of South America. However, along the Brazilian coast, there are only two nonbreeding sites for the species (Refúgio de Vida Silvestre da Ilha dos Lobos and Refúgio de Vida Silvestre do Molhe Leste da Barra do Rio Grande, both in Southern Brazil. In this region, the species is continuously under the effect of anthropic activities, mainly those related to environmental contamination with organic and inorganic chemicals and fishery interactions. This paper reports, for the first time, the genetic diversity of O. flavescens found along the Southern Brazilian coast. A 287-bp fragment of the mitochondrial DNA control region (D-loop was analyzed. Seven novel haplotypes were found in 56 individuals (OFA1-OFA7, with OFA1 being the most frequent (47.54%. Nucleotide diversity was moderate (π = 0.62% and haplotype diversity was relatively low (67%. Furthermore, the median joining network analysis indicated that Brazilian haplotypes formed a reciprocal monophyletic clade when compared to the haplotypes from the Peruvian population on the Pacific coast. These two populations do not share haplotypes and may have become isolated some time back. Further genetic studies covering the entire species distribution are necessary to better understand the biological implications of the results reported here for the management and conservation of South American sea lions.

  5. Mitochondrial control region haplotypes of the South American sea lion Otaria flavescens (Shaw, 1800).

    Science.gov (United States)

    Artico, L O; Bianchini, A; Grubel, K S; Monteiro, D S; Estima, S C; Oliveira, L R de; Bonatto, S L; Marins, L F

    2010-09-01

    The South American sea lion, Otaria flavescens, is widely distributed along the Pacific and Atlantic coasts of South America. However, along the Brazilian coast, there are only two nonbreeding sites for the species (Refúgio de Vida Silvestre da Ilha dos Lobos and Refúgio de Vida Silvestre do Molhe Leste da Barra do Rio Grande), both in Southern Brazil. In this region, the species is continuously under the effect of anthropic activities, mainly those related to environmental contamination with organic and inorganic chemicals and fishery interactions. This paper reports, for the first time, the genetic diversity of O. flavescens found along the Southern Brazilian coast. A 287-bp fragment of the mitochondrial DNA control region (D-loop) was analyzed. Seven novel haplotypes were found in 56 individuals (OFA1-OFA7), with OFA1 being the most frequent (47.54%). Nucleotide diversity was moderate (π = 0.62%) and haplotype diversity was relatively low (67%). Furthermore, the median joining network analysis indicated that Brazilian haplotypes formed a reciprocal monophyletic clade when compared to the haplotypes from the Peruvian population on the Pacific coast. These two populations do not share haplotypes and may have become isolated some time back. Further genetic studies covering the entire species distribution are necessary to better understand the biological implications of the results reported here for the management and conservation of South American sea lions.

  6. Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: A systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Mohamed N. Saad

    2016-01-01

    Full Text Available Genetics of autoimmune diseases represent a growing domain with surpassing biomarker results with rapid progress. The exact cause of Rheumatoid Arthritis (RA is unknown, but it is thought to have both a genetic and an environmental bases. Genetic biomarkers are capable of changing the supervision of RA by allowing not only the detection of susceptible individuals, but also early diagnosis, evaluation of disease severity, selection of therapy, and monitoring of response to therapy. This review is concerned with not only the genetic biomarkers of RA but also the methods of identifying them. Many of the identified genetic biomarkers of RA were identified in populations of European and Asian ancestries. The study of additional human populations may yield novel results. Most of the researchers in the field of identifying RA biomarkers use single nucleotide polymorphism (SNP approaches to express the significance of their results. Although, haplotype block methods are expected to play a complementary role in the future of that field.

  7. Full mtGenome reference data: development and characterization of 588 forensic-quality haplotypes representing three U.S. populations.

    Science.gov (United States)

    Just, Rebecca S; Scheible, Melissa K; Fast, Spence A; Sturk-Andreaggi, Kimberly; Röck, Alexander W; Bush, Jocelyn M; Higginbotham, Jennifer L; Peck, Michelle A; Ring, Joseph D; Huber, Gabriela E; Xavier, Catarina; Strobl, Christina; Lyons, Elizabeth A; Diegoli, Toni M; Bodner, Martin; Fendt, Liane; Kralj, Petra; Nagl, Simone; Niederwieser, Daniela; Zimmermann, Bettina; Parson, Walther; Irwin, Jodi A

    2015-01-01

    Though investigations into the use of massively parallel sequencing technologies for the generation of complete mitochondrial genome (mtGenome) profiles from difficult forensic specimens are well underway in multiple laboratories, the high quality population reference data necessary to support full mtGenome typing in the forensic context are lacking. To address this deficiency, we have developed 588 complete mtGenome haplotypes, spanning three U.S. population groups (African American, Caucasian and Hispanic) from anonymized, randomly-sampled specimens. Data production utilized an 8-amplicon, 135 sequencing reaction Sanger-based protocol, performed in semi-automated fashion on robotic instrumentation. Data review followed an intensive multi-step strategy that included a minimum of three independent reviews of the raw data at two laboratories; repeat screenings of all insertions, deletions, heteroplasmies, transversions and any additional private mutations; and a check for phylogenetic feasibility. For all three populations, nearly complete resolution of the haplotypes was achieved with full mtGenome sequences: 90.3-98.8% of haplotypes were unique per population, an improvement of 7.7-29.2% over control region sequencing alone, and zero haplotypes overlapped between populations. Inferred maternal biogeographic ancestry frequencies for each population and heteroplasmy rates in the control region were generally consistent with published datasets. In the coding region, nearly 90% of individuals exhibited length heteroplasmy in the 12418-12425 adenine homopolymer; and despite a relatively high rate of point heteroplasmy (23.8% of individuals across the entire molecule), coding region point heteroplasmies shared by more than one individual were notably absent, and transversion-type heteroplasmies were extremely rare. The ratio of nonsynonymous to synonymous changes among point heteroplasmies in the protein-coding genes (1:1.3) and average pathogenicity scores in

  8. Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve.

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    Eric C Wooten

    Full Text Available Bicuspid Aortic Valve (BAV is a highly heritable congenital heart defect. The low frequency of BAV (1% of general population limits our ability to perform genome-wide association studies. We present the application of four a priori SNP selection techniques, reducing the multiple-testing penalty by restricting analysis to SNPs relevant to BAV in a genome-wide SNP dataset from a cohort of 68 BAV probands and 830 control subjects. Two knowledge-based approaches, CANDID and STRING, were used to systematically identify BAV genes, and their SNPs, from the published literature, microarray expression studies and a genome scan. We additionally tested Functionally Interpolating SNPs (fitSNPs present on the array; the fourth consisted of SNPs selected by Random Forests, a machine learning approach. These approaches reduced the multiple testing penalty by lowering the fraction of the genome probed to 0.19% of the total, while increasing the likelihood of studying SNPs within relevant BAV genes and pathways. Three loci were identified by CANDID, STRING, and fitSNPS. A haplotype within the AXIN1-PDIA2 locus (p-value of 2.926x10(-06 and a haplotype within the Endoglin gene (p-value of 5.881x10(-04 were found to be strongly associated with BAV. The Random Forests approach identified a SNP on chromosome 3 in association with BAV (p-value 5.061x10(-06. The results presented here support an important role for genetic variants in BAV and provide support for additional studies in well-powered cohorts. Further, these studies demonstrate that leveraging existing expression and genomic data in the context of GWAS studies can identify biologically relevant genes and pathways associated with a congenital heart defect.

  9. Radiation Protection

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    ... EPA United States Environmental Protection Agency Search Search Radiation Protection Share Facebook Twitter Google+ Pinterest Contact Us Radiation Protection Document Library View and download EPA radiation ...

  10. Mendel-GPU: haplotyping and genotype imputation on graphics processing units.

    Science.gov (United States)

    Chen, Gary K; Wang, Kai; Stram, Alex H; Sobel, Eric M; Lange, Kenneth

    2012-11-15

    In modern sequencing studies, one can improve the confidence of genotype calls by phasing haplotypes using information from an external reference panel of fully typed unrelated individuals. However, the computational demands are so high that they prohibit researchers with limited computational resources from haplotyping large-scale sequence data. Our graphics processing unit based software delivers haplotyping and imputation accuracies comparable to competing programs at a fraction of the computational cost and peak memory demand. Mendel-GPU, our OpenCL software, runs on Linux platforms and is portable across AMD and nVidia GPUs. Users can download both code and documentation at http://code.google.com/p/mendel-gpu/. gary.k.chen@usc.edu. Supplementary data are available at Bioinformatics online.

  11. Haplotype diversity of 17 Y-str loci in an admixed population from the Brazilian Amazon

    Science.gov (United States)

    Francez, Pablo Abdon da Costa; Ramos, Luiz Patrick Vidal; de Jesus Brabo Ferreira Palha, Teresinha; dos Santos, Sidney Emanuel Batista

    2012-01-01

    The allelic and haplotype frequencies of 17 Y-STR loci most commonly used in forensic testing were estimated in a sample of 138 unrelated healthy males from Macapá, in the northern Amazon region of Brazil. The average gene diversity was 0.6554 ± 0.3315. 134 haplotypes of the 17 loci were observed, 130 of them unique and four present in two individuals each. The haplotype diversity index was 0.9996 + 0.0009, with the most frequent haplogroups being R1b (52.2%), E1b1b (11.6%), J2 (10.1%) and Q (7.2%). Most haplogroups of this population belonged to European male lineages (89.2%), followed by Amerindian (7.2%) and African (3.6%) lineages. PMID:22481873

  12. Data supporting the high-accuracy haplotype imputation using unphased genotype data as the references

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    Wenzhi Li

    2016-09-01

    Full Text Available The data presented in this article is related to the research article entitled “High-accuracy haplotype imputation using unphased genotype data as the references” which reports the unphased genotype data can be used as reference for haplotyping imputation [1]. This article reports different implementation generation pipeline, the results of performance comparison between different implementations (A, B, and C and between HiFi and three major imputation software tools. Our data showed that the performances of these three implementations are similar on accuracy, in which the accuracy of implementation-B is slightly but consistently higher than A and C. HiFi performed better on haplotype imputation accuracy and three other software performed slightly better on genotype imputation accuracy. These data may provide a strategy for choosing optimal phasing pipeline and software for different studies.

  13. 电力信息-物理相互依存网络脆弱性评估及加边保护策略%Vulnerability Evaluation and Link Addition Protection Strategy Research of Electrical Cyber-Physical Interdependent Networks

    Institute of Scientific and Technical Information of China (English)

    冀星沛; 王波; 董朝阳; 陈果; 刘涤尘; 魏大千; 汪勋婷

    2016-01-01

    With deep mutual integration between power grid and cyber network, it is of great theoretical value and practical importance to study electrical cyber-physical system’s interactive cascade failures and their protection strategy. Based on interdependent networks theory, this paper builds electrical cyber-physical interdependent networks model. Due to impacts of dependency link and topological inter-similarity, this paper firstly compares topological characteristics between power grid and its cyber network of Central China. Then considering interdependent relationships between coupled nodes, topological inter-similarities are quantitatively evaluated. Vulnerability analysis results under random failures reveal that though interdependency increases vulnerability of cyber-physical interdependent networks, high inter-similarity between networks can avoid first-order transition. Based on structural characteristic of power grid and cyber network, low degree node link addition strategy is proposed to improve its robustness. Simulations verify effectiveness of the proposed link addition strategy and link allocation strategy has important effect on robustness of interdependent networks.%随着一次电网与信息系统深度融合,研究电力信息−物理系统的交互连锁故障机理与保护措施具有十分重要的理论价值与现实意义。基于相互依存网络理论,建立了电力信息-物理相互依存网络模型。由于相依网络的脆弱性同时受到依存边与网间拓扑互相似性的影响,文章首先基于复杂网络理论,对华中500 kV电力网及其信息网的拓扑结构特性进行对比分析。其次,考虑网间节点的相互依存关系,定量评估了信息网与电力网的拓扑互相似性。通过对华中500 kV电力信息−物理相依网络在随机故障下的连通脆弱性进行评估,发现:虽然网间的相互依存提高了电力系统的脆弱性,但由于信息网与电力网的拓扑

  14. Casein haplotypes and their association with milk production traits in Norwegian Red cattle.

    Science.gov (United States)

    Nilsen, Heidi; Olsen, Hanne Gro; Hayes, Ben; Sehested, Erling; Svendsen, Morten; Nome, Torfinn; Meuwissen, Theo; Lien, Sigbjørn

    2009-02-20

    A high resolution SNP map was constructed for the bovine casein region to identify haplotype structures and study associations with milk traits in Norwegian Red cattle. Our analyses suggest separation of the casein cluster into two haplotype blocks, one consisting of the CSN1S1, CSN2 and CSN1S2 genes and another one consisting of the CSN3 gene. Highly significant associations with both protein and milk yield were found for both single SNPs and haplotypes within the CSN1S1-CSN2-CSN1S2 haplotype block. In contrast, no significant association was found for single SNPs or haplotypes within the CSN3 block. Our results point towards CSN2 and CSN1S2 as the most likely loci harbouring the underlying causative DNA variation. In our study, the most significant results were found for the SNP CSN2_67 with the C allele consistently associated with both higher protein and milk yields. CSN2_67 calls a C to an A substitution at codon 67 in beta-casein gene resulting in histidine replacing proline in the amino acid sequence. This polymorphism determines the protein variants A1/B (CSN2_67 A allele) versus A2/A3 (CSN2_67 C allele). Other studies have suggested that a high consumption of A1/B milk may affect human health by increasing the risk of diabetes and heart diseases. Altogether these results argue for an increase in the frequency of the CSN2_67 C allele or haplotypes containing this allele in the Norwegian Red cattle population by selective breeding.

  15. Establishment of a resource population of SLA haplotype-defined Korean native pigs.

    Science.gov (United States)

    Cho, Han-Ok; Ho, Chak-Sum; Lee, Yu-Joo; Cho, In-Cheol; Lee, Sung-Soo; Ko, Moon-Suck; Park, Chankyu; Smith, Douglas M; Jeon, Jin-Tae; Lee, Jun-Heon

    2010-05-01

    The highly polymorphic porcine major histocompatibility complex (MHC), or the swine leukocyte antigens (SLA), has been repeatedly associated with variations in swine immune response to pathogens and vaccines as well as with production traits. The SLA antigens are also important targets for immunological recognition of foreign tissue grafts. We recently established a resource population of Korean native pigs as models for human transplantation and xenotransplantation research. In this study, 115 animals derived from three generations of the Korean native pigs were genotyped for three SLA class I (SLA-2, SLA-3 and SLA-1) and three SLA class II loci (DRB1, DQB1, DQA) using PCR with sequence-specific primers (PCR-SSP) at the allele group resolution. A total of seven SLA haplotypes (Lr-5.34, Lr-7.23, Lr-31.13, Lr-56.23, Lr-56.30, Lr-59.1, Lr-65.34), comprising six unique class I and five unique class II haplotypes, were characterized in the founding animals. Class I haplotype Lr-65.0 and class II haplotype Lr-0.34 were novel; and together with Lr-56.0 these haplotypes appeared to be breed-specific. In the progeny population, Lr-7.23 and Lr-56.30 appeared to be the most prevalent haplotypes with frequencies of 34.7% and 31.6%, respectively; the overall homozygosity was 27.4%. This resource population of SLA-defined Korean native pigs will be useful as large animal models for various transplantation and xenotransplantation experiments, as well as for dissecting the roles of SLA proteins in swine disease resistance and production traits.

  16. Vitamin K epoxide reductase complex subunit 1 (Vkorc1 haplotype diversity in mouse priority strains

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    Kohn Michael H

    2008-12-01

    Full Text Available Abstract Background Polymorphisms in the vitamin K-epoxide reductase complex subunit 1 gene, Vkorc1, could affect blood coagulation and other vitamin K-dependent proteins, such as osteocalcin (bone Gla protein, BGP. Here we sequenced the Vkorc1 gene in 40 mouse priority strains. We analyzed Vkorc1 haplotypes with respect to prothrombin time (PT and bone mineral density and composition (BMD and BMC; phenotypes expected to be vitamin K-dependent and represented by data in the Mouse Phenome Database (MPD. Findings In the commonly used laboratory strains of Mus musculus domesticus we identified only four haplotypes differing in the intron or 5' region sequence of the Vkorc1. Six haplotypes differing by coding and non-coding polymorphisms were identified in the other subspecies of Mus. We detected no significant association of Vkorc1 haplotypes with PT, BMD and BMC within each subspecies of Mus. Vkorc1 haplotype sequences divergence between subspecies was associated with PT, BMD and BMC. Conclusion Phenotypic variation in PT, BMD and BMC within subspecies of Mus, while substantial, appears to be dominated by genetic variation in genes other than the Vkorc1. This was particularly evident for M. m. domesticus, where a single haplotype was observed in conjunction with virtually the entire range of PT, BMD and BMC values of all 5 subspecies of Mus included in this study. Differences in these phenotypes between subspecies also should not be attributed to Vkorc1 variants, but should be viewed as a result of genome wide genetic divergence.

  17. Kidney dysfunction and beta S-haplotypes in patients with sickle cell disease

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    Lilianne Brito da Silva Rocha

    2013-06-01

    Full Text Available Objective: To investigate the association between kidney dysfunction and haplotypes in sickle cell disease. Methods: A cohort of 84 sickle cell disease patients, treated in a public health service in Fortaleza, Brazil, was studied. Hemoglobin S haplotypes were obtained from 57 patients as they had recently received blood transfusions with 18 of them agreeing to undertake urinary concentrating ability and acidification tests. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease Study equation. Urinary concentration was evaluated utilizing the urinary and serum osmolality ratio (U/Posm after 12 hours of water deprivation. Urinary acidification was evaluated by measuring the urinary pH before and after the administration of oral CaCl2. The analysis of the haplotypes of the beta S gene cluster was carried out by polymerase chain reaction-restriction fragment length polymorphism. The analysis of variance (ANOVA test was used for multiple comparisons of means and the Newman-Keuls test was used to identify which groups were significantly different. Results: The mean age of the patients was 33 ± 13 years with 64.2% being females. The glomerular filtration rate was normal in 25 cases (30% and a rate > 120 mL/min was seen in 52 cases (62%. Urinary concentration deficit was found in all patients who underwent the test and urinary acidification in 22%. There was no significant difference when comparing patients with the Bantu/Bantu and Benin/Benin haplotypes. On comparing patients with the Central African Republic-haplotype however, a higher number had glomerular filtration rates between 60 and 120 mL/min. Conclusion: There was no significant difference among sickle cell disease patients regarding the haplotypes and kidney dysfunction.

  18. Two independent apolipoprotein a5 Haplotypes influence human plasma triglyceride levels

    Energy Technology Data Exchange (ETDEWEB)

    Pennacchio, Len A.; Olivier, Michael; Hubacek, Jaroslav A.; Krauss, Ronald M.; Rubin, Edward M.; Cohen, Jonathan C.

    2002-09-16

    The recently identified apolipoprotein A5 gene (APOA5) has been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. We previously identified an APOA5 haplotype (designated APOA5*2) that is present in {approx}16 percent of Caucasians and is associated with increased plasma triglyceride concentrations. In this report we describe another APOA5 haplotype (APOA5*3) containing the rare allele of the single nucleotide polymorphism c.56C>G that changes serine to tryptophan at codon 19 and is independently associated with high plasma triglyceride levels in three different populations. In a sample of 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, the APOA5*3 haplotype was more than three-fold more common in the group with high plasma triglyceride levels. In a second independently ascertained sample of Caucasian men and women (n 1/4 419) who were studied while consuming their self-selected diets as well as after high-carbohydrate diets and high-fat diets, the APOA5*3 haplotype was associated with increased plasma triglyceride levels on all three dietary regimens. In a third population comprising 2660 randomly selected individuals, the APOA5*3 haplotype was found in 12 percent of Caucasians, 14 percent of African-Americans and 28 percent of Hispanics and was associated with increased plasma triglyceride levels in both men and women in each ethnic group. These findings establish that the APOA5 locus contributes significantly to inter-individual variation in plasma triglyceride levels in humans. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25 50 percent of African-Americans, Hispanics and Caucasians and support the contribution of common human variation to quantitative phenotypes in the general population.

  19. Altered transmission of maternal angiotensin II receptor haplotypes in fetal growth restriction.

    Science.gov (United States)

    Tower, Clare; Chappell, Sally; Acharya, Meera; Crane, Richard; Szolin, Stephanie; Symonds, Lyneth; Chevins, Helen; Kalsheker, Noor; Baker, Philip; Morgan, Linda

    2006-02-01

    Fetal growth restriction (FGR) predisposes to significant short- and long-term health problems. Epidemiological studies have suggested a role for inherited factors in its pathogenesis. The angiotensin II receptor genes, AGTR1 and AGTR2, are candidate genes because they mediate processes that are important for placentation. This study investigated AGTR1 and AGTR2 haplotypes and genotypes in FGR. A total of 107 families (father, mother, and baby) with FGR, and 101 families with normal pregnancies were genotyped at five sites in AGTR1 and six sites across AGTR2. All of the participants were white western Europeans. FGR was identified antenatally by ultrasound scans and confirmed postnatally by correcting the birth weight centile for gestation, infant sex, maternal height, weight, and parity. Fetal genes were investigated using transmission disequilibrium testing (TDT), and a case-control comparison of maternal haplotypes was conducted. FGR was associated with maternal (but not paternal) transmission of the AGTR1 haplotype (GenBank AF245699.1) g.4955T, g.5052T, g.5245C, g.5612A, and haplotype g.4955T, g.5052T, g.5245T, g.5612A. Haplotype g.4955A, g.5052G, g.5245T, g.5612G was undertransmitted (P = 0.002). TDT of the AGTR1 genotype showed undertransmission of maternal AGTR1 genotypes g.4955T>A (odds ratio (OR), 0.34 (95% confidence interval (CI), 0.14-0.86); P = 0.02), g.5052T>G (OR, 0.18 (0.06-0.48); PG (OR, 0.21 (0.08-0.55); P AGTR1 or AGTR2 (P > 0.10). This is the first study to show distortion of transmission of maternal AGTR1 haplotypes in FGR, which suggests that this gene plays a role in FGR. In particular, maternal-fetal gene sharing may be an important factor. 2006 Wiley-Liss, Inc.

  20. Association between Osteopontin Promoter Gene Polymorphisms and Haplotypes with Risk of Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Balneek Singh Cheema

    2015-06-01

    Full Text Available Background: Osteopontin (OPN C-443T promoter polymorphism has been shown as a genetic risk factor for diabetic nephropathy (DN in type 2 diabetic patients (T2D. Methods: In the present study we investigated the association of three functional promoter gene polymorphisms C-443T, delG-156G, and G-66T and their haplotypes with the risk of DN and estimated Glomerular Filtration Rate (eGFR in Asian Indians T2D patients using Real time PCR based Taqman assay. A total of 1165 T2D patients, belonging to two independently ascertained Indian Asian cohorts, were genotyped for three OPN promoter polymorphisms C-443T (rs11730582, delG-156G (rs17524488 and G-66T (rs28357094. Results: -156G allele and GG genotypes (delG-156G and haplotypes G-C-G and T-C-G (G-66T, C-443T, delG-156G were associated with decreased risk of DN and higher eGFR. Haplotype G-T-delG and T-T-delG (G-66T, C-443T, delG-156G were identified as risk haplotypes, as shown by lower eGFR. Conclusion: This is the first study to report an association of OPN promoter gene polymorphisms; G-66T and delG-156G and their haplotypes with DN in T2D. Our results suggest an association between OPN promoter gene polymorphisms and their haplotypes with DN.

  1. Congruence as a measurement of extended haplotype structure across the genome

    Directory of Open Access Journals (Sweden)

    Baschal Erin E

    2012-02-01

    Full Text Available Abstract Background Historically, extended haplotypes have been defined using only a few data points, such as alleles for several HLA genes in the MHC. High-density SNP data, and the increasing affordability of whole genome SNP typing, creates the opportunity to define higher resolution extended haplotypes. This drives the need for new tools that support quantification and visualization of extended haplotypes as defined by as many as 2000 SNPs. Confronted with high-density SNP data across the major histocompatibility complex (MHC for 2,300 complete families, compiled by the Type 1 Diabetes Genetics Consortium (T1DGC, we developed software for studying extended haplotypes. Methods The software, called ExHap (Extended Haplotype, uses a similarity measurement we term congruence to identify and quantify long-range allele identity. Using ExHap, we analyzed congruence in both the T1DGC data and family-phased data from the International HapMap Project. Results Congruent chromosomes from the T1DGC data have between 96.5% and 99.9% allele identity over 1,818 SNPs spanning 2.64 megabases of the MHC (HLA-DRB1 to HLA-A. Thirty-three of 132 DQ-DR-B-A defined haplotype groups have > 50% congruent chromosomes in this region. For example, 92% of chromosomes within the DR3-B8-A1 haplotype are congruent from HLA-DRB1 to HLA-A (99.8% allele identity. We also applied ExHap to all 22 autosomes for both CEU and YRI cohorts from the International HapMap Project, identifying multiple candidate extended haplotypes. Conclusions Long-range congruence is not unique to the MHC region. Patterns of allele identity on phased chromosomes provide a simple, straightforward approach to visually and quantitatively inspect complex long-range structural patterns in the genome. Such patterns aid the biologist in appreciating genetic similarities and differences across cohorts, and can lead to hypothesis generation for subsequent studies.

  2. Haplotype analysis of seven Y-STRs (eleven loci) in two Japanese populations.

    Science.gov (United States)

    Yuasa, Isao; Irizawa, Yoshito; Nakamura, Hiroaki; Matusue, Aya; Umetsu, Kazuo

    2008-11-01

    We analyzed 11 Y-STR loci (DYS446, DYS447, DYS449, DYS450, DYS459a/b, DYS463 and DYS464a/b/c/d) in a total of 324 Japanese males from western and southern Japan. Gene diversity ranged from 0.958 at DYS464 in western Japan to 0.259 at DYS450 in southern Japan. A total of 272 different haplotypes were observed, of which 240 were found in single individuals. The overall haplotype diversity and discrimination capacity was 0.9982 and 0.8395, respectively.

  3. Novel harmful recessive haplotypes identified for fertility traits in Nordic Holstein cattle

    DEFF Research Database (Denmark)

    Sahana, Goutam; Nielsen, Ulrik Sander; Aamand, Gert Pedersen;

    2013-01-01

    Using genomic data, lethal recessives may be discovered from haplotypes that are common in the population but never occur in the homozygote state in live animals. This approach only requires genotype data from phenotypically normal (i.e. live) individuals and not from the affected embryos that die...... harboring possible recessive lethal alleles. Effects of the identified haplotypes were estimated on two fertility traits: non-return rates and calving interval. Out of the eight identified genomic regions, six regions were confirmed as having an effect on fertility. The information can be used to avoid...

  4. Phylogeny and Haplotype Analysis of Fungi Within the Fusarium incarnatum-equiseti Species Complex.

    Science.gov (United States)

    Ramdial, H; Latchoo, R K; Hosein, F N; Rampersad, S N

    2017-01-01

    Fusarium spp. are ranked among the top 10 most economically and scientifically important plant-pathogenic fungi in the world and are associated with plant diseases that include fruit decay of a number of crops. Fusarium isolates infecting bell pepper in Trinidad were identified based on sequence comparisons of the translation elongation factor gene (EF-1a) with sequences of Fusarium incarnatum-equiseti species complex (FIESC) verified in the FUSARIUM-ID database. Eighty-two isolates were identified as belonging to one of four phylogenetic species within the subclades FIESC-1, FIESC-15, FIESC-16, and FIESC-26, with the majority of isolates belonging to FIESC-15. A comparison of the level of DNA polymorphism and phylogenetic inference for sequences of the internal transcribed spacer region (ITS1-5.8S-ITS2) and EF-1a sequences for Trinidad and FUSARIUM-ID type species was carried out. The ITS sequences were less informative, had lower haplotype diversity and restricted haplotype distribution, and resulted in poor resolution and taxa placement in the consensus maximum-likelihood tree. EF-1a sequences enabled strongly supported phylogenetic inference with highly resolved branching patterns of the 30 phylogenetic species within the FIESC and placement of representative Trinidad isolates. Therefore, global phylogeny was inferred from EF-1a sequences representing 11 countries, and separation into distinct Incarnatum and Equiseti clades was again evident. In total, 42 haplotypes were identified: 12 were shared and the remaining were unique haplotypes. The most diverse haplotype was represented by sequences from China, Indonesia, Malaysia, and Trinidad and consisted exclusively of F. incarnatum isolates. Spain had the highest haplotype diversity, perhaps because both F. equiseti and F. incarnatum sequences were represented; followed by the United States, which contributed both F. equiseti and F. incarnatum sequences to the data set; then by countries representing Southeast

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

    Science.gov (United States)

    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.

  6. Haplotype identity between individuals who share a CFTR mutation allele 'identical by descent': Demonstration of the usefulness of the haplotype-sharing concept for gene mapping in real populations

    NARCIS (Netherlands)

    H.G. de Vries (Hendrik); M.A. van der Meulen (Martin); R. Rozen (Rima); D.J.J. Halley (Dicky); H. Scheffer (Hans); L.P. ten Kate; C.H.C.M. Buys; G.J. Te Meerman (Gerard)

    1996-01-01

    markdownabstractAbstract Cystic fibrosis (CF) patients with the A455E mutation, in both the French Canadian and the Dutch population, share a common haplotype over distances of up to 25 cM. French Canadian patients with the 621+1G→T mutation share a common haplotype of more than 14 cM. In contras

  7. Addition of a UL5 helicase-primase subunit point mutation eliminates bursal-thymic atrophy of Marek's disease virus ∆Meq recombinant virus but reduces vaccinal protection.

    Science.gov (United States)

    Hildebrandt, Evin; Dunn, John R; Cheng, Hans H

    2015-01-01

    Marek's disease virus (MDV) is an oncogenic alphaherpesvirus and the causative agent of Marek's disease (MD), characterized by immunosuppression, paralysis, nerve enlargement and induction of T-cell lymphomas in chickens. Despite widespread usage of vaccines since the 1970s to control MD, more virulent field strains of MDV have emerged that overcome vaccinal protection, necessitating the development of new and more protective MD vaccines. The ∆Meq virus, a recombinant Md5 strain MDV lacking the viral oncogene Meq, is one candidate MD vaccine with great potential but unfortunately it also causes bursal-thymic atrophy (BTA) in maternal antibody negative chickens, raising concerns that impede commercial use as a vaccine. Previously, we identified a point mutation within UL5 that reduced in vivo replication in attenuated viruses. We proposed that introduction of the UL5 point mutation into the ∆Meq virus would reduce in vivo replication and eliminate BTA yet potentially retain high protective abilities. In birds, the ∆Meq+UL5 recombinant MDV had reduced replication compared to the original ∆Meq virus, while weights of lymphoid organs indicated that ∆Meq+UL5 did not induce BTA, supporting the hypothesis that reduction of in vivo replication would also abolish BTA. Vaccine trials of the ∆Meq+UL5 virus compared to other ∆Meq-based viruses and commercial vaccines show that, while the ∆Meq+UL5 does provide vaccinal protection, this protection was also reduced compared to the original ∆Meq virus. Therefore, it appears that a very delicate balance is required between levels of replication able to induce high vaccinal protection, yet not so high as to induce BTA.

  8. Functional Polymorphisms in PRODH Are Associated with Risk and Protection for Schizophrenia and Fronto-Striatal Structure and Function

    Science.gov (United States)

    Kempf, Lucas; Nicodemus, Kristin K.; Kolachana, Bhaskar; Vakkalanka, Radhakrishna; Verchinski, Beth A.; Egan, Michael F.; Straub, Richard E.; Mattay, Venkata A.; Callicott, Joseph H.; Weinberger, Daniel R.; Meyer-Lindenberg, Andreas

    2008-01-01

    PRODH, encoding proline oxidase (POX), has been associated with schizophrenia through linkage, association, and the 22q11 deletion syndrome (Velo-Cardio-Facial syndrome). Here, we show in a family-based sample that functional polymorphisms in PRODH are associated with schizophrenia, with protective and risk alleles having opposite effects on POX activity. Using a multimodal imaging genetics approach, we demonstrate that haplotypes constructed from these risk and protective functional polymorphisms have dissociable correlations with structure, function, and connectivity of striatum and prefrontal cortex, impacting critical circuitry implicated in the pathophysiology of schizophrenia. Specifically, the schizophrenia risk haplotype was associated with decreased striatal volume and increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity. Our findings suggest a role for functional genetic variation in POX on neostriatal-frontal circuits mediating risk and protection for schizophrenia. PMID:18989458

  9. Association of a new FCN3 haplotype with high ficolin-3 levels in leprosy.

    Science.gov (United States)

    Andrade, Fabiana Antunes; Beltrame, Marcia Holsbach; Bini, Valéria Bumiller; Gonçalves, Letícia Boslooper; Boldt, Angelica Beate Winter; Messias-Reason, Iara Jose de

    2017-02-01

    Leprosy is a chronic inflammatory disease caused by Mycobacterium leprae that mainly affects the skin and peripheral nervous system, leading to a high disability rate and social stigma. Previous studies have shown a contribution of genes encoding products of the lectin pathway of complement in the modulation of the susceptibility to leprosy; however, the ficolin-3/FCN3 gene impact on leprosy is currently unknown. The aim of the present study was to investigate if FCN3 polymorphisms (rs532781899: g.1637delC, rs28362807: g.3524_3532insTATTTGGCC and rs4494157: g.4473C>A) and ficolin-3 serum levels play a role in the susceptibility to leprosy. We genotyped up to 190 leprosy patients (being 114 (60%) lepromatous), and up to 245 controls with sequence-specific PCR. We also measured protein levels using ELISA in 61 leprosy and 73 controls. FCN3 polymorphisms were not associated with disease, but ficolin-3 levels were higher in patients with FCN3 *2B1 (CinsA) haplotype (p = 0.032). Median concentration of ficolin-3 was higher in leprosy per se (26034 ng/mL, p = 0.005) and lepromatous patients (28295 ng/mL, p = 0.016) than controls (18231 ng/mL). In addition, high ficolin-3 levels (>33362 ng/mL) were more common in leprosy per se (34.4%) and in lepromatous patients (35.5%) than controls (19.2%; p = 0.045 and p = 0.047, respectively). Our results lead us to suggest that polymorphisms in the FCN3 gene cooperate to increase ficolin-3 concentration and that it might contribute to leprosy susceptibility by favoring M. leprae infection.

  10. A genomic portrait of haplotype diversity and signatures of selection in indigenous southern African populations.

    Directory of Open Access Journals (Sweden)

    Emile R Chimusa

    2015-03-01

    Full Text Available We report a study of genome-wide, dense SNP (∼ 900K and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region.

  11. Molecular phylogeny and biogeography of Picea (Pinaceae): implications for phylogeographical studies using cytoplasmic haplotypes.

    Science.gov (United States)

    Ran, Jin-Hua; Wei, Xiao-Xin; Wang, Xiao-Quan

    2006-11-01

    The center of diversity is not necessarily the place of origin, as has been established by many plant molecular phylogenies. Picea is a complicated but very important genus in coniferous forests of the Northern Hemisphere, with a high species diversity in Asia. Its phylogeny and biogeography were investigated here using sequence analysis of the paternally inherited chloroplast trnC-trnD and trnT-trnF regions and the maternally inherited mitochondrial nad5 intron 1. We found that the North American P. breweriana and P. sitchensis were basal to the other spruces that were further divided into three clades in the cpDNA phylogeny, and that the New World species harbored four of five mitotypes detected, including two ancestral ones and three endemics. These results, combined with biogeographic analyses using DIVA and MacClade and fossil evidence, suggest that Picea originated in North America, and that its present distribution could stem from two times of dispersal from North America to Asia by the Beringian land bridge, and then from Asia to Europe. Most of the northeastern Asian species and the European P. abies could arise from a recent radiation given the very low interspecific genetic differentiation and pure mitotype of them. Considering that the ancestral mtDNA polymorphism can be preserved in many descendant species, even distantly related ones, we suggest that more species, at least the closely related ones, should be sampled in the phylogeographical study using cytoplasmic haplotypes if possible. In addition, we also discussed the evolution and phylogenetic utility of morphological characters in Picea.

  12. Haplotype Diversity and Reconstruction of Ancestral Haplotype Associated with the c.35delG Mutation in the GJB2 (Cx26) Gene among the Volgo-Ural Populations of Russia.

    Science.gov (United States)

    Dzhemileva, L U; Posukh, O L; Barashkov, N A; Fedorova, S A; Teryutin, F M; Akhmetova, V L; Khidiyatova, I M; Khusainova, R I; Lobov, S L; Khusnutdinova, E K

    2011-07-01

    The mutations in theGJB2(Сх26) gene make the biggest contribution to hereditary hearing loss. The spectrum and prevalence of theGJB2gene mutations are specific to populations of different ethnic origins. For severalGJB2 mutations, their origin from appropriate ancestral founder chromosome was shown, approximate estimations of "age" obtained, and presumable regions of their origin outlined. This work presents the results of the carrier frequencies' analysis of the major (for European countries) mutation c.35delG (GJB2gene) among 2,308 healthy individuals from 18 Eurasian populations of different ethnic origins: Bashkirs, Tatars, Chuvashs, Udmurts, Komi-Permyaks, Mordvins, and Russians (the Volga-Ural region of Russia); Byelorussians, Ukrainians (Eastern Europe); Abkhazians, Avars, Cherkessians, and Ingushes (Caucasus); Kazakhs, Uzbeks, Uighurs (Central Asia); and Yakuts, and Altaians (Siberia). The prevalence of the c.35delG mutation in the studied ethnic groups may act as additional evidence for a prospective role of the founder effect in the origin and distribution of this mutation in various populations worldwide. The haplotype analysis of chromosomes with the c.35delG mutation in patients with nonsyndromic sensorineural hearing loss (N=112) and in population samples (N =358) permitted the reconstruction of an ancestral haplotype with this mutation, established the common origin of the majority of the studied mutant chromosomes, and provided the estimated time of the c.35delG mutation carriers expansion (11,800 years) on the territory of the Volga-Ural region.

  13. Identification of bovine leukocyte antigen class II haplotypes associated with variations in bovine leukemia virus proviral load in Japanese Black cattle.

    Science.gov (United States)

    Miyasaka, T; Takeshima, S-n; Jimba, M; Matsumoto, Y; Kobayashi, N; Matsuhashi, T; Sentsui, H; Aida, Y

    2013-02-01

    Bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukosis, which is the most common neoplastic disease of cattle. Bovine leukocyte antigen (BoLA) is strongly involved in the subclinical progression of BLV infections. Recent studies show that the BoLA-DRB3 gene might play a direct role in controlling the number of BLV-infected peripheral B lymphocytes in vivo in Holstein cattle. However, the specific BoLA class II allele and DRB3-DQA1 haplotypes determining the BLV proviral load in Japanese Black cattle are yet to be identified. In this study, we focused on the association of BLV proviral load and polymorphism of BoLA class II in Japanese Black cattle. We genotyped 186 BLV-infected, clinically normal cattle for BoLA-DRB3 and BoLA-DQA1 using a polymerase chain reaction-sequence-based typing method. BoLA-DRB3*0902 and BoLA-DRB3*1101 were associated with a low proviral load (LPVL), and BoLA-DRB3*1601 was associated with a high proviral load (HPVL). Furthermore, BoLA-DQA1*0204 and BoLA-DQA1*10012 were related to LPVL and HPVL, respectively. Furthermore, we confirmed the correlation between the DRB3-DQA1 haplotype and BLV proviral load. Two haplotypes, namely 0902B or C (DRB3*0902-DQA1*0204) and 1101A (DRB3*1101-DQA1*10011), were associated with a low BLV proviral load, whereas one haplotype 1601B (DRB3*1601-DQA1*10012) was associated with a high BLV proviral load. We conclude that resistance is a dominant trait and susceptibility is a recessive trait. Additionally, resistant alleles were common between Japanese Black and Holstein cattle, and susceptible alleles differed. This is the first report to identify an association between the DRB3-DQA1 haplotype and variations in BLV proviral load.

  14. Multilocus analysis in candidate genes ACE, AGT, and AGTR1 and predisposition to peripheral arterial disease: role of ACE D/-240T haplotype.

    Science.gov (United States)

    Fatini, Cinzia; Sticchi, Elena; Sofi, Francesco; Said, Abdihakim Abdullahi; Pratesi, Giovanni; Pulli, Raffaele; Pratesi, Carlo; Abbate, Rosanna

    2009-12-01

    Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis. Apart from traditional cardiovascular risk factors, several novel biologic mediators and genetic predisposing factors appear relevant in determining the atherogenetic process leading to PAD. Genes encoding for renin angiotensin system (RAS) components have been proposed as candidate in atherosclerosis. This study investigated four polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1), genes of RAS, in both predicting PAD and modulating the severity of the disease. The ACE I/D and -240A>T, AGT M235T, and AGTR1 1166A>C polymorphisms were analyzed in 281 PAD patients and in 485 controls comparable for age and sex. The ACE D and -240T alleles both significantly influenced the predisposition to PAD. The ACE D, but not -240 T, allele remained associated with PAD after Bonferroni correction (P = .004) and adjustment for cardiovascular risk factors (P = .03). The ACE D allele influenced PAD predisposition with a dose-dependent effect (odds ratio for ACE ID vs II genotype, 1.77; P = .006; ACE DD vs II genotype, 2.15; P = .001). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T haplotype significantly and independently influenced the predisposition to PAD (P = .02). In 190 PAD patients with no additional atherosclerotic localizations (isolated PAD), a significant association between ACE D and -240T alleles and PAD was observed. Only the ACE D allele remained associated with isolated PAD after Bonferroni correction (P = .02) and after adjustment for cardiovascular risk factors (P = .02). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T, but not the D/-240A haplotype significantly influenced the predisposition to PAD (P = .0003). No influence of the polymorphisms analyzed on the severity of the disease, according to Rutherford categories, was found. The present study

  15. Inheritance of hetero-diploid pollen S-haplotype in self-compatible tetraploid Chinese cherry (Prunus pseudocerasus Lindl.

    Directory of Open Access Journals (Sweden)

    Chao Gu

    Full Text Available The breakdown of self-incompatibility, which could result from the accumulation of non-functional S-haplotypes or competitive interaction between two different functional S-haplotypes, has been studied extensively at the molecular level in tetraploid Rosaceae species. In this study, two tetraploid Chinese cherry (Prunus pseudocerasus cultivars and one diploid sweet cherry (Prunus avium cultivar were used to investigate the ploidy of pollen grains and inheritance of pollen-S alleles. Genetic analysis of the S-genotypes of two intercross-pollinated progenies showed that the pollen grains derived from Chinese cherry cultivars were hetero-diploid, and that the two S-haplotypes were made up of every combination of two of the four possible S-haplotypes. Moreover, the distributions of single S-haplotypes expressed in self- and intercross-pollinated progenies were in disequilibrium. The number of individuals of the two different S-haplotypes was unequal in two self-pollinated and two intercross-pollinated progenies. Notably, the number of individuals containing two different S-haplotypes (S1- and S5-, S5- and S8-, S1- and S4-haplotype was larger than that of other individuals in the two self-pollinated progenies, indicating that some of these hetero-diploid pollen grains may have the capability to inactivate stylar S-RNase inside the pollen tube and grow better into the ovaries.

  16. Association of A Common Haplotype of Hepatocyte Nuclear Factor 1α With Type 2 Diabetes in Chinese Population

    Institute of Scientific and Technical Information of China (English)

    CONG-RONG WANG; CHENG HU; RONG ZHANG; QI-CHEN FANG; XIAO-JING MA; WEI-PING JIA; KUN-SAN XIANG

    2007-01-01

    Objective To analyze the association of variants of hepatocyte nuclear factor-1α (HNF-1α) gene with type 2 diabetes in Chinese population. Methods In 152 unrelated type 2 diabetes patients and 93 unrelated controls, eleven single nucleotide polymorphisms (SNPs) were identified and genotyped. Statistical analyses were performed to investigate whether these SNPs were associated with diabetes status in our samples. Results In the indivi