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Sample records for 9-bp deletion polymorphism

  1. Origins and dispersal of the mitochondrial DNA region V 9 bp deletion and insertion in Nigeria and the Ivory Coast

    SciTech Connect

    Merriwether, D.A.; Huston, S.L.; Bunker, C.A.

    1994-09-01

    An intergenic region V Mitochondrial DNA (mtDNA) 9 bp deletion located between the genes for tRNA{sup LYS} and cytochrome oxidase II was discovered in a small percentage of Nigerian and Ivory Coast natives. Previously this deletion has been described as Asian-specific and has been reported throughout the New World, Asia, S.E. Asia, and the Pacific Islands at frequencies ranging from 0% to 100%. In the New World and the Pacific Islands, the deletion is almost always accompanied by an Hae III restriction site gain at nt 16517. All 9 occurrences of the deletion observed in Africa (from four different populations) co-occur with the Hae III 16517 site gain, indicating that the African deletion probably shares a common origin with the deletion described as {open_quotes}Asian-specific{close_quotes}. The deletion was found in Benin and Sokoto, Nigeria in 2/54 Edo Bini, 1/2 Edo Ishan, 3/99 Hausa, 0/18 Fulani, and 0/16 other Nigerians. The deletion was also detected in 3/115 Ivory Coast natives from Abidjan. A 9 bp insertion (triplication) was observed in 1/115 Ivory Coast natives. The triplicated individual also possessed the Hae III 16517 site gain. The fragment containing the African deletion was sequenced and found to be identical in sequence to the Asian deletion region. D-loop sequence of nts 15975 to 00048 revealed that 2 of the 3 Ivory Coast deleted individuals and 1 of the 6 Nigerians deleted (Hausa) had a T-C transition at nt position 16189 which is common in New World-deleted individuals. These results raise the possibility that the occurrence of this deletion predates the separation of Asian and African populations from a common ancestral populations, or that the deletion has occurred more than once in human evolution. Either explanation requires that caution be exercised when using the 9 bp deletion as a population marker.

  2. mtDNA control-region sequence variation suggests multiple independent origins of an "Asian-specific" 9-bp deletion in sub-Saharan Africans.

    PubMed Central

    Soodyall, H.; Vigilant, L.; Hill, A. V.; Stoneking, M.; Jenkins, T.

    1996-01-01

    The intergenic COII/tRNA(Lys) 9-bp deletion in human mtDNA, which is found at varying frequencies in Asia, Southeast Asia, Polynesia, and the New World, was also found in 81 of 919 sub-Saharan Africans. Using mtDNA control-region sequence data from a subset of 41 individuals with the deletion, we identified 22 unique mtDNA types associated with the deletion in Africa. A comparison of the unique mtDNA types from sub-Saharan Africans and Asians with the 9-bp deletion revealed that sub-Saharan Africans and Asians have sequence profiles that differ in the locations and frequencies of variant sites. Both phylogenetic and mismatch-distribution analysis suggest that 9-bp deletion arose independently in sub-Saharan Africa and Asia and that the deletion has arisen more than once in Africa. Within Africa, the deletion was not found among Khoisan peoples and was rare to absent in western and southwestern African populations, but it did occur in Pygmy and Negroid populations from central Africa and in Malawi and southern African Bantu-speakers. The distribution of the 9-bp deletion in Africa suggests that the deletion could have arisen in central Africa and was then introduced to southern Africa via the recent "Bantu expansion." PMID:8644719

  3. Molecular instability in the COII-tRNA(Lys) intergenic region of the human mitochondrial genome: multiple origins of the 9-bp deletion and heteroplasmy for expanded repeats.

    PubMed Central

    Thomas, M G; Cook, C E; Miller, K W; Waring, M J; Hagelberg, E

    1998-01-01

    We have identified two individuals from Glasgow in Scotland who have a deletion of one of two copies of the intergenic 9-bp sequence motif CCCCCTCTA, located between the cytochrome oxidase II (COII) and lysine tRNA (tRNA(Lys)) genes of the human mitochondrial genome. Although this polymorphism is common in Africa and Asia, it has not been reported in Northern Europe. Analysis of the mitochondrial DNA control region sequences of these two individuals suggests that they belong to a lineage that originated independently of the previously characterized African and Asian 9-bp deleted lineages. Among the Scottish population we have also identified a maternal lineage of three generations exhibiting heteroplasmy for two, three and four copies of the CCCCCTCTA motif. Polymerase chain reaction amplification across the COII-tRNA(Lys) intergenic region of these individuals gives different ratios of the three product lengths that are dependent on the concentration of the DNA-binding dye crystal violet. To investigate whether changes in repeat number were generated de novo, we constructed clones containing known numbers of the CCCCCTCTA motif. In the presence of high concentrations of crystal violet we obtained two, three and four copies of this motif when the amplification template contained only four copies. Various DNA-binding drugs are known to stabilize bulged structures in DNA and contribute to the process of slipped-strand mispairing during DNA replication. These results suggest that the COII-tRNA(Lys) intergenic region is unstable owing to slipped-strand mispairing. Although sequences containing four copies of the CCCCCTCTA motif are less stable in vitro, we observed an increase in the proportion of mitochondrial genomes with four repeats between-a mother and a daughter in the heteroplasmic lineage. From this we conclude that drift in the germ-line lineage is a main factor in the maintenance or loss of heteroplasmy. PMID:9684291

  4. Polymorphic insertions and deletions in parabasalian enolase genes.

    PubMed

    Keeling, Patrick J

    2004-05-01

    Insertions and deletions in gene sequences have been used as characters to infer phylogenetic relationships and, like any character, the information they contain varies in utility between different levels of evolution. In one case, the absence of two otherwise highly conserved deletions in the enolase genes of parabasalian protists has been interpreted as a primitive characteristic that suggests these were among the first eukaryotes. Here, semi-environmental 3'-RACE was used to sample enolases from parabasalia in the hindgut of the termite Zootermopsis angusticolis to examine the conservation of this character within the parabasalia. Parabasalian homologues were found to be polymorphic for these deletions, and the phylogeny of parabasalian enolases shows that the deletion-possessing genes branch within deletion-lacking genes (i.e., they did not form two clearly distinct groups). Phylogenetic incongruence was detected in the carboxy-terminal third of the sequence (in the region of the deletions), but there is no unambiguous evidence for recombination. The polymorphism of this character discredits these deletions as strong evidence for the early origin of parabasalia, although the complex distribution makes it impossible to state whether parabasalian enolases were ancestrally like those of other eukaryotes. These observations stress the importance of strong corroborating evidence when considering insertion and deletion data, and raises some interesting questions about the apparent variation in degree of conservation of these deletions between different eukaryotic groups.

  5. Ped gene deletion polymorphism frequency in wild mice.

    PubMed

    Newmark, Judith A; Sacher, Frank; Jones, Gwilym S; Warner, Carol M

    2002-07-01

    The Ped gene influences the rate of cleavage of preimplantation embryos and their subsequent survival. Embryos that express the product of the Ped gene, Qa-2 protein, cleave at a faster rate than embryos with an absence of Qa-2 protein. In addition, the Ped gene has pleiotropic effects on reproduction. Thus, there is a reproductive advantage to those mouse strains that are Qa-2 positive. The presence or absence of Qa-2 is reflected at the DNA level by the presence or absence (deletion polymorphism) of the gene(s) encoding Qa-2 protein. Many inbred and wild-derived mouse strains have been characterized as Qa-2 positive or negative, but no previous studies have looked at the distribution of the Ped gene in a population of free-living wild mice. The purpose of this study was to determine the Ped gene deletion polymorphism frequency in a sample of free-living wild mice. Twenty-nine mice were collected and identified as Mus musculus. Genomic DNA extraction was performed on tail tips, and PCR was used to amplify a region from the Ped gene. Known Qa-2 positive and negative mice were used as controls. Results showed that all 29 wild mice were positive for the Ped gene. Since the Ped gene is dominant and provides a reproductive advantage, it is not surprising that all of the wild mice were Qa-2 positive. However, our assay could not distinguish homozygous from heterozygous mice. It is possible that the Qa-2 deletion polymorphism is segregating in the population, and a larger sample size would identify some Qa-2 negative mice. PMID:12115912

  6. [Preplacentation pregnancy loss in cases of angiotensin-converting enzyme insertion/deletion polymorphism].

    PubMed

    Ivanov, P; Konova, E; Komsa-Penkova, R; Kovacheva, K; Nikolov, N; Simeonova, M; Tanchev, St

    2014-01-01

    The balance between coagulation and fibrinolysis processes is critical for establishment and development of early pregnancy. Angiotensin-converting enzyme (ACE) is related with plasminogen activator inhibitor-1 activity which is a key regulator in embryo implantation. Therefor polymorphisms in ACE gene and variation in ACE activity could be associated with an early pregnancy wastage risk. This study investigated carrier status for insertion/deletion (I/D) polymorphism in introne 16 of ACE gene in 71 women with two or more pregnancy loss in preplacentation period (between 10 and 14 weeks of gestation) and 75 women without pregnancy complications. DD genotype for I/D polymorphism was found respectively in 31% and 24% in patients and controls. Heterozygosity of D allele was found correspondingly in 47.9% and 54.7%. The dominant genetic model was used for allele prevalence comparison. D allele in DD genotype was not significantly prevalent in women with early pregnancy wastage compared with the control subjects, OR = 1.42, 95% CI (0.64-3.15). The study found a weak association between I/D polymorphism and preplacentation pregnancy loss. The additive effect over the pregnancy loss risk of I/D polymorphism could be supposed in a presence of other inherited or acquired factors connected with endometrial receptivity and implantation process. PMID:25510065

  7. Angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphism in Mexican populations.

    PubMed

    Vargas-Alarcón, Gilberto; Hernández-Pacheco, Guadalupe; Rodríguez-Pérez, José Manuel; Pérez-Hernández, Nonanzit; Pavón, Zinnia; Fragoso, José Manuel; Juarez-Cedillo, Teresa; Villarreal-Garza, Cynthia; Granados, Julio

    2003-12-01

    The angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphism was determined in 211 Mexican healthy individuals belonging to different Mexican ethnic groups (98 Mestizos, 64 Teenek, and 49 Nahuas). ACE polymorphism differed among Mexicans with a high frequency of the D allele and the D/D genotype in Mexican Mestizos. The D/D genotype was absent in Teenek and present in only one Nahua individual (2.0%). When comparisons were made, we observed that Caucasian, African, and Asian populations presented the highest frequencies of the D allele, whereas Amerindian (Teenek and Pima) and Australian Aboriginals showed the highest frequencies of the I allele. The distribution of I/D genotype was heterogeneous in all populations: Australian Aboriginals presented the lowest frequency (4.9%), whereas Nahuas presented the highest (73.4%). The present study shows the frequencies of a polymorphism not analyzed previously in Mexican populations and establishes that this polymorphism distinguishes the Amerindian populations of other groups. On the other hand, since ACE alleles have been associated with genetic susceptibility to developing cardiovascular diseases and hypertension, knowledge of the distribution of these alleles could help to define the true significance of ACE polymorphism as a genetic susceptibility marker in the Amerindian populations.

  8. Relationship between angiotensin I-converting enzyme insertion/deletion gene polymorphism and retinal vein occlusion

    PubMed Central

    2014-01-01

    To evaluate the association between angiotensin I-converting enzyme insertion/deletion (ACE I/D) gene polymorphism and retinal vein occlusion (RVO). A total of 80 patients with retinal vein occlusion who was admitted to the Eye Department of Kartal Training and Research Hospital between 2008 and 2011, and 80 subjects were enrolled in this retrospective case–control study. Patients who experienced RVO within one week to six months of study enrolment were included, and those with coronary artery diseases, prior myocardial infarction history and coagulation disturbances were excluded from the study. The diagnosis was made by ophthalmoscopic fundus examination and fluorescein angiography. The ACE gene I/D polymorphism was determined by polymerase chain reaction, and the ACE gene was classified into three types: I/I, I/D and D/D. In multivariate logistic regression analysis, ACE D/D genotype (p = 0.035), diabetes-mellitus (p = 0.019) and hypertension (p = 0.001) were found to be independent predictive factors for RVO. The results of the present study reveal that ACE D/D polymorphism is an independent predictive factor for RVO. However, one cannot definitely conclude that ACE gene polymorphism is a risk factor for retinal vein occlusion. PMID:25161389

  9. Hypertension and ace gene insertion/deletion polymorphism in pediatric renal transplant patients.

    PubMed

    Serdaroglu, Erkin; Mir, Sevgi; Berdeli, Afig

    2005-10-01

    The objective of the present study was to define the risk factors for hypertension and to analyze the influence of insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) on hypertension in pediatric renal transplant recipients. Twenty-six pediatric renal transplant recipients with stable renal function and treated with the same immunosuppression protocol were included in the study. Their mean age was 12.5 +/- 3.3 yr and mean time after transplantation was 38.5 +/- 39.8 month. Twenty-four hour ambulatory blood pressure monitoring (ABPM) was performed by SpaceLabs (90207) device. The I/D polymorphism of the ACE was determined by PCR and ACE serum level was analyzed by colorimetric method. Hypertension was present in 15 patients (57.7%) by causal blood pressure measurements and 19 patients (73.1%) by ABPM. Twenty-two patients (84.6%) were found to be non-dipper and eight of them had reverse dipping. Only time after transplantation (38 +/- 31 vs. 79 +/-49 month, p = 0.016) and cyclosporin A trough plasma levels (206 +/-78 vs. 119 +/- 83 ng/mL, p = 0.020) influenced the presence of hypertension by multiple logistic regression analysis. The distribution of genotypes were II = 2 (7.7%), ID = 8 (30.8%), DD = 16 (61.5%). There was no effect of ACE gene I/D polymorphism or serum ACE levels on hypertension prevalence and circadian variability of blood pressures. Hypertension was related to the time after transplantation and cyclosporin A levels. The ACE gene I/D polymorphism and serum ACE levels did not influence the blood pressure values or circadian variability of blood pressure among pediatric renal transplant patients. PMID:16176418

  10. Characterization and polymerase chain reaction (PCR) detection of an Alu deletion polymorphism in total linkage disequilibrium with myotonic dystrophy

    SciTech Connect

    Mahadevan, M.S. ); Foitzik, M.A. ); Surh, L.C.; Korneluk, R.G. Univ. of Ottawa )

    1993-02-01

    The mutation causing myotonic dystrophy has been identified as an unstable trinucleotide CRG repeat located in the 3[prime] untranslated region of a gene putatively encoding a serine-threonine protein kinase. The mutation has been reported to be in total linkage disequilibrium with an insertion/deletion polymorphism located within the kinase gene. To determine the nature of this polymorphism, we have sequenced this genomic fragment and have found that the sequence of this region consists of five consecutive Alu repeats. Further analysis suggests that the smaller of two alleles is actually due to a proposed deletion event that resulted in the loss of an equivalent of three Alu repeats. We have developed a PCR-based assay to detect this polymorphism, the closest, distal marker to the DM mutation. 12 refs., 2 figs.

  11. MULTINDELS-BOV: Zebu traceback method based on DNA insertion-deletion polymorphisms.

    PubMed

    Groenner-Penna, M; Croce, E F D; Pimenta, C G; Bicalho, H M S; Pena, S D J

    2014-01-01

    Brazil is a major producer and exporter of beef, with a herd of approximately 210 million animals. For the meat industry, a reliable animal traceback from its origin to the consumer market is paramount. Of all available identification systems, DNA is the only one that survives the slaughterhouse and reaches the dish of the consumer. DNA polymorphisms are already used for cattle traceback, but primarily for the subspecies Bos taurus taurus. However, in Brazil, another subspecies, B. taurus indicus predominates. We describe here the development of a DNA traceback method designed primarily for B. taurus indicus (Zebu), without leaving B. taurus taurus aside. We used insertion/deletion (indel) polymorphisms, which have the advantage of being simple and easily automatable, since in most cases, the variable loci are biallelic. We studied 94 indels, with a difference of two or more base pairs, in DNA pools of 60 Zebu and 60 taurine animals. A set of 22 indels with heterozygosity greater than 0.3 were selected and used to construct two multiplex PCRs. On the basis of the allelic frequency of these indels, the probability of random match was calculated to be 1.12 x 10(-8) for B. taurus indicus and 1.60 x 10(-6) for B. taurus taurus. Moreover, we estimated that an analysis would cost less than US$15.00 per animal. Thus, this system (MULTINDELS-BOV) is perfectly suited for building large genetic databases and offering viable prospects of a national system for cattle traceback DNA in Brazil. PMID:25501139

  12. Screening the dystrophin gene suggests a high rate of polymorphism in general but no exonic deletions in schizophrenics

    SciTech Connect

    Lindor, N.M.; Sobell, J.L.; Thibodeau, S.N.

    1994-03-15

    The dystrophin gene, located at chromosome Xp21, was evaluated as a candidate gene in chronic schizophrenia in response to the report of a large family in which schizophrenia cosegregated with Becker muscular dystrophy. Genomic DNA from 94 men with chronic schizophrenia was evaluated by Southern blot analysis using cDNA probes that span exons 1-59. No exonic deletions were identified. An unexpectedly high rate of polymorphism was calculated in this study and two novel polymorphisms were found, demonstrating the usefulness of the candidate gene approach even when results of the original study are negative. 41 refs., 1 fig., 4 tabs.

  13. Detection of insertion/deletion polymorphisms from challenged samples using the Investigator DIPplex® kit.

    PubMed

    Klein, Rebecca; Neumann, Cedric; Roy, Reena

    2015-05-01

    This research focuses on detection of bi-allelic insertion/deletion polymorphisms (InDels) from challenged samples using the Investigator DIPplex® Kit from Qiagen. The study included analyzing body fluids from humans, as well as pristine and degraded samples. For the purpose of assessing species specificity, samples from various animals were included. At first, an analytical threshold (AT) for the detection of alleles was established based on an assessment of the noise in the system. Then, InDel profiles were obtained from samples exposed to detrimental environmental conditions, washed bloodstains, lipsticks, ChapStick®, ancient Croatian bone samples, and every day products such as toothbrushes and dental floss. Concordant profiles were obtained from different body fluids of the same donor. InDel profiles were also generated successfully when body fluids were deposited on substrates and directly amplified without pre-treatment with buffer or washing reagents. InDels can provide additional information when only partial STR profiles are generated from challenged samples.

  14. The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia.

    PubMed

    Ko, Tun Kiat; Chin, Hui San; Chuah, Charles T H; Huang, John W J; Ng, King-Pan; Khaw, Seong Lin; Huang, David C S; Ong, S Tiong

    2016-01-19

    Both germline polymorphisms and tumor-specific genetic alterations can determine the response of a cancer to a given therapy. We previously reported a germline deletion polymorphism in the BIM gene that was sufficient to mediate intrinsic resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), as well as other cancers [1]. The deletion polymorphism favored the generation of BIM splice forms lacking the pro-apoptotic BH3 domain, conferring a relative resistance to the TKI imatinib (IM). However, CML patients with the BIM deletion polymorphism developed both partial and complete IM resistance. To understand the mechanisms underlying the latter, we grew CML cells either with or without the BIM deletion polymorphism in increasing IM concentrations. Under these conditions, the BIM deletion polymorphism enhanced the emergence of populations with complete IM resistance, mimicking the situation in patients. Importantly, the combined use of TKIs with the BH3 mimetic ABT-737 overcame the BCR-ABL1-dependent and -independent resistance mechanisms found in these cells. Our results illustrate the interplay between germline and acquired genetic factors in confering TKI resistance, and suggest a therapeutic strategy for patients with complete TKI resistance associated with the BIM deletion polymorphism.

  15. The 29.5 kb APOBEC3B Deletion Polymorphism Is Not Associated with Clinical Outcome of Breast Cancer.

    PubMed

    Liu, Jingjing; Sieuwerts, Anieta M; Look, Maxime P; van der Vlugt-Daane, Michelle; Meijer-van Gelder, Marion E; Foekens, John A; Hollestelle, Antoinette; Martens, John W M

    2016-01-01

    Increased APOBEC3B mRNA levels are associated with a hypermutator phenotype and poor prognosis in ER-positive breast cancer patients. In addition, a 29.5 kb deletion polymorphism of APOBEC3B, resulting in an APOBEC3A-B hybrid transcript, has been associated with an increased breast cancer risk and the hypermutator phenotype. Here we evaluated whether the APOBEC3B deletion polymorphism also associates with clinical outcome of breast cancer. Copy number analysis was performed by quantitative PCR (qPCR) in primary tumors of 1,756 Dutch breast cancer patients. The APOBEC3B deletion was found in 187 patients of whom 16 carried a two-copy deletion and 171 carried a one-copy deletion. The prognostic value of the APOBEC3B deletion for the natural course of the disease was evaluated among 1,076 lymph-node negative (LNN) patients who did not receive adjuvant systemic treatment. No association was found between APOBEC3B copy number values and the length of metastasis-free survival (MFS; hazard ratio (HR) = 1.00, 95% confidence interval (CI) = 0.90-1.11, P = 0.96). Subgroup analysis by ER status also did not reveal an association between APOBEC3B copy number values and the length of MFS. The predictive value of the APOBEC3B deletion was assessed among 329 ER-positive breast cancer patients who received tamoxifen as the first-line therapy for recurrent disease and 226 breast cancer patients who received first-line chemotherapy for recurrent disease. No association between APOBEC3B copy number values and the overall response rate (ORR) to either tamoxifen (odds ratio (OR) = 0.88, 95% CI = 0.69-1.13, P = 0.31) or chemotherapy (OR = 0.97, 95% CI = 0.71-1.33, P = 0.87) was found. Thus, in contrast to APOBEC3B mRNA levels, the APOBEC3B deletion polymorphism has neither a prognostic nor a predictive value for breast cancer patients. Although a correlation exists between APOBEC3B copy number and mRNA expression, it is relatively weak. This suggests that other mechanisms exist that may

  16. The 29.5 kb APOBEC3B Deletion Polymorphism Is Not Associated with Clinical Outcome of Breast Cancer

    PubMed Central

    Look, Maxime P.; van der Vlugt-Daane, Michelle; Meijer-van Gelder, Marion E.; Foekens, John A.; Martens, John W. M.

    2016-01-01

    Increased APOBEC3B mRNA levels are associated with a hypermutator phenotype and poor prognosis in ER-positive breast cancer patients. In addition, a 29.5 kb deletion polymorphism of APOBEC3B, resulting in an APOBEC3A-B hybrid transcript, has been associated with an increased breast cancer risk and the hypermutator phenotype. Here we evaluated whether the APOBEC3B deletion polymorphism also associates with clinical outcome of breast cancer. Copy number analysis was performed by quantitative PCR (qPCR) in primary tumors of 1,756 Dutch breast cancer patients. The APOBEC3B deletion was found in 187 patients of whom 16 carried a two-copy deletion and 171 carried a one-copy deletion. The prognostic value of the APOBEC3B deletion for the natural course of the disease was evaluated among 1,076 lymph-node negative (LNN) patients who did not receive adjuvant systemic treatment. No association was found between APOBEC3B copy number values and the length of metastasis-free survival (MFS; hazard ratio (HR) = 1.00, 95% confidence interval (CI) = 0.90–1.11, P = 0.96). Subgroup analysis by ER status also did not reveal an association between APOBEC3B copy number values and the length of MFS. The predictive value of the APOBEC3B deletion was assessed among 329 ER-positive breast cancer patients who received tamoxifen as the first-line therapy for recurrent disease and 226 breast cancer patients who received first-line chemotherapy for recurrent disease. No association between APOBEC3B copy number values and the overall response rate (ORR) to either tamoxifen (odds ratio (OR) = 0.88, 95% CI = 0.69–1.13, P = 0.31) or chemotherapy (OR = 0.97, 95% CI = 0.71–1.33, P = 0.87) was found. Thus, in contrast to APOBEC3B mRNA levels, the APOBEC3B deletion polymorphism has neither a prognostic nor a predictive value for breast cancer patients. Although a correlation exists between APOBEC3B copy number and mRNA expression, it is relatively weak. This suggests that other mechanisms exist

  17. Insertion/Deletion Polymorphisms in the ΔNp63 Promoter Are a Risk Factor for Bladder Exstrophy Epispadias Complex

    PubMed Central

    Wilkins, Simon; Zhang, Ke Wei; Mahfuz, Istiak; Quantin, Renaud; D'Cruz, Nancy; Hutson, John; Ee, Michael; Bagli, Darius; Aitken, Karen; Fong, Fion Nga-Yin; Ng, Patrick Kwok-Shing; Tsui, Stephen Kwok-Wing; Fung, Wendy Yin-Wan; Banu, Tahmina; Thakre, Atul; Johar, Kaid; Jaureguizar, Enrique; Li, Long; Cheng, Wei

    2012-01-01

    Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian development. It plays a role in bladder development. We have previously shown that p63−/− mouse embryos developed a bladder exstrophy phenotype identical to human BEEC. We hypothesised that TP63 is involved in human BEEC pathogenesis. RNA was extracted from BEEC foreskin specimens and, as in mice, ΔNp63 was the predominant p63 isoform. ΔNp63 expression in the foreskin and bladder epithelium of BEEC patients was reduced. DNA was sequenced from 163 BEEC patients and 285 ethnicity-matched controls. No exon mutations were detected. Sequencing of the ΔNp63 promoter showed 7 single nucleotide polymorphisms and 4 insertion/deletion (indel) polymorphisms. Indel polymorphisms were associated with an increased risk of BEEC. Significantly the sites of indel polymorphisms differed between Caucasian and non-Caucasian populations. A 12-base-pair deletion was associated with an increased risk with only Caucasian patients (p = 0.0052 Odds Ratio (OR) = 18.33), whereas a 4-base-pair insertion was only associated with non-Caucasian patients (p = 0.0259 OR = 4.583). We found a consistent and statistically significant reduction in transcriptional efficiencies of the promoter sequences containing indel polymorphisms in luciferase assays. These findings suggest that indel polymorphisms of the ΔNp63 promoter lead to a reduction in p63 expression, which could lead to BEEC. PMID:23284286

  18. Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex.

    PubMed

    Wilkins, Simon; Zhang, Ke Wei; Mahfuz, Istiak; Quantin, Renaud; D'Cruz, Nancy; Hutson, John; Ee, Michael; Bagli, Darius; Aitken, Karen; Fong, Fion Nga-Yin; Ng, Patrick Kwok-Shing; Tsui, Stephen Kwok-Wing; Fung, Wendy Yin-Wan; Banu, Tahmina; Thakre, Atul; Johar, Kaid; Jaureguizar, Enrique; Li, Long; Cheng, Wei

    2012-01-01

    Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian development. It plays a role in bladder development. We have previously shown that p63(-/-) mouse embryos developed a bladder exstrophy phenotype identical to human BEEC. We hypothesised that TP63 is involved in human BEEC pathogenesis. RNA was extracted from BEEC foreskin specimens and, as in mice, ΔNp63 was the predominant p63 isoform. ΔNp63 expression in the foreskin and bladder epithelium of BEEC patients was reduced. DNA was sequenced from 163 BEEC patients and 285 ethnicity-matched controls. No exon mutations were detected. Sequencing of the ΔNp63 promoter showed 7 single nucleotide polymorphisms and 4 insertion/deletion (indel) polymorphisms. Indel polymorphisms were associated with an increased risk of BEEC. Significantly the sites of indel polymorphisms differed between Caucasian and non-Caucasian populations. A 12-base-pair deletion was associated with an increased risk with only Caucasian patients (p = 0.0052 Odds Ratio (OR) = 18.33), whereas a 4-base-pair insertion was only associated with non-Caucasian patients (p = 0.0259 OR = 4.583). We found a consistent and statistically significant reduction in transcriptional efficiencies of the promoter sequences containing indel polymorphisms in luciferase assays. These findings suggest that indel polymorphisms of the ΔNp63 promoter lead to a reduction in p63 expression, which could lead to BEEC.

  19. Identification of tissue contamination by polymorphic deletion probe fluorescence in situ hybridization.

    PubMed

    Chiang, Sarah; Yip, Stephen; Betensky, Rebecca A; Batten, Julie M; Misdraji, Joseph; John Iafrate, A

    2012-10-01

    Potential sources of error in surgical pathology include specimen misidentification, unidentified tissue, and tissue contamination of paraffin blocks and slides. Current molecular approaches to characterize unidentified or misidentified tissue include fluorescence in situ hybridization identification of sex chromosomes (XY FISH) and microsatellite analysis. Polymorphic deletion probe (PDP) FISH, a novel FISH assay based on copy number variants, can distinguish between cells and tissues from 2 individuals in situ, independent of gender. Using a panel of 3 PDPs, we compared the genotypes of potential tissue contaminants (n=19) and unidentified tissues (n=6) with patient tissues to determine the utility of PDP FISH in resolving specimen identity. XY FISH was added to increase the informative potential of the assay, and microsatellite analysis was used as a gold standard to confirm PDP FISH results. PDP FISH distinguished between putative contaminants and patient tissues in 13 of 14 cases and indicated a high likelihood of 2 tissues originating from the same source in 11 of 11 cases. The assay has a sensitivity and specificity of 86% [6/7, exact 95% confidence interval (CI): 42%, 97%] and 100% (9/9, exact 1-sided 97.5% CI: 68%, 100%), respectively, and a positive predictive value and negative predictive value of 100% (6/6, exact 1-sided 97.5% CI: 54%, 100%) and 90% (9/10, exact 95% CI: 55%, 98%), respectively. PDP FISH is an accurate and practical molecular assay for the genetic characterization of potential tissue contaminants and unidentified tissues, especially in the setting of small sample size, and permits concomitant assessment of morphology.

  20. Association of an HLA-G 14-bp Insertion/Deletion polymorphism with high HBV replication in chronic hepatitis.

    PubMed

    Laaribi, A B; Zidi, I; Hannachi, N; Ben Yahia, H; Chaouch, H; Bortolotti, D; Zidi, N; Letaief, A; Yacoub, S; Boudabous, A; Rizzo, R; Boukadida, J

    2015-10-01

    Identification of an HLA-G 14-bp Insertion/Deletion (Ins/Del) polymorphism at the 3' untranslated region of HLA-G revealed its importance in HLA-G mRNA stability and HLA-G protein level variation. We evaluated the association between the HLA-G 14-bp Ins/Del polymorphism in patients with chronic Hepatitis B virus (HBV) infection in a case-control study. Genomic DNA was extracted from 263 patients with chronic HBV hepatitis and 246 control subjects and was examined for the HLA-G 14-bp Ins/Del polymorphism by PCR. The polymorphic variants were genotyped in chronic HBV seropositive cases stratified according to HBV DNA levels, fibrosis stages and in a control population. There was no statistical significant association between the 14-bp Ins/Del polymorphism and increased susceptibility to HBV infection neither for alleles (P = 0.09) nor for genotypes (P = 0.18). The stratification of HBV patients based on HBV DNA levels revealed an association between the 14-bp Ins/Del polymorphism and an enhanced HBV activity with high HBV DNA levels. In particular, the Ins allele was significantly associated with high HBV DNA levels (P = 0.0024, OR = 1.71, 95% CI 1.2-2.4). The genotype Ins/Ins was associated with a 2.5-fold (95% CI, 1.29-4.88) increased risk of susceptibility to high HBV replication compared with the Del/Del and Ins/Del genotypes. This susceptibility is linked to the presence of two Ins alleles. No association was observed between the 14-bp Ins/Del polymorphism and fibrosis stage of HBV infection. We observed an association between the 14-bp Ins/Del polymorphism and high HBV replication characterized by high HBV DNA levels in chronic HBV patients. These results suggest a potential prognostic value for disease outcome evaluation.

  1. Association of an HLA-G 14-bp Insertion/Deletion polymorphism with high HBV replication in chronic hepatitis.

    PubMed

    Laaribi, A B; Zidi, I; Hannachi, N; Ben Yahia, H; Chaouch, H; Bortolotti, D; Zidi, N; Letaief, A; Yacoub, S; Boudabous, A; Rizzo, R; Boukadida, J

    2015-10-01

    Identification of an HLA-G 14-bp Insertion/Deletion (Ins/Del) polymorphism at the 3' untranslated region of HLA-G revealed its importance in HLA-G mRNA stability and HLA-G protein level variation. We evaluated the association between the HLA-G 14-bp Ins/Del polymorphism in patients with chronic Hepatitis B virus (HBV) infection in a case-control study. Genomic DNA was extracted from 263 patients with chronic HBV hepatitis and 246 control subjects and was examined for the HLA-G 14-bp Ins/Del polymorphism by PCR. The polymorphic variants were genotyped in chronic HBV seropositive cases stratified according to HBV DNA levels, fibrosis stages and in a control population. There was no statistical significant association between the 14-bp Ins/Del polymorphism and increased susceptibility to HBV infection neither for alleles (P = 0.09) nor for genotypes (P = 0.18). The stratification of HBV patients based on HBV DNA levels revealed an association between the 14-bp Ins/Del polymorphism and an enhanced HBV activity with high HBV DNA levels. In particular, the Ins allele was significantly associated with high HBV DNA levels (P = 0.0024, OR = 1.71, 95% CI 1.2-2.4). The genotype Ins/Ins was associated with a 2.5-fold (95% CI, 1.29-4.88) increased risk of susceptibility to high HBV replication compared with the Del/Del and Ins/Del genotypes. This susceptibility is linked to the presence of two Ins alleles. No association was observed between the 14-bp Ins/Del polymorphism and fibrosis stage of HBV infection. We observed an association between the 14-bp Ins/Del polymorphism and high HBV replication characterized by high HBV DNA levels in chronic HBV patients. These results suggest a potential prognostic value for disease outcome evaluation. PMID:25619305

  2. Single nucleotide polymorphism discovery in TBX1 in individuals with and without 22q11.2 deletion syndrome

    PubMed Central

    Heike, Carrie L.; Starr, Jacqueline R.; Rieder, Mark J.; Cunningham, Michael L.; Edwards, Karen L.; Stanaway, Ian; Crawford, Dana C.

    2015-01-01

    BACKGROUND Children with 22q11.2 deletion syndrome (22q11.2DS) have a wide range of clinical features. TBX1 has been proposed as a candidate gene for some of the features in this condition. Polymorphisms in the non-deleted TBX1, which may affect the function of the sole TBX1 gene in individuals with the 22q11.2DS, may be a key to understanding the phenotypic variability among individuals with a shared deletion. Comprehensive single nucleotide polymorphism (SNP) discovery by resequencing candidate genes can identify genetic variants that influence a given phenotype. The purpose of this study was to further characterize the sequence variability in TBX1 by identifying all common SNPs in this gene. METHODS We resequenced TBX1 in 29 children with a documented 22q11.2 deletion and 95 non-deleted, healthy individuals. We estimated allele frequencies, performed tagSNP selection, and inferred haplotypes. We also compared SNP frequencies between 22q11.2DS and control samples. RESULTS We identified 355 biallelic markers among the 190 chromosomes resequenced in the control panel. The vast majority of the markers identified were SNPs (n=331), and the remainder indels (n=24). We did not identify SNPs or indels in the cis- regulatory element (FOX–binding site) upstream of TBX1. In children with 22q11.2DS we detected 187 biallelic markers, six of which were indels. Four of the seven coding SNPs identified in the controls were identified in children with 22q11.2DS. CONCLUSIONS This comprehensive SNP discovery data can be used to select SNPs to genotype for future association studies assessing the role of TBX1 and phenotypic variability in individuals with 22q11.2DS. PMID:19645056

  3. Angiotensin-converting enzyme insertion/deletion polymorphism and gastric cancer: a systematic review and meta-analysis

    PubMed Central

    Gan, Lu; Liu, Xinyang; Wu, Zhenhua; Huang, Mingzu; Zhang, Xiaowei; Guo, Weijian

    2015-01-01

    Previous case-control studies on the association of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with gastric cancer were controversial. A meta-analysis was conducted to further evaluate the association between polymorphism in the ACE gene I/D and gastric cancer. We searched MEDLINE (PubMed), EMBASE, Web of Science, and CBM without language restrictions to Nov 20, 2014. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Eight studies involving 1480 gastric cancer cases and 3773 cancer-free controls were included. Overall, no significant association between ACE I/D polymorphism and gastric cancer risk was observed (OR = 1.15; 95% CI 0.90-1.46, P = 0.26). The subgroup analysis on the basis of H. Pylori status showed the decreased gastric cancer risk in H. Pylori negative subgroup (OR = 0.40; 95% CI: 0.27-0.59; P < 0.00001) rather than in H. Pylori positive subgroup (OR = 1.82, 95% CI: 0.87-3.82, P = 0.11). Subgroup analysis was performed according to ethnicity (Caucasian and Asian). The results showed no genetic effects between ACE I/D polymorphism and gastric cancer risk. This meta-analysis suggested that the ACE gene I/D polymorphism was associated gastric cancer risk in H. Pylori negative subjects. PMID:26131166

  4. An angiotensin I-converting enzyme insertion/deletion polymorphism is associated with Pakistani asthmatic cases and controls.

    PubMed

    Saba, Nusrat; Yusuf, Osman; Rehman, Sadia; Munir, Saeeda; Ahmad, Sheeraz; Mansoor, Atika; Raja, Ghazala K

    2016-09-01

    Asthma is a chronic disease due to inflammation of the airways of lungs that is clinically characterized by variable symptoms including wheezing, coughing and shortness of breath. Angiotensin I-converting enzyme (ACE) plays a major role in fibrous tissue formation and is highly expressed in lungs. The main aim of this research work was to study the role of ACE insertion/deletion (I/D) polymorphism, rs4646994, in asthma in Pakistani patients. A total of 854 subjects, including 333 asthma patients and 521 ethnically matched controls, were studied. The ACE (I/D) polymorphism was genotyped using polymerase chain reaction (PCR). Chi-square, Fisher's exact and Hardy-Weinberg equilibrium tests were used to compare groups. Homozygous insertion genotype II (p less than 0.0001, OR=3.38) and insertion allele (I) was significantly more frequent in Pakistani asthmatics than in healthy controls (p=0.0007, OR=1.40). The ID genotype (p less than 0.0001, OR=0.43) and the deletion allele (D) were associated with protection of disease in Pakistani patients (p=0.0007, OR=0.71). These data suggest the involvement of ACE I/D polymorphism in asthma risk in the Pakistani population. This marker may be an important indication in the molecular mechanism of asthma and can become a useful tool in risk assessment and help in designing strategy to combat disease.

  5. An angiotensin I-converting enzyme insertion/deletion polymorphism is associated with Pakistani asthmatic cases and controls.

    PubMed

    Saba, Nusrat; Yusuf, Osman; Rehman, Sadia; Munir, Saeeda; Ahmad, Sheeraz; Mansoor, Atika; Raja, Ghazala K

    2016-09-01

    Asthma is a chronic disease due to inflammation of the airways of lungs that is clinically characterized by variable symptoms including wheezing, coughing and shortness of breath. Angiotensin I-converting enzyme (ACE) plays a major role in fibrous tissue formation and is highly expressed in lungs. The main aim of this research work was to study the role of ACE insertion/deletion (I/D) polymorphism, rs4646994, in asthma in Pakistani patients. A total of 854 subjects, including 333 asthma patients and 521 ethnically matched controls, were studied. The ACE (I/D) polymorphism was genotyped using polymerase chain reaction (PCR). Chi-square, Fisher's exact and Hardy-Weinberg equilibrium tests were used to compare groups. Homozygous insertion genotype II (p less than 0.0001, OR=3.38) and insertion allele (I) was significantly more frequent in Pakistani asthmatics than in healthy controls (p=0.0007, OR=1.40). The ID genotype (p less than 0.0001, OR=0.43) and the deletion allele (D) were associated with protection of disease in Pakistani patients (p=0.0007, OR=0.71). These data suggest the involvement of ACE I/D polymorphism in asthma risk in the Pakistani population. This marker may be an important indication in the molecular mechanism of asthma and can become a useful tool in risk assessment and help in designing strategy to combat disease. PMID:27581935

  6. Association between a functional insertion/deletion polymorphism in IL1A gene and risk of papillary thyroid carcinoma.

    PubMed

    Gao, Linbo; Zhu, Xinxin; Li, Zhihui; Li, Lijuan; Wang, Tao; Hu, Huaizhong; Guo, Wanli; Chen, Peng; Zhu, Jingqiang; Zhang, Lin

    2014-04-01

    The aim of this study was to evaluate whether an insertion/deletion polymorphism (rs3783553) locating in the miR-122 target gene IL1A 3' untranslated region was related to the risk of papillary thyroid carcinoma (PTC). Genomic DNA was extracted from peripheral venous blood of 273 patients with PTC and 509 controls. The IL1A rs3783553 polymorphism was genotyped by using a polymerase chain reaction assay. No significant difference of the distribution of the IL1A rs3783553 polymorphism was observed between PTC patients and controls. However, patients carrying the IL1A rs3783553 ins/ins genotype and ins allele had significantly decreased risks for developing T3 and T4 when compared with patients carrying the IL1A rs3783553 del/del genotype and del allele (ins/ins vs. del/del: OR = 0.22, 95% confidence interval (CI), 0.09-0.54; ins vs. del: OR = 0.58, 95% CI, 0.41-0.83, respectively). These results suggest that the rs3783553 polymorphism may be used as a genetic marker to predict the size/extension of PTC. PMID:24453029

  7. Possible association between DBH 19 bp insertion/deletion polymorphism and clinical symptoms in schizophrenia with tardive dyskinesia.

    PubMed

    Hui, Li; Han, Mei; Huang, Xu Feng; Ye, Min Jie; Zheng, Ke; He, Jin Cai; Lv, Meng Han; Zhang, Bao Hua; Soares, Jair C; Zhang, Xiang Yang

    2015-06-01

    Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Previous studies have found dysfunction in plasma dopamine beta-hydoxylase (DBH) in schizophrenia with TD. Moreover, DBH, whose activity and levels are strongly controlled by the DBH gene, is a key enzyme in the conversion of dopamine (DA) to norepinephrine (NE) associated with excited behavior. This study examined whether the DBH5'-insertion/deletion (Ins/Del) polymorphism was associated with excited behavior in schizophrenia with TD. The presence of the DBH5'-Ins/Del polymorphism was determined in 741 schizophrenia with TD (n = 345) and without TD (n = 396). The Abnormal Involuntary Movement Scale and Positive and Negative Syndrome Scale were used to assess the severity of TD and psychopathology of schizophrenia. There was no significant difference in the allelic and genotypic frequencies of the DBH5'-Ins/Del polymorphism between schizophrenia with and without TD (both p > 0.05). However, the excited symptoms score was significantly different to the DBH5'-Ins/Del genotypic groups in schizophrenia with TD (p < 0.05) but not in the two groups of non-TD and total patients (both p > 0.05). The excited symptoms score was higher in TD patients with the Del/Del genotype than those with Ins alleles (p = 0.015). Our findings suggest that the DBH5'-Ins/Del polymorphism may not contribute directly to the development of TD in schizophrenia, but it may be involved in the excited behavior of TD patients. PMID:25336319

  8. Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Small Vessel Cerebral Stroke in Indian Population

    PubMed Central

    Prabhakar, Puttachandra; De, Tanima; Nagaraja, Dindagur

    2014-01-01

    Background. Hypertension is an established risk factor for small-vessel cerebral stroke and the renin-angiotensin system plays an important role in the maintenance of blood pressure. We aimed at evaluating the contribution of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism to the risk of small-vessel stroke in south Indian population. Materials and Methods. We investigated 128 patients diagnosed with small-vessel stroke and 236 age, and gender-matched healthy controls. ACE I/D polymorphism was detected by polymerase chain reaction. Results. Hypertension was significantly more prevalent in the patient group and was associated with 6-fold increase in risk for stroke. ACE genotypes were in Hardy-Weinberg equilibrium in both patients and controls. Prevalence of DD, ID, and II genotypes in cases (34.4%, 43.7%, and 28%) did not differ significantly from controls (31.8%, 43.2%, and 25%). The polymorphism was not associated with small-vessel stroke (OR: 1.34; 95% CI: 0.52–1.55). However, diastolic blood pressure was associated with the ACE I/D genotypes in the patients. (DD; 90.2 ± 14.2> ID; 86.2 ± 11.9> II; 82.3 ± 7.8 mm Hg,  P = 0.047). Conclusion. Our study showed that hypertension, but not ACE I/D polymorphism, increased the risk of small-vessel stroke. PMID:24523965

  9. Absence of association between two insertion/deletion coding genetic polymorphisms of TIM-1 gene and asthma in Chinese Han population.

    PubMed

    Li, J S; Liu, Q J; Wang, P; Li, H C; Wei, C H; Guo, C H; Gong, Y Q

    2006-12-01

    TIM-1, a member of T-cell immunoglobulin domain and mucin domain (TIM) gene family, was implicated as an asthma susceptibility gene in previous studies. TIM-1 was expressed on CD4(+) T cells after activation and its expression was sustained preferentially in T-helper type 2 (T(H)2) but not in T(H)1 cells, therefore TIM-1 became a good candidate gene for atopic diseases. Recent studies indicated that two insertion/deletion (ins/del) coding genetic polymorphisms in exon 4 of TIM-1 were associated with asthma susceptibility in some but not in all populations. In order to investigate the relationship between TIM-1 genetic polymorphisms and asthma in Chinese Han population, we performed a case-control study for two insertion/deletion polymorphisms in TIM-1 exon 4 (5383_5397ins/del and 5509_5511delCAA) and a single nucleotide polymorphism (SNP) in intron 8 (IVS 8+9 G/A) between a healthy control group of 309 people and an asthma patient group of 352 people recruited from Chinese Han population. The polymorphisms were genotyped and the allele and genotype frequencies were analysed, but none of the three polymorphisms showed association with asthma susceptibility in single-locus association analyses. Linkage disequilibrium (LD) analyses demonstrated that the two insertion/deletion polymorphisms were in strong LD but the haplotypes constructed from these two polymorphisms showed no significant association with asthma. In conclusion, our findings suggest that 5383_5397ins/del, 5509_5511delCAA and SNP IVS 8+9 G/A polymorphisms are not associated with asthma susceptibility in Chinese Han population.

  10. Population genetic analysis of insertion-deletion polymorphisms in a Brazilian population using the Investigator DIPplex kit.

    PubMed

    Ferreira Palha, Teresinha de Jesus Brabo; Ribeiro Rodrigues, Elzemar Martins; Cavalcante, Giovanna Chaves; Marrero, Andrea; de Souza, Ilíada Rainha; Seki Uehara, Clineu Julien; Silveira da Motta, Carlos Henrique Ares; Koshikene, Daniela; da Silva, Dayse Aparecida; de Carvalho, Elizeu Fagundes; Chemale, Gustavo; Freitas, Jorge M; Alexandre, Lídia; Paranaiba, Renato T F; Soler, Mirella Perruccio; Santos, Sidney

    2015-11-01

    The aim of this study was to estimate the diversity of 30 insertion/deletion (INDEL) markers (Investigator(®) DIPplex kit) in a sample of 519 individuals from six Brazilian states and to evaluate their applicability in forensic genetics. All INDEL markers were found to be highly polymorphic in the Brazilian population and were in Hardy-Weinberg equilibrium. To determine their forensic suitability in the Brazilian population, the markers were evaluated for discrimination power, match probability and exclusion power. The combined discrimination power (CDP), combined match power (CMP) and combined power of exclusion (CPE) were higher than 0.999999, 3.4 × 10(-13) and 0.9973, respectively. Further comparison of 29 worldwide populations revealed significant genetic differences between continental populations and a closer relationship between the Brazilian and European populations. PMID:26036184

  11. Population genetic analysis of insertion-deletion polymorphisms in a Brazilian population using the Investigator DIPplex kit.

    PubMed

    Ferreira Palha, Teresinha de Jesus Brabo; Ribeiro Rodrigues, Elzemar Martins; Cavalcante, Giovanna Chaves; Marrero, Andrea; de Souza, Ilíada Rainha; Seki Uehara, Clineu Julien; Silveira da Motta, Carlos Henrique Ares; Koshikene, Daniela; da Silva, Dayse Aparecida; de Carvalho, Elizeu Fagundes; Chemale, Gustavo; Freitas, Jorge M; Alexandre, Lídia; Paranaiba, Renato T F; Soler, Mirella Perruccio; Santos, Sidney

    2015-11-01

    The aim of this study was to estimate the diversity of 30 insertion/deletion (INDEL) markers (Investigator(®) DIPplex kit) in a sample of 519 individuals from six Brazilian states and to evaluate their applicability in forensic genetics. All INDEL markers were found to be highly polymorphic in the Brazilian population and were in Hardy-Weinberg equilibrium. To determine their forensic suitability in the Brazilian population, the markers were evaluated for discrimination power, match probability and exclusion power. The combined discrimination power (CDP), combined match power (CMP) and combined power of exclusion (CPE) were higher than 0.999999, 3.4 × 10(-13) and 0.9973, respectively. Further comparison of 29 worldwide populations revealed significant genetic differences between continental populations and a closer relationship between the Brazilian and European populations.

  12. Automated Genotyping of Biobank Samples by Multiplex Amplification of Insertion/Deletion Polymorphisms

    PubMed Central

    Mathot, Lucy; Falk-Sörqvist, Elin; Moens, Lotte; Allen, Marie; Sjöblom, Tobias; Nilsson, Mats

    2012-01-01

    The genomic revolution in oncology will entail mutational analyses of vast numbers of patient-matched tumor and normal tissue samples. This has meant an increased risk of patient sample mix up due to manual handling. Therefore, scalable genotyping and sample identification procedures are essential to pathology biobanks. We have developed an efficient alternative to traditional genotyping methods suited for automated analysis. By targeting 53 prevalent deletions and insertions found in human populations with fluorescent multiplex ligation dependent genome amplification, followed by separation in a capillary sequencer, a peak spectrum is obtained that can be automatically analyzed. 24 tumor-normal patient samples were successfully matched using this method. The potential use of the developed assay for forensic applications is discussed. PMID:23300761

  13. Voltage-programming-based capillary gel electrophoresis for the fast detection of angiotensin-converting enzyme insertion/deletion polymorphism with high sensitivity.

    PubMed

    Woo, Nain; Kim, Su-Kang; Kang, Seong Ho

    2016-08-01

    A voltage-programming-based capillary gel electrophoresis method with a laser-induced fluorescence detector was developed for the fast and highly sensitive detection of DNA molecules related to angiotensin-converting enzyme insertion/deletion polymorphism, which has been reported to influence predisposition to various diseases such as cardiovascular disease, high blood pressure, myocardial infarction, and Alzheimer's disease. Various voltage programs were investigated for fast detection of specific DNA molecules of angiotensin-converting enzyme insertion/deletion polymorphism as a function of migration time and separation efficiency to establish the effect of voltage strength to resolution. Finally, the amplified products of the angiotensin-converting enzyme insertion/deletion polymorphism (190 and 490 bp DNA) were analyzed in 3.2 min without losing resolution under optimum voltage programming conditions, which were at least 75 times faster than conventional slab gel electrophoresis. In addition, the capillary gel electrophoresis method also successfully applied to the analysis of real human blood samples, although no polymorphism genes were detected by slab gel electrophoresis. Consequently, the developed voltage-programming capillary gel electrophoresis method with laser-induced fluorescence detection is an effective, rapid analysis technique for highly sensitive detection of disease-related specific DNA molecules.

  14. An insertion/deletion TEX28 polymorphism and its application to analysis of red/green visual pigment gene arrays.

    PubMed

    Ueyama, Hisao; Torii, Ryuzo; Tanabe, Shoko; Oda, Sanae; Yamade, Shinichi

    2004-01-01

    TEX28 gene (fTEX) is present immediately downstream of the red/green visual pigment gene array on the human X chromosome. Its pseudogene (pTEX) that lacks exon 1 is present within the array between pigment genes. We found that both fTEX and pTEX genes had a 697 bp insertion/deletion polymorphism in their introns 3. In color-normal male subjects, the frequency of the 697 bp region was 43% (40/94) in pTEX and 97% (91/94) in fTEX in the array of Red-pTEX-Green-fTEX and 10% (9/94) in pTEX and 87% (41/47) in fTEX in the array of Red-pTEX-Green-pTEX-Green-fTEX. These results suggest that normal arrays with multiple green genes may have arisen through gene duplication rather than unequal homologous crossover. In color-vision-deficient male subjects with a single-gene array, the frequency of the 697 bp region was 83% (25/30) in the array of Green-fTEX and 66% (74/112) in the array of Red-fTEX. In color-vision-deficient male subjects with a 2-gene array, the frequency of the region was 44% (16/36) in pTEX and 97% (35/36) in fTEX in the array of Green-pTEX-Green-fTEX and 75% (18/24) in pTEX and 92% (22/24) in fTEX in the array of Red-pTEX-Red-fTEX. These results suggest that 2-green-gene arrays have arisen through unequal homologous crossover between a normal 2-gene array and a single-green-gene array. With data from a long-range PCR method using the insertion/deletion polymorphism, we proposed a structure of the second gene of 3-gene arrays, Green-pTEX-Green-pTEX-Green-fTEX and Red-pTEX-Red-pTEX-Red-fTEX, in color-vision-deficient subjects. PMID:15378397

  15. Positive Selection on a Regulatory Insertion–Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid

    PubMed Central

    Kothapalli, Kumar S. D.; Ye, , Kaixiong; Gadgil, Maithili S.; Carlson, Susan E.; O’Brien, Kimberly O.; Zhang, Ji Yao; Park, Hui Gyu; Ojukwu, Kinsley; Zou, James; Hyon, Stephanie S.; Joshi, Kalpana S.; Gu, Zhenglong; Keinan, Alon; Brenna, J.Thomas

    2016-01-01

    Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion–deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product–precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice. PMID:27188529

  16. Positive Selection on a Regulatory Insertion-Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid.

    PubMed

    Kothapalli, Kumar S D; Ye, Kaixiong; Gadgil, Maithili S; Carlson, Susan E; O'Brien, Kimberly O; Zhang, Ji Yao; Park, Hui Gyu; Ojukwu, Kinsley; Zou, James; Hyon, Stephanie S; Joshi, Kalpana S; Gu, Zhenglong; Keinan, Alon; Brenna, J Thomas

    2016-07-01

    Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice. PMID:27188529

  17. Forensic evaluation and population genetic study of 30 insertion/deletion polymorphisms in a Chinese Yi group.

    PubMed

    Zhang, Yu-Dang; Shen, Chun-Mei; Jin, Rui; Li, Ya-Ni; Wang, Bo; Ma, Li-Xia; Meng, Hao-Tian; Yan, Jiang-Wei; Dan Wang, Hong-; Yang, Ze-Long; Zhu, Bo-Feng

    2015-05-01

    Insertion/deletion polymorphisms have become a research hot spot in forensic science due to their tremendous potential in recent years. In the present study, we investigated 30 indel loci in a Chinese Yi ethnic group. The allele frequencies of the short allele of the 30 indel loci were in the range of 0.1025-0.9221. The power of discrimination values were observed ranging from to 0.2630 (HLD111 locus) to 0.6607 (HLD70 locus) and probability of exclusion values ranged from 0.0189 (HLD111 locus) to 0.2343 (HLD56 locus). The combined power of discrimination and power of exclusion for 30 loci in the studied Yi group were 0.99999999995713 and 0.97746, respectively, which showed tremendous potential for forensic personal identification in the Yi group. Moreover, the DA distances, phylogenetic tree, principal component analysis, and cluster analysis showed the Yi group had close genetic relationships with the Tibetan, South Korean, Chinese Han, and She groups.

  18. The association of GSTT1 deletion polymorphism with lung cancer risk among Chinese population: evidence based on a cumulative meta-analysis

    PubMed Central

    Wang, Yadong; Yang, Haiyan; Wang, Haiyu

    2015-01-01

    Objective Previous studies investigating the relationship between glutathione S-transferase T1 (GSTT1) gene deletion polymorphism and lung cancer risk among Chinese population produced inconsistent results. To obtain a precise conclusion, we performed this meta-analysis to evaluate the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population. Methods The databases of Medline/PubMed, Embase, Web of Science, Wanfang Med Online, and Chinese National Knowledge Infrastructure were searched. The strength of the association was assessed by odds ratio (OR) with 95% confidence intervals (95% CI). Results Overall, we found an increased lung cancer risk among subjects carrying GSTT1 null genotype compared with those carrying present genotype (OR =1.31, 95% CI: 1.12–1.52) on the basis of 20 studies with 3,351 cases and 4,683 controls. We also observed an increased risk of lung cancer among subjects carrying GSTT1 null genotype compared with those carrying present genotype in stratified analyses (OR =1.31, 95% CI: 1.11–1.55 for healthy subjects-based control; OR =2.29, 95% CI: 1.84–2.85 for squamous cell carcinoma and OR =1.47, 95% CI: 1.22–1.77 for adenocarcinoma, respectively). Conclusion This meta-analysis suggested that GSTT1 deletion polymorphism might contribute to lung cancer risk among Chinese population. PMID:26491361

  19. Distribution of Angiotensin-1 Converting Enzyme Insertion/Deletion and α-Actinin-3 Codon 577 Polymorphisms in Turkish Male Soccer Players

    PubMed Central

    Ulucan, Korkut; Sercan, Canan; Biyikli, Türker

    2015-01-01

    Angiotensin-1 converting enzyme (ACE) gene and α-actinin-3 (ACTN3) gene polymorphisms are considered to be the most important candidate genes for genetic predisposition to human athletic performance. In the present study, we aimed to analyze the distribution of ACE and ACTN3 polymorphisms for the first time in male Turkish soccer players. In this prospective study, our cohort consisted of 25 professional players, all with Turkish ancestry. Polymerase chain reaction (PCR)-restriction length polymorphism was used for the characterization of the genotype of ACTN3 and single PCR for ACE. For ACE genotype, 16%, 44%, and 40% of the players had insertion/insertion (II), insertion/deletion (ID), and deletion/deletion (DD) genotypes, respectively, whereas 20% had XX, 36% had RX, and 44% had RR genotypes for ACTN3. When we examined the allelic percentages, for ACE, D allele was recorded as 62 and I as 38, and for ACTN3, R allele was 62 and X was 38. Our results were in agreement with the previous reports, indicating the presence of ACTN3 D and ACE X allele in soccer players. We suggest that ACE and ACTN3 genotypes are important biomarkers for genetic counseling for the individuals who are prone to be successful soccer players. PMID:26448692

  20. GPX1 Pro198Leu polymorphism and GSTM1 deletion do not affect selenium and mercury status in mildly exposed Amazonian women in an urban population.

    PubMed

    Rocha, Ariana V; Rita Cardoso, Bárbara; Zavarize, Bruna; Almondes, Kaluce; Bordon, Isabella; Hare, Dominic J; Teixeira Favaro, Déborah Inês; Franciscato Cozzolino, Silvia Maria

    2016-11-15

    Mercury is potent toxicant element, but its toxicity can be reduced by forming a complex with selenium for safe excretion. Considering the impact of mercury exposure in the Amazon region and the possible interaction between these two elements, we aimed to assess the effects of Pro198Leu polymorphism to GPX1 and GSTM1 deletion, on mercury levels in a population from Porto Velho, an urban locality in the Brazilian Amazon region. Two hundred women from the capital city of Rondônia state were recruited for this study with 149 deemed suitable to participate. We assessed dietary intake using 24-hour recall. Selenium levels in plasma and erythrocytes were measured using hydride generation quartz tube atomic absorption spectroscopy and total hair mercury using cold vapor atomic absorption spectrometry. Oxidative stress parameters (GPx activity, oxygen radical absorbency capacity [ORAC] and malondialdehyde [MDA]) were also analyzed. All participants were genotyped for Pro198Leu polymorphism and GSTM1 deletion. We observed that this population presented high prevalence of selenium deficiency, and also low levels of mercury, likely due to food habits that did not include selenium-rich food sources or significant consumption of fish (mercury biomagnifiers) regularly. Univariate statistical analysis showed that Pro198Leu and GSTM1 genotypes did not affect selenium and mercury levels in this population. Pro198Leu polymorphism and GSTM1 deletion had no effect on mercury levels in mildly exposed people, suggesting these genetic variants impact mercury levels only in highly exposed populations. PMID:27450956

  1. Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study.

    PubMed Central

    Parving, H. H.; Jacobsen, P.; Tarnow, L.; Rossing, P.; Lecerf, L.; Poirier, O.; Cambien, F.

    1996-01-01

    OBJECTIVE: To evaluate the concept that an insertion/deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of inhibition of angiotensin converting enzyme on progression of diabetic nephropathy. DESIGN: Observational follow up study of patients with insulin dependent diabetes and nephropathy who had been treated with captopril for a median of 7 years (range 3-9 years). SETTING: Outpatient diabetic clinic in a tertiary referral centre. PATIENTS: 35 patients with insulin dependent diabetes and nephropathy were investigated during captopril treatment (median 75 mg/day (range 12.5 to 150 mg/day)) that was in many cases combined with a loop diuretic, 11 patients were homozygous for the deletion allele and 24 were heterozygous or homozygous for the insertion allele of the angiotensin converting enzyme gene. MAIN OUTCOME MEASURES: Albuminuria, arterial blood pressure, and glomerular filtration rate according to insertion/deletion polymorphism. RESULTS: The two groups had comparable glomerular filtration rate, albuminuria, blood pressure, and haemoglobin A1c concentration at baseline. Captopril induced nearly the same reduction in mean blood pressure in the two groups-to 103 (SD 5) mm Hg in the group with the deletion and 102 (8) mm Hg in the group with the insertion-and in geometric mean albumin excretion-573 (antilog SE 1.3) micrograms/min and 470 (1.2) micrograms/min, respectively. The rate of decline in glomerular filtration rate (linear regression of all glomerular filtration rate measurements during antihypertensive treatment) was significantly steeper in the group homozygous for the double deletion allele than in the other group (mean 5.7 (3.7) ml/min/year and 2.6 (2.8) ml/min/year, respectively; P = 0.01). Multiple linear regression analysis showed that haemoglobin A1c concentration, albuminuria, and the double deletion genotype independently influenced the sustained rate of decline in glomerular filtration rate (R1

  2. Interaction between angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin-converting enzyme inhibition on survival in hemodialyzed patients.

    PubMed

    Kiss, István; Ambrus, Csaba; Kulcsár, Imre; Szegedi, János; Kerkovits, Lóránt; Tislér, András; Kiss, Zoltán

    2014-12-01

    The association between ACE (angiotensin-converting enzyme) gene insertion/deletion (I/D) polymorphism and mortality has been inconsistently observed in earlier studies in patients on maintenance hemodialysis. We hypothesized that the effect of ACE gene I/D polymorphism on mortality may be influenced by concurrent ACE inhibitor therapy in this population. In this prospective, multicenter cohort, observational study, data was collected from 716 prevalent chronic hemodialysis patients, blood samples were genotyped for I/D single nucleotide polymorphism. Patient mortality was assessed in tree genotype groups insertion/insertion, insertion/deletion and deletion/deletion (I/I, I/D, and D/D) using multivariate Cox proportional hazard models. The most frequent genotype was I/D (42.6%), followed by D/D (37.7%) and I/I (19.7%) genotypes. The mean age was 54.9±15.5 years, 53.2% of all patients were male and in the total group the prevalence of diabetes was 19.3%. ACE inhibitor therapy was prescribed for 47.9% of all patients. The median duration of dialysis before blood sampling was 23.8 months (IQR 11.2-47.1). Patients were followed for 10 years, the median follow-up time was 29.8 months (IQR 12.6-63.4). Patient characteristics were well balanced among the genotype groups. D/D genotype, was associated with inferior survival (I/I vs D/D: log-rank test: P=0.04) in patients not receiving ACE inhibitor therapy, and the presence of this therapy diminished this difference. There was no difference in survival among unselected patients with different genotypes. In multivariate Cox regression models, D/D genotype (compared to I/I) was a significant predictor of mortality only in patients without ACE inhibitor therapy (HR 0.67, 95% CI 0.46-0.97, P=0.03). Our data suggests that hemodialyzed patients with the deletion/deletion (D/D) genotype might have inferior outcome, and ACE inhibitor therapy may be associated with improved survival in this subgroup. PMID:25526485

  3. DHFR 19-bp Deletion and SHMT C1420T Polymorphisms and Metabolite Concentrations of the Folate Pathway in Individuals with Down Syndrome

    PubMed Central

    Mendes, Cristiani Cortez; Raimundo, Aline Maria Zanchetta de Aquino; Oliveira, Luciana Dutra; Zampieri, Bruna Lancia; Marucci, Gustavo Henrique; Biselli, Joice Matos; Goloni-Bertollo, Eny Maria; Eberlin, Marcos Nogueira; Haddad, Renato; Riccio, Maria Francesca; Vannucchi, Hélio; Carvalho, Valdemir Melechco

    2013-01-01

    Background: Down syndrome (DS) results from the presence and expression of three copies of the genes located on chromosome 21. Studies have shown that, in addition to overexpression of the Cystathionine β-synthase (CBS) gene, polymorphisms in genes involved in folate/homocysteine (Hcy) metabolism may also influence the concentrations of metabolites of this pathway. Aim: Investigate the association between Dihydrofolate reductase (DHFR) 19-base pair (bp) deletion and Serine hydroxymethyltransferase (SHMT) C1420T polymorphisms and serum folate and plasma Hcy and methylmalonic acid (MMA) concentrations in 85 individuals with DS. Methods: Molecular analysis of the DHFR 19-bp deletion and SHMT C1420T polymorphisms was performed by polymerase chain reaction (PCR) by difference in the size of fragments and real-time PCR allelic discrimination, respectively. Serum folate was quantified by chemiluminescence and plasma Hcy and MMA by liquid chromatography–tandem mass spectrometry. Results: Individuals with DHFR DD/SHMT TT genotypes presented increased folate concentrations (p=0.004) and the DHFR II/SHMT TT genotypes were associated with increased MMA concentrations (p=0.008). In addition, the MMA concentrations were negatively associated with age (p=0.04). Conclusion: There is an association between DHFR DD/SHMT TT and DHFR II/SHMT TT combined genotypes and folate and MMA concentrations in individuals with DS. PMID:23421317

  4. Association between a Functional HLA-G 14-bp Insertion/deletion Polymorphism and Susceptibility to Autoimmune Diseases: A Meta-analysis.

    PubMed

    Lee, Y H; Bae, S-C

    2015-12-09

    The aim of this study was to determine whether a functional human leukocyte antigen-G (HLA-G) 14-bp insertion (I)/deletion (D) polymorphism is associated with susceptibility to autoimmune diseases. A meta-analysis was conducted to assess the association between an HLA-G 14-bp I/D polymorphism and autoimmune diseases using 1) allele contrast, as well as 2) recessive, 3) dominant, and 4) codominant models. Sixteen articles that included 20 comparative studies with 3,555 patients and 5,225 controls were included in the meta-analysis. These studies were performed on nine Caucasian, six South American, three Asian, one Arab, and one African population samples. Our meta-analysis revealed no association between autoimmune diseases and the HLA-G 14-bp I/D polymorphism [odds ratio (OR) for allele I = 1.055; 95% confidence interval (CI) = 0.963-1.156; p = 0.251)]. However, meta-analysis according to autoimmune disease type revealed an association between systemic lupus erythematosus (SLE) and the II+ID genotype of the HLA-G 14-bp I/D polymorphism (OR = 1.205; 95% CI = 1.036-1.403; p = 0.016). Furthermore, analysis using a codominant model revealed an association between this polymorphism and SLE (OR for ID vs. DD = 1.203; 95% CI = 1.024-1.413; p = 0.024). In contrast, our meta-analysis revealed no association between rheumatoid arthritis (RA), multiple sclerosis (MS), or Crohn's disease (CD) and the HLA-G 14-bp I/D polymorphism. This meta-analysis showed that the HLA-G 14-bp I/D polymorphism is associated with susceptibility to a subgroup of autoimmune diseases such as SLE, but not RA, MS, or CD. These results support the existence of an association between the HLA-G gene and a subgroup of autoimmune diseases.

  5. Genomic variability of Mycobacterium tuberculosis strains of the Euro-American lineage based on large sequence deletions and 15-locus MIRU-VNTR polymorphism.

    PubMed

    Rindi, Laura; Medici, Chiara; Bimbi, Nicola; Buzzigoli, Andrea; Lari, Nicoletta; Garzelli, Carlo

    2014-01-01

    A sample of 260 Mycobacterium tuberculosis strains assigned to the Euro-American family was studied to identify phylogenetically informative genomic regions of difference (RD). Mutually exclusive deletions of regions RD115, RD122, RD174, RD182, RD183, RD193, RD219, RD726 and RD761 were found in 202 strains; the RD(Rio) deletion was detected exclusively among the RD174-deleted strains. Although certain deletions were found more frequently in certain spoligotype families (i.e., deletion RD115 in T and LAM, RD174 in LAM, RD182 in Haarlem, RD219 in T and RD726 in the "Cameroon" family), the RD-defined sublineages did not specifically match with spoligotype-defined families, thus arguing against the use of spoligotyping for establishing exact phylogenetic relationships between strains. Notably, when tested for katG463/gyrA95 polymorphism, all the RD-defined sublineages belonged to Principal Genotypic Group (PGG) 2, except sublineage RD219 exclusively belonging to PGG3; the 58 Euro-American strains with no deletion were of either PGG2 or 3. A representative sample of 197 isolates was then analyzed by standard 15-locus MIRU-VNTR typing, a suitable approach to independently assess genetic relationships among the strains. Analysis of the MIRU-VNTR typing results by using a minimum spanning tree (MST) and a classical dendrogram showed groupings that were largely concordant with those obtained by RD-based analysis. Isolates of a given RD profile show, in addition to closely related MIRU-VNTR profiles, related spoligotype profiles that can serve as a basis for better spoligotype-based classification.

  6. The 19-bp deletion polymorphism of dihydrofolate reductase (DHFR) and nonsyndromic cleft lip with or without cleft palate: evidence for a protective role

    PubMed Central

    RAFIGHDOOST, Firoozeh; RAFIGHDOOST, Amir; RAFIGHDOOST, Houshang; RIGI-LADEZ, Mohammad-Ayoob; HASHEMI, Mohammad; ESKANDARI-NASAB, Ebrahim

    2015-01-01

    Objective Nonsyndromic cleft lip with or without cleft palate (NS-CL/P) are among the most common congenital birth defects worldwide. Several lines of evidence point to the involvement of folate, as well as folate metabolizing enzymes in risk reduction of orofacial clefts. Dihydrofolate reductase (DHFR) enzyme participates in the metabolic cycle of folate and has a crucial role in DNA synthesis, a fundamental feature of gestation and development. A functional polymorphic 19-bp deletion within intron-1 of DHFR has been associated with the risk of common congenital malformations. The present study aimed to evaluate the possible association between DHFR 19-bp deletion polymorphism and susceptibility to NS-CL/P in an Iranian population. Material and Methods The current study recruited 100 NS-CL/P patients and 100 healthy controls. DHFR 19-bp deletion was determined using an allele specific-PCR method. Results We observed the DHFR 19-bp homozygous deletion genotype (D/D) vs. homozygous wild genotype (WW) was more frequent in controls than in NS-CL/P patients (25% vs. 13%), being associated with a reduced risk of NS-CL/P in both codominant (OR=0.33, P=0.027) and recessive (OR=0.45, P=0.046) tested inheritance models. We also stratified the cleft patients and reanalyzed the data. The association trend for CL+CL/P group compared to the controls revealed that the DD genotype in both codominant (OR=0.30, P=0.032) and recessive models (OR=0.35, P=0.031) was associated with a reduced risk of CL+CL/P. Conclusions Our results for the first time suggested the DHFR 19-bp D/D genotype may confer a reduced risk of NS-CL/P and might act as a protective factor against NS-CL/P in the Iranian subjects. PMID:26221921

  7. Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Spurdle, Amanda B; Fahey, Paul; Chen, Xiaoqing; McGuffog, Lesley; Easton, Douglas; Peock, Susan; Cook, Margaret; Simard, Jacques; Rebbeck, Tim R; Antoniou, Antonis C; Chenevix-Trench, Georgia

    2010-07-01

    The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies.

  8. Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Spurdle, Amanda B.; Fahey, Paul; Chen, Xiaoqing; McGuffog, Lesley; Easton, Douglas; Peock, Susan; Cook, Margaret; Simard, Jacques; Rebbeck, Tim R.; Antoniou, Antonis C.

    2011-01-01

    The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies. PMID:19921428

  9. InPhaDel: integrative shotgun and proximity-ligation sequencing to phase deletions with single nucleotide polymorphisms

    PubMed Central

    Patel, Anand; Edge, Peter; Selvaraj, Siddarth; Bansal, Vikas; Bafna, Vineet

    2016-01-01

    Phasing of single nucleotide (SNV), and structural variations into chromosome-wide haplotypes in humans has been challenging, and required either trio sequencing or restricting phasing to population-based haplotypes. Selvaraj et al. demonstrated single individual SNV phasing is possible with proximity ligated (HiC) sequencing. Here, we demonstrate HiC can phase structural variants into phased scaffolds of SNVs. Since HiC data is noisy, and SV calling is challenging, we applied a range of supervised classification techniques, including Support Vector Machines and Random Forest, to phase deletions. Our approach was demonstrated on deletion calls and phasings on the NA12878 human genome. We used three NA12878 chromosomes and simulated chromosomes to train model parameters. The remaining NA12878 chromosomes withheld from training were used to evaluate phasing accuracy. Random Forest had the highest accuracy and correctly phased 86% of the deletions with allele-specific read evidence. Allele-specific read evidence was found for 76% of the deletions. HiC provides significant read evidence for accurately phasing 33% of the deletions. Also, eight of eight top ranked deletions phased by only HiC were validated using long range polymerase chain reaction and Sanger. Thus, deletions from a single individual can be accurately phased using a combination of shotgun and proximity ligation sequencing. InPhaDel software is available at: http://l337x911.github.io/inphadel/. PMID:27105843

  10. A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate.

    PubMed

    Kalmbach, Renee D; Choumenkovitch, Silvina F; Troen, Aron P; Jacques, Paul F; D'Agostino, Ralph; Selhub, Jacob

    2008-12-01

    Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. The functional impact of this polymorphism has not yet been demonstrated. The objective of this research was to determine the effects of the DHFR mutation with respect to folate status and assess influence of folic acid intake on these relations. The relationship between DHFR genotype and plasma concentrations of circulating folic acid, total folate, total homocysteine, and concentrations of RBC folate was determined in 1215 subjects from the Framingham Offspring Study. There was a significant interaction between DHFR genotype and folic acid intake with respect to the prevalence of high circulating unmetabolized folic acid (defined as >85th percentile). Folic acid intake of >or=500 microg/d increased the prevalence of high circulating unmetabolized folic acid in subjects with the deletion (del/del genotype (47.0%) compared with the wild type (WT)/del (21.4%) and wild type (WT)/WT genotypes (24.4%) (P for interaction = 0.03). Interaction between the DHFR polymorphism and folic acid intake was also seen with respect to RBC folate (P for interaction = 0.01). When folic acid intake was <250 microg/d, the del/del genotype was associated with significantly lower RBC folate (732.3 nmol/L) compared with the WT/WT genotype (844.4 nmol/L). Our results suggest the del/del polymorphism in DHFR is a functional polymorphism, because it limits assimilation of folic acid into cellular folate stores at high and low folic acid intakes.

  11. Susceptibility to gastric cancer and polymorphisms of insertion/deletion at the intron 3 of the XRCC4 and VNTR at the promoter region of the XRCC5.

    PubMed

    Saadat, Mostafa; Pashaei, Samira; Amerizade, Foroozan

    2015-07-01

    The genes encoding X-ray repair cross-complementing group 4 (XRCC4; OMIM: 194363) and 5 (XRCC5; OMIM: 194364) are involved in repair of DNA double-strand breaks. To investigating the associations between polymorphisms of Insertion/Deletion (I/D, rs28360071) in the intron 3 of the XRCC4 and VNTR in the promoter region of the XRCC5 and risk of gastric cancer, the present study was carried out. We included 159 (56 females, 103 males) with gastric cancer and 242 (75 females, 167 males) healthy blood donors frequency matched for age and gender. Using PCR-based methods, the genotypes of the study polymorphisms were determined. The alleles of VNTR XRCC5 polymorphism divided into two groups: L (0 and 1 repeats) and H (2 and 3 repeats) alleles. For the I/D XRCC4 polymorphism, after stratification of the subjects according to their family history (FH) of cancer, either the ID (OR = 3.19, 95%CI: 1.35-7.50, P = 0.008) or the DD genotypes (OR = 4.62, 95%CI: 1.63-13.0, P = 0.004) among positive FH persons, increased the risk of gastric cancer compared with the reference group (persons who have negative FH and II genotype). For the VNTR XRCC5 polymorphism, the LH + HH genotypes among positive FH persons, increased the risk of gastric cancer compared with the reference group (persons who have negative FH and LL genotype) (OR = 2.88, 95%CI: 1.34-6.18, P = 0.006). Sensitivity analysis showed that the above mentioned associations were not occurred due to the maldistribution of the genotypes among missing data. The present study suggests that both polymorphisms of the XRCC4 and XRCC5 might be risk factors for gastric cancer development especially among persons with positive FH.

  12. Insertion/deletion polymorphism in intron 16 of ACE gene in idiopathic recurrent spontaneous abortion: case-control study, systematic review and meta-analysis.

    PubMed

    Pereza, Nina; Ostojić, Saša; Zdravčević, Matea; Volk, Marija; Kapović, Miljenko; Peterlin, Borut

    2016-02-01

    The insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin I-converting enzyme gene (ACE) has been extensively studied as a predisposing factor for idiopathic recurrent spontaneous abortion (IRSA). A case-control study including 149 women with ≥3 spontaneous abortions and 149 controls was performed to test the association of ACE I/D polymorphism with IRSA. A systematic review was conducted of previous case-control studies, with strict selection criteria for meta-analyses. We also aimed to evaluate the potential differences in summary estimates between studies defining IRSA as ≥2 and ≥3 spontaneous abortions. Genotyping was performed by PCR, and systematic review conducted using PubMed and Scopus. There was no association of the polymorphism with IRSA in Slovenian women. Sixteen case-control studies, showing substantial differences regarding IRSA definition and selection criteria for women were identified. Meta-analysis was performed and included four studies defining IRSA as ≥2 spontaneous abortions and the current study, which defined IRSA as ≥3 spontaneous abortions. Based on random effects model, meta-analysis conducted on 1192 patients and 736 controls showed no association with IRSA under dominant(DD+IDvsII) and recessive(DDvsID+II) genetic models. Well-designed studies are needed to evaluate the role of ACE I/D polymorphism in IRSA defined as ≥3 spontaneous abortions. PMID:26673102

  13. Insertion/deletion polymorphism in intron 16 of ACE gene in idiopathic recurrent spontaneous abortion: case-control study, systematic review and meta-analysis.

    PubMed

    Pereza, Nina; Ostojić, Saša; Zdravčević, Matea; Volk, Marija; Kapović, Miljenko; Peterlin, Borut

    2016-02-01

    The insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin I-converting enzyme gene (ACE) has been extensively studied as a predisposing factor for idiopathic recurrent spontaneous abortion (IRSA). A case-control study including 149 women with ≥3 spontaneous abortions and 149 controls was performed to test the association of ACE I/D polymorphism with IRSA. A systematic review was conducted of previous case-control studies, with strict selection criteria for meta-analyses. We also aimed to evaluate the potential differences in summary estimates between studies defining IRSA as ≥2 and ≥3 spontaneous abortions. Genotyping was performed by PCR, and systematic review conducted using PubMed and Scopus. There was no association of the polymorphism with IRSA in Slovenian women. Sixteen case-control studies, showing substantial differences regarding IRSA definition and selection criteria for women were identified. Meta-analysis was performed and included four studies defining IRSA as ≥2 spontaneous abortions and the current study, which defined IRSA as ≥3 spontaneous abortions. Based on random effects model, meta-analysis conducted on 1192 patients and 736 controls showed no association with IRSA under dominant(DD+IDvsII) and recessive(DDvsID+II) genetic models. Well-designed studies are needed to evaluate the role of ACE I/D polymorphism in IRSA defined as ≥3 spontaneous abortions.

  14. Fast high-throughput screening of angiotensin-converting enzyme insertion/deletion polymorphism by variable programmed electric field strength-based microchip electrophoresis.

    PubMed

    Sun, Yucheng; Kim, Su-Kang; Zhang, Peng; Woo, Nain; Kang, Seong Ho

    2016-08-15

    An insertion (I)/deletion (D) polymorphism in angiotensin-converting enzyme (ACE) has been associated with susceptibility to various diseases in numerous studies. Traditionally, slab gel electrophoresis (SGE) after polymerase chain reaction (PCR) has been used to genotype this ACE I/D polymorphism. In this study, single- and multi-channel microchip electrophoresis (ME) methods based on variable programmed electric field strength (PEFS) (i.e., low constant, high constant, (+)/(-) staircase, and random electric field strengths) were developed for fast high-throughput screening of this specific polymorphism. The optimum PEFS conditions were set as 470V/cm for 0-9s, 129V/cm for 9-13s, 470V/cm for 13-13.9s, 294V/cm for 13.9-16s, and 470V/cm for 16-20s for single-channel ME, and 615V/cm for 0-22.5s, 231V/cm for 22.5-28.5s, and 615V/cm for 28.5-40s for multi-channel ME, respectively. In the multi-channel PEFS-ME, target ACE I/D polymorphism DNA fragments (D=190bp and I=490bp) were identified within 25s without loss of resolving power, which was ∼300 times faster than conventional SGE. In addition, PCR products of the ACE gene from human blood samples were detected after only 10 cycles by multi-channel PEFS-ME, but not by SGE. This parallel detection multichannel-based PEFS-ME method offers a powerful tool for fast high-throughput ACE I/D polymorphism screening with high sensitivity. PMID:27322633

  15. Fast high-throughput screening of angiotensin-converting enzyme insertion/deletion polymorphism by variable programmed electric field strength-based microchip electrophoresis.

    PubMed

    Sun, Yucheng; Kim, Su-Kang; Zhang, Peng; Woo, Nain; Kang, Seong Ho

    2016-08-15

    An insertion (I)/deletion (D) polymorphism in angiotensin-converting enzyme (ACE) has been associated with susceptibility to various diseases in numerous studies. Traditionally, slab gel electrophoresis (SGE) after polymerase chain reaction (PCR) has been used to genotype this ACE I/D polymorphism. In this study, single- and multi-channel microchip electrophoresis (ME) methods based on variable programmed electric field strength (PEFS) (i.e., low constant, high constant, (+)/(-) staircase, and random electric field strengths) were developed for fast high-throughput screening of this specific polymorphism. The optimum PEFS conditions were set as 470V/cm for 0-9s, 129V/cm for 9-13s, 470V/cm for 13-13.9s, 294V/cm for 13.9-16s, and 470V/cm for 16-20s for single-channel ME, and 615V/cm for 0-22.5s, 231V/cm for 22.5-28.5s, and 615V/cm for 28.5-40s for multi-channel ME, respectively. In the multi-channel PEFS-ME, target ACE I/D polymorphism DNA fragments (D=190bp and I=490bp) were identified within 25s without loss of resolving power, which was ∼300 times faster than conventional SGE. In addition, PCR products of the ACE gene from human blood samples were detected after only 10 cycles by multi-channel PEFS-ME, but not by SGE. This parallel detection multichannel-based PEFS-ME method offers a powerful tool for fast high-throughput ACE I/D polymorphism screening with high sensitivity.

  16. Quantitative assessment of the association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and digestive system cancer risk.

    PubMed

    Wang, J; Yang, S; Guo, F H; Mao, X; Zhou, H; Dong, Y Q; Wang, Z M; Luo, F

    2015-01-01

    The angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been reported to be associated with digestive system cancer; however, the results from previous studies have been conflicting. The present study aimed to investigate the association between the ACE I/D polymorphism and the risk of digestive system cancer using a meta-analysis of previously published studies. Databases were systematically searched to identify relevant studies published prior to December 2014. We estimated the pooled OR with its 95%CI to assess the association. The meta-analysis consisted of thirteen case-control studies that included 2557 patients and 4356 healthy controls. Meta-analysis results based on all the studies showed no significant association between the ACE I/D polymorphism and the risk of digestive system cancer (DD vs II: OR = 0.85, 95%CI = 0.59-1.24; DI vs II: OR = 0.94, 95%CI = 0.78-1.15; dominant model: OR = 0.96, 95%CI = 0.81- 1.15; recessive model: OR = 1.06, 95%CI = 0.76-1.48). Subgroup analyses by race and cancer type did not detect an association between the ACE I/D polymorphism and digestive system cancer risk. However, when the analyses were restricted to smaller studies (N < 500 patients), the summary OR of DI vs II was 0.80 (95%CI = 0.66-0.97). Our analyses detected a possibility of publication bias with a misestimate of the true association by smaller studies. Overall, meta-analysis results suggest the ACE I/D polymorphism might not be associated with susceptibility to digestive system cancer. Further large and well-designed studies are needed to confirm these conclusions.

  17. Association between angiotensin converting enzyme gene insertion/deletion polymorphism and renal scar risk in children vesicoureteral reflex: a reappraise meta-analysis

    PubMed Central

    Ai, Jin-Wei; Zeng, Xian-Tao; Liu, Ying; Fu, Yu; Liu, Tong-Zu; Pei, Bin

    2016-01-01

    Vesicoureteral reflex(VUR) is a common disease in children. Some studies indicated that the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism associated with the renal scar in VUR, but not all researchers agreed with it. To clarify the effect of ACE I/D polymorphism on renal scar risk in children with VUR, we performed the present meta-analysis. PubMed, CNKI, CBM, and Embase databases were searched for studies that examined the relationship between ACE I/D polymorphism and renal scar risk in children with VUR. The Stata 12.0 software was used for statistical analyses. 11 case-control studies with 1,032 VUR patients were analyzed. The results showed that the DD genotype and D allele were associated with renal scar risk in overall VUR patients, DD vs. DI + II: OR = 1.61, 95% CI = 1.04–2.49, P = 0.03; DD vs. II: OR = 1.78, 95% CI = 1.20–2.65, P < 0.01; D vs. I: OR = 1.38, 95% CI = 1.02–1.86, P = 0.04. Similar results were revealed in Turks, but not in Caucasians and Asians. Our meta-analysis indicated that the ACE DD genotype may increase the risk of renal scar in children with VUR. PMID:27506878

  18. Association between angiotensin converting enzyme gene insertion/deletion polymorphism and renal scar risk in children vesicoureteral reflex: a reappraise meta-analysis.

    PubMed

    Ai, Jin-Wei; Zeng, Xian-Tao; Liu, Ying; Fu, Yu; Liu, Tong-Zu; Pei, Bin

    2016-08-10

    Vesicoureteral reflex(VUR) is a common disease in children. Some studies indicated that the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism associated with the renal scar in VUR, but not all researchers agreed with it. To clarify the effect of ACE I/D polymorphism on renal scar risk in children with VUR, we performed the present meta-analysis. PubMed, CNKI, CBM, and Embase databases were searched for studies that examined the relationship between ACE I/D polymorphism and renal scar risk in children with VUR. The Stata 12.0 software was used for statistical analyses. 11 case-control studies with 1,032 VUR patients were analyzed. The results showed that the DD genotype and D allele were associated with renal scar risk in overall VUR patients, DD vs. DI + II: OR = 1.61, 95% CI = 1.04-2.49, P = 0.03; DD vs. II: OR = 1.78, 95% CI = 1.20-2.65, P < 0.01; D vs. I: OR = 1.38, 95% CI = 1.02-1.86, P = 0.04. Similar results were revealed in Turks, but not in Caucasians and Asians. Our meta-analysis indicated that the ACE DD genotype may increase the risk of renal scar in children with VUR.

  19. Relationship between the 19 base pair deletion polymorphism in DHFR and unmetabolized folic and in plasma and RBC folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: A 19 base pair (bp) deletion allele of dihydrofolate reductase (DHFR), an enzyme that makes folic acid metabolically active and reduces dihydrofolate to tetrahydrofolate to stimulate folate turnover, has been implicated in folate related health outcomes. Objective: Examine the effect ...

  20. Dihydrofolate reductase 19-bp deletion polymorphism modifies the association of folate status with memory in a cross-sectional multi-ethnic study of adults123

    PubMed Central

    Philip, Dana; Buch, Assaf; Moorthy, Denish; Scott, Tammy M; Parnell, Laurence D; Lai, Chao-Qiang; Ordovás, José M; Selhub, Jacob; Rosenberg, Irwin H; Tucker, Katherine L; Troen, Aron M

    2015-01-01

    Background: Folate status has been positively associated with cognitive function in many studies; however, some studies have observed associations of poor cognitive outcomes with high folate. In search of an explanation, we hypothesized that the association of folate with cognition would be modified by the interaction of high-folate status with a common 19-bp deletion polymorphism in the dihydrofolate reductase (DHFR) gene. To our knowledge, the cognitive effects of this gene have not been studied previously. Objective: We examined the association between cognitive outcomes with the 19-bp deletion DHFR polymorphism, folate status, and their interaction with high or normal plasma folate. Design: This was a pooled cross-sectional study of the following 2 Boston-based cohorts of community living adults: the Boston Puerto Rican Health Study and the Nutrition, Aging, and Memory in Elders study. Individuals were genotyped for the DHFR 19-bp deletion genotype, and plasma folate status was determined. Cognitive outcomes included the Mini-Mental State Examination, Center for Epidemiologic Studies Depression Scale, and factor scores for the domains of memory, executive function, and attention from a set of cognitive tests. Results: The prevalence of the homozygous deletion (del/del) genotype was 23%. In a multivariable analysis, high folate status (>17.8 ng/mL) was associated with better memory scores than was normal-folate status (fourth–fifth quintiles compared with first–third quintiles: β ± SE = −0.22 ± 0.06, P < 0.01). Carriers of the DHFR del/del genotype had worse memory scores (β ± SE = −0.24 ± 0.10, P < 0.05) and worse executive scores (β = −0.19, P < 0.05) than did those with the del/ins and ins/ins genotypes. Finally, we observed an interaction such that carriers of the del/del genotype with high folate had significantly worse memory scores than those of both noncarriers with high-folate and del/del carriers with normal-folate (β-interaction = 0

  1. Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants.

    PubMed Central

    Schneider, P M; Carroll, M C; Alper, C A; Rittner, C; Whitehead, A S; Yunis, E J; Colten, H R

    1986-01-01

    Several autoimmune disorders as well as congenital adrenal hyperplasia (CAH) are either associated or closely linked with genetic variants of the fourth component of complement (C4A and C4B) and the enzyme steroid 21-hydroxylase (21-OH). These proteins are encoded by genes that are located downstream from the genes for complement proteins, C2 and factor B (BF) between HLA-B and -DR in the major histocompatibility complex (MHC). Previous studies of variants and null alleles were based on electrophoretic mobility of C4 protein and linkage with disease phenotypes. These data did not permit analysis of the basis for the observed null alleles and duplicated variants. We studied this region of the MHC in 126 haplotypes for a structural analysis of the four adjacent loci, C4A, 21-OHA, C4B, and 21-OHB. About half of the C4 genes typed as C4 null are deleted and several unrecognized homoduplicated C4 alleles were detected. Hence the frequencies of different C4 structural variants must be recalculated based on a direct analysis of the genes. Analysis of the C4/21-OH genes of patients with the classical (salt-wasting) form of CAH showed that some involve a deletion of the C4B and 21-OHB genes; whereas for two only the 21-OHB gene is deleted, i.e., the C4B gene is present. Together, these data provide a better understanding of the mechanisms generating and importance of deleted C4 and 21-OH null alleles in human disease. Images PMID:3018042

  2. Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status

    PubMed Central

    Alsafar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Almaini, Mustafa; Odama, Unini; Rais, Naushad

    2015-01-01

    The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped for ACE I/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of the ACE I/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status, ACE DD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34, p = 0.086] or hypertension [odd ratio (OR) = 1.02, p = 0.93]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotype ACE DD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80, p = 0.02] but was found to be protective against the hypertension in the obese group ((OR) = 0.54, p = 0.01). However, there was no effect of obesity status on the association of ACE genotypes with T2DM. The risk of hypertension associated with ACE DD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed that ACE I/D polymorphism is not associated with T2DM risk in Emirati population. PMID:26491214

  3. Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status.

    PubMed

    Alsafar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Almaini, Mustafa; Odama, Unini; Rais, Naushad

    2015-01-01

    The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped for ACE I/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of the ACE I/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status, ACE DD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34, p = 0.086] or hypertension [odd ratio (OR) = 1.02, p = 0.93]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotype ACE DD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80, p = 0.02] but was found to be protective against the hypertension in the obese group ((OR) = 0.54, p = 0.01). However, there was no effect of obesity status on the association of ACE genotypes with T2DM. The risk of hypertension associated with ACE DD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed that ACE I/D polymorphism is not associated with T2DM risk in Emirati population.

  4. Angiotensin-converting enzyme insertion/deletion polymorphism is not a major determining factor in the development of sporadic Alzheimer disease: evidence from an updated meta-analysis.

    PubMed

    Wang, Xue-bin; Cui, Ning-hua; Yang, Jie; Qiu, Xue-ping; Gao, Jia-jia; Yang, Na; Zheng, Fang

    2014-01-01

    Angiotensin-converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism have long been linked to sporadic Alzheimer disease (SAD), but the established data remained controversial. To clarify this inconsistency, a comprehensive meta-analysis was conducted. Through searching of Pubmed, Embase, Alzgene, China National Knowledge Infrastructure (CNKI) and manually searching relevant references, 53 independent studies from 48 articles were included, involving a total of 8153 cases and 14932 controls. The strength of association was assessed by using odds ratios (ORs) with 95% confidence intervals (CIs). Further stratified analyses and heterogeneity analyses were tested, as was publication bias. Overall, significant associations were revealed between I/D polymorphism and SAD risk using allelic comparison (OR = 1.09, 95%CI = 1.01-1.17, p = 0.030), homozygote comparison (OR = 1.17, 95%CI = 1.01-1.34, p = 0.030) and the dominant model (OR = 1.16, 95%CI = 1.04-1.29, p = 0.008), but they were not sufficiently robust to withstand the false-positive report probability (FPRP) analyses. Otherwise, in subgroup analyses restricted to the high quality studies, the large sample size studies and studies with population-based controls, no significant association was observed in any genetic models. In summary, the current meta-analysis suggested that the ACE I/D polymorphism is unlikely to be a major determining factor in the development of SAD. PMID:25360660

  5. Growth hormone (GH1) gene variation and the growth hormone receptor (GHR) exon 3 deletion polymorphism in a West-African population.

    PubMed

    Millar, David S; Lewis, Mark D; Horan, Martin; Newsway, Vicky; Rees, D Aled; Easter, Tammy E; Pepe, Guglielmina; Rickards, Olga; Norin, Martin; Scanlon, Maurice F; Krawczak, Michael; Cooper, David N

    2008-12-16

    Among Europeans, functionally significant GH1 gene variants occur not only in individuals with idiopathic growth hormone (GH) deficiency and/or short stature but also fairly frequently in the general population. To assess the generality of these findings, 163 individuals from Benin, West Africa were screened for mutations and polymorphisms in their GH1 genes. A total of 37 different sequence variants were identified in the GH1 gene region, 24 of which occurred with a frequency of >1%. Although four of these variants were novel missense substitutions (Ala13Val, Arg19His, Phe25Tyr and Ser95Arg), none of these had any measurable effect on either GH function or secretion in vitro. Some 37 different GH1 promoter haplotypes were identified, 23 of which are as yet unreported in Europeans. The mean in vitro expression level of the GH1 promoter haplotypes observed in the African population was significantly higher than that previously measured in Britons (p<0.001). A gene conversion in the GH1 promoter, previously reported in a single individual of British origin, was found to occur at polymorphic frequency (5%) in the West-African population and was associated with a 1.7-fold increase in promoter activity relative to the wild-type. The d3 allele of the GHR exon 3 deletion polymorphism, known to be associated with increased GH responsiveness, was also found to occur at an elevated frequency in these individuals from Benin. We speculate that both elevated GH1 gene expression and increased GHR-mediated GH responsiveness may constitute adaptive responses to the effects of scarce food supply in this West-African population since increased circulating GH appears to form part of a physiological response to nutritional deprivation.

  6. Developmental validation of an X-Insertion/Deletion polymorphism panel and application in HAN population of China

    PubMed Central

    Zhang, Suhua; Sun, Kuan; Bian, Yingnan; Zhao, Qi; Wang, Zheng; Ji, Chaoneng; Li, Chengtao

    2015-01-01

    InDels are short-length polymorphisms characterized by low mutation rates, high inter-population diversity, short amplicon strategy and simplicity of laboratory analysis. This work describes the developmental validation of an X-InDels panel amplifying 18 bi-allelic markers and Amelogenin in one single PCR system. Developmental validation indicated that this novel panel was reproducible, accurate, sensitive and robust for forensic application. Sensitivity testing of the panel was such that a full profile was obtainable even with 125 pg of human DNA with intra-locus balance above 70%. Specificity testing was demonstrated by the lack of cross-reactivity with a variety of commonly encountered animal species and microorganisms. For the stability testing in cases of PCR inhibition, full profiles have been obtained with hematin (≤1000 μM) and humic acid (≤150 ng/μL). For the forensic investigation of the 18 X-InDels in the HAN population of China, no locus deviated from the Hardy–Weinberg equilibrium and linkage disequilibrium. Since they are independent from each other, the CDPfemale was 0.999999726 and CDPmale was 0.999934223. The forensic parameters suggested that this X-Indel panel is polymorphic and informative, which provides valuable X-linked information for deficient relationship cases where autosomal markers are uninformative. PMID:26655948

  7. Genomic diversity of Mycobacterium tuberculosis Beijing strains isolated in Tuscany, Italy, based on large sequence deletions, SNPs in putative DNA repair genes and MIRU-VNTR polymorphisms.

    PubMed

    Garzelli, Carlo; Lari, Nicoletta; Rindi, Laura

    2016-03-01

    The Beijing genotype of Mycobacterium tuberculosis is cause of global concern as it is rapidly spreading worldwide, is considered hypervirulent, and is most often associated to massive spread of MDR/XDR TB, although these epidemiological or pathological properties have not been confirmed for all strains and in all geographic settings. In this paper, to gain new insights into the biogeographical heterogeneity of the Beijing family, we investigated a global sample of Beijing strains (22% from Italian-born, 78% from foreign-born patients) by determining large sequence polymorphism of regions RD105, RD181, RD150 and RD142, single nucleotide polymorphism of putative DNA repair genes mutT4 and mutT2 and MIRU-VNTR profiles based on 11 discriminative loci. We found that, although our sample of Beijing strains showed a considerable genomic heterogeneity, yielding both ancient and recent phylogenetic strains, the prevalent successful Beijing subsets were characterized by deletions of RD105 and RD181 and by one nucleotide substitution in one or both mutT genes. MIRU-VNTR analysis revealed 47 unique patterns and 9 clusters including a total of 33 isolates (41% of total isolates); the relatively high proportion of Italian-born Beijing TB patients, often occurring in mixed clusters, supports the possibility of an ongoing cross-transmission of the Beijing genotype to autochthonous population. High rates of extra-pulmonary localization and drug-resistance, particularly MDR, frequently reported for Beijing strains in other settings, were not observed in our survey. PMID:26597137

  8. Dose-dependent testosterone sensitivity of the steroidal passport and GC-C-IRMS analysis in relation to the UGT2B17 deletion polymorphism.

    PubMed

    Strahm, Emmanuel; Mullen, Jenny E; Gårevik, Nina; Ericsson, Magnus; Schulze, Jenny J; Rane, Anders; Ekström, Lena

    2015-01-01

    The newly implemented Steroid Module of the Athlete Biological Passport has improved doping tests for steroids. A biomarker included in this passport is the urinary testosterone glucuronide to epitestosterone glucuronide (T/E) ratio, a ratio greatly affected by a deletion polymorphism in UGT2B17. Suspect urine doping tests are further analyzed with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to determine the origin of the androgen. In this study, we investigated the sensitivity of the steroidal module and the IRMS analysis, in subjects administered with three doses of testosterone enanthate (500, 250, and 125 mg), in relation to the UGT2B17 polymorphism. All subjects carrying the UGT2B17 enzyme reached the traditionally used threshold, a T/E ratio of 4, after all three administered doses, whereas none of the subjects devoid of this enzyme reached a T/E of 4. On the other hand, using the athlete biological passport and IRMS analysis, all three doses could be detected to a high degree of sensitivity. The concentrations of all steroids included in the steroidal module were dose dependently increased, except for epitestosterone which decreased independent of dose. The decrease in epitestosterone was significantly associated with circulatory levels of testosterone post dose (rs =0.60 and p=0.007). In conclusion, these results demonstrate that administration of a single dose of 125-500 mg testosterone enanthate could be detected using the athlete biological passport, together with IRMS. Since IRMS is sensitive to testosterone doping independent of UGT2B17 genotype, also very small changes in the steroidal passport should be investigated with IRMS.

  9. Dose-dependent testosterone sensitivity of the steroidal passport and GC-C-IRMS analysis in relation to the UGT2B17 deletion polymorphism.

    PubMed

    Strahm, Emmanuel; Mullen, Jenny E; Gårevik, Nina; Ericsson, Magnus; Schulze, Jenny J; Rane, Anders; Ekström, Lena

    2015-01-01

    The newly implemented Steroid Module of the Athlete Biological Passport has improved doping tests for steroids. A biomarker included in this passport is the urinary testosterone glucuronide to epitestosterone glucuronide (T/E) ratio, a ratio greatly affected by a deletion polymorphism in UGT2B17. Suspect urine doping tests are further analyzed with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to determine the origin of the androgen. In this study, we investigated the sensitivity of the steroidal module and the IRMS analysis, in subjects administered with three doses of testosterone enanthate (500, 250, and 125 mg), in relation to the UGT2B17 polymorphism. All subjects carrying the UGT2B17 enzyme reached the traditionally used threshold, a T/E ratio of 4, after all three administered doses, whereas none of the subjects devoid of this enzyme reached a T/E of 4. On the other hand, using the athlete biological passport and IRMS analysis, all three doses could be detected to a high degree of sensitivity. The concentrations of all steroids included in the steroidal module were dose dependently increased, except for epitestosterone which decreased independent of dose. The decrease in epitestosterone was significantly associated with circulatory levels of testosterone post dose (rs =0.60 and p=0.007). In conclusion, these results demonstrate that administration of a single dose of 125-500 mg testosterone enanthate could be detected using the athlete biological passport, together with IRMS. Since IRMS is sensitive to testosterone doping independent of UGT2B17 genotype, also very small changes in the steroidal passport should be investigated with IRMS. PMID:26198073

  10. A deletion polymorphism in the Caenorhabditis elegans RIG-I homolog disables viral RNA dicing and antiviral immunity

    PubMed Central

    Ashe, Alyson; Bélicard, Tony; Le Pen, Jérémie; Sarkies, Peter; Frézal, Lise; Lehrbach, Nicolas J; Félix, Marie-Anne; Miska, Eric A

    2013-01-01

    RNA interference defends against viral infection in plant and animal cells. The nematode Caenorhabditis elegans and its natural pathogen, the positive-strand RNA virus Orsay, have recently emerged as a new animal model of host-virus interaction. Using a genome-wide association study in C. elegans wild populations and quantitative trait locus mapping, we identify a 159 base-pair deletion in the conserved drh-1 gene (encoding a RIG-I-like helicase) as a major determinant of viral sensitivity. We show that DRH-1 is required for the initiation of an antiviral RNAi pathway and the generation of virus-derived siRNAs (viRNAs). In mammals, RIG-I-domain containing proteins trigger an interferon-based innate immunity pathway in response to RNA virus infection. Our work in C. elegans demonstrates that the RIG-I domain has an ancient role in viral recognition. We propose that RIG-I acts as modular viral recognition factor that couples viral recognition to different effector pathways including RNAi and interferon responses. DOI: http://dx.doi.org/10.7554/eLife.00994.001 PMID:24137537

  11. Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Susceptibility to Osteoarthritis of the Knee: A Case-Control Study and Meta-Analysis

    PubMed Central

    Wang, Chih-Chien; Peng, Yi-Jen; Lee, Herng-Sheng; Chang, Hung; Chu, Chi-Ming; Huang, Guo-Shu; Chen, Wei-Teing; Tsai, Yu-Jui; Lin, Hong-Ling; Lin, Fu-Huang; Su, Sui-Lung

    2016-01-01

    Background Studies of angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and the risks of knee osteoarthritis (OA) have yielded conflicting results. Objective To determine the association between ACE I/D and knee OA, we conducted a combined case-control study and meta-analysis. Methods For the case-control study, 447 knee OA cases and 423 healthy controls were recruited between March 2010 and July 2011. Knee OA cases were defined using the Kellgren-Lawrence grading system, and the ACE I/D genotype was determined using a standard polymerase chain reaction. The association between ACE I/D and knee OA was detected using allele, genotype, dominant, and recessive models. For the meta-analysis, PubMed and Embase databases were systematically searched for prospective observational studies published up until August 2015. Studies of ACE I/D and knee OA with sufficient data were selected. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for the D versus I allele with regard to knee OA risk. Results We found no significant association between the D allele and knee OA [OR: 1.09 (95% CI: 0.76–1.89)] in the present case-control study, and the results of other genetic models were also nonsignificant. Five current studies were included, and there were a total of six study populations after including our case-control study (1165 cases and 1029 controls). In the meta-analysis, the allele model also yielded nonsignificant results [OR: 1.37 (95% CI: 0.95–1.99)] and a high heterogeneity (I2: 87.2%). Conclusions The association between ACE I/D and knee OA tended to yield negative results. High heterogeneity suggests a complex, multifactorial mechanism, and an epistasis analysis of ACE I/D and knee OA should therefore be conducted. PMID:27657933

  12. Prevalence of the angiotensin I converting enzyme insertion/deletion polymorphism, plasma angiotensin converting enzyme activity, and left ventricular mass in a normotensive Chilean population.

    PubMed

    Jalil, J E; Piddo, A M; Cordova, S; Chamorro, G; Braun, S; Jalil, R; Vega, J; Jadue'P, L; Lavandero, S; Lastra, P

    1999-07-01

    The aim of this study was to estimate the prevalence of the different alleles of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and associated plasma ACE activity, as well as cardiac echocardiographic structure, in a healthy Chilean population. We selected 117 healthy normotensive subjects (aged 45 to 60 years, middle socioeconomic status, nonobese, and nondiabetic) from a population-based study concerning the prevalence of risk factors for chronic diseases (Conjunto de Acciones Para la Reducción Multifactorial de las Enfermedades no Transmisibles [CARMEN]). The frequencies of the I and D alleles were 0.57 and 0.43, respectively. Mean plasma ACE activity was 15.3 +/- 3.9 U/mL. Compared with subjects with the II genotype, plasma ACE activity was significantly higher in subjects with the ID and DD genotypes with no difference between them. No correlation was observed between blood pressure and plasma ACE activity. Among the three different genotypes there was no difference in left ventricular (LV) dimensions or in LV mass. No correlation between plasma ACE activity and LV mass was observed for either gender or different genotypes. Multivariate linear regression analysis using LV mass and LV mass index as dependent variables showed independent effects (P < .05) for gender (higher LV mass in men) and diastolic blood pressure, but not for the DD genotype. In conclusion, in this population, the presence of the D allele on the ACE gene determined higher circulating ACE activity. However, in this normotensive healthy population, male gender and diastolic blood pressure, but not the presence of the D allele, were associated with increased LV mass.

  13. Meta-analysis of the human leukocyte antigen-G (HLA-G) 14 bp insertion/deletion polymorphism as a risk factor for preeclampsia.

    PubMed

    Pabalan, N; Jarjanazi, H; Sun, C; Iversen, A C

    2015-09-01

    The non-classical major histocompatibility complex, human leukocyte antigen (HLA)-G, plays an important role in pregnancy. HLA-G mediates proper interaction between maternal immune cells and fetal trophoblasts invading the uterine wall, to ensure successful placental development and function. Several HLA-G gene variants have been shown to be associated with development of preeclampsia (PE), but the reported associations of the HLA-G 14 base pair (bp) insertion/deletion (I/D) polymorphism (rs66554220) with PE are inconsistent. In this meta-analysis of HLA-G 14 bp I/D in each member of the family triad, we estimated risk (odds ratio [OR], 95% confidence interval) of associations with PE based on nine published offspring, nine mother and three father case-control studies. No significant increased risk associations between PE and HLA-G 14 bp I/D were detected in any of the family triad members (offspring: OR = 1.08-1.21, P = 0.57-0.74; mothers: OR = 1.11-1.28, P = 0.07-0.44; fathers: OR = 1.09-1.65, P = 0.07-0.70). Of the 20 comparisons performed, 14 (70%) were non-heterogeneous and seven of these had zero heterogeneity (I(2) = 0%). Sensitivity treatment confirmed robustness for the overall lack of association for HLA-G 14 bp I/D. In subgroup analysis, significant association between HLA-G 14 bp I/D and PE was shown in offspring from primipara (OR = 1.66-1.95, P = 0.04) and European Caucasian pregnancies (OR = 1.37-2.03, P = 0.02-0.03). However, heterogeneity and sensitivity tests suggest that further investigation is needed to determine if HLA-G 14 bp I/D is involved in trophoblast HLA-G expression and PE development in these subgroups.

  14. What is the impact of the ACE gene insertion/deletion (I/D) polymorphism on the clinical effectiveness and adverse events of ACE inhibitors? – Protocol of a systematic review

    PubMed Central

    Scharplatz, M; Puhan, MA; Steurer, J; Bachmann, LM

    2004-01-01

    Background The Angiotensin Converting Enzyme (ACE) insertion/deletion (I/D) polymorphism has received much attention in pharmacogenetic research because observed variations in response to ACE inhibitors might be associated with this polymorphism. Pharmacogenetic testing raises the hope to individualise ACE inhibitor therapy in order to optimise its effectiveness and to reduce adverse effects for genetically different subgroups. However, the extent of its effect modification in patients treated with ACE inhibitors remains inconclusive. Therefore our objective is to quantify the effect modification of the insertion/deletion polymorphism of the angiotensin converting enzyme gene on any surrogate and clinically relevant parameters in patients with cardiovascular diseases, diabetes, renal transplantation and/or renal failure. Methods Systematic Review. We will perform literature searches in six electronic databases to identify randomised controlled trials comparing the effectiveness and occurrence of adverse events of ACE inhibitor therapy against placebo or any active treatment stratified by the I/D gene polymorphism. In addition, authors of trials, experts in pharmacogenetics and pharmaceutical companies will be contacted for further published or unpublished data. Hand searching will be accomplished by reviewing the reference lists of all included studies. The methodological quality of included papers will be assessed. Data analyses will be performed in clinically and methodologically cogent subgroups. The results of the quantitative assessment will be pooled statistically where appropriate to produce an estimate of the differences in the effect of ACE inhibitors observed between the three ACE genotypes. Discussion This protocol describes a strategy to quantify the effect modification of the ACE polymorphism on ACE inhibitors in relevant clinical domains using meta-epidemiological research methods. The results may provide evidence for the usefulness of pharmacogenetic

  15. Dopamine metabolism in adults with 22q11 deletion syndrome, with and without schizophrenia--relationship with COMT Val¹⁰⁸/¹⁵⁸Met polymorphism, gender and symptomatology.

    PubMed

    Boot, Erik; Booij, Jan; Abeling, Nico; Meijer, Julia; da Silva Alves, Fabiana; Zinkstok, Janneke; Baas, Frank; Linszen, Don; van Amelsvoort, Thérèse

    2011-07-01

    22q11 Deletion syndrome (22q11DS) is a major risk factor for schizophrenia. In addition, both conditions are associated with alterations of the dopaminergic system. The catechol-O-methyltransferase (COMT) gene, located within the deleted region, encodes for the enzyme COMT that is important for degradation of catecholamines, including dopamine (DA). COMT activity is sexually dimorphic and its gene contains a functional polymorphism, Val¹⁰⁸/¹⁵⁸ Met; the Met allele is associated with lower enzyme activity. We report the first controlled catecholamine study in 22q11DS-related schizophrenia. Twelve adults with 22q11DS with schizophrenia (SCZ+) and 22 adults with 22q11DS without schizophrenia (SCZ-) were genotyped for the COMT Val¹⁰⁸/¹⁵⁸ Met genotype. We assessed dopaminergic markers in urine and plasma. We also correlated these markers with scores on the Positive and Negative Symptom Scale (PANSS). Contrary to our expectations, we found SCZ+ subjects to be more often Val hemizygous and SCZ- subjects more often Met hemizygous. Significant COMT cross gender interactions were found on dopaminergic markers. In SCZ+ subjects there was a negative correlation between prolactin levels and scores on the general psychopathology subscale of the PANSS scores. These findings suggest intriguing, but complex, interactions of the COMT Val¹⁰⁸/¹⁵⁸ Met polymorphism, gender and additional factors on DA metabolism, and its relationship with schizophrenia.

  16. A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. T...

  17. Insertions, Deletions, and Single-Nucleotide Polymorphisms at Rare Restriction Enzyme Sites Enhance Discriminatory Power of Polymorphic Amplified Typing Sequences, a Novel Strain Typing System for Escherichia coli O157:H7

    PubMed Central

    Kudva, Indira T.; Griffin, Robert W.; Murray, Megan; John, Manohar; Perna, Nicole T.; Barrett, Timothy J.; Calderwood, Stephen B.

    2004-01-01

    Polymorphic amplified typing sequences (PATS) for Escherichia coli O157:H7 (O157) was previously based on indels containing XbaI restriction enzyme sites occurring in O-island sequences of the O157 genome. This strain-typing system, referred to as XbaI-based PATS, typed every O157 isolate tested in a reproducible, rapid, straightforward, and easy-to-interpret manner and had technical advantages over pulsed-field gel electrophoresis (PFGE). However, the system was less discriminatory than PFGE and was unable to differentiate fully between unrelated isolates. To overcome this drawback, we enhanced PATS by using another infrequently cutting restriction enzyme, AvrII (also known as BlnI), to identify additional polymorphic regions that could increase the discriminatory ability of PATS typing. Referred to as AvrII-based PATS, the system identified seven new polymorphic regions in the O157 genome. Unlike XbaI, polymorphisms involving AvrII sites were caused by both indels and single-nucleotide polymorphisms occurring in O-island and backbone sequences of the O157 genome. AvrII-based PATS by itself provided poor discrimination of the O157 isolates tested. However, when primer pairs amplifying the seven polymorphic AvrII sites were combined with those amplifying the eight polymorphic XbaI sites (combined PATS), the discriminatory power of PATS was enhanced. Combined PATS matched related O157 isolates better than PFGE while differentiating between unrelated isolates. PATS typed every O157 isolate tested and directly targeted polymorphic sequences responsible for differences in the restriction digest patterns of O157 genomic DNA, utilizing PCR rather than relying on gel electrophoresis. This enabled PATS to resolve the ambiguity in PFGE typing, including that arising from the “more distantly related” and “untypeable” profiles. PMID:15184409

  18. Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to allergic rhinitis in Chinese populations: a systematic review and meta-analysis.

    PubMed

    Huang, Ruo-Fei; Dong, Pin; Zhang, Tian-Zhen; Ying, Xin-Jiang; Hu, Hua

    2016-02-01

    In view of the controversies surrounding the angiotensin-converting enzyme (ACE)-allergic rhinitis (AR) association, a systematic review and meta-analysis of the ACE genetic association studies of AR was performed in Chinese populations. PubMed, Springer Link, OvidSP, Chinese biomedical database, Chinese national knowledge infrastructure, Chinese VIP and Wanfang databases were searched for related studies. A total of 4 studies including 415 AR patients and 309 controls were involved in this meta-analysis. Overall, significant association was found between ACE I/D polymorphism and AR risk when all studies in Chinese populations pooled into the meta-analysis (allele, OR 1.50, 95 % CI 1.19-1.90; homozygous, OR 2.59, 95 % CI 1.52-4.41, recessive, OR 2.05, 95 % CI 1.27-3.32). In the subgroup analysis by ethnicity, ACE I/D polymorphism was associated with significant elevated risks of AR in Chinese Han under homozygous and recessive models (homozygous, OR 4.36, 95 % CI 1.76-10.82, recessive, OR 2.51, 95 % CI 1.18-5.34). In conclusion, this meta-analysis provides the evidence that ACE I/D polymorphism may contribute to the AR development in Chinese populations and studies with large sample size and wider spectrum of population are warranted to verify this finding.

  19. Evaluation of glutathione S-transferase T1 deletion polymorphism on type 2 diabetes mellitus risk in Zoroastrian females in Yazd, Iran

    PubMed Central

    Afrand, Mohammadhosain; Khalilzadeh, Saeedhossein; Bashardoost, Nasrollah; Sheikhha, Mohammad Hasan

    2015-01-01

    Background: There has been much interest in the role of free radicals and oxidative stress in the pathogenesis of diabetes mellitus (DM). The aim of this study was to assess the possible association between genetic polymorphisms of the glutathione S-transferase-Theta (GSTT1) and the risk of the development of DM in Zoroastrian females in Yazd, Iran. Materials and Methods: This was a case-control study in which GSTT1 polymorphism was genotyped in 51 randomly selected DM patients and 50 randomly selected healthy controls among Zoroastrian females whose ages ranged from 40 to 70. Results: The frequencies of GSTT1 null genotype and GSTT1 present were 72% and 28%, respectively, in control samples, while in patients with type 2 diabetes (T2DM), the frequencies of GSTT1 null genotype and GSTT1 present were 27.5% and 72.5%, respectively. There were higher levels of triglyceride (TG), fasting blood sugar (FBS), total cholesterol (TC), low-density lipoprotein (LDL), Urea, and high-density lipoprotein (HDL) in cases of GSTT1 null genotype compared to the GSTT1 present genotype in controls. Conclusions: Our results indicated that healthy subjects had a higher frequency of the GSTT1 null genotype than patients with T2DM. However, we observed no significant association between the GSTT1 null genotype and T2DM in the current study. PMID:25593839

  20. Association and interaction of NFKB1 rs28362491 insertion/deletion ATTG polymorphism and PPP1R13L and CD3EAP related to lung cancer risk in a Chinese population.

    PubMed

    Yin, Jiaoyang; Wang, Huiwen; Vogel, Ulla; Wang, Chunhong; Hou, Wei; Ma, Yegang

    2016-04-01

    The nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NFKB1) gene encodes p105 and p50 kD which are both subunits of the transcription factor NF-kB, involved in a wide variety of diseases and pathological states associated with inflammation, immunity, and tumorigenesis. The NFKB1 rs28362491 polymorphism in the promoter region (-94 insertion/deletion ATTG) has been associated with risk of various cancers. Our study aims were to evaluate the associations of NFKB1 rs28362491 polymorphism and interactions of this single-nucleotide polymorphism (SNP) and PPP1R13L and CD3EAP and smoking duration in relation to lung cancer risk in a Chinese population. The study population consisted of 544 Chinese lung cancer cases and 550 cancer-free matched (age, sex, and ethnicity) controls. No associations were found between NFKB1 rs28362491 and lung cancer risk. CD3EAP rs967591 was associated with increased lung cancer risk in the dominant model [OR (95 % CI) = 1.38 (1.05-1.80), P = 0.018]. The common haplotype containing PPP1R13L rs1970764(G), CD3EAP rs967591(A), and CD3EAP rs735482(C) was associated with lung cancer [adjusted OR (95 % CI) = 1.29 (1.03-1.62), P = 0.028]. Multifactor dimensionality reduction (MDR) analysis revealed two-way and three-way interactions between CD3EAP rs735482 and smoking and between NFKB1 rs28362491, PPP1R13L rs1970764, and smoking. In conclusion, we were able to reproduce previously found associations between PPP1R13L and CD3EAP polymorphisms and lung cancer risk in an increased study group, and we found interactions between NFKB1 rs28362491-PPP1R13L rs1970764 and smoking duration and between CD3EAP rs735482 and smoking duration. These results suggest that these genes and smoking are part of the same biological pathway leading to smoking-induced lung cancer. PMID:26563375

  1. Association of glutathione S-transferase GSTM1 and GSTT1 deletion polymorphisms with obesity and their relationship with body mass index, lipoprotein and hypertension among young age Saudis

    PubMed Central

    Almoshabek, Hamoud A; Mustafa, Md; Al-Asmari, Mohammed M; Alajmi, Tahani K

    2016-01-01

    Objectives Persistent oxidative stress is one of the several risk factors that may be associated with the etiology of obesity. The present study is aimed to investigate association between GSTM1 and GSTT1 polymorphisms with obesity and their relationship with plasma lipoproteins, body mass index (BMI) and hypertension. Design The GSTM1 and GSTT1 deletion polymorphisms were analyzed by multiplex polymerase chain reaction. The lipoproteins were measured in plasma using commercially available kit and the weight, height, systolic (SBP) and diastolic (DBP) blood pressures by standard procedure of measurements. Setting Prince Sultan Military Medical City, Riyadh Saudi Arabia. Participants A total of 420 overweight/obese cases and 234 normal weight controls belong to young age Saudis. Main outcomes measures GSTM1/GSTT1 polymorphisms may be associated with obesity. Results Weight, BMI, low-density lipoprotein (LDL) and SBP were significantly higher while high-density lipoprotein (HDL) was significantly lower in cases in comparison to controls. Frequency of GSTM1+/GSTT1− (OR = 2.70, 95% CI = 1.52–4.81, p = <0.001) and GSTM1−/GSTT1− (OR = 2.43, 95% CI = 1.15–5.15, p = 0.018) was significantly higher in cases as compared to controls. BMI and weight were significantly higher in GSTM1+/GSTT1− and GSTM1−/GSTT1− genotypes, and LDL, DBP and SBP significantly higher in GSTM1−/GSTT1− null genotype while HDL was significantly lower in GSTM1−/GSTT1+ and GSTM1−/GSTT1− genotypes in comparison to GSTM1+/GSTT1+ genotype. Conclusions The GSTM1+/GSTT1− and GSTM1−/GSTT1− null genotypes were significantly associated with obesity and have shown relationship with obesity risk factors in cases. Hence, these genes may be associative genetic risk factor for obesity among young age Saudis. PMID:27721975

  2. Identification of sequence-related amplified polymorphism and insertion-deletion markers linked to the male fertility restorer gene of pol-like CMS06J45 in heading Chinese cabbage (Brassica rapa subsp pekinensis).

    PubMed

    Xu, X Y; Zhang, Y; Zhang, L G; Fang, Z Y

    2014-11-14

    In order to map the restorer gene BrRfp of the polima (pol)-like cytoplasmic male sterility (CMS) 06J45 line in heading Chinese cabbage, an F2 segregating population with 258 individuals of CMS06J45 and the restorer line 01S325 were tested by sequence-related amplified polymorphism (SRAP) and insertion-deletion (InDel) technologies combined with the bulked segregant analysis method. As a result, two SRAP markers, me3em3.366 and pm88bg5.263, that were linked with the BrRfp gene were identified from 463 SRAP primer pairs. By cloning, sequencing, and basic local alignment search tool analysis, the two markers were targeted to the BGIScaffold000053 of Brassica rapa in the Brassica database. Using the BGIScaffold000053 sequence, four InDel primer pairs were designed and identified to be linked with the BrRfp gene in this population. Linkage analysis showed that these markers were distributed on both sides of the BrRfp gene, the linkage distances of two nearest markers InDel878.1125 and InDel920.713 were 0.82 and 0.46 cM, respectively, and the BrRfp gene was restricted to a 243-kb genomic region of B. rapa. These specific markers provided basic information for map-based cloning of the BrRfp gene and will be very valuable for the marker-assisted selection of a new restorer line in heading Chinese cabbage.

  3. Schizophrenia and chromosomal deletions

    SciTech Connect

    Lindsay, E.A.; Baldini, A.; Morris, M. A.

    1995-06-01

    Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

  4. Comprehensive Analysis of Pathogenic Deletion Variants in Fanconi Anemia Genes

    PubMed Central

    Flynn, Elizabeth K.; Kamat, Aparna; Lach, Francis P.; Donovan, Frank X.; Kimble, Danielle C.; Narisu, Narisu; Sanborn, Erica; Boulad, Farid; Davies, Stella M.; Gillio, Alfred P.; Harris, Richard E.; MacMillan, Margaret L.; Wagner, John E.; Smogorzewska, Agata; Auerbach, Arleen D.; Ostrander, Elaine A.; Chandrasekharappa, Settara C.

    2014-01-01

    Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution Comparative Genome Hybridization arrays (arrayCGH), Single Nucleotide Polymorphism arrays (SNParrays) and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by Non-Allelic Homologous Recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants. PMID:25168418

  5. Deletions of the elastin gene in Williams Syndrome

    SciTech Connect

    Greenberg, F.; Nickerson, E.; McCaskill, C.

    1994-09-01

    To investigate deletions in the elastin gene in patients with Williams Syndrome (WS), we screened 37 patients and their parents for deletions in the elastin gene by both fluorescence in situ hybridization (FISH) using cosmid cELN272 containing the 5{prime} end of the elastin gene and by polymerase chain reaction (PCR) using a primer pair which amplifies intron 17 in the elastin gene, producing a polymorphic amplification product. Thirty-two patients have been investigated by both the FISH and PCR techniques, one patient was studied only by PCR, and 4 patients were studied only by FISH. Overall, 34 of 37 patients (92%) were deleted for the elastin gene. Using the PCR marker, 14 patients were informative and 12 were shown to be deleted [maternal (n=5) and paternal (n=7)]. Using cosmid cELN272, 33 of 36 patients demonstrated a deletion of chromosome 7q11.23. In one family, both the mother and daughter were deleted due to an apparently de novo deletion arising in the mother. Three patients were not deleted using the elastin cosmid; 2 of these patients have classic WS. Another non-deleted patient has the typical facial features and hypercalcemia but normal intelligence. These three patients will be important in delineating the critical region(s) responsible for the facial features, hypercalcemia, mental retardation and supravalvular aortic stenosis (SVAS). There was not an absolute correlation between deletions in elastin and SVAS, although these individuals may be at risk for other cardiovascular complications such as hypertention. Since the majority of WS patients are deleted for a portion of the elastin gene, most likely this marker will be an important diagnostic tool, although more patients will need to be studied. Those patients who are not deleted but clinically have WS will be missed using only this one marker. Expansion of the critical region to other loci and identification of additional markers will be essential for identifying all patients with WS.

  6. Angiotensin-converting enzyme gene insertion/deletion, not bradykinin B2 receptor -58T/C gene polymorphism, associated with angiotensin-converting enzyme inhibitor-related cough in Chinese female patients with non-insulin-dependent diabetes mellitus.

    PubMed

    Lee, Y J; Tsai, J C

    2001-11-01

    To investigate the genetic susceptibility associated with cough related to angiotensin-converting enzyme inhibitor (ACEI) therapy in patients with type 2 diabetes, 189 non-insulin-dependent diabetes mellitus (NIDDM) patients with proteinuria or hypertension treated with perindopril were studied. Cough was considered to be present if the patients had been bothered by a cough during treatment and if they had had related symptoms for at least 2 weeks without an identifiable cause. Polymerase chain reaction (PCR) coupled with single-strand conformation polymorphism (SSCP) was used to detect polymorphisms of ACE and bradykinin B2-receptor genes. After 8 weeks of treatment, 49.2% (93 of 189) of our NIDDM patients were found to be suffering from ACEI-related cough. ACEI-related cough was mainly associated with female patients, with 71.7% (76 of 106) of female and only 20.5% (17 of 83) of male patients experiencing cough after ACEI treatment. There was a significant association of ACE II genotype with ACEI-related cough. The genotype frequencies were 58.2% for II, 47.8% for ID, and 16.7% for DD in patients with ACEI-associated cough and 41.8% for II, 52.2% for ID, and 83.3% for DD in subjects without ACEI-associated cough (chi(2) = 10.268; df = 2, P =.006). As female patients made up the majority of the subjects suffering from ACEI-related cough, we further analyzed the association of ACE I/D genotype with ACEI-related cough separately by sex. Male patients with ACEI-related cough were not associated with ACE I/D genotype distribution, while female patients were strongly associated with ACE I/D genotype polymorphism (chi(2) = 16.12; df = 2; P <.001). There was no association between the bradykinin B2 receptor gene -58T/C polymorphism with ACEI-related cough. In conclusion, our results indicate that Chinese diabetic female subjects are susceptible to ACEI-related cough, and this susceptibility may be genetically predetermined. PMID:11699055

  7. Prioritizing sequence polymorphisms for potential association with phenotype

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The millions of SNP, insertions and deletions revealed by next generation sequencing (NGS), are certain to include polymorphisms responsible for phenotypic variation. Distinguishing causal from benign variants may allow genomic predictions that are robust across populations. While variants underly...

  8. Constitutional Ip36 deletion in a child with neuroblastoma

    SciTech Connect

    Biegel, J.A.; Zackai, E.H.; Scher, C.D.; Emanuel, B.S. Univ. of Pennsylvania, Philadelphia ); White, P.S.; Marshall, H.N.; Fujimori, Minoru; Brodeur, G.M. )

    1993-01-01

    The authors describe a child with dysmorphic features, as well as developmental and growth delay, who developed neuroblastoma at 5 mo of age. Cytogenetic analysis of blood lymphocytes revealed an interstitial deletion of 1p36.1 [r arrow] 1p36.2, which was apparent only with high-resolution banding. Molecular analysis with a collection of polymorphic DNA probes for 1p confirmed an interstitial deletion involving subbands of 1p36. Deletions of this region are a common finding in neuroblastoma cells from patients with advanced stages of disease. Therefore, these results (a) suggest that constitutional deletion of this region predisposed the patient to the development of neuroblastoma and (b) support the localization of a neuroblastoma tumor-suppressor locus to 1p36. 48 refs., 2 figs.

  9. Molecular cytogenetic detection of chromosome 15 deletions in patients with Prader-Willi and Angelman syndromes

    SciTech Connect

    Chadwick, D.E.; Weksberg, R.; Shuman, C.

    1994-09-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct genetic disorders involving alterations of chromosome 15q11-q13. Approximately 75% of individuals with PWS and AS have deletions within 15q11-q13 by molecular analysis. We have evaluated fluorescence in situ hybridization (FISH) for the clinical laboratory detection of del(15)(q11q13) using the cosmid probes D15S11 and GABRB3 (ONCOR, Gaithersburg, NY). 4/4 PWS and 1/1 AS patients previously identified as having cytogenetic deletions were deleted for both probes. In a prospectively ascertained series of 54 patient samples referred to rule out either PWS or AS, 8 were deleted for D15S11 and GABRB3. In addition, an atypical deletion patient with PWS was also identified who was found to be deleted for GABRB3 but not D15S11. The SNRPN locus was also deleted in this patient. Only 4 of the 9 patient samples having molecular cytogenetic deletions were clearly deleted by high resolution banding (HRB) analysis. The microscopic and submicroscopic deletions have been confirmed by dinucleotide (CA) repeat analysis. Microsatellite polymorphism analysis was also used to demonstrate that five non-deletion patients in this series had biparental inheritance of chromosome 15, including region q11-q13. Deletions were not detected by either HRB, FISH or microsatellite polymorphism analysis in samples obtained from parents of the deletion patients. Methylation studies of chromosome 15q11-q13 are in progress for this series of PWS and AS families. FISH analysis of chromosome 15q11-q13 in patients with PWS and AS is a rapid, sensitive and reliable method for deletion detection.

  10. Deletion (2)(q37)

    SciTech Connect

    Stratton, R.F.; Tolworthy, J.A.; Young, R.S.

    1994-06-01

    We report on a 5-month-old girl with widely spaced nipples, redundant nuchal skin, coarctation of the aorta, anal atresia with distal fistula, postnatal growth retardation, hypotonia, and sparse scalp hair. Initial clinical assessment suggested the diagnosis of Ullrich-Turner syndrome. Chromosome analysis showed a 46,XX,del(2)(q37) karyotype in peripheral lymphocytes. We compare her findings to those of other reported patients with terminal deletions of 2q. 8 refs., 2 figs., 1 tab.

  11. [MOLECULAR-GENETIC POLYMORPHISM OF chs_H1 GENE IN UKRAINIAN HOP VARIETIES].

    PubMed

    Venzer, A M; Volkova, N E; Sivolap, Yu M

    2015-01-01

    Polymorphism of chs_H1 gene encoding the "true" chalcone synthase was determined by alignment of sequences. The polymorphism associates with single nucleotide changes, insertions or deletions (indels) in the promoter, exons, intron, 3'-untranslated region. The molecular-genetic polymorphism in gene chs_H1 different regions of hop varieties of Polessye Agriculture Institute' breeding NAAS was analyzed. PMID:26638493

  12. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale

    PubMed Central

    Handsaker, Robert E.; Korn, Joshua M.; Nemesh, James; McCarroll, Steven A.

    2016-01-01

    Accurate and complete analysis of genome variation in large populations will be required to understand the role of genome variation in complex disease. We present an analytical framework for characterizing genome deletion polymorphism in populations, using sequence data that are distributed across hundreds or thousands of genomes. Our approach uses population-level relationships to re-interpret the technical features of sequence data that often reflect structural variation. In the 1000 Genomes Project pilot, this approach identified deletion polymorphism across 168 genomes (sequenced at 4x average coverage) with sensitivity and specificity unmatched by other algorithms. We also describe a way to determine the allelic state or genotype of each deletion polymorphism in each genome; the 1000 Genomes Project used this approach to type 13,826 deletion polymorphisms (48 bp – 960 kbp) at high accuracy in populations. These methods offer a way to relate genome structural polymorphism to complex disease in populations. PMID:21317889

  13. Recurring exon deletions in the haptoglobin (HP) gene associate with lower blood cholesterol levels

    PubMed Central

    Boettger, Linda M.; Salem, Rany M.; Handsaker, Robert E.; Peloso, Gina; Kathiresan, Sekar; Hirschhorn, Joel; McCarroll, Steven A.

    2016-01-01

    Two exons of the human haptoglobin (HP) gene exhibit copy number variation that affects HP multimerization and underlies one of the first protein polymorphisms identified in humans. The evolutionary origins and medical significance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from the recurring reversion of an ancient hominin-specific duplication of these exons. Though this polymorphism has been largely invisible to genome-wide genetic studies to date, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We show that these deletions, and a SNP that affects HP expression, are the likely drivers of the strong but complex association of cholesterol levels to SNPs near HP. Recurring exonic deletions in the haptoglobin gene likely enhance human health by lowering cholesterol levels in the blood. PMID:26901066

  14. Molecular analysis of three patients with interstitial deletions of chromosome band 14q31.

    PubMed Central

    Byth, B C; Costa, M T; Teshima, I E; Wilson, W G; Carter, N P; Cox, D W

    1995-01-01

    Two patients and one three generation family with interstitial deletions of distal chromosome band 14q31 are described. The deletions were initially identified by chromosome analysis; we have used highly informative simple sequence repeat polymorphisms to define the deletions at the molecular level. This analysis also establishes the parental origin of the deleted chromosome. One of the patients was initially described as having a terminal deletion of chromosome 14 from 14q31 to 14qter; we show here that this child has instead an interstitial deletion of band 14q31. The smallest deletion involves a single anonymous DNA marker and is associated with an almost normal phenotype. The two patients with larger deletions have phenotypes similar to those seen in previously described cases of interstitial deletions of chromosome 14, including minor dysmorphic features and developmental delay. Delineation of these deletions allows the ordering of markers within the 14q31 region, in which the gene for the degenerative neurological disorder Machado-Joseph disease is localised. Images PMID:7562974

  15. De novo proximal interstitial deletions of 14q: Cytogenetic and molecular investigations

    SciTech Connect

    Shapira, S.K.; Anderson, K.L.; Orr-Urtregar, A.; Craigen, W.J.; Lupski, J.R.; Shaffer, L.G.

    1994-08-01

    We report on 2 unrelated patients who had chromosome analysis performed because of psychomotor delay, failure to thrive, and minor anomalies. Each patient had a novel proximal 14q deletion (q11.2 to q21.1 in patient 737 and q12 to q22 in patient 777). Polymorphic (C-A){sub n} microsatellite markers distributed along the length of chromosome 14q were examined in both patients and their parents in order to determine which marker loci were deleted. The deletion in patient 737 was found to be paternal in origin, based on the analysis of 2 marker loci (D14S54 and D14S70), thus assigning these loci to the deleted interval q11.2 q21.1. Furthermore, 3 loci were not deleted (TCRD, D14S50, and D14S80), suggesting that they are within or proximal to 14q11.2. In the other family (patient 777), none of the markers were fully informative, but the deleted chromosome was determined to be paternally derived based on cytogenetic heteromorphisms. Despite having overlapping proximal 14q deletions, these 2 patients shared few phenotypic similarities except for failure to thrive, micrognathia, and hypoplasia of the corpus callosum. Therefore, a distinct proximal 14q deletion syndrome is not yet apparent. However, the molecular analyses facilitated the localization of several 14q DNA markers to the deletion regions in these 2 patients, while excluding other markers from each deletion. 24 refs., 4 figs.

  16. The evolution and functional impact of human deletion variants shared with archaic hominin genomes.

    PubMed

    Lin, Yen-Lung; Pavlidis, Pavlos; Karakoc, Emre; Ajay, Jerry; Gokcumen, Omer

    2015-04-01

    Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human-Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn's disease. Our analyses suggest that these "exonic" deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes.

  17. Mutations and a polymorphism in the tuberin gene

    SciTech Connect

    Northup, H.; Rodriguez, J.A.; Au, K.S.; Rodriguez, E.

    1994-09-01

    Two deletions and a polymorphism have been identified in the recently described tuberin gene. The tuberin gene (designated TSC2) when mutated causes tuberous sclerosis complex (TSC). Fifty-three affected individuals (30 from families with multiple affected and 23 isolated cases) were screened with the tuberin cDNA for gross deletions or rearrangements. Both deletions were found in families with multiple affected members (family designations: HOU-5 and HOU-22). The approximate size of the deletion in HOU-5 is ten kilobases and eliminates a BamHI restriction site. The deletion includes a portion of the 5{prime} half of the tuberin cDNA. The deletion in HOU-22 occurs in the 3{prime} half of the gene. The deletions are being further characterized. A HindIII restriction site polymorphism was detected by a 0.5 kilobase probe from the 5{prime} coding region of the tuberin gene in an individual from a family linked to chromosome 9 (posterior probability of linkage 93%). The polymorphism did not segregate with TSC in the family. The family had previously been shown to give negative results with multiple markers on chromosome 16. The polymorphism was also seen in one individual among a panel of 20 randomly selected unaffected individuals. Thirty-five additional affected probands (five from families and 30 isolated cases) are being tested with the tuberin cDNA. Testing for subtle mutations is our panel of 80 affected probands is underway utilizing SSCP. Additional mutations or polymorphisms detected will be reported. The tuberin cDNA was a kind gift of The European Chromosome 16 Tuberous Sclerosis Consortium.

  18. Genomic anatomy of the Tyrp1 (brown) deletion complex

    SciTech Connect

    Hunsicker, Patricia R; Johnson, Dabney K

    2006-01-01

    Chromosome deletions in the mouse have proven invaluable in the dissection of gene function. The brown deletion complex comprises >28 independent genome rearrangements, which have been used to identify several functional loci on chromosome 4 required for normal embryonic and postnatal development. We have constructed a 172-bacterial artificial chromosome contig that spans this 22- egabase (Mb) interval and have produced a contiguous, finished, and manually annotated sequence from these clones. The deletion complex is strikingly gene- oor, containing only 52 protein-coding genes (of which only 39 are supported by human homologues) and has several further notable genomic features, including several segments of >1 Mb, apparently devoid of a coding sequence. We have used sequence polymorphisms to finely map the deletion breakpoints and identify strong candidate genes for the known phenotypes that map to this region, including three lethal loci (l4Rn1, l4Rn2, and l4Rn3) and the fitness mutant brown-associated fitness (baf). We have also characterized misexpression of the basonuclin homologue, Bnc2, associated with the inversion-ediated coat color mutant white-based brown (Bw). This study provides a molecular insight into the basis of several characterized mouse mutants, which will allow further dissection of this region by targeted or chemical mutagenesis.

  19. Molecular analysis of the Duchenne muscular dystrophy gene in Spanish individuals: Deletion detection and familial diagnosis

    SciTech Connect

    Patino, A.; Garcia-Delgado, M.; Narbona, J.

    1995-11-06

    Deletion studies were performed in 26 Duchenne muscular dystrophy (DMD) patients through amplification of nine different exons by multiplex polymerase chain reaction (PCR). DNA from paraffin-embedded muscle biopsies was analyzed in 12 of the 26 patients studied. Optimization of this technique is of great utility because it enables analysis of material stored in pathology archives. PCR deletion detection, useful in DMD-affected boys, is problematic in determining the carrier state in female relatives. For this reason, to perform familial linkage diagnosis, we made use of a dinucleotide repeat polymorphism (STRP, or short tandem repeat polymorphism) located in intron 49 of the gene. We designed a new pair of primers that enabled the detection of 22 different alleles in relatives in the 14 DMD families studied. The use of this marker allowed familial diagnosis in 11 of the 14 DMD families and detection of de novo deletions in 3 of the probands. 8 refs., 5 figs., 2 tabs.

  20. A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review

    PubMed Central

    Fernández, Luis; Nevado, Julián; Santos, Fernando; Heine-Suñer, Damià; Martinez-Glez, Victor; García-Miñaur, Sixto; Palomo, Rebeca; Delicado, Alicia; Pajares, Isidora López; Palomares, María; García-Guereta, Luis; Valverde, Eva; Hawkins, Federico; Lapunzina, Pablo

    2009-01-01

    Background Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date. Methods We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents. Results Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial de novo 1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping. Conclusion The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors. PMID

  1. Structural Polymorphism in Amyloids

    PubMed Central

    Jones, Eric M.; Wu, Bo; Surewicz, Krystyna; Nadaud, Philippe S.; Helmus, Jonathan J.; Chen, Shugui; Jaroniec, Christopher P.; Surewicz, Witold K.

    2011-01-01

    The C-terminally-truncated human prion protein variant Y145Stop (or PrP23–144), associated with a familial prion disease, provides a valuable model for studying the fundamental properties of protein amyloids. In previous solid-state NMR experiments, we established that the β-sheet core of the PrP23–144 amyloid is composed of two β-strand regions encompassing residues ∼113–125 and ∼130–140. The former segment contains a highly conserved hydrophobic palindrome sequence, 113AGAAAAGA120, which has been considered essential to PrP conformational conversion. Here, we examine the role of this segment in fibrillization of PrP23–144 using a deletion variant, Δ113–120 PrP23–144, in which the palindrome sequence is missing. Surprisingly, we find that deletion of the palindrome sequence affects neither the amyloidogenicity nor the polymerization kinetics of PrP23–144, although it does alter amyloid conformation and morphology. Using two-dimensional and three-dimensional solid-state NMR methods, we find that Δ113–120 PrP23–144 fibrils contain an altered β-core extended N-terminally to residue ∼106, encompassing residues not present in the core of wild-type PrP23–144 fibrils. The C-terminal β-strand of the core, however, is similar in both fibril types. Collectively, these data indicate that amyloid cores of PrP23–144 variants contain “essential” (i.e. nucleation-determining) and “nonessential” regions, with the latter being “movable” in amino acid sequence space. These findings reveal an intriguing new mechanism for structural polymorphism in amyloids and suggest a potential means for modulating the physicochemical properties of amyloid fibrils without compromising their polymerization characteristics. PMID:22002245

  2. A 50 kb L1-type deletion mutation of the HEXB gene in Sandhoff disease

    SciTech Connect

    Zhang, Z.X.; Wakamatsu, N.; Akerman, B.R.

    1994-09-01

    Sandhoff disease is an autosomal recessive lysosomal storage disease resulting from mutations of the HEXB gene encoding the {beta}-subunit of {beta}-hexosaminidase A. A 16 kb deletion spanning the promoter region to intron 5 of the HEXB gene, occurring in {approximately}25% of mutant alleles, is the most common mutation known. We have identified a second large deletion in a patient with the severe, infantile form of Sandhoff disease. Single strand conformational polymorphism (SSCP) analysis revealed that the proband, a carrier sister and their mother had one dose of the HEXB gene. This was distinguished through the identification of several polymorphic sites between the promoter and exon 5 (father heterozygous at all sites, others {open_quotes}hemizygous{close_quotes}). Using a combination of pulse field electrophoresis and fine mapping by Southern blot analysis, we found that the deletion begins {approximately}25 kb 5{prime} of the HEXB promoter and ends within a BamHI/MscI fragment in intron 6. Sequence analysis of the region abutting the site of the deletion in intron 6 suggests that the deletion arose from recombination between L1-type sequence repeats. The second mutation, inherited from the father, was found by SSCP analysis and direct sequencing of exon 1 PCR products to be C{sub 185}{yields}T (S62T) and was not present in 60 control chromosomes.

  3. Molecular Definition of the 22q11 Deletions in Velo-Cardio-Facial Syndrome

    PubMed Central

    Morrow, Bernice; Goldberg, Rosalie; Carlson, Christine; Gupta, Ruchira Das; Sirotkin, Howard; Collins, John; Dunham, Ian; O'Donnell, Hilary; Scambler, Peter; Shprintzen, Robert; Kucherlapati, Raju

    1995-01-01

    Velo-cardio-facial syndrome (VCFS) is a common genetic disorder among individuals with cleft palate and is associated with hemizygous deletions in human chromosome 22q11. Toward the molecular definition of the deletions, we constructed a physical map of 22q11 in the form of overlapping YACs. The physical map covers >9 cM of genetic distance, estimated to span 5 Mb of DNA, and contains a total of 64 markers. Eleven highly polymorphic short tandem-repeat polymorphic (STRP) markers were placed on the physical map, and 10 of these were unambiguously ordered. The 11 polymorphic markers were used to type the DNA from a total of 61 VCFS patients and 49 unaffected relatives. Comparison of levels of heterozygosity of these markers in VCFS patients and their unaffected relatives revealed that four of these markers are commonly hemizygous among VCFS patients. To confirm these results and to define further the breakpoints in VCFS patients, 15 VCFS individuals and their unaffected parents were genotyped for the 11 STRP markers. Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers. The results revealed that all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. The results also show that the parental origin of the deleted chromosome does not have any effect on the phenotypic manifestation ImagesFigure 2Figure 3 PMID:7762562

  4. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3

    SciTech Connect

    White, P.S.; Maris, J.M.; Beltinger, C.

    1995-06-06

    Deletion of the short arm of human chromosome 1 is the most common cytogenetic abnormality observed in neuroblastoma. To characterize the region of consistent deletion, we performed loss of heterozygosity (LOH) studies on 122 neuroblastoma tumor samples with 30 distal chromosome 1p polymorphisms. LOH was detected in 32 of the 122 tumors (26%). A single region of LOH, marked distally by D1Z2 and proximally by D1S228, was detected in all tumors demonstrating loss. Also, cells from a patient with a constitutional deletion of 1p36, and from a neuroblastoma cell line with a small 1p36 deletion, were analyzed by fluorescence in situ hybridization. Cells from both sources had interstitial deletions of 1p36.2-36.3 which overlapped the consensus region of LOH defined by the tumors. Interstitial deletion in the constitutional case was confirmed by allelic loss studies using the panel of polymorphic markers. Four proposed candidate genes-DAN, ID3 (heir-1), CDC2L1 (p58), and TNFR2-were shown to lie outside of the consensus region of allelic loss, as defined by the above deletions. These results more precisely define the location of a neuroblastoma suppressor gene within 1p36.2-36.3, eliminating 33 centimorgans of proximal 1p36 from consideration. Furthermore, a consensus region of loss, which excludes the four leading candidate genes, was found in all tumors with 1p36 LOH. 31 refs., 4 figs.

  5. Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1.

    PubMed Central

    Devriendt, K; Matthijs, G; Van Dael, R; Gewillig, M; Eyskens, B; Hjalgrim, H; Dolmer, B; McGaughran, J; Bröndum-Nielsen, K; Marynen, P; Fryns, J P; Vermeesch, J R

    1999-01-01

    Deletions in the distal region of chromosome 8p (del8p) are associated with congenital heart malformations. Other major manifestations include microcephaly, intrauterine growth retardation, mental retardation, and a characteristic hyperactive, impulsive behavior. We studied genotype-phenotype correlations in nine unrelated patients with a de novo del8p, by using the combination of classic cytogenetics, FISH, and the analysis of polymorphic DNA markers. With the exception of one large terminal deletion, all deletions were interstitial. In five patients, a commonly deleted region of approximately 6 Mb was present, with breakpoints clustering in the same regions. One patient without a heart defect or microcephaly but with mild mental retardation and characteristic behavior had a smaller deletion within this commonly deleted region. Two patients without a heart defect had a more proximal interstitial deletion that did not overlap with the commonly deleted region. Taken together, these data allowed us to define the critical deletion regions for the major features of a del8p. PMID:10090897

  6. Genetics Home Reference: 18q deletion syndrome

    MedlinePlus

    ... Veltman JA, van Ravenswaaij-Arts CM. Genotype-phenotype mapping of chromosome 18q deletions by high-resolution array ... L, Pihko H. 18q deletions: clinical, molecular, and brain MRI findings of 14 individuals. Am J Med ...

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  12. The Evolution and Functional Impact of Human Deletion Variants Shared with Archaic Hominin Genomes

    PubMed Central

    Lin, Yen-Lung; Pavlidis, Pavlos; Karakoc, Emre; Ajay, Jerry; Gokcumen, Omer

    2015-01-01

    Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human–Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn’s disease. Our analyses suggest that these “exonic” deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes. PMID:25556237

  13. Interstitial deletions are not the main mechanism leading to 18q deletions

    SciTech Connect

    Strathdee, G.; Harrison, W.; Goodart, S.A.; Overhauser, J. ); Riethman, H.C. )

    1994-06-01

    Most patients who present with the 18q- syndrome have an apparent terminal deletion of the long arm of chromosome 18. For precise phenotypic mapping of this syndrome, it is important to determine whether the deletions are terminal deletions or interstitial deletions. A human telomeric YAC clone has been identified that hybridizes specifically to the telomeric end of 18q. This clone was characterized and used to analyze seven patients with 18q deletions. By FISH and Southern blotting analysis, all patients were found to lack this chromosomal region on their deleted chromosome, demonstrating that the patients do not have cryptic interstitial deletions. 30 refs., 3 figs.

  14. Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

    PubMed Central

    El Khattabi, Laïla; Guimiot, Fabien; Pipiras, Eva; Andrieux, Joris; Baumann, Clarisse; Bouquillon, Sonia; Delezoide, Anne-Lise; Delobel, Bruno; Demurger, Florence; Dessuant, Hélène; Drunat, Séverine; Dubourg, Christelle; Dupont, Céline; Faivre, Laurence; Holder-Espinasse, Muriel; Jaillard, Sylvie; Journel, Hubert; Lyonnet, Stanislas; Malan, Valérie; Masurel, Alice; Marle, Nathalie; Missirian, Chantal; Moerman, Alexandre; Moncla, Anne; Odent, Sylvie; Palumbo, Orazio; Palumbo, Pietro; Ravel, Aimé; Romana, Serge; Tabet, Anne-Claude; Valduga, Mylène; Vermelle, Marie; Carella, Massimo; Dupont, Jean-Michel; Verloes, Alain; Benzacken, Brigitte; Delahaye, Andrée

    2015-01-01

    6q16 deletions have been described in patients with a Prader–Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype–phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed. PMID:25351778

  15. Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion.

    PubMed

    Kayano, Shuji; Kure, Shigeo; Suzuki, Yoichi; Kanno, Kiyoshi; Aoki, Yoko; Kondo, Shinji; Schutte, Brian C; Murray, Jeffrey C; Yamada, Atsushi; Matsubara, Yoichi

    2003-01-01

    Three Japanese families with Van der Woude syndrome (VWS) were screened for mutations in the interferon regulatory factor 6 gene (IRF6) by sequencing its entire coding region. Two novel missense mutations, R45Q in exon 3 and P396S in exon 9, were identified in families 1 and 2, respectively. In family 3, no causative base change was found by the sequencing analysis, but a deletion involving exons 4-9 was suggested by multiplex PCR analysis. To confirm the deletion and to determine its 5'- and 3'-boundaries, we amplified a DNA fragment containing a heterozygous polymorphic site in exon 2 by using a 5'-upstream forward PCR primer and eight different reverse primers located 3'-downstream of exon 2. The amplified product was subjected to nested PCR to generate a DNA fragment containing the polymorphic site. When a reverse primer located within the deletion was used for the first PCR amplification, only the nondeletion allele was detected after the second PCR. Repeated analyses with eight different reverse primers allowed us to map the boundaries of the deletion, and subsequently a heterozygous 17,162-bp deletion involving exons 4-9 was identified. Since IRF6 mutations in a significant portion of VWS patients remain undetected by conventional sequencing analysis, it may be important to search for a large deletion in those patients. Our simple methods to identify deletions and to determine the boundaries of a deletion would facilitate the identification of such patients.

  16. Gene Deletion by Synthesis in Yeast.

    PubMed

    Kim, Jinsil; Kim, Dong-Uk; Hoe, Kwang-Lae

    2017-01-01

    Targeted gene deletion is a useful tool for understanding the function of a gene and its protein product. We have developed an efficient and robust gene deletion approach in yeast that employs oligonucleotide-based gene synthesis. This approach requires a deletion cassette composed of three modules: a central 1397-bp KanMX4 selection marker module and two 366-bp gene-specific flanking modules. The invariable KanMX4 module can be used in combination with different pairs of flanking modules targeting different genes. The two flanking modules consist of both sequences unique to each cassette (chromosomal homologous regions and barcodes) and those common to all deletion constructs (artificial linkers and restriction enzyme sites). Oligonucleotides for each module and junction regions are designed using the BatchBlock2Oligo program and are synthesized on a 96-well basis. The oligonucleotides are ligated into a single deletion cassette by ligase chain reaction, which is then amplified through two rounds of nested PCR to obtain sufficient quantities for yeast transformation. After removal of the artificial linkers, the deletion cassettes are transformed into wild-type diploid fission yeast SP286 cells. Verification of correct clone and gene deletion is achieved by performing check PCR and tetrad analysis. This method with proven effectiveness, as evidenced by a high success rate of gene deletion, can be potentially applicable to create systematic gene deletion libraries in a variety of yeast species. PMID:27671940

  17. Polymorphism of SARS-CoV genomes.

    PubMed

    Shang, Lei; Qi, Yan; Bao, Qi-Yu; Tian, Wei; Xu, Jian-Cheng; Feng, Ming-Guang; Yang, Huan-Ming

    2006-04-01

    In this work, severe acute respiratory syndrome associated coronavirus (SARS-CoV) genome BJ202 (AY864806) was completely sequenced. The genome was directly accessed from the stool sample of a patient in Beijing. Comparative genomics methods were used to analyze the sequence variations of 116 SARS-CoV genomes (including BJ202) available in the NCBI GenBank. With the genome sequence of GZ02 as the reference, there were 41 polymorphic sites identified in BJ202 and a total of 278 polymorphic sites present in at least two of the 116 genomes. The distribution of the polymorphic sites was biased over the whole genome. Nearly half of the variations (50.4%, 140/278) clustered in the one third of the whole genome at the 3' end (19.0 kb-29.7 kb). Regions encoding Orf10-11, Orf3/4, E, M and S protein had the highest mutation rates. A total of 15 PCR products (about 6.0 kb of the genome) including 11 fragments containing 12 known polymorphic sites and 4 fragments without identified polymorphic sites were cloned and sequenced. Results showed that 3 unique polymorphic sites of BJ202 (positions 13 804, 15 031 and 20 792) along with 3 other polymorphic sites (26 428, 26 477 and 27 243) all contained 2 kinds of nucleotides. It is interesting to find that position 18379 which has not been identified to be polymorphic in any of the other 115 published SARS-CoV genomes is actually a polymorphic site. The nucleotide composition of this site is A (8) to G (6). Among 116 SARS-CoV genomes, 18 types of deletions and 2 insertions were identified. Most of them were related to a 300 bp region (27,700-28,000) which encodes parts of the putative ORF9 and ORF10-11. A phylogenetic tree illustrating the divergence of whole BJ202 genome from 115 other completely sequenced SARS-CoVs was also constructed. BJ202 was phylogeneticly closer to BJ01 and LLJ-2004. PMID:16625834

  18. 78 FR 56679 - Procurement List; Deletions

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  19. Alagille syndrome and deletion of 20p.

    PubMed Central

    Anad, F; Burn, J; Matthews, D; Cross, I; Davison, B C; Mueller, R; Sands, M; Lillington, D M; Eastham, E

    1990-01-01

    We add five cases of 20p deletion to the 10 cases already published. Four had craniofacial, vertebral, ocular, and cardiovascular features of Alagille syndrome, which adds weight to the assignment of this disorder to the short arm of chromosome 20. Included in our series is the first report of familial transmission of a 20p deletion. Images PMID:2074558

  20. Total alpha-globin gene cluster deletion has high frequency in Filipinos

    SciTech Connect

    Hunt, J.A.; Haruyama, A.Z.; Chu, B.M.

    1994-09-01

    Most {alpha}-thalassemias [Thal] are due to large deletions. In Southeast Asians, the (--{sup SEA}) double {alpha}-globin gene deletion is common, 3 (--{sup Tot}) total {alpha}-globin cluster deletions are known: Filipino (--{sup Fil}), Thai (--{sup Thai}), and Chinese (--{sup Chin}). In a Hawaii Thal project, provisional diagnosis of {alpha}-Thal-1 heterozygotes was based on microcytosis, normal isoelectric focusing, and no iron deficiency. One in 10 unselected Filipinos was an {alpha}-Thal-1 heterozygote, 2/3 of these had a (--{sup Tot}) deletion: a {var_sigma}-cDNA probe consistently showed fainter intensity of the constant 5.5 kb {var_sigma}{sub 2} BamHI band, with no heterzygosity for {var_sigma}-globin region polymorphisms; {alpha}-cDNA or {var_sigma}-cDNA probes showed no BamHI or BglII bands diagnostic of the (--{sup SEA}) deletion; bands for the (-{alpha}) {alpha}-Thal-2 single {alpha}-globin deletions were only seen in Hb H cases. A reliable monoclonal anti-{var_sigma}-peptide antibody test for the (--{sup SEA}) deletion was always negative in (--{sup Tot}) samples. Southern digests with the Lo probe, a gift from D. Higgs of Oxford Univ., confirmed that 49 of 50 (--{sup Tot}) chromosomes in Filipinos were (--{sup Fil}). Of 20 {alpha}-Thal-1 hydrops born to Filipinos, 11 were (--{sup Fil}/--{sup SEA}) compound heterozygotes; 9 were (--{sup SEA}/--{sup SEA}) homozygotes, but none was a (--{sup Fil}/--{sup Fil}).

  1. Type I oculocutaneous albinism (OCA1) associated with a large deletion of the tyrosinase (TYR) gene

    SciTech Connect

    Spritz, R.A.; Wick, P.A.; Holmes, S.A.; Schnur, R.E. |

    1994-09-01

    OCA1 is an autosomal recessive disorder in which the biosynthesis of melanin is reduced or absent in skin, hair, and eyes, due to deficient enzymatic activity of tyrosinase. TYR consists of 5 exons spanning over 65 kb at 11q14-q21. Analyses of TYR in >400 unrelated patients with OCA1 have identified more than 50 different point mutations; however, no large deletions have been detected. Here we report a large deletion of TYR in a Caucasian boy with OCA1B. Simultaneous SSCP/heteroduplex screening and DNA sequence analysis indicated that the patient was apparently homozygous for a previously described TYR mutation, adjacent to the 3` splice site of IVS2 (-7, t{r_arrow}a). To distinguish between possible gene deletion vs. maternal uniparental isodisomy, we characterized several chromosome 11 polymorphisms. Maternal uniparental isodisomy was excluded by the patient`s heterozygosity for alleles at D11S35 (11q21-122) and HBG2 (11p15.5). In addition, the patient failed to inherit paternal alleles at an MboI RFLP in exon 1 of TYR and at a TaqI RFLP in the promoter region of the gene. To detect a possible submicroscopic deletion, we performed quantitative Southern blot hybridization using a full length TYR cDNA. Compared with controls, both the patient and his father appeared deleted for two or three TYR-derived PstI fragments; the two TYRL-derived fragments appeared normal. These data indicate that the patient and his father have a partial TYR deletion, including at least exons 1, 2, and IVS2. Based on the organization of the gene, this deletion is at least 50 kb in size. The patient is thus hemizygous for the maternally-inherited mutation in IVS2, accounting for his OCA1B phenotype.

  2. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.

    PubMed Central

    Carlson, C; Sirotkin, H; Pandita, R; Goldberg, R; McKie, J; Wadey, R; Patanjali, S R; Weissman, S M; Anyane-Yeboa, K; Warburton, D; Scambler, P; Shprintzen, R; Kucherlapati, R; Morrow, B E

    1997-01-01

    Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs. PMID:9326327

  3. Forensic performance of two insertion-deletion marker assays.

    PubMed

    Fondevila, M; Phillips, C; Santos, C; Pereira, R; Gusmão, L; Carracedo, A; Butler, J M; Lareu, M V; Vallone, P M

    2012-09-01

    Improving the amplification and analysis of highly degraded DNA extracts has been a longstanding area of research in forensic genetics. One of the most promising recent developments in analysis of degraded DNA is the availability of short, biallelic insertion-deletion length polymorphisms (InDels) in highly multiplexed assays. InDels share many of the favourable characteristics of single-nucleotide polymorphisms (SNPs) that make them ideal markers for analysis of degraded DNA, including: analysis in short amplicon size ranges, high multiplexing capability and low mutation rates. In addition, as length-based polymorphisms, InDels can be analysed with the same simple dye-labelled PCR primer methods as standard forensic short tandem repeats. Separation and detection of fluorescently dye-labelled PCR products by capillary electrophoresis eliminate the multiple step protocols required by SNP typing with single-base extension assays and provide a closer relationship between the input DNA and the profile peak height ratios. Therefore InDel genotyping represents an effective new approach for human identification that adds informative new loci to the existing battery of forensic markers. To assess the utility of InDels for forensic analysis, we characterised population variation with two InDel identification assays: the 30-plex Qiagen DIPplex panel and a 38-plex panel developed by Pereira et al. in 2009. Allele frequencies were generated for the 68 markers in US African American, Caucasian, East Asian and Hispanic samples. We made a thorough assessment of the individual and combined performance of the InDel sets, as well as characterising profile artifacts and other issues related to the routine use of these newly developed forensic assays based on artificially degraded DNA and mixed source samples.

  4. Targeted chromosomal deletions and inversions in zebrafish.

    PubMed

    Gupta, Ankit; Hall, Victoria L; Kok, Fatma O; Shin, Masahiro; McNulty, Joseph C; Lawson, Nathan D; Wolfe, Scot A

    2013-06-01

    Zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) provide powerful platforms for genome editing in plants and animals. Typically, a single nuclease is sufficient to disrupt the function of protein-coding genes through the introduction of microdeletions or insertions that cause frameshifts within an early coding exon. However, interrogating the function of cis-regulatory modules or noncoding RNAs in many instances requires the excision of this element from the genome. In human cell lines and invertebrates, two nucleases targeting the same chromosome can promote the deletion of intervening genomic segments with modest efficiencies. We have examined the feasibility of using this approach to delete chromosomal segments within the zebrafish genome, which would facilitate the functional study of large noncoding sequences in a vertebrate model of development. Herein, we demonstrate that segmental deletions within the zebrafish genome can be generated at multiple loci and are efficiently transmitted through the germline. Using two nucleases, we have successfully generated deletions of up to 69 kb at rates sufficient for germline transmission (1%-15%) and have excised an entire lincRNA gene and enhancer element. Larger deletions (5.5 Mb) can be generated in somatic cells, but at lower frequency (0.7%). Segmental inversions have also been generated, but the efficiency of these events is lower than the corresponding deletions. The ability to efficiently delete genomic segments in a vertebrate developmental system will facilitate the study of functional noncoding elements on an organismic level.

  5. 1p36 deletion syndrome: an update.

    PubMed

    Jordan, Valerie K; Zaveri, Hitisha P; Scott, Daryl A

    2015-01-01

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes.

  6. 1p36 deletion syndrome: an update

    PubMed Central

    Jordan, Valerie K; Zaveri, Hitisha P; Scott, Daryl A

    2015-01-01

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes. PMID:26345236

  7. GSTT1 deletion is related to polycyclic aromatic hydrocarbons-induced DNA damage and lymphoma progression.

    PubMed

    Yang, Fan; Xiong, Jie; Jia, Xiao-E; Gu, Zhao-Hui; Shi, Jing-Yi; Zhao, Yan; Li, Jun-Min; Chen, Sai-Juan; Zhao, Wei-Li

    2014-01-01

    The interrelationship between genetic susceptibility and carcinogenic exposure is important in cancer development. Polymorphisms in detoxification enzymes of the glutathione-S-transferases (GST) family are associated with an increased incidence of lymphoma. Here we investigated the molecular connection of the genetic polymorphism of GSTT1 to the response of lymphocytes to polycyclic aromatic hydrocarbons (PAH). In neoplastic situation, GSTT1 deletions were more frequently observed in lymphoma patients (54.9%) than in normal controls (42.0%, P = 0.009), resulting in an increased risk for lymphoma in individuals with GSTT1-null genotype (Odds ratio = 1.698, 95% confidence interval = 1.145-2.518). GSTT1 gene and protein expression were accordingly decreased in GSTT1-deleting patients, consistent with activated profile of cell cycle regulation genes. Mimicking environmental exposure using long-term repeat culture with low-dose PAH metabolite Hydroquinone, malignant B- and T-lymphocytes presented increased DNA damage, pCHK1/MYC expression and cell proliferation, which were counteracted by ectopic expression of GSTT1. Moreover, GSTT1 expression retarded xenograft tumor formation of Hydroquinone-treated lymphoma cells in nude mice. In non-neoplastic situation, when zebrafish was exposed to PAH Benzo(a)pyrene, molecular silencing of gstt1 enhanced the proliferation of normal lymphocytes and upregulated myca expression. Collectively, these findings suggested that GSTT1 deletion is related to genetic predisposition to lymphoma, particularly interacting with environmental pollutants containing PAH.

  8. GSTT1 deletion is related to polycyclic aromatic hydrocarbons-induced DNA damage and lymphoma progression.

    PubMed

    Yang, Fan; Xiong, Jie; Jia, Xiao-E; Gu, Zhao-Hui; Shi, Jing-Yi; Zhao, Yan; Li, Jun-Min; Chen, Sai-Juan; Zhao, Wei-Li

    2014-01-01

    The interrelationship between genetic susceptibility and carcinogenic exposure is important in cancer development. Polymorphisms in detoxification enzymes of the glutathione-S-transferases (GST) family are associated with an increased incidence of lymphoma. Here we investigated the molecular connection of the genetic polymorphism of GSTT1 to the response of lymphocytes to polycyclic aromatic hydrocarbons (PAH). In neoplastic situation, GSTT1 deletions were more frequently observed in lymphoma patients (54.9%) than in normal controls (42.0%, P = 0.009), resulting in an increased risk for lymphoma in individuals with GSTT1-null genotype (Odds ratio = 1.698, 95% confidence interval = 1.145-2.518). GSTT1 gene and protein expression were accordingly decreased in GSTT1-deleting patients, consistent with activated profile of cell cycle regulation genes. Mimicking environmental exposure using long-term repeat culture with low-dose PAH metabolite Hydroquinone, malignant B- and T-lymphocytes presented increased DNA damage, pCHK1/MYC expression and cell proliferation, which were counteracted by ectopic expression of GSTT1. Moreover, GSTT1 expression retarded xenograft tumor formation of Hydroquinone-treated lymphoma cells in nude mice. In non-neoplastic situation, when zebrafish was exposed to PAH Benzo(a)pyrene, molecular silencing of gstt1 enhanced the proliferation of normal lymphocytes and upregulated myca expression. Collectively, these findings suggested that GSTT1 deletion is related to genetic predisposition to lymphoma, particularly interacting with environmental pollutants containing PAH. PMID:24586676

  9. Independent De Novo 22q11.2 Deletions in First Cousins With DiGeorge/Velocardiofacial Syndrome

    PubMed Central

    Saitta, Sulagna C.; Harris, Stacy E.; McDonald-McGinn, Donna M.; Emanuel, Beverly S.; Tonnesen, Melissa K.; Zackai, Elaine H.; Seitz, Suzanne C.; Driscoll, Deborah A.

    2010-01-01

    Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). This most frequent microdeletion syndrome is estimated to occur in 1 in 4,000 live births. The majority of deletions are de novo, with 10% or less inherited from an affected parent. Here, we report two separate families with recurrence of a 22q11.2 deletion in first cousins. In each family, unaffected siblings (brother and sister) had an affected child. Fluorescence in situ hybridization (FISH) studies of the parents of each affected child were normal and hence, relatives were not considered at an increased risk for recurrence in another pregnancy. We used highly polymorphic microsatellite repeat markers from within 22q11.2 to determine the parental origin of each cousin’s deletion and to assess whether parental germline mosaicism for the 22q11.2 deletion might be a factor in these cases. This analysis confirmed that in each case, the deletion occurred on a chromosome 22 derived from unrelated parents, consistent with independent de novo deletion events. Thus, we concluded that germline mosaicism as the underlying mechanism for affected cousins in these families was unlikely. Our findings underscore the high frequency with which the 22q11.2 deletion occurs in the general population and demonstrate the important role that PCR-based parental origin determination can have in recurrence risk counselling. Furthermore, relatives of affected individuals may benefit from genetic counselling and consider prenatal testing for the 22q11.2 deletion in future pregnancies, despite a low recurrence risk. PMID:14708107

  10. Polymorphous computing fabric

    DOEpatents

    Wolinski, Christophe Czeslaw; Gokhale, Maya B.; McCabe, Kevin Peter

    2011-01-18

    Fabric-based computing systems and methods are disclosed. A fabric-based computing system can include a polymorphous computing fabric that can be customized on a per application basis and a host processor in communication with said polymorphous computing fabric. The polymorphous computing fabric includes a cellular architecture that can be highly parameterized to enable a customized synthesis of fabric instances for a variety of enhanced application performances thereof. A global memory concept can also be included that provides the host processor random access to all variables and instructions associated with the polymorphous computing fabric.

  11. Common promoter deletion is associated with 3.9-fold differential transcription of ovine CCR5 and reduced proviral level of ovine progressive pneumonia virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    CCR5 is a chemokine receptor that regulates immune cell recruitment in inflammation and serves as a coreceptor for human immunodeficiency virus (HIV). A human CCR5 coding deletion (termed delta-32) results in strong resistance to HIV infection, and polymorphisms in CCR5 regulatory regions have been ...

  12. Amplified and Homozygously Deleted Genes in Glioblastoma: Impact on Gene Expression Levels

    PubMed Central

    Crespo, Inês; Tão, Hermínio; Nieto, Ana Belen; Rebelo, Olinda; Domingues, Patrícia; Vital, Ana Luísa; Patino, Maria del Carmen; Barbosa, Marcos; Lopes, Maria Celeste; Oliveira, Catarina Resende; Orfao, Alberto; Tabernero, María Dolores

    2012-01-01

    Background Glioblastoma multiforme (GBM) displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown. Methodology Single-nucleotide polymorphism (SNP)-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46), and to evaluate the impact of copy number alterations (CNA) on mRNA levels of the genes involved. Principal Findings Recurrent amplicons were detected for chromosomes 7 (50%), 12 (22%), 1 (11%), 4 (9%), 11 (4%), and 17 (4%), whereas homozygous deletions involved chromosomes 9p21 (52%) and 10q (22%). Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2), while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1–q15 and 4q12, respectively). Despite homozygous del(9p21) and del(10q23.31) included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene. Conclusions Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes. PMID:23029397

  13. Mitochondrial DNA deletion in a patient with combined features of Leigh and Pearson syndromes

    SciTech Connect

    Blok, R.B.; Thorburn, D.R.; Danks, D.M.

    1994-09-01

    We describe a heteroplasmic 4237 bp mitochondrial DNA (mtDNA) deletion in an 11 year old girl who has suffered from progressive illness since birth. She has some features of Leigh syndrome (global developmental delay with regression, brainstem dysfunction and lactic acidosis), together with other features suggestive of Pearson syndrome (history of pancytopenia and failure to thrive). The deletion was present at a level greater than 50% in skeletal muscle, but barely detectable in skin fibroblasts following Southern blot analysis, and only observed in blood following PCR analysis. The deletion spanned nt 9498 to nt 13734, and was flanked by a 12 bp direct repeat. Genes for cytochrome c oxidase subunit III, NADH dehydrogenase subunits 3, 4L, 4 and 5, and tRNAs for glycine, arginine, histidine, serine({sup AGY}) and leucine({sup CUN}) were deleted. Southern blotting also revealed an altered Apa I restriction site which was shown by sequence analysis to be caused by G{r_arrow}A nucleotide substitution at nt 1462 in the 12S rRNA gene. This was presumed to be a polymorphism. No abnormalities of mitochondrial ultrastructure, distribution or of respiratory chain enzyme complexes I-IV in skeletal muscle were observed. Mitochondrial disorders with clinical features overlapping more than one syndrome have been reported previously. This case further demonstrates the difficulty in correlating observed clinical features with a specific mitochondrial DNA mutation.

  14. Epilepsy phenotype associated with a chromosome 2q24.3 deletion involving SCN1A: Migrating partial seizures of infancy or atypical Dravet syndrome?

    PubMed

    Lim, Byung Chan; Hwang, Hee; Kim, Hunmin; Chae, Jong-Hee; Choi, Jieun; Kim, Ki Joong; Hwang, Yong Seung; Yum, Mi-Sun; Ko, Tae-Sung

    2015-01-01

    The deletion of a sodium channel gene cluster located on chromosome 2q24.3 is associated with variable epilepsy phenotypes, including Dravet syndrome and migrating partial seizures of infancy. Although SCN1A is considered as the major contributor to the epilepsy phenotype, the role of other sodium channel genes that map within this cluster has not been delineated. We presented five new cases with a chromosome 2q24.3 deletion involving SCN1A and investigated their epilepsy phenotype in relation to the extent of the deletion. Three cases with deletion of the whole sodium channel gene cluster (SCN3A, SCN2A, SCN1A, SCN9A, and SCN7A) exhibited a complex epilepsy phenotype that was atypical for Dravet syndrome and suggestive of migrating partial seizures of infancy: early seizure onset (before 2 months of age), severe developmental delay from seizure onset, multifocal interictal spikes, polymorphous focal seizures, and acquired microcephaly. Two cases with partial deletion of SCN1A and SCN9A and whole SCN1A deletion had an epilepsy phenotype of Dravet syndrome. A literature review of cases with chromosome 2q24.3 deletion revealed that, in most Dravet syndrome cases, it does not involve SCN2A and SCN3A, whereas a complex epilepsy phenotype that is shared with migrating partial seizures of infancy was associated with cases of deletion of the whole sodium channel gene cluster.

  15. Analysis of chromosome 22 deletions in neurofibromatosis type 2-related tumors.

    PubMed Central

    Wolff, R K; Frazer, K A; Jackler, R K; Lanser, M J; Pitts, L H; Cox, D R

    1992-01-01

    The neurofibromatosis type 2 (NF2) gene has been hypothesized to be a recessive tumor suppressor, with mutations at the same locus on chromosome 22 that lead to NF2 also leading to sporadic tumors of the types seen in NF2. Flanking markers for this gene have previously been defined as D22S1 centromeric and D22S28 telomeric. Identification of subregions of this interval that are consistently rearranged in the NF2-related tumors would aid in better defining the disease locus. To this end, we have compared tumor and constitutional DNAs, isolated from 39 unrelated patients with sporadic and NF2-associated acoustic neuromas, meningiomas, schwannomas, and ependymomas, at eight polymorphic loci on chromosome 22. Two of the tumors studied revealed loss-of-heterozygosity patterns, which is consistent with the presence of chromosome 22 terminal deletions. By using additional polymorphic markers, the terminal deletion breakpoint found in one of the tumors, an acoustic neuroma from an NF2 patient, was mapped within the previously defined NF2 region. The breakpoint occurred between the haplotyped markers D22S41/D22S46 and D22S56. This finding redefines the proximal flanking marker and localizes the NF2 gene between markers D22S41/D22S46 and D22S28. In addition, we identified a sporadic acoustic neuroma that reveals a loss-of-heterozygosity pattern consistent with mitotic recombination or deletion and reduplication, which are mechanisms not previously seen in studies of these tumors. This finding, while inconsistent with models of tumorigenesis that invoke single deletions and their gene-dosage effects, lends further support to the recessive tumor-suppressor model. Images Figure 1 Figure 2 PMID:1496981

  16. Parameterized Complexity of Eulerian Deletion Problems.

    PubMed

    Cygan, Marek; Marx, Dániel; Pilipczuk, Marcin; Pilipczuk, Michał; Schlotter, Ildikó

    2014-01-01

    We study a family of problems where the goal is to make a graph Eulerian, i.e., connected and with all the vertices having even degrees, by a minimum number of deletions. We completely classify the parameterized complexity of various versions: undirected or directed graphs, vertex or edge deletions, with or without the requirement of connectivity, etc. The collection of results shows an interesting contrast: while the node-deletion variants remain intractable, i.e., W[1]-hard for all the studied cases, edge-deletion problems are either fixed-parameter tractable or polynomial-time solvable. Of particular interest is a randomized FPT algorithm for making an undirected graph Eulerian by deleting the minimum number of edges, based on a novel application of the color coding technique. For versions that remain NP-complete but fixed-parameter tractable we consider also possibilities of polynomial kernelization; unfortunately, we prove that this is not possible unless NP⊆coNP/poly. PMID:24415818

  17. Somatic mosaicism for a DMD gene deletion

    SciTech Connect

    Saito, Kayoko; Ikeya, Kiyoko; Kondo, Eri

    1995-03-13

    Mosaicism is a mixed state, with two cell populations of different genetic origins caused by a cell mutation occurring after fertilization. In the present case, DNA analysis of lymphocytes led to a DMD diagnosis before death. Postmortem immunocytochemical and DNA analysis showed somatic mosaicism. At age 18 years, blood lymphocyte DNA analysis showed a DMD gene deletion, upstream from exon 7 to the 5{prime} end containing both muscle and brain promoters. As the patient`s mother and elder sister had no deletions, he was considered to have a new mutation. Immunocytochemical studies of postmortem tissues showed that dystrophin was absent from the tongue, deltoid, intercostal, psoas and rectus femoris muscles, but there was a mix of dystrophin-positive and negative fibers in the rectus abdominis, cardiac, temporalis and sternocleidomastoid muscles. All diaphragm cells were dystrophin positive. Polymerase chain reaction (PCR) amplification from all tissues except the temporalis and sternocleidomastoid muscles, diaphragm and kidney, in which no deletion was found, showed the deletion from at least exon 6 to the 5{prime} end containing both muscle and brain promoters. In this case, a genomic deletion of the DMD gene contributed to the formation of tissues derived from both ectoderm and endoderm, and cells of mesodermal origin showed genotypic and phenotypic heterogeneity. Our results indicate a mutation of the present case may have occurred just before the period of germ layer formation. 34 refs., 7 figs.

  18. Genetic Analysis of the Atrial Natriuretic Peptide Gene Polymorphisms among Essential Hypertensive Patients in Malaysia.

    PubMed

    Ghodsian, Nooshin; Ismail, Patimah; Ahmadloo, Salma; Eskandarian, Narges; Etemad, Ali

    2016-01-01

    Background. Atrial natriuretic peptide (ANP) considerably influences blood pressure regulation through water and sodium homoeostasis. Several of the studies have utilized anonymous genetic polymorphic markers and made inconsequent claims about the ANP relevant disorders. Thus, we screened Insertion/Deletion (ID) and G191A polymorphisms of ANP to discover sequence variations with potential functional significance and to specify the linkage disequilibrium pattern between polymorphisms. The relationships of detected polymorphisms with EH with or without Type 2 Diabetes Mellitus (T2DM) status were tested subsequently. Method. ANP gene polymorphisms (I/D and A191G) were specified utilizing mutagenically separated Polymerase Chain Reaction (PCR) in 320 subjects including 163 EH case subjects and 157 controls. Result. This case-control study discovered a significant association between I/D polymorphisms of ANP gene in EH patient without T2DM. However, the study determined no association between G191A polymorphisms of ANP in EH with or without T2DM. In addition, sociodemographic factors in the case and healthy subjects exhibited strong differences (P < 0.05). Conclusion. As a risk factor, ANP gene polymorphisms may affect hypertension. Despite the small sample size in this study, it is the first research assessing the ANP gene polymorphisms in both EH and T2DM patients among Malaysian population. PMID:27413750

  19. Genetic Analysis of the Atrial Natriuretic Peptide Gene Polymorphisms among Essential Hypertensive Patients in Malaysia

    PubMed Central

    Ghodsian, Nooshin; Ismail, Patimah; Ahmadloo, Salma; Eskandarian, Narges; Etemad, Ali

    2016-01-01

    Background. Atrial natriuretic peptide (ANP) considerably influences blood pressure regulation through water and sodium homoeostasis. Several of the studies have utilized anonymous genetic polymorphic markers and made inconsequent claims about the ANP relevant disorders. Thus, we screened Insertion/Deletion (ID) and G191A polymorphisms of ANP to discover sequence variations with potential functional significance and to specify the linkage disequilibrium pattern between polymorphisms. The relationships of detected polymorphisms with EH with or without Type 2 Diabetes Mellitus (T2DM) status were tested subsequently. Method. ANP gene polymorphisms (I/D and A191G) were specified utilizing mutagenically separated Polymerase Chain Reaction (PCR) in 320 subjects including 163 EH case subjects and 157 controls. Result. This case-control study discovered a significant association between I/D polymorphisms of ANP gene in EH patient without T2DM. However, the study determined no association between G191A polymorphisms of ANP in EH with or without T2DM. In addition, sociodemographic factors in the case and healthy subjects exhibited strong differences (P < 0.05). Conclusion. As a risk factor, ANP gene polymorphisms may affect hypertension. Despite the small sample size in this study, it is the first research assessing the ANP gene polymorphisms in both EH and T2DM patients among Malaysian population. PMID:27413750

  20. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, John J.; Quesada, Mark A.; Randesi, Matthew

    2001-01-01

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment in the context of a cloning vector which contains an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment. Also disclosed is a method for producing single-stranded DNA probes utilizing the same cloning vector. An optimal vector, PZIP is described. Methods for introducing unidirectional deletions into a terminal location of a cloned DNA sequence which is inserted into the vector of the present invention are also disclosed. These methods are useful for introducing deletions into either or both ends of a cloned DNA insert, for high throughput sequencing of any DNA of interest.

  1. IAP gene deletion and conditional knockout models.

    PubMed

    Silke, John; Vaux, David L

    2015-03-01

    Gene deletion studies have helped reveal the unique and overlapping roles played by IAP proteins. Crossing IAP mutant mice has helped unravel the complex feed-back regulatory circuits in which cIAP1, cIAP2 and XIAP allow innate defensive responses to microbial pathogens, without the development of auto-inflammatory syndromes. Deletion of genes for Survivin and its homologs in yeasts, invertebrates and mammals has shown that it functions differently, as it is not a regulator of innate immunity or apoptosis, but acts together with INCENP, aurora kinase B and Borealin to allow chromosome segregation during mitosis. PMID:25545814

  2. Deletion mapping of genetic regions associated with apomixis in Hieracium.

    PubMed

    Catanach, Andrew S; Erasmuson, Sylvia K; Podivinsky, Ellen; Jordan, Brian R; Bicknell, Ross

    2006-12-01

    Although apomixis has been quoted as a technology with the potential to deliver benefits similar in scale to those achieved with the Green Revolution, very little is currently known of the genetic mechanisms that control this trait in plants. To address this issue, we developed Hieracium, a genus of daisies native to Eurasia and North America, as a genetic model to study apomixis. In a molecular mapping study, we defined the number of genetic loci involved in apomixis, and we explored dominance and linkage relationships between these loci. To avoid difficulties often encountered with inheritance studies of apomicts, we based our mapping effort on the use of deletion mutagenesis, coupled with amplified fragment length polymorphism (AFLP) as a genomic fingerprinting tool. The results indicate that apomixis in Hieracium caespitosum is controlled at two principal loci, one of which regulates events associated with the avoidance of meiosis (apomeiosis) and the other, an unlinked locus that controls events associated with the avoidance of fertilization (parthenogenesis). AFLP bands identified as central to both loci were isolated, sequenced, and used to develop sequence-characterized amplified region (SCAR) markers. The validity of the AFLP markers was verified by using a segregating population generated by hybridization. The validity of the SCAR markers was verified by their pattern of presence/absence in specific mutants. The mutants, markers, and genetic data derived from this work are now being used to isolate genes controlling apomixis in this system.

  3. Deletion mapping of genetic regions associated with apomixis in Hieracium.

    PubMed

    Catanach, Andrew S; Erasmuson, Sylvia K; Podivinsky, Ellen; Jordan, Brian R; Bicknell, Ross

    2006-12-01

    Although apomixis has been quoted as a technology with the potential to deliver benefits similar in scale to those achieved with the Green Revolution, very little is currently known of the genetic mechanisms that control this trait in plants. To address this issue, we developed Hieracium, a genus of daisies native to Eurasia and North America, as a genetic model to study apomixis. In a molecular mapping study, we defined the number of genetic loci involved in apomixis, and we explored dominance and linkage relationships between these loci. To avoid difficulties often encountered with inheritance studies of apomicts, we based our mapping effort on the use of deletion mutagenesis, coupled with amplified fragment length polymorphism (AFLP) as a genomic fingerprinting tool. The results indicate that apomixis in Hieracium caespitosum is controlled at two principal loci, one of which regulates events associated with the avoidance of meiosis (apomeiosis) and the other, an unlinked locus that controls events associated with the avoidance of fertilization (parthenogenesis). AFLP bands identified as central to both loci were isolated, sequenced, and used to develop sequence-characterized amplified region (SCAR) markers. The validity of the AFLP markers was verified by using a segregating population generated by hybridization. The validity of the SCAR markers was verified by their pattern of presence/absence in specific mutants. The mutants, markers, and genetic data derived from this work are now being used to isolate genes controlling apomixis in this system. PMID:17047034

  4. RAI1 variations in Smith–Magenis syndrome patients without 17p11.2 deletions

    PubMed Central

    Girirajan, S; Elsas, L; Devriendt, K; Elsea, S

    2005-01-01

    Background: Smith–Magenis syndrome (SMS) (OMIM No 182290) is a mental retardation syndrome characterised by behavioural abnormalities, including self injurious behaviours, sleep disturbance, and distinct craniofacial and skeletal anomalies. It is usually associated with deletion involving 17p11.2 and is estimated to occur in 1/25 000 births. Heterozygous frameshift mutations leading to protein truncation in retinoic acid induced 1 gene (RAI1) have been identified in individuals with phenotypic features consistent with SMS. RAI1 lies within the 17p11.2 locus, but these patients did not have 17p11.2 deletions. Objective: Analysis of four individuals with features consistent with SMS for variations in RAI1, using a polymerase chain reaction and sequencing strategy. None of these patients carry 17p11.2 deletions. Results: Two patients had small deletions in RAI1 resulting in frameshift and premature truncation of the protein. Missense mutations were identified in the other two. Orthologs across other genomes showed that these missense mutations occurred in identically conserved regions of the gene. The mutations were de novo, as all parental samples were normal. Several polymorphisms were also observed, including new and reported SNPs. The patients' clinical features differed from those found in 17p11.2 deletion by general absence of short stature and lack of visceral anomalies. All four patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioural anomalies, and sleep disturbance. Seizures, not previously thought to be associated with RAI1 mutations, were observed in one patient of the cohort. Conclusions: Haploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioural, and neurological signs and symptoms. PMID:15788730

  5. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects.

    PubMed

    Varela, Monica Castro; Kok, Fernando; Otto, Paulo Alberto; Koiffmann, Celia Priszkulnik

    2004-12-01

    Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

  6. Adaptive gains through repeated gene loss: parallel evolution of cyanogenesis polymorphisms in the genus Trifolium (Fabaceae).

    PubMed

    Olsen, Kenneth M; Kooyers, Nicholas J; Small, Linda L

    2014-08-01

    Variation in cyanogenesis (hydrogen cyanide release following tissue damage) was first noted in populations of white clover more than a century ago, and subsequent decades of research have established this system as a classic example of an adaptive chemical defence polymorphism. Here, we document polymorphisms for cyanogenic components in several relatives of white clover, and we determine the molecular basis of this trans-specific adaptive variation. One hundred and thirty-nine plants, representing 13 of the 14 species within Trifolium section Trifoliastrum, plus additional species across the genus, were assayed for cyanogenic components (cyanogenic glucosides and their hydrolysing enzyme, linamarase) and for the presence of underlying cyanogenesis genes (CYP79D15 and Li, respectively). One or both cyanogenic components were detected in seven species, all within section Trifoliastrum; polymorphisms for the presence/absence (PA) of components were detected in six species. In a pattern that parallels our previous findings for white clover, all observed biochemical polymorphisms correspond to gene PA polymorphisms at CYP79D15 and Li. Relationships of DNA sequence haplotypes at the cyanogenesis loci and flanking genomic regions suggest independent evolution of gene deletions within species. This study thus provides evidence for the parallel evolution of adaptive biochemical polymorphisms through recurrent gene deletions in multiple species.

  7. Identification of null alleles and deletions from SNP genotypes for an intercross between domestic and wild chickens.

    PubMed

    Crooks, Lucy; Carlborg, Örjan; Marklund, Stefan; Johansson, Anna M

    2013-08-01

    We analyzed genotypes from ~10K single-nucleotide polymorphisms (SNPs) in two families of an F2 intercross between Red Junglefowl and White Leghorn chickens. Possible null alleles were found by patterns of incompatible and missing genotypes. We estimated that 2.6% of SNPs had null alleles compared with 2.3% with genotyping errors and that 40% of SNPs in which a parent and offspring were genotyped as different homozygotes had null alleles. Putative deletions were identified by null alleles at adjacent markers. We found two candidate deletions that were supported by fluorescence intensity data from a 60K SNP chip. One of the candidate deletions was from the Red Junglefowl, and one was present in both the Red Junglefowl and White Leghorn. Both candidate deletions spanned protein-coding regions and were close to a previously detected quantitative trait locus affecting body weight in this population. This study demonstrates that the ~50K SNP genotyping arrays now available for several agricultural species can be used to identify null alleles and deletions in data from large families. We suggest that our approach could be a useful complement to linkage analysis in experimental crosses. PMID:23708300

  8. Identification of null alleles and deletions from SNP genotypes for an intercross between domestic and wild chickens.

    PubMed

    Crooks, Lucy; Carlborg, Örjan; Marklund, Stefan; Johansson, Anna M

    2013-08-07

    We analyzed genotypes from ~10K single-nucleotide polymorphisms (SNPs) in two families of an F2 intercross between Red Junglefowl and White Leghorn chickens. Possible null alleles were found by patterns of incompatible and missing genotypes. We estimated that 2.6% of SNPs had null alleles compared with 2.3% with genotyping errors and that 40% of SNPs in which a parent and offspring were genotyped as different homozygotes had null alleles. Putative deletions were identified by null alleles at adjacent markers. We found two candidate deletions that were supported by fluorescence intensity data from a 60K SNP chip. One of the candidate deletions was from the Red Junglefowl, and one was present in both the Red Junglefowl and White Leghorn. Both candidate deletions spanned protein-coding regions and were close to a previously detected quantitative trait locus affecting body weight in this population. This study demonstrates that the ~50K SNP genotyping arrays now available for several agricultural species can be used to identify null alleles and deletions in data from large families. We suggest that our approach could be a useful complement to linkage analysis in experimental crosses.

  9. Chronic lymphocytic leukemia cells with allelic deletions at 13q14 commonly have one intact RB1 gene: Evidence for a role of an adjacent locus

    SciTech Connect

    Leu, Y.; Grander, D.; Linder, S.; Einhorn, S.; Soederhall, S. ); Szekely, L. ); Juliusson, G.; Gahrton, G. )

    1993-09-15

    The authors have previously shown that 30% of patients with B-cell chronic lymphocytic leukemia (B-CLL) have hemizygous deletions of the retinoblastoma (RB1) gene at 13q14. RB1 gene deletions may thus participate in malignant transformation of B-CLL, but is it also possible that a neighboring gene on 13q is the relevant one. To answer this question the remaining RB1 allele of eight clones with hemizygous deletions was studied by reverse transcription-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP) analysis, and immunofluorescense techniques. Cells from 10 patients without RB1 gene deletions were also studied by these methods. Lack of RB1 mRNA and RB protein expression was seen in leukemia cells from one of the patients. All other cases were found to be normal with regard to immunofluorescense, RT-PCR, and SSCP analysis, indicating at least one functional RB1 allele and supporting the importance of another gene in the 13q14 deletions. The authors then performed extended Southern blot analysis of the 13q region, using probes for 10 different loci. In 14 of 31 CLL clones (45%), deletions of a region telomeric to the RB1 gene (D13S25) were observed. In 4 of the cases the deletions were homozygous. Hemizygous deletions of the RB1 gene were observed in 11 of these patients and in one of the patients without D13S25 deletions. These data thus indicate that a gene(s) telomeric to RB1 is involved in the malignant transformation of CLL clones and that deletions of this region are a common event in this disease. 20 refs., 3 figs., 3 tabs.

  10. 77 FR 68737 - Procurement List, Proposed Deletions

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  11. 78 FR 65618 - Procurement List; Proposed Deletions

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    2013-11-01

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  12. Deletion 5q35.3

    SciTech Connect

    Stratton, R.F.; Tedrowe, N.A.; Tolworthy, J.A.; Patterson, R.M.; Ryan, S.G.; Young, R.S.

    1994-06-01

    The authors report on a 15-month-old boy with a de novo deletion of the terminal band of 5q, macrocephaly, mild retrognathia, anteverted nares with low flat nasal bridge, telecanthus, minor earlobe anomalies, bellshaped chest, diastasis recti, short fingers, and mild developmental delay.

  13. Interstitial deletion (6)q13q15

    SciTech Connect

    Gershoni-Baruch, R.; Mandel, H.; Bar El, H.; Bar-Nizan, N.; Borochowitz, Z.; Dar, Hanna

    1996-04-24

    We report on a 2-year-old child with psychomotor retardation, facial and urogenital anomalies. His chromosome constitution was 46,XY,del(6)(q13q15). This case further contributes to the karyotype-phenotype correlation of proximal deletion 6q syndromes. 18 refs., 3 figs., 1 tab.

  14. 78 FR 23543 - Procurement List Deletions

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    2013-04-19

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  15. 22q11 deletion syndrome: current perspective

    PubMed Central

    Hacıhamdioğlu, Bülent; Hacıhamdioğlu, Duygu; Delil, Kenan

    2015-01-01

    Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome (22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems; therefore, it has a very wide phenotypic spectrum. An increasing amount of information is available related to the pathogenesis, clinical phenotypes, and management of this syndrome in recent years. This review summarizes the current clinical and genetic status related to 22q11DS. PMID:26056486

  16. Deletion of GPIHBP1 causing severe chylomicronemia.

    PubMed

    Rios, Jonathan J; Shastry, Savitha; Jasso, Juan; Hauser, Natalie; Garg, Abhimanyu; Bensadoun, André; Cohen, Jonathan C; Hobbs, Helen H

    2012-05-01

    Lipoprotein lipase (LPL) is a hydrolase that cleaves circulating triglycerides to release fatty acids to the surrounding tissues. The enzyme is synthesized in parenchymal cells and is transported to its site of action on the capillary endothelium by glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Inactivating mutations in LPL; in its cofactor, apolipoprotein (Apo) C2; or in GPIHBP1 cause severe hypertriglyceridemia. Here we describe an individual with complete deficiency of GPIHBP1. The proband was an Asian Indian boy who had severe chylomicronemia at 2 months of age. Array-based copy-number analysis of his genomic DNA revealed homozygosity for a 17.5-kb deletion that included GPIHBP1. A 44-year-old aunt with a history of hypertriglyceridemia and pancreatitis was also homozygous for the deletion. A bolus of intravenously administered heparin caused a rapid increase in circulating LPL and decreased plasma triglyceride levels in control individuals but not in two GPIHBP1-deficient patients. Thus, short-term treatment with heparin failed to attenuate the hypertriglyceridemia in patients with GPIHBP1 deficiency. The increasing resolution of copy number microarrays and their widespread adoption for routine cytogenetic analysis is likely to reveal a greater role for submicroscopic deletions in Mendelian conditions. We describe the first neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1. PMID:22008945

  17. 78 FR 77106 - Procurement List; Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-20

    ... INFORMATION: Deletions On 11/8/2013 (78 FR 67129-67130) and 11/15/2013 (78 FR 68823- 68824), the Committee for... Building and Courthouse, 205 4th Street, Coeur d'Alene, ID, U.S. Federal Building, St. Maries, ID NPA: TESH, Inc., Coeur d'Alene, ID Contracting Activity: GENERAL SERVICES ADMINISTRATION, FPDS AGENCY...

  18. Possible deletion of a developmentally regulated heavy-chain variable region gene in autoimmune diseases

    SciTech Connect

    Yang, Pei-Ming; Olee, Tsaiwei; Kozin, F.; Carson, D.A.; Chen, P.P. ); Olsen, N.J. ); Siminovitch, K.A. )

    1990-10-01

    Several autoantibody-associated variable region (V) genes are preferentially expressed during early ontogenic development, suggesting strongly that they are of developmental and physiological importance. As such, it is possible that polymorphisms in one or more of these genes may alter susceptibility to autoimmune disease. The authors have searched extensively for a probe related to a developmentally regulated V gene that has the power to differentiate among highly homologous V genes in human populations. Using such a probe (i.e., Humhv3005/P1) related to both anti-DNA and anti-IgG autoantibodies, they studied restriction fragment length polymorphisms in patients with rheumatoid arthritis and systemic lupus erythematosus and found an apparent heavy-chain V (V{sub H}) gene deletion that was nearly restricted to the autoimmune patients. These data suggest that deletions of physiologically important V{sub H} genes may increase the risk of autoimmunity through indirect effects on the development and homeostasis of the B-cell repertoire.

  19. A deletion mutant defines DQ beta variants with DR4 positive DQw3 positive haplotypes.

    PubMed

    Nepom, B S; Kim, S J; Nepom, G T

    1986-10-01

    We describe the production of an HLA deletion mutation by radiation mutagenesis of a DR4- and DQw3-homozygous, Dw4- and Dw14-heterozygous cell line designed to analyze polymorphisms associated with DR4 and DQw3. Southern blot analysis confirms a deletion of class I and class II genes on one haplotype. Variation in DQ beta alleles associated with DQw3 was previously described by characteristic RFLP patterns for a DQ beta bene. One pattern, which correlated precisely with A-10-83 monoclonal antibody reactivity (TA10), defined an allele which we call DQ"3.1". The mutant cell line has lost the polymorphic bands on Southern blots corresponding to the DQ"3.1" allele, while the intact Dw14 haplotype retains the alternate allele at DQ beta which is DQw-3 positive. TA10-negative. These data demonstrate the segregation of two DQw3 positive DQ beta allelic variants, both associated with DR4, which can be distinguished on the basis of both RFLP and monoclonal antibody reactivity. PMID:2875977

  20. X-linked deafness: De novo deletion of a cosmid using dosage studies

    SciTech Connect

    Bitner-Glindzicz, M.; Pembrey, M.E.; deKok, Y.

    1994-09-01

    We have used three polymorphic microsatellite repeats at Xq21, (DXS986, DXS995 and DXS1002) to test for linkage in families with X-linked deafness. Close linkage was demonstrated between all three markers and the disease locus in families with and without a bony abnormality on the CT scan. DXS995 gave a maximum two point lod score of l0.37 with no recombinations. This marker was used to type an additional small sibship. Analysis showed that the two brothers, one deaf and one hearing, both inherited the same maternal allele indicating either the first recombination seen to date or a de novo mutation in the proband. Using a cosmid from the critical region, a deletion was detected in the proband of this sibship. By using a phoshorimager, dosage of an EcoR1 fragment from this cosmid and a control probe was compared to normal subjects and obligate carriers from another family with a similar deletion. Results show that the mother of this isolated case does not carry the deletion, confirming that it is de novo. These markers may be useful for carrier ascertainment in families with a radiological change on CT scan or a pedigree which is linked to Xq21.

  1. Enhancing allele-specific PCR for specifically detecting short deletion and insertion DNA mutations.

    PubMed

    Wang, Yiran; Rollin, Joseph A; Zhang, Y-H Percival

    2010-02-01

    Allele-specific PCR (AS-PCR) has been widely used for the detection of single nucleotide polymorphism. But there are some challenges in using AS-PCR for specifically detecting DNA variations with short deletions or insertions. The challenges are associated with designing selective allele-specific primers as well as the specificity of AS-PCR in distinguishing some types of single base-pair mismatches. In order to address such problems and enhance the applicability of AS-PCR, a general primer design method was developed to create a multiple base-pair mismatch between the primer 3'-terminus and the template DNA. This approach can destabilize the primer-template complex more efficiently than does a single base-pair mismatch, and can dramatically increase the specificity of AS-PCR. As a proof-of-principle demonstration, the method of primer design was applied in colony PCR for identifying plasmid DNA deletion or insertion mutants after site-directed mutagenesis. As anticipated, multiple base-pair mismatches achieved much more specific PCR amplification than single base-pair mismatches. Therefore, with the proposed primer design method, the detection of short nucleotide deletion and insertion mutations becomes simple, accurate and more reliable.

  2. Influence of the LILRA3 Deletion on Multiple Sclerosis Risk: Original Data and Meta-Analysis

    PubMed Central

    Ortiz, Miguel A.; Núñez, Concepción; Ordóñez, David; Alvarez-Cermeño, José C.; Martínez-Rodriguez, José E.; Sánchez, Antonio J.; Arroyo, Rafael; Izquierdo, Guillermo; Malhotra, Sunny; Montalban, Xavier; García-Merino, Antonio; Munteis, Elvira; Alcina, Antonio; Comabella, Manuel; Matesanz, Fuencisla

    2015-01-01

    Background Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. Objectives In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. Results and Conclusion Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95–1.19)], even after stratification by gender and the HLA-DRB1*15:01 risk allele. PMID:26274821

  3. A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy.

    PubMed

    Utine, G Eda; Haliloğlu, Göknur; Salanci, Bilge; Çetinkaya, Arda; Kiper, P Özlem; Alanay, Yasemin; Aktas, Dilek; Boduroğlu, Koray; Alikaşifoğlu, Mehmet

    2013-07-01

    GRID2 is a member of the ionotropic glutamate receptor family of excitatory neurotransmitter receptors. GRID2 encodes the glutamate receptor subunit delta-2, selectively expressed in cerebellar Purkinje cells. The phenotype associated with loss of GRID2 function was described only in mice until now, characterized by different degrees of cerebellar ataxia and usually relatively mild abnormalities of the cerebellum. This work describes for the first time the human phenotype associated with homozygous partial deletion of GRID2 in 3 children in one large consanguineous Turkish family. Homozygous deletion of exons 3 and 4 of GRID2 (94 153 589-94 298 037 bp) in the proband and similarly affected cousins, and heterozygous deletions in parental DNA were shown using Affymetrix® 6.0 single-nucleotide polymorphism array, confirmed by real-time polymerase chain reaction. The phenotype includes nystagmus, hypotonia with marked developmental delay in gross motor skills in early infancy followed by a static encephalopathy course with development of cerebellar ataxia, oculomotor apraxia, and pyramidal tract involvement.

  4. Mitochondrial DNA polymorphisms in Carib people of Belize.

    PubMed Central

    Monsalve, M V; Hagelberg, E

    1997-01-01

    Analysis of mitochondrial DNA (mtDNA) control region polymorphisms in 28 Carib people of Belize, former British Honduras, revealed high levels of genetic admixture with West African populations. A previously characterized length mutation consisting of a deletion of nine base pairs in an intergenic mtDNA region was observed in two of the individuals. Phylogenetic analysis of mtDNA control region sequences associated with the mutation suggested that it arose independently in different geographical locations. Whereas in one individual the deletion reflects the Amerindian ancestry of the Caribs, in the second case it seems to be of African origin, as it occurred in conjunction with an mtDNA type found in sub-Saharan Africa. Our results agree with historical accounts on the origins of the Caribs of Belize. PMID:9308194

  5. Interstitial deletion of distal 13q associated with Hirschsprung's disease.

    PubMed Central

    Lamont, M A; Fitchett, M; Dennis, N R

    1989-01-01

    Three cases of interstitial deletion of chromosome 13 involving the common segment 13q22.1----q32.1 are reported. In addition to the recognised clinical features of this deletion, two had Hirschsprung's disease. Images PMID:2918536

  6. Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients

    SciTech Connect

    Christian, S.L.; Huang, B.; Ledbetter, D.H.

    1995-07-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation syndromes caused by paternal and maternal deficiencies, respectively, in chromosome 15q11{minus}q13. Approximately 70% of these patients have a large deletion of {approximately}4 Mb extending from D15S9 (ML34) through D15S12 (IR10A). To further characterize the deletion breakpoints proximal to D15S9, three new polymorphic microsatellite markers were developed that showed observed heterozygosities of 60%-87%. D15S541 and D15S542 were isolated for YAC A124A3 containing the D15S18 (IR39) locus. D15S543 was isolated from a cosmid cloned from the proximal right end of YAC 254B5 containing the D15S9 (ML34) locus. Gene-centromere mapping of these markers, using a panel of ovarian teratomas of known meiotic origin, extended the genetic map of chromosome 15 by 2-3 cM toward the centromere. Analysis of the more proximal S541/S542 markers on 53 Prader-Willi and 33 Angelman deletion patients indicated two classes of patients: 44% (35/80) of the informative patients were deleted for these markers (class I), while 56% (45/80) were not deleted (class II), with no difference between PWS and AS. In contrast, D15S543 was deleted in all informative patients (13/48) or showed the presence of a single allele (in 35/48 patients), suggesting that this marker is deleted in the majority of PWS and AS cases. These results confirm the presence of two common proximal deletion breakpoint regions in both Prader-Willi and Angelman syndromes and are consistent with the same deletion mechanism being responsible for paternal and maternal deletions. One breakpoint region lies between D15S541/S542 and D15S543, with an additional breakpoint region being proximal to D15S541/S542. 46 refs., 2 figs., 3 tabs.

  7. Genetics Home Reference: 22q11.2 deletion syndrome

    MedlinePlus

    ... Home Health Conditions 22q11.2 deletion syndrome 22q11.2 deletion syndrome Enable Javascript to view the expand/ ... Download PDF Open All Close All Description 22q11.2 deletion syndrome (which is also known by several ...

  8. Genetics Home Reference: 22q13.3 deletion syndrome

    MedlinePlus

    ... Home Health Conditions 22q13.3 deletion syndrome 22q13.3 deletion syndrome Enable Javascript to view the expand/ ... Download PDF Open All Close All Description 22q13.3 deletion syndrome , which is also commonly known as ...

  9. Rac1 deletion causes thymic atrophy.

    PubMed

    Hunziker, Lukas; Benitah, Salvador Aznar; Aznar Benitah, Salvador; Braun, Kristin M; Jensen, Kim; McNulty, Katrina; Butler, Colin; Potton, Elspeth; Nye, Emma; Boyd, Richard; Laurent, Geoff; Glogauer, Michael; Wright, Nick A; Watt, Fiona M; Janes, Sam M

    2011-04-29

    The thymic stroma supports T lymphocyte development and consists of an epithelium maintained by thymic epithelial progenitors. The molecular pathways that govern epithelial homeostasis are poorly understood. Here we demonstrate that deletion of Rac1 in Keratin 5/Keratin 14 expressing embryonic and adult thymic epithelial cells leads to loss of the thymic epithelial compartment. Rac1 deletion led to an increase in c-Myc expression and a generalized increase in apoptosis associated with a decrease in thymic epithelial proliferation. Our results suggest Rac1 maintains the epithelial population, and equilibrium between Rac1 and c-Myc may control proliferation, apoptosis and maturation of the thymic epithelial compartment. Understanding thymic epithelial maintenance is a step toward the dual goals of in vitro thymic epithelial cell culture and T cell differentiation, and the clinical repair of thymic damage from graft-versus-host-disease, chemotherapy or irradiation.

  10. Duplication/deletion of chromosome 8p

    SciTech Connect

    Priest, J.H.

    1995-09-11

    The article by Guo et al. provides evidence for deletion of D8S596 loci (assigned to 8p23) in at least some patients with inverted duplications of 8p. Cytogenetic break points forming the inverted duplication are remarkably similar among most of their patients and those reported previously, suggesting a common mechanism for this interesting rearrangement. Why should similar breaks occur in 8p and why is a FISH signal absent in the distal short arm when the ONCOR digoxigenin-labeled probe for loci D8S596 is used? Other studies also indicate that duplication for the region 8p12-p22 is associated with a deletion distal to the duplication itself. 4 refs.

  11. Disappearing Polymorphs Revisited

    PubMed Central

    Bučar, Dejan-Krešimir; Lancaster, Robert W; Bernstein, Joel

    2015-01-01

    Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law. PMID:26031248

  12. A review of 18p deletions.

    PubMed

    Hasi-Zogaj, Minire; Sebold, Courtney; Heard, Patricia; Carter, Erika; Soileau, Bridgette; Hill, Annice; Rupert, David; Perry, Brian; Atkinson, Sidney; O'Donnell, Louise; Gelfond, Jon; Lancaster, Jack; Fox, Peter T; Hale, Daniel E; Cody, Jannine D

    2015-09-01

    Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development. PMID:26250845

  13. Probabilistic phylogenetic inference with insertions and deletions.

    PubMed

    Rivas, Elena; Eddy, Sean R

    2008-01-01

    A fundamental task in sequence analysis is to calculate the probability of a multiple alignment given a phylogenetic tree relating the sequences and an evolutionary model describing how sequences change over time. However, the most widely used phylogenetic models only account for residue substitution events. We describe a probabilistic model of a multiple sequence alignment that accounts for insertion and deletion events in addition to substitutions, given a phylogenetic tree, using a rate matrix augmented by the gap character. Starting from a continuous Markov process, we construct a non-reversible generative (birth-death) evolutionary model for insertions and deletions. The model assumes that insertion and deletion events occur one residue at a time. We apply this model to phylogenetic tree inference by extending the program dnaml in phylip. Using standard benchmarking methods on simulated data and a new "concordance test" benchmark on real ribosomal RNA alignments, we show that the extended program dnamlepsilon improves accuracy relative to the usual approach of ignoring gaps, while retaining the computational efficiency of the Felsenstein peeling algorithm. PMID:18787703

  14. YAC contigs covering an 8-megabase region of 3p deleted in the small-cell lung cancer cell line U2020.

    PubMed

    Todd, S; Roche, J; Hahner, L; Bolin, R; Drabkin, H A; Gemmill, R M

    1995-01-01

    Somatic deletions of chromosome 3p occur at high frequencies in cancers of kidney, breast, cervix, head and neck, nasopharynx, and lung. The frequency of 3p deletion in lung cancer approaches 100% among small cell lesions and 70 to 80% in non-small cell lesions. This evidence strongly implies that one or more tumor suppressor genes of potentially widespread significance reside within the deleted region(s). Precise definition of the deleted target region(s) has been difficult due to the extensive area(s) lost and use of markers with low informativeness. However, improved definition remains essential to permit isolation of putative tumor suppressor genes from 3p. The identification of several small, homozygous 3p deletions in lung cancer cell lines has provided a critical resource that will assist this search. The U2020 cell line contains a small homozygous deletion that maps to a very proximal region of 3p and includes the marker D3S3. We previously identified a subset of DNA markers located within the deleted region and determined their relative order by pulsed-field gel mapping studies. In the present report, we describe the development of YAC contigs that span the majority of the deleted region and link up to flanking markers on both sides. The centromere proximal portion of the contig crosses the breakpoint from an X;3 translocation located within 3p12 providing both location and orientation to the map. PCR-based (CA)n microsatellite polymorphisms have been localized within and flanking the deletion region. These markers should greatly facilitate loss-of-heterozygosity studies of this region in human cancer. The contig provides a direct means for isolation of putative tumor suppressor genes from this segment of 3p. PMID:7774917

  15. Mice with a heterozygous Lrp6 deletion have impaired fracture healing

    PubMed Central

    Burgers, Travis A; Vivanco, Juan F; Zahatnansky, Juraj; Moren, Andrew J Vander; Mason, James J; Williams, Bart O

    2016-01-01

    Bone fracture non-unions, the failure of a fracture to heal, occur in 10%–20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 +/−) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 +/− mice and wild-type controls (Lrp6 +/+). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 +/− mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing. PMID:27635281

  16. Mice with a heterozygous Lrp6 deletion have impaired fracture healing

    PubMed Central

    Burgers, Travis A; Vivanco, Juan F; Zahatnansky, Juraj; Moren, Andrew J Vander; Mason, James J; Williams, Bart O

    2016-01-01

    Bone fracture non-unions, the failure of a fracture to heal, occur in 10%–20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 +/−) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 +/− mice and wild-type controls (Lrp6 +/+). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 +/− mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.

  17. CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients

    PubMed Central

    Muntinghe, Friso L.H.; Verduijn, Marion; Zuurman, Mike W.; Grootendorst, Diana C.; Carrero, Juan Jesus; Qureshi, Abdul Rashid; Luttropp, Karin; Nordfors, Louise; Lindholm, Bengt; Brandenburg, Vincent; Schalling, Martin; Stenvinkel, Peter; Boeschoten, Elisabeth W.; Krediet, Raymond T.; Navis, Gerjan; Dekker, Friedo W.

    2009-01-01

    The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR5Δ32) leads to deficiency of the receptor. We hypothesized that CCR5Δ32 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP ≤ 10 mg/L (n = 225), those carrying the deletion allele with hsCRP ≤ 10 mg/L (n = 55) had similar mortality, and those carrying the wild-type genotype with hsCRP > 10 mg/L (n = 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP > 10 mg/L (n = 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR5Δ32 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD. PMID:19389855

  18. Mice with a heterozygous Lrp6 deletion have impaired fracture healing.

    PubMed

    Burgers, Travis A; Vivanco, Juan F; Zahatnansky, Juraj; Moren, Andrew J Vander; Mason, James J; Williams, Bart O

    2016-01-01

    Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 (+/-)) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 (+/-) mice and wild-type controls (Lrp6 (+/+)). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 (+/-) mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing. PMID:27635281

  19. Experimental quantum deletion in an NMR quantum information processor

    NASA Astrophysics Data System (ADS)

    Long, Yu; Feng, GuanRu; Pearson, Jasong; Long, GuiLu

    2014-07-01

    We report an NMR experimental realization of a rapid quantum deletion algorithm that deletes marked states in an unsorted database. Unlike classical deletion, where search and deletion are equivalent, quantum deletion can be implemented with only a single query, which achieves exponential speed-up compared to the optimal classical analog. In the experimental realization, the GRAPE algorithm was used to obtain an optimized NMR pulse sequence, and the efficient method of maximum-likelihood has been used to reconstruct the experimental output state.

  20. Deletion of pyruvate decarboxylase by a new method for efficient markerless gene deletions in Gluconobacter oxydans.

    PubMed

    Peters, Björn; Junker, Anja; Brauer, Katharina; Mühlthaler, Bernadette; Kostner, David; Mientus, Markus; Liebl, Wolfgang; Ehrenreich, Armin

    2013-03-01

    Gluconobacter oxydans, a biotechnologically relevant species which incompletely oxidizes a large variety of carbohydrates, alcohols, and related compounds, contains a gene for pyruvate decarboxylase (PDC). This enzyme is found only in very few species of bacteria where it is normally involved in anaerobic ethanol formation via acetaldehyde. In order to clarify the role of PDC in the strictly oxidative metabolism of acetic acid bacteria, we developed a markerless in-frame deletion system for strain G. oxydans 621H which uses 5-fluorouracil together with a plasmid-encoded uracil phosphoribosyltransferase as counter selection method and used this technique to delete the PDC gene (GOX1081) of G. oxydans 621H. The PDC deletion mutant accumulated large amounts of pyruvate but almost no acetate during growth on D-mannitol, D-fructose or in the presence of L-lactate. This suggested that in G. oxydans acetate formation occurs by decarboxylation of pyruvate and subsequent oxidation of acetaldehyde to acetate. This observation and the efficiency of the markerless deletion system were confirmed by constructing deletion mutants of two acetaldehyde dehydrogenases (GOX1122 and GOX2018) and of the acetyl-CoA-synthetase (GOX0412). Acetate formation during growth of these mutants on mannitol did not differ significantly from the wild-type strain.

  1. Association of mitochondrial deoxyribonucleic acid mutation with polymorphism in CYP2E1 gene in oral carcinogenesis

    PubMed Central

    Pandey, Rahul; Mehrotra, Divya; Catapano, Carlo; Choubey, Vimal; Sarin, Rajiv; Mahdi, Abbas Ali; Singh, Stuti

    2012-01-01

    Background Oral carcinogenesis is a complex process affected by genetic as well as environmental factors. CYP2E1 gene is involved in metabolism of number of compounds and carcinogens. Its normal functioning is required for homeostasis of free radical. Mitochondrial deoxyribonucleic acid (mtDNA) is 10–100 times more susceptible to damage than nuclear DNA. Mitochondrial DNA large scale deletions are well documented in oral cancer. However, the relationship between CYP2E1 gene polymorphisms and mtDNA damage is still not documented in literature. Materials and Methods Case–control study involving 50 subjects was carried out. Deoxyribonucleic acid extraction was done from study subject tissue samples. Restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) amplification was done to confirm CYP2E1 gene polymorphisms. The PCR amplification was done for mtDNA 4977 bp deletion. Statistical analysis was carried out using SPSS version 11.5 with χ2 tests. Results c1c1 and DD polymorphisms are prevalent in North Indian population having oral cancer. These polymorphisms are significantly associated with mtDNA 4977 bp deletion. Conclusion Mitochondrial DNA damage induced by wild CYP2E1 forms and imperfect DNA repair in mtDNA may act synergistically to greatly enhance oral cancer risk. PMID:25756024

  2. PopAlu: population-scale detection of Alu polymorphisms

    PubMed Central

    Qian, Yu; Kehr, Birte

    2015-01-01

    Alu elements are sequences of approximately 300 basepairs that together comprise more than 10% of the human genome. Due to their recent origin in primate evolution some Alu elements are polymorphic in humans, present in some individuals while absent in others. We present PopAlu, a tool to detect polymorphic Alu elements on a population scale from paired-end sequencing data. PopAlu uses read pair distance and orientation as well as split reads to identify the location and precise breakpoints of polymorphic Alus. Genotype calling enables us to differentiate between homozygous and heterozygous carriers, making the output of PopAlu suitable for use in downstream analyses such as genome-wide association studies (GWAS). We show on a simulated dataset that PopAlu calls Alu elements inserted and deleted with respect to a reference genome with high accuracy and high precision. Our analysis of real data of a human trio from the 1000 Genomes Project confirms that PopAlu is able to produce highly accurate genotype calls. To our knowledge, PopAlu is the first tool that identifies polymorphic Alu elements from multiple individuals simultaneously, pinpoints the precise breakpoints and calls genotypes with high accuracy. PMID:26417547

  3. Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy.

    PubMed

    Saleem, Saba; Azam, Aisha; Maqsood, Sundus Ijaz; Muslim, Irfan; Bashir, Shaheena; Fazal, Nosheen; Riaz, Moeen; Ali, Syeda Hafiza Benish; Niazi, Muhammad Khizar; Ishaq, Mazhar; Waheed, Nadia Khalida; Qamar, Raheel; Azam, Maleeha

    2015-01-01

    In the present study we determined the association of angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR) 1.870 [95% confidence interval (CI) = 1.04-3.36]) and its sub-clinical class non-proliferative DR (NPDR) (p = 0.006, OR 2.250 [95% CI = 1.098-4.620]), while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR). PMID:26658948

  4. rs621554 single nucleotide polymorphism of DLC1 is associated with breast cancer susceptibility and prognosis.

    PubMed

    Ding, Xia; Gao, Sumei; Yang, Qifeng

    2016-05-01

    Deleted in liver cancer 1 (DLC1) on chromosome 8p22, is an important tumor suppressor gene originally identified to be deleted in hepatocellular carcinoma. It can regulate the structure of the actin cytoskeleton and inhibit cell proliferation, motility and angiogenesis, which predominantly depends on its homology to rat RhoGAP. There are many genetic variants in DLC1, which may influence its antitumor efficacy. The rs621554 (IVS19+108C>T) polymorphism is a synonymous single nucleotide polymorphism (SNP) previously found to be associated with hepatocellular carcinoma. In the present study, 453 patients with breast cancer and 330 healthy females were analyzed using a cycling probe method. It was determined that the rs621554 polymorphism of DLC1 was associated with breast cancer susceptibility, with the CC and CT genotypes resulting in a higher risk of developing breast cancer. In regard to clinicopathological variables, it was demonstrated that the CT and CC genotype were associated with tumor size, lymph node metastasis and progesterone receptor status. Patients with the CT and CC genotype had shorter disease-free survival and overall survival rates compared with those with the TT genotype. Additionally, it was demonstrated that the rs621554 polymorphism was correlated with DLC1 expression at the mRNA level. These results suggested that the rs621554 polymorphism is associated with breast cancer susceptibility and prognosis, and may serve as a biomarker for breast cancer development and progression.

  5. Enzyme polymorphisms in Canarium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fifty-two accessions of Canarium involving seven species, C. ovatum, C. album, C. megalanthum, C. harveyi, C. indicum, C. mehenbethene, and C. odontophyllum were studied for isozyme polymorphisms. Starch gel electrophoresis with a histidine-citrate buffer system (pH 6.5) was employed to assay six en...

  6. Polymorphous Perversity in Texts

    ERIC Educational Resources Information Center

    Johnson-Eilola, Johndan

    2012-01-01

    Here's the tricky part: If we teach ourselves and our students that texts are made to be broken apart, remixed, remade, do we lose the polymorphous perversity that brought us pleasure in the first place? Does the pleasure of transgression evaporate when the borders are opened?

  7. Polymorphism of sorbitol

    NASA Astrophysics Data System (ADS)

    Nezzal, Amale; Aerts, Luc; Verspaille, Marleen; Henderickx, Geert; Redl, Andreas

    2009-07-01

    The polymorphism of sorbitol was investigated, confirming the existence of four anhydrous crystalline phases plus the hydrate. The crystallised melt (CM), the alpha form, and the gamma form were obtained via a dry route. The CM was confirmed to be a crystalline state with a spherulite morphology. The alpha form was obtained via direct conversion from the CM, in contrast to more complicated routes previously reported, and was found to have a very high crystallinity. Gamma crystals were obtained by seeding the melt at high temperature; however, crystallinity was clearly less than for alpha crystals. Despite its lower crystallinity, the gamma polymorph was found to be the most stable of the anhydrous crystalline forms; this was confirmed by its high melting point and low hygroscopicity. In contrast, the alpha polymorph has a relatively high melting point but lacks moisture stability at high relative humidity. The hydrate form has the same resistance to moisture as the gamma form, but melts at a lower temperature. The combination of both a high melting point and high stability in the presence of water makes the gamma polymorph best suited for confectionary applications.

  8. Investigation of Uranium Polymorphs

    SciTech Connect

    Sweet, Lucas E.; Henager, Charles H.; Hu, Shenyang Y.; Johnson, Timothy J.; Meier, David E.; Peper, Shane M.; Schwantes, Jon M.

    2011-08-01

    The UO3-water system is complex and has not been fully characterized, even though these species are common throughout the nuclear fuel cycle. As an example, most production schemes for UO3 result in a mixture of up to six or more different polymorphic phases, and small differences in these conditions will affect phase genesis that ultimately result in measureable changes to the end product. As a result, this feature of the UO3-water system may be useful as a means for determining process history. This research effort attempts to better characterize the UO3-water system with a variety of optical techniques for the purpose of developing some predictive capability for estimating process history in polymorphic phases of unknown origin. Three commercially relevant preparation methods for the production of UO3 were explored. Previously unreported low temperature routes to β- and γ-UO3 were discovered. Raman and fluorescence spectroscopic libraries were established for pure and mixed polymorphic forms of UO3 in addition to the common hydrolysis products of UO3. An advantage of the sensitivity of optical fluorescence microscopy over XRD has been demonstrated. Preliminary aging studies of the α and γ forms of UO3 have been conducted. In addition, development of a 3-D phase field model used to predict phase genesis of the system was initiated. Thermodynamic and structural constants that will feed the model have been gathered from the literature for most of the UO3 polymorphic phases.

  9. Polymorphic Alu Insertion/Deletion in Different Caste and Tribal Populations from South India

    PubMed Central

    Chinniah, Rathika; Vijayan, Murali; Thirunavukkarasu, Manikandan; Mani, Dhivakar; Raju, Kamaraj; Ravi, Padma Malini; Sivanadham, Ramgopal; C, Kandeepan; N, Mahalakshmi; Karuppiah, Balakrishnan

    2016-01-01

    Seven human-specific Alu markers were studied in 574 unrelated individuals from 10 endogamous groups and 2 hill tribes of Tamil Nadu and Kerala states. DNA was isolated, amplified by PCR-SSP, and subjected to agarose gel electrophoresis, and genotypes were assigned for various Alu loci. Average heterozygosity among caste populations was in the range of 0.292–0.468. Among tribes, the average heterozygosity was higher for Paliyan (0.3759) than for Kani (0.2915). Frequency differences were prominent in all loci studied except Alu CD4. For Alu CD4, the frequency was 0.0363 in Yadavas, a traditional pastoral and herd maintaining population, and 0.2439 in Narikuravars, a nomadic gypsy population. The overall genetic difference (Gst) of 12 populations (castes and tribes) studied was 3.6%, which corresponds to the Gst values of 3.6% recorded earlier for Western Asian populations. Thus, our study confirms the genetic similarities between West Asian populations and South Indian castes and tribes and supported the large scale coastal migrations from Africa into India through West Asia. However, the average genetic difference (Gst) of Kani and Paliyan tribes with other South Indian tribes studied earlier was 8.3%. The average Gst of combined South and North Indian Tribes (CSNIT) was 9.5%. Neighbor joining tree constructed showed close proximity of Kani and Paliyan tribal groups to the other two South Indian tribes, Toda and Irula of Nilgiri hills studied earlier. Further, the analysis revealed the affinities among populations and confirmed the presence of North and South India specific lineages. Our findings have documented the highly diverse (micro differentiated) nature of South Indian tribes, predominantly due to isolation, than the endogamous population groups of South India. Thus, our study firmly established the genetic relationship of South Indian castes and tribes and supported the proposed large scale ancestral migrations from Africa, particularly into South India through West Asian corridor. PMID:27315142

  10. The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism

    PubMed Central

    Vaughan, David; Brogioli, Michael; Maier, Thomas; White, Andy; Waldron, Sarah; Rittweger, Jörn; Toigo, Marco; Wettstein, Jessica; Laczko, Endre; Flück, Martin

    2016-01-01

    Objective A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle. Methods Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER), serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS), were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc. Results Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09). The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and –3%, respectively). Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione) were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon. Conclusion The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in working skeletal muscle. ACE-DD genotypes thereby transit into a pre-diabetic state with exhaustive exercise, which relates to a lowered muscle capillarisation, and deregulation of mitochondria-associated metabolism. PMID:26982073

  11. Evaluating the X Chromosome-Specific Diversity of Colombian Populations Using Insertion/Deletion Polymorphisms

    PubMed Central

    Ibarra, Adriana; Restrepo, Tomás; Rojas, Winston; Castillo, Adriana; Amorim, António; Martínez, Beatriz; Burgos, German; Ostos, Henry; Álvarez, Karen; Camacho, Mauricio; Suarez, Zuleyma; Pereira, Rui; Gusmão, Leonor

    2014-01-01

    The European and African contribution to the pre-existing Native American background has influenced the complex genetic pool of Colombia. Because colonisation was not homogeneous in this country, current populations are, therefore, expected to have different proportions of Native American, European and African ancestral contributions. The aim of this work was to examine 11 urban admixed populations and a Native American group, called Pastos, for 32 X chromosome indel markers to expand the current knowledge concerning the genetic background of Colombia. The results revealed a highly diverse genetic background comprising all admixed populations, harbouring important X chromosome contributions from all continental source populations. In addition, Colombia is genetically sub-structured, with different proportions of European and African influxes depending on the regions. The samples from the North Pacific and Caribbean coasts have a high African ancestry, showing the highest levels of diversity. The sample from the South Andean region showed the lowest diversity and significantly higher proportion of Native American ancestry than the other samples from the North Pacific and Caribbean coasts, Central-West and Central-East Andean regions, and the Orinoquian region. The results of admixture analysis using X-chromosomal markers suggest that the high proportion of African ancestry in the North Pacific coast was primarily male driven. These men have joined to females with higher Native American and European ancestry (likely resulting from a classic colonial asymmetric mating type: European male x Amerindian female). This high proportion of male-mediated African contributions is atypical of colonial settings, suggesting that the admixture occurred during a period when African people were no longer enslaved. In the remaining regions, the African contribution was primarily female-mediated, whereas the European counterpart was primarily male driven and the Native American ancestry contribution was not gender biased. PMID:24498042

  12. FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax.

    PubMed

    Ding, Yibing; Zhu, Chengchu; Zou, Wei; Ma, Dehua; Min, Haiyan; Chen, Baofu; Ye, Minhua; Pan, Yanqing; Cao, Lei; Wan, Yueming; Zhang, Wenwen; Meng, Lulu; Mei, Yuna; Yang, Chi; Chen, Shilin; Gao, Qian; Yi, Long

    2015-05-01

    Primary spontaneous pneumothorax (PSP) is a significant clinical problem, affecting tens of thousands patients annually. Germline mutations in the FLCN gene have been implicated in etiology of familial PSP (FPSP). Most of the currently identified FLCN mutations are small indels or point mutations that detected by Sanger sequencing. The aim of this study was to determine large FLCN deletions in PSP families that having no FLCN sequence-mutations. Multiplex ligation-dependent probe amplification (MLPA) assays and breakpoint analyses were used to detect and characterize the deletions. Three heterozygous FLCN intragenic deletions were identified in nine unrelated Chinese families including the exons 1-3 deletion in two families, the exons 9-14 deletion in five families and the exon 14 deletion in two families. All deletion breakpoints are located in Alu repeats. A 5.5 Mb disease haplotype shared in the five families with exons 9-14 deletion may date the appearance of this deletion back to approximately 16 generations ago. Evidences for founder effects of the other two deletions were also observed. This report documents the first identification of founder mutations in FLCN, as well as expands mutation spectrum of the gene. Our findings strengthen the view that MLPA analysis for intragenic deletions/duplications, as an important genetic testing complementary to DNA sequencing, should be used for clinical molecular diagnosis in FPSP.

  13. Characterization of a large deletion in the {beta}-globin gene cluster in a newborn with hemoglobin FE

    SciTech Connect

    Louie, E.; Dietz, L.; Shafer, F.

    1994-09-01

    A sample on a newborn with hemoglobin FE screen results was obtained to investigate whether E/E or B/{beta}{degrees} thalassemia was present using polymerase chain reaction (PCR) methodology. The newborn appeared homozygous for the hemoglobin E mutation in our initial study, but the parents` genotypes did not support this diagnosis. The father is homozygous for the absence of the hemoglobin E mutation (non E/non E) and the mother is heterozygous (E/non E) for this mutation. The limitation of PCR analysis is an assumption that the amplification of the two {beta}-globin alleles is equivalent. A large deletion on one {beta}-globin gene, which would produce E/{beta}{degrees} thalassemia, would be missed if it included part or the entire region subjected to amplification. The family results were consistent with either non-paternity, sample mix-up or such a deletion of the {beta}-globin gene in the father and child. To rule out the possibility of non-paternity, two polymorphic loci (HLA on chromosome 6 and a VNTR system of chromosome 17) that are outside of the {beta}-globin gene were analyzed and show that inheritance is consistent and the likelihood of a sample mix-up is then reduced. We therefore believe there is a gene deletion in this family. At the present time, analyses of the RFLPs that are 5{prime} of the {beta}-globin gene cluster show that the polymorphisms most distal from the 5{prime} {beta}-globin gene are not being inherited as expected. These results support our interpretation that a deletion exists in the father and was inherited by the child. The father`s clinical picture of possible HPFH (the father has 12% hemoglobin F) also supports the interpretation of a deletion in this family. Deletions of the {beta}-globin gene within this ethnic group are rare. Currently, Southern blots on the family are being probed to determine the extent of the putative deletion.

  14. [Intraspecific polymorphism of the sucrose synthase genes in Russian and Kazakhstan potato cultivars].

    PubMed

    Slugina, M A; Boris, K V; Kakimzhanova, A A; Kochieva, E Z

    2014-06-01

    In 12 different Russian and Kazakhstan potato cultivars, the polymorphism of the glycosyltransferase domain of the sucrose synthase gene was first examined, as well as the polymorphism of the sucrose synthase domain fragment of the same gene in the potato cultivars of Kazakhstan breed. It was demonstrated that the examined sequences contained point mutations, as well as insertions and deletions, including those not described earlier. Amino acid substitutions specific to heat- and drought-tolerant varieties were also identified and could be associated with the development of abiotic stress resistance. PMID:25715458

  15. Phenotypic characterization of rare interstitial deletion of chromosome 4

    PubMed Central

    Ismail, Samira; Helmy, Nivine A.; Mahmoud, Wael M.; El-Ruby, Mona O.

    2012-01-01

    Interstitial deletion of the long arm of chromosome 4 is rare. Patients with interstitial deletion of the long arm of chromosome 4 differ from those with terminal deletions. Phenotypes may be variable, depending upon the specific length and location of the deleted portion. Here, we report on a boy exhibiting most of the congenital malformations encountered in terminal 4q syndrome. The conventional karyotyping and Fluorescence in-situ hybridization revealed a de novo interstitial del (4)(q31q32). The current report is a further document highlighting that deletion of segment q31 could be contributing to the expression of most of the phenotype of 4q deletion syndrome. Using array comparative genome hybridization methodology is recommended for investigating further cases with similar segmental interstitial deletions to support and delineate findings and to define genes implicated in the pathogenesis of the disorder.

  16. Polymorphism of 4-bromobenzophenone.

    PubMed

    Strzhemechny, Mikhail A; Baumer, Vyacheslav N; Avdeenko, Anatoli A; Pyshkin, Oleg S; Romashkin, Roman V; Buravtseva, Lyubov M

    2007-04-01

    A combination of single-crystal and powder X-ray diffractometry was used to study the structure of two polymorphs of 4-bromobenzophenone over the temperature range from 100 to 300 K. One of the polymorphs of the title compound was known previously and its structure has been determined at room temperature [Ebbinghaus et al. (1997). Z. Kristallogr. 212, 339-340]. Two crystal growth methods were employed, one of which (a modification of the Bridgman-Stockbarger technique) resulted in single crystals of a previously unknown structure. The basic physical properties of the stable polymorph are: growth method, from 2-propanol solutions or gradient sublimation; space group, monoclinic P2(1)/c; melting point, T(m) = 355.2 K; X-ray density (at 100 K), D(x) = 1.646 g cm(-3). The same properties of the metastable polymorph (triclinic P\\overline 1 ) are: growth method, modified Bridgman-Stockbarger method; X-ray density (at 100 K), D(x) = 1.645 g cm(-3); T(m) = 354 K. Thermograms suggest that the melting of the metastable form is accompanied by at least a partial crystallization presumably into the monoclinic form; the transformation is therefore monotropic. Analysis of short distances in both polymorphs shows that numerous weak hydrogen bonds of the C-H...pi type ensure additional stabilization within the respective planes normal to the longest dimension of the molecules. The strong temperature dependence of the lattice constants and of the weak bond distances in the monoclinic form suggest that the weak bond interactions might be responsible for both the large thermal expansion within plane bc and the considerable thermal expansion anisotropy. PMID:17374940

  17. Mapping of chromosome 20 for loss of heterozygosity in childhood ALL reveals a 1,000-kb deletion in one patient.

    PubMed

    Couque, N; Chambon-Pautas, C; Cavé, H; Bardet, V; Duval, M; Vilmer, E; Grandchamp, B

    1999-12-01

    The long arm of chromosome 20 displays recurrent loss of heterozygosity (LOH) for microsatellite markers in blast cells from children with acute lymphoblastic leukemia. To further characterize the region of deletion and to precisely establish its frequency, we searched for LOH in 103 children with ALL using polymorphic markers in the previously described region of interest, namely between D20S101 and D20S887. LOH was detected in nine patients (ie with a frequency of 8.7%). Interestingly, in one patient, a small deletion was found, flanked proximally by D20S850 and distally by M201, a dinucleotide repeat identified from chromosome 20 sequences. The distance between these two markers is approximately 1000 kb. The occurrence of non-random deletions of the long arm of chromosome 20 has previously been observed in myeloid malignancies (myeloproliferative disorders and myelodysplastic syndromes) in 5-10% of patients. The small deletion in our patient is located within the common region of deletion of myeloproliferative disorders suggesting that a tumor suppressor gene may be the common target of the deletions in various types of hematological malignancies.

  18. Molecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions.

    PubMed Central

    Yang, S P; Bidichandani, S I; Figuera, L E; Juyal, R C; Saxon, P J; Baldini, A; Patel, P I

    1997-01-01

    A male child with multiple congenital anomalies initially was clinically diagnosed as having Smith-Lemli-Opitz syndrome (SLOS). Subsequent cytogenetic studies revealed an interstitial deletion of 17p11.2, which is associated with Smith-Magenis syndrome (SMS). Biochemical studies were not supportive of a diagnosis of SLOS, and the child did not display the typical SMS phenotype. The father's karyotype showed a paracentric inversion of 17p, with breakpoints in p11.2 and p13.3, and the same inversion was also found in two of the father's sisters. FISH analyses of the deleted and inverted 17p chromosomes indicated that the deletion was similar to that typically seen in SMS patients and was found to bracket the proximal inversion breakpoint. Available family members were genotyped at 33 polymorphic DNA loci in 17p. These studies determined that the deletion was of paternal origin and that the inversion was of grandpaternal origin. Haplotype analysis demonstrated that the 17p11.2 deletion arose following a recombination event involving the father's normal and inverted chromosome 17 homologues. A mechanism is proposed to explain the simultaneous deletion and apparent "reinversion" of the recombinant paternal chromosome. These findings have implications for prenatal counseling of carriers of paracentric inversions, who typically are considered to bear minimal reproductive risk. Images Figure 1 Figure 2 Figure 3 PMID:9150166

  19. Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12

    SciTech Connect

    Rand, E.B.; Piccoli, D.A.; Spinner, N.B.

    1995-11-01

    Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormalities. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this region. The presence of interstitial deletions of varying size led to the hypothesis that AGS is a contiguous gene deletion syndrome. This molecular analysis of cytogenetically normal AGS patients was performed in order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagille families led to the identification of a single submicroscopic deletion. The deletion included loci D20S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome. 29 refs., 4 figs., 1 tab.

  20. Escape from Het-6 Incompatibility in Neurospora Crassa Partial Diploids Involves Preferential Deletion within the Ectopic Segment

    PubMed Central

    Smith, M. L.; Yang, C. J.; Metzenberg, R. L.; Glass, N. L.

    1996-01-01

    Self-incompatible het-6(OR)/het-6(PA) partial diploids of Neurospora crassa were selected from a cross involving the translocation strain, T(IIL -> IIIR)AR18, and a normal sequence strain. About 25% of the partial diploids exhibited a marked increase in growth rate after 2 weeks, indicating that ``escape'' from het-6 incompatibility had occurred. Near isogenic tester strains with different alleles (het-6(OR) and het-6(PA)) were constructed and used to determine that 80 of 96 escape strains tested were het-6(PA), retaining the het-6 allele found in the normal-sequence LGII position; 16 were het-6(OR), retaining the allele in the translocated position. Restriction fragment length polymorphisms in 45 escape strains were examined with probes made from cosmids that spanned the translocated region. Along with electrophoretic analysis of chromosomes from three escape strains, RFLPs showed that escape is associated with deletion of part of one or the other of the duplicated DNA segments. Deletions ranged in size from ~70 kbp up to putatively the entire 270-kbp translocated region but always included a 35-kbp region wherein we hypothesize het-6 is located. The deletion spectrum at het-6 thus resembles other cases where mitotic deletions occur such as of tumor suppressor genes and of the hprt gene (coding for hypoxanthine-guanine phosphoribosyl-transferase) in humans. PMID:8889517

  1. Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort.

    PubMed

    Begum, Ferdouse; Ruczinski, Ingo; Li, Shengchao; Silverman, Edwin K; Cho, Michael H; Lynch, David A; Curran-Everett, Douglas; Crapo, James; Scharpf, Robert B; Parker, Margaret M; Hetmanski, Jacqueline B; Beaty, Terri H

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is a progressive disease with both environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified multiple genomic regions influencing risk of COPD. To thoroughly investigate the genetic etiology of COPD, however, it is also important to explore the role of copy number variants (CNVs) because the presence of structural variants can alter gene expression and can be causal for some diseases. Here, we investigated effects of polymorphic CNVs on quantitative measures of pulmonary function and chest computed tomography (CT) phenotypes among subjects enrolled in COPDGene, a multisite study. COPDGene subjects consist of roughly one-third African American (AA) and two-thirds non-Hispanic white adult smokers (with or without COPD). We estimated CNVs using PennCNV on 9,076 COPDGene subjects using Illumina's Omni-Express genome-wide marker array. We tested for association between polymorphic CNV components (defined as disjoint intervals of copy number regions) for several quantitative phenotypes associated with COPD within each racial group. Among the AAs, we identified a polymorphic CNV on chromosome 5q35.2 located between two genes (FAM153B and SIMK1, but also harboring several pseudo-genes) giving genome-wide significance in tests of association with total lung capacity (TLCCT ) as measured by chest CT scans. This is the first study of genome-wide association tests of polymorphic CNVs and TLCCT . Although the ARIC cohort did not have the phenotype of TLCCT , we found similar counts of CNV deletions and amplifications among AA and European subjects in this second cohort. PMID:26643968

  2. Direct demonstration that the A gamma T globin gene is linked to the 4 bp promoter deletion in the beta A chromosome of sickle cell traits.

    PubMed

    Gilman, J G; Josifovska, O; Erlingsson, S; Milner, P F; Nagel, R L

    1993-08-01

    In beta zero-thalassemia and sickle cell patients, a 4 bp deletion at -222 to -225 of the A gamma globin promoter was associated with low expression of the A gamma T variant (threonine at codon 75 of A gamma), whereas A gamma I (isoleucine at 75) had the normal A gamma promoter and higher expression. However, it has been reported that the beta A chromosomes of sickle cell trait cases have the 4 bp deletion as a common polymorphism unlinked to the A gamma T allele. We now present data demonstrating the association of the A gamma T allele with the 4 bp deletion in beta A chromosomes of sickle cell traits.

  3. Chemokine receptor V Δ32 deletion in multiple sclerosis patients in Csongrád County in Hungary and the North-Bácska region in Serbia.

    PubMed

    Török, Nóra; Molnár, Kinga; Füvesi, Judit; Karácsony, Mária; Zsiros, Viktória; Fejes-Szabó, Annamária; Fiatal, Szilvia; Ádány, Róza; Somogyvári, Ferenc; Stojiljković, Olivera; Vécsei, László; Bencsik, Krisztina

    2015-01-01

    The roles of chemokine receptor V (CCR5) and its polymorphism, rs333 in multiple sclerosis (MS) are controversial. We investigated the receptor and its deletion in a large MS (428) and a numerous control (831) population in Csongrád County (Hungary) and North-Bácska (Serbia). Taqman probes firstly were used for the allele discrimination. There was no significant difference in genotype (OR=1.092, 95% CI=0.807-1.478, p=0.568 for wt/wt (wt=wild type allele) vs wt/Δ32, Δ32/Δ32 (Δ32=Δ32 base pair deletion allele)) or allele frequency (OR=0.914, 95% CI=0.692-1.207, p=0.525). Neither the deletion nor the wt allele affected the Expanded Disability Status Scale score or the age at onset. Our results indicate no association between the CCR5 Δ32 allele and MS.

  4. Naturally Occurring Deletions of Hunchback Binding Sites in the Even-Skipped Stripe 3+7 Enhancer

    PubMed Central

    Palsson, Arnar; Wesolowska, Natalia; Reynisdóttir, Sigrún; Ludwig, Michael Z.; Kreitman, Martin

    2014-01-01

    Changes in regulatory DNA contribute to phenotypic differences within and between taxa. Comparative studies show that many transcription factor binding sites (TFBS) are conserved between species whereas functional studies reveal that some mutations segregating within species alter TFBS function. Consistently, in this analysis of 13 regulatory elements in Drosophila melanogaster populations, single base and insertion/deletion polymorphism are rare in characterized regulatory elements. Experimentally defined TFBS are nearly devoid of segregating mutations and, as has been shown before, are quite conserved. For instance 8 of 11 Hunchback binding sites in the stripe 3+7 enhancer of even-skipped are conserved between D. melanogaster and Drosophila virilis. Oddly, we found a 72 bp deletion that removes one of these binding sites (Hb8), segregating within D. melanogaster. Furthermore, a 45 bp deletion polymorphism in the spacer between the stripe 3+7 and stripe 2 enhancers, removes another predicted Hunchback site. These two deletions are separated by ∼250 bp, sit on distinct haplotypes, and segregate at appreciable frequency. The Hb8Δ is at 5 to 35% frequency in the new world, but also shows cosmopolitan distribution. There is depletion of sequence variation on the Hb8Δ-carrying haplotype. Quantitative genetic tests indicate that Hb8Δ affects developmental time, but not viability of offspring. The Eve expression pattern differs between inbred lines, but the stripe 3 and 7 boundaries seem unaffected by Hb8Δ. The data reveal segregating variation in regulatory elements, which may reflect evolutionary turnover of characterized TFBS due to drift or co-evolution. PMID:24786295

  5. Polymorphisms of the prion protein gene (PRNP) in a Korean population.

    PubMed

    Jeong, Byung-Hoon; Nam, Jae-Hwan; Lee, Yun-Jung; Lee, Kyung-Hee; Jang, Myoung-Kuk; Carp, Richard I; Lee, Ho-Dong; Ju, Young-Ran; Ahn Jo, Sangmee; Park, Keun-Yong; Kim, Yong-Sun

    2004-01-01

    Human prion protein gene (PRNP) has been considered to be involved in the susceptibility of humans to prion diseases. Polymorphisms of methionine (Met)/valine (Val) at codon 129 and of glutamic acid (Glu)/lysine (Lys) at codon 219 are thought to play an important role in susceptibility to sporadic, iatrogenic and variant Creutzfeldt-Jakob disease (CJD). Although the genotype distribution of polymorphisms in PRNP open reading frame (ORF) has been reported in many European populations, among Asian groups, it has been reported only in the Japanese population. We examined the PRNP polymorphisms in 529 healthy Koreans. We observed that genotype frequencies at codon 129 was 94.33% Met/Met, 5.48% Met/Val, and 0.19% Val/Val with an allele frequency of 0.971:0.029 Met:Val, and that genotype frequencies at codon 219 was 92.06% Glu/Glu, 7.94% Glu/Lys, and 0% Lys/Lys with an allele frequency of 0.96:0.04 Glu:Lys. The frequencies of the Glu/Glu genotype ( chi(2)=10.075, P=0.0015) and of the Glu allele ( chi(2)=9.486, P=0.0021) at codon 219 were significantly higher in the Korean population than the Japanese population. In addition, the genotype frequency of heterozygotes (12.7%) at codons 129 or/and 219 was significantly lower in Koreans than in people from Great Britain ( chi(2)=89.52, P<0.0001). The deletion rate of one octarepeat (R2 deletion) was 0.38%, with 99.62% undeleted homozygotes and 0% deleted homozygote. To our knowledge, the R2 octarepeat deletion has never been found in people from countries other than Korea. The data of PRNP polymorphism at codon 219 suggest that Koreans may be more sensitive to sporadic CJD than the Japanese population.

  6. Y-chromosome polymorphism: Possible largest Y chromosome in man?

    SciTech Connect

    Murthy, D.S.K.; Al-Awadi, S.A.; Bastaki, L.

    1994-09-01

    The role of variations (inversions/deletion or duplication) in the heterochromatin in gonadal development and function, reproductive fitness, and malignant disease has been extensively studied. However, the causal-relationship of large Y (Yqh+) and repeated fetal loss has not been established unequivocally. An Arab couple (?Bedouin origin) with a history of repeated abortions were investigated. Karyotype analysis of the husband showed a very large Y chromosome, confirmed by GTG-, QFQ- and CBG-banding techniques. C-banding showed discontinuous distribution of the heterochromatin blocks separated by pale bands. The origin of the large heterochromatin segment could be due to tandem duplication of the Yq region or translocation (Yq:Yq). No other relatives (males) of the propositus have been available for investigation. Polymorphism of the Y chromosome could be attributed to evolutionary changes from an ancestral type, either by deletion or duplication of the heterochromatin segment. More detailed studies on isolated, aboriginal/tribal human populations will enable us to better understand the significance of the Y chromosome polymorphism.

  7. Polymorphism of phosphoric oxide

    USGS Publications Warehouse

    Hill, W.L.; Faust, G.T.; Hendricks, S.B.

    1943-01-01

    The melting points and monotropic relationship of three crystalline forms of phosphoric oxide were determined by the method of quenching. Previous vapor pressure data are discussed and interpreted to establish a pressure-temperature diagram (70 to 600??) for the one-component system. The system involves three triple points, at which solid, liquid and vapor (P4O10) coexist in equilibrium, namely: 420?? and 360 cm., 562?? and 43.7 cm. and 580?? and 55.5 cm., corresponding to the hexagonal, orthorhombic and stable polymorphs, respectively, and at least two distinct liquids, one a stable polymer of the other, which are identified with the melting of the stable form and the hexagonal modification, respectively. Indices of refraction of the polymorphs and glasses were determined. The density and the thermal, hygroscopic and structural properties of the several phases are discussed.

  8. Deletion of ultraconserved elements yields viable mice

    SciTech Connect

    Ahituv, Nadav; Zhu, Yiwen; Visel, Axel; Holt, Amy; Afzal, Veena; Pennacchio, Len A.; Rubin, Edward M.

    2007-07-15

    Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lacking these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.

  9. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, John J.; Quesada, Mark A.; Randesi, Matthew

    1999-07-27

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment. More specifically, the method comprises providing a recombinant DNA construct comprising a DNA segment of interest inserted in a cloning vector, the cloning vector having an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment of interest. The recombinant DNA construct is then contacted with the protein pII encoded by gene II of phage f1 thereby generating a single-stranded nick. The nicked DNA is then contacted with E. coli Exonuclease III thereby expanding the single-stranded nick into a single-stranded gap. The single-stranded gapped DNA is then contacted with a single-strand-specific endonuclease thereby producing a linearized DNA molecule containing a double-stranded deletion corresponding in size to the single-stranded gap. The DNA treated in this manner is then incubated with DNA ligase under conditions appropriate for ligation. Also disclosed is a method for producing single-stranded DNA probes. In this embodiment, single-stranded gapped DNA, produced as described above, is contacted with a DNA polymerase in the presence of labeled nucleotides to fill in the gap. This DNA is then linearized by digestion with a restriction enzyme which cuts outside the DNA segment of interest. The product of this digestion is then denatured to produce a labeled single-stranded nucleic acid probe.

  10. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, J.J.; Quesada, M.A.; Randesi, M.

    1999-07-27

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment. More specifically, the method comprises providing a recombinant DNA construct comprising a DNA segment of interest inserted in a cloning vector. The cloning vector has an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment of interest. The recombinant DNA construct is then contacted with the protein pII encoded by gene II of phage f1 thereby generating a single-stranded nick. The nicked DNA is then contacted with E. coli Exonuclease III thereby expanding the single-stranded nick into a single-stranded gap. The single-stranded gapped DNA is then contacted with a single-strand-specific endonuclease thereby producing a linearized DNA molecule containing a double-stranded deletion corresponding in size to the single-stranded gap. The DNA treated in this manner is then incubated with DNA ligase under conditions appropriate for ligation. Also disclosed is a method for producing single-stranded DNA probes. In this embodiment, single-stranded gapped DNA, produced as described above, is contacted with a DNA polymerase in the presence of labeled nucleotides to fill in the gap. This DNA is then linearized by digestion with a restriction enzyme which cuts outside the DNA segment of interest. The product of this digestion is then denatured to produce a labeled single-stranded nucleic acid probe. 1 fig.

  11. [Polymorphs of clopidogrel bisulfate].

    PubMed

    Liu, Yi; Huang, Hai-Wei; Wu, Jian-Min; Shi, Ya-Qin; Yang, La-Hu

    2013-08-01

    This paper is to report the polymorphism of raw materials of clopidogrel bisulfate at home and abroad. By the analysis of Fourier transform infrared spectroscopy (FTIR) and powder X-ray diffraction (p-XRD), samples are roughly classified into two groups, except one patent material. And the differential scanning calorimeter (DSC) examination showed more detailed information for these materials. The results of the study could provide comprehensive basis for the quality evaluation of clopidogrel bisulfate. PMID:24187849

  12. Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment

    PubMed Central

    2012-01-01

    Background Hepatitis B virus (HBV), because of its error-prone viral polymerase, has a high mutation rate leading to widespread substitutions, deletions, and insertions in the HBV genome. Deletions may significantly change viral biological features complicating the progression of liver diseases. However, the clinical conditions correlating to the accumulation of deleted mutants remain unclear. In this study, we explored HBV deletion patterns and their association with disease status and antiviral treatment by performing whole genome sequencing on samples from 51 hepatitis B patients and by monitoring changes in deletion variants during treatment. Clone sequencing was used to analyze preS regions in another cohort of 52 patients. Results Among the core, preS, and basic core promoter (BCP) deletion hotspots, we identified preS to have the highest frequency and the most complex deletion pattern using whole genome sequencing. Further clone sequencing analysis on preS identified 70 deletions which were classified into 4 types, the most common being preS2. Also, in contrast to the core and BCP regions, most preS deletions were in-frame. Most deletions interrupted viral surface epitopes, and are possibly involved in evading immuno-surveillance. Among various clinical factors examined, logistic regression showed that antiviral medication affected the accumulation of deletion mutants (OR = 6.81, 95% CI = 1.296 ~ 35.817, P = 0.023). In chronic carriers of the virus, and individuals with chronic hepatitis, the deletion rate was significantly higher in the antiviral treatment group (Fisher exact test, P = 0.007). Particularly, preS2 deletions were associated with the usage of nucleos(t)ide analog therapy (Fisher exact test, P = 0.023). Dynamic increases in preS1 or preS2 deletions were also observed in quasispecies from samples taken from patients before and after three months of ADV therapy. In vitro experiments demonstrated that preS2 deletions alone

  13. Are there ethnic differences in deletions in the dystrophin gene?

    SciTech Connect

    Banerjee, M.; Verma, I.C.

    1997-01-20

    We studied 160 cases of Duchenne muscular dystrophy (DMD) drawn from all parts of India, using multiplex PCR of 27 exons. Of these, 103 (64.4%) showed intragenic deletions. Most (69.7%) of the deletions involved exons 45-51. The phenotype of cases with deletion of single exons did not differ significantly from those with deletion of multiple exons. The distribution of deletions in studies from different countries was variable, but this was accounted for either by the small number of cases studied, or by fewer exons analyzed. It is concluded that there is likely to be no ethnic difference with respect to deletions in the DMD gene. 38 refs., 2 figs., 3 tabs.

  14. Assessing interethnic admixture using an X-linked insertion-deletion multiplex.

    PubMed

    Ribeiro-Rodrigues, Elzemar Martins; dos Santos, Ney Pereira Carneiro; dos Santos, Andrea Kely Campos Ribeiro; Pereira, Rui; Amorim, António; Gusmão, Leonor; Zago, Marco Antonio; dos Santos, Sidney Emanuel Batista

    2009-01-01

    In this study, a PCR multiplex was optimized, allowing the simultaneous analysis of 13 X-chromosome Insertion/deletion polymorphisms (INDELs). Genetic variation observed in Africans, Europeans, and Native Americans reveals high inter-population variability. The estimated proportions of X-chromosomes in an admixed population from the Brazilian Amazon region show a predominant Amerindian contribution (approximately 41%), followed by European (approximately 32%) and African (approximately 27%) contributions. The proportion of Amerindian contribution based on X-linked data is similar to the expected value based on mtDNA and Y-chromosome information. The accuracy for assessing interethnic admixture, and the high differentiation between African, European, and Native American populations, demonstrates the suitability of this INDEL set to measure ancestry proportions in three-hybrid populations, as it is the case of Latin American populations.

  15. Enhanced Deletion Formation by Aberrant DNA Replication in Escherichia Coli

    PubMed Central

    Saveson, C. J.; Lovett, S. T.

    1997-01-01

    Repeated genes and sequences are prone to genetic rearrangements including deletions. We have investigated deletion formation in Escherichia coli strains mutant for various replication functions. Deletion was selected between 787 base pair tandem repeats carried either on a ColE1-derived plasmid or on the E. coli chromosome. Only mutations in functions associated with DNA Polymerase III elevated deletion rates in our assays. Especially large increases were observed in strains mutant in dnaQ, the ε editing subunit of Pol III, and dnaB, the replication fork helicase. Mutations in several other functions also altered deletion formation: the α polymerase (dnaE), the γ clamp loader complex (holC, dnaX), and the β clamp (dnaN) subunits of Pol III and the primosomal proteins, dnaC and priA. Aberrant replication stimulated deletions through several pathways. Whereas the elevation in dnaB strains was mostly recA- and lexA-dependent, that in dnaQ strains was mostly recA- and lexA-independent. Deletion product analysis suggested that slipped mispairing, producing monomeric replicon products, may be preferentially increased in a dnaQ mutant and sister-strand exchange, producing dimeric replicon products, may be elevated in dnaE mutants. We conclude that aberrant Polymerase III replication can stimulate deletion events through several mechanisms of deletion and via both recA-dependent and independent pathways. PMID:9177997

  16. An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy

    PubMed Central

    Eidinger, Osnat; Leibu, Rina; Newman, Hadas; Rizel, Leah; Perlman, Ido

    2015-01-01

    Purpose To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family. Methods Patients underwent a detailed ophthalmic evaluation, including eye examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potential (VEP). Genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing. Results The affected family members are three siblings who have various degrees of progressive visual deterioration, glare, color vision abnormalities, and night vision difficulties. Visual field tests revealed central scotomas of different extension. Cone and rod ERG responses were reduced, with cones more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice sites. However, in intron 21, proximate to the intron–exon junction, we observed a homozygous 10 bp deletion between positions −26 and −17 (c.2281–26_-17del). The deletion was linked to a known SNP, c.2281–6C>G. The deletion cosegregated with the disease in the family, and was not detected in public databases or in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence. The in vitro splicing assay demonstrated that c.2281–26_-17del leads to

  17. Large Deletions at the SHOX Locus in the Pseudoautosomal Region Are Associated with Skeletal Atavism in Shetland Ponies

    PubMed Central

    Rafati, Nima; Andersson, Lisa S.; Mikko, Sofia; Feng, Chungang; Raudsepp, Terje; Pettersson, Jessica; Janecka, Jan; Wattle, Ove; Ameur, Adam; Thyreen, Gunilla; Eberth, John; Huddleston, John; Malig, Maika; Bailey, Ernest; Eichler, Evan E.; Dalin, Göran; Chowdary, Bhanu; Andersson, Leif; Lindgren, Gabriella; Rubin, Carl-Johan

    2016-01-01

    Skeletal atavism in Shetland ponies is a heritable disorder characterized by abnormal growth of the ulna and fibula that extend the carpal and tarsal joints, respectively. This causes abnormal skeletal structure and impaired movements, and affected foals are usually killed. In order to identify the causal mutation we subjected six confirmed Swedish cases and a DNA pool consisting of 21 control individuals to whole genome resequencing. We screened for polymorphisms where the cases and the control pool were fixed for opposite alleles and observed this signature for only 25 SNPs, most of which were scattered on genome assembly unassigned scaffolds. Read depth analysis at these loci revealed homozygosity or compound heterozygosity for two partially overlapping large deletions in the pseudoautosomal region (PAR) of chromosome X/Y in cases but not in the control pool. One of these deletions removes the entire coding region of the SHOX gene and both deletions remove parts of the CRLF2 gene located downstream of SHOX. The horse reference assembly of the PAR is highly fragmented, and in order to characterize this region we sequenced bacterial artificial chromosome (BAC) clones by single-molecule real-time (SMRT) sequencing technology. This considerably improved the assembly and enabled size estimations of the two deletions to 160−180 kb and 60−80 kb, respectively. Complete association between the presence of these deletions and disease status was verified in eight other affected horses. The result of the present study is consistent with previous studies in humans showing crucial importance of SHOX for normal skeletal development. PMID:27207956

  18. Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion

    SciTech Connect

    Boultwood, J.; Rack, K.; Buckle, V.J.; Wainscoat, J.S. ); Kelly, S. ); Madden, J.; Oscier, D.G. ); Sakaguchi, A.Y.; Wang, Lingmei )

    1991-07-15

    A high proportion of patients with myelodysplasia show characteristic karyotypic abnormalities in bone marrow cells. The most distinctive of the myelodysplastic syndromes is the 5q- syndrome characterized by refractory anemia, poorly lobulated megakaryocytes, and an interstitial deletion of the long arm of chromosome 5 (5q deletion) as the sole karyotypic abnormality. Recently, several genes encoding hemopoietic growth factors and receptors, have been localized to the long arm of chromosome 5, and there has been much speculation that deletion of one or more of these genes may be critical to the pathogenesis of the associated myeloid disorders. One candidate gene is CSF1R. The authors have carried out a molecular examination of the CSF1R, both on the 5q- chromosome and on the apparently normal homologous chromsome 5, in 10 patients with myelodysplasia and a 5q deletion. They have found, using restriction fragment length polymorphism analysis and gene dosage experiments, that all 10 patients showed deletion of CSF1R. The homozygous CSF1R loss has been confirmed in 2 patients by an in situ hybridization technique comparing the signal in affected cells to that in control sex-mismatched cells on the same slides. This loss of one CSF1R allele, together with loss in some cells of the remaining allele on the homologous chromsome 5, in patients with myelodysplasia indicates that this is a region of critical gene loss on 5q. The loss of the hemopoietic growth factor receptor gene CSF1R may be important in the pathogenesis of human myeloid leukemia.

  19. Large Deletions at the SHOX Locus in the Pseudoautosomal Region Are Associated with Skeletal Atavism in Shetland Ponies.

    PubMed

    Rafati, Nima; Andersson, Lisa S; Mikko, Sofia; Feng, Chungang; Raudsepp, Terje; Pettersson, Jessica; Janecka, Jan; Wattle, Ove; Ameur, Adam; Thyreen, Gunilla; Eberth, John; Huddleston, John; Malig, Maika; Bailey, Ernest; Eichler, Evan E; Dalin, Göran; Chowdary, Bhanu; Andersson, Leif; Lindgren, Gabriella; Rubin, Carl-Johan

    2016-01-01

    Skeletal atavism in Shetland ponies is a heritable disorder characterized by abnormal growth of the ulna and fibula that extend the carpal and tarsal joints, respectively. This causes abnormal skeletal structure and impaired movements, and affected foals are usually killed. In order to identify the causal mutation we subjected six confirmed Swedish cases and a DNA pool consisting of 21 control individuals to whole genome resequencing. We screened for polymorphisms where the cases and the control pool were fixed for opposite alleles and observed this signature for only 25 SNPs, most of which were scattered on genome assembly unassigned scaffolds. Read depth analysis at these loci revealed homozygosity or compound heterozygosity for two partially overlapping large deletions in the pseudoautosomal region (PAR) of chromosome X/Y in cases but not in the control pool. One of these deletions removes the entire coding region of the SHOX gene and both deletions remove parts of the CRLF2 gene located downstream of SHOX. The horse reference assembly of the PAR is highly fragmented, and in order to characterize this region we sequenced bacterial artificial chromosome (BAC) clones by single-molecule real-time (SMRT) sequencing technology. This considerably improved the assembly and enabled size estimations of the two deletions to 160-180 kb and 60-80 kb, respectively. Complete association between the presence of these deletions and disease status was verified in eight other affected horses. The result of the present study is consistent with previous studies in humans showing crucial importance of SHOX for normal skeletal development. PMID:27207956

  20. A nucleotide deletion and frame-shift cause analbuminemia in a Turkish family

    PubMed Central

    Caridi, Gianluca; Gulec, Elif Yilmaz; Campagnoli, Monica; Lugani, Francesca; Onal, Hasan; Kilic, Duzgun; Galliano, Monica; Minchiotti, Lorenzo

    2016-01-01

    Congenital analbuminemia is an autosomal recessive disorder, in which albumin, the major blood protein, is present only in a minute amount. The condition is a rare allelic heterogeneous defect, only about seventy cases have been reported worldwide. To date, more than twenty different mutations within the albumin gene have been found to cause the trait. In our continuing study of the molecular genetics of congenital analbuminemia, we report here the clinical and biochemical findings and the mutation analysis of the gene in two Turkish infants. For the molecular analysis, we used our strategy, based on the screening of the gene by single-strand conformation polymorphism, heteroduplex analysis and direct DNA sequencing. The results showed that both patients are homozygous for the deletion of a cytosine residue in exon 5, in a stretch of four cytosines starting from nucleotide position 524 and ending at position 527 (NM_000477.5(ALB):c.527delC). The subsequent frame-shift inserts a stop codon in position 215, markedly reducing the size of the predicted protein product. The parents are both heterozygous for the same mutation, for which we propose the name Erzurum from the city of origin of the family. In conclusion, our results show that in this family congenital analbuminemia is caused by a novel frame-shift/deletion defect, confirm the inheritance of the trait, and contribute to advance our understanding of the molecular basis underlying this condition. PMID:27346974

  1. A nucleotide deletion and frame-shift cause analbuminemia in a Turkish family.

    PubMed

    Caridi, Gianluca; Gulec, Elif Yilmaz; Campagnoli, Monica; Lugani, Francesca; Onal, Hasan; Kilic, Duzgun; Galliano, Monica; Minchiotti, Lorenzo

    2016-01-01

    Congenital analbuminemia is an autosomal recessive disorder, in which albumin, the major blood protein, is present only in a minute amount. The condition is a rare allelic heterogeneous defect, only about seventy cases have been reported worldwide. To date, more than twenty different mutations within the albumin gene have been found to cause the trait. In our continuing study of the molecular genetics of congenital analbuminemia, we report here the clinical and biochemical findings and the mutation analysis of the gene in two Turkish infants. For the molecular analysis, we used our strategy, based on the screening of the gene by single-strand conformation polymorphism, heteroduplex analysis and direct DNA sequencing. The results showed that both patients are homozygous for the deletion of a cytosine residue in exon 5, in a stretch of four cytosines starting from nucleotide position 524 and ending at position 527 (NM_000477.5(ALB):c.527delC). The subsequent frame-shift inserts a stop codon in position 215, markedly reducing the size of the predicted protein product. The parents are both heterozygous for the same mutation, for which we propose the name Erzurum from the city of origin of the family. In conclusion, our results show that in this family congenital analbuminemia is caused by a novel frame-shift/deletion defect, confirm the inheritance of the trait, and contribute to advance our understanding of the molecular basis underlying this condition. PMID:27346974

  2. Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria.

    PubMed

    Turner, Samantha J; Hildebrand, Michael S; Block, Susan; Damiano, John; Fahey, Michael; Reilly, Sheena; Bahlo, Melanie; Scheffer, Ingrid E; Morgan, Angela T

    2013-09-01

    Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems.

  3. Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria.

    PubMed

    Turner, Samantha J; Hildebrand, Michael S; Block, Susan; Damiano, John; Fahey, Michael; Reilly, Sheena; Bahlo, Melanie; Scheffer, Ingrid E; Morgan, Angela T

    2013-09-01

    Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems. PMID:23918746

  4. PTPRD is homozygously deleted and epigenetically downregulated in human hepatocellular carcinomas.

    PubMed

    Acun, Tolga; Demir, Kubilay; Oztas, Emin; Arango, Diego; Yakicier, M Cengiz

    2015-04-01

    PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5'UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in

  5. No Association of the rs17822931 Polymorphism in ABCC11 with Breast Cancer Risk in Koreans.

    PubMed

    Na, Ann-Yae; Heo, Jin-Chul; Sung, Jin Young; Lee, Jong-Ha; Kim, Yoon-Nyun; Kim, Dae-Kwang

    2016-01-01

    ABCC11 is reported to be associated with breast cancer. However, whether ABCC11 polymorphisms relate to breast cancer risk remains unclear. This study aimed to evaluate any association of a single nucleotide polymorphism (SNP), rs17822931, in ABCC11 with breast cancer in Koreans. Genomic DNA samples of 170 women with breast cancer and 100 controls were assessed for SNP rs17822931 of ABCC11 by single-strand conformation polymorphism (SSCP) and DNA sequencing. A 27-bp deletion (Δ27) of ABCC11 was analyzed by PCR amplification. The genotype of SNP rs17822931 was confirmed to be AA in all samples from breast cancer patients and Δ27 was found in none of the samples. Our finding indicated that the SNP rs17822931 in ABCC11 is not associated with breast cancer. However, this study does provide information on fundamental genetic aspects of ABCC11 with regard to breast cancer risk in Koreans. PMID:27268641

  6. Genetic polymorphism of serotonin transporter 5-HTTLPR: involvement in smoking behaviour.

    PubMed

    Watanabe, Maria Angelica Ehara; Nunes, Sandra Odebrecht Vargas; Nunes, Sandra Odebrechet Vargas; Amarante, Marla Karine; Guembarovski, Roberta Losi; Oda, Julie Massayo Maeda; Lima, Kalil William Alves De; Fungaro, Maria Helena Pelegrinelli

    2011-04-01

    Data suggest that the serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the pathogenesis of multiple neuropsychiatric disorders and may also be involved in smoking behaviour since nicotine increases brain serotonin secretion. It is known that smoking behaviour is influenced by both genetic and environmental factors. The present review examines the role of the serotonin transporter gene (5-HTT) in smoking behaviour and investigating studies that showed association of 5-HTT gene with smoking. This study discusses a polymorphism which has been investigated by many researchers, as the bi-allelic insertion/deletion polymorphism in the 5'- flanking promoter region (5-HTTLPR). This gene has received considerable attention in attempts to understand the molecular determinants of smoking. Therefore, in the present study, the relationship between genetic polymorphism of serotonin transporter in smoking behaviour is reviewed considering the interactive effect of genetic factors.

  7. Genome-wide discovery of DNA polymorphism in Brassica rapa.

    PubMed

    Park, Soomin; Yu, Hee-Ju; Mun, Jeong-Hwan; Lee, Seung-Chan

    2010-02-01

    Single nucleotide polymorphisms (SNPs) and/or insertion/deletions (InDels) are frequent sequence variations in the plant genome, which can be developed as molecular markers for genetic studies on crop improvement. The ongoing Brassica rapa genome sequencing project has generated vast amounts of sequence data useful in genetic research. Here, we report a genome-wide survey of DNA polymorphisms in the B. rapa genome based on the 557 bacterial artificial clone sequences of B. rapa ssp. pekinensis cv. Chiifu. We identified and characterized 21,311 SNPs and 6,753 InDels in the gene space of the B. rapa genome by re-sequencing 1,398 sequence-tagged sites (STSs) in eight genotypes. Comparison of our findings with a B. rapa genetic linkage map confirmed that STS loci were distributed randomly over the B. rapa whole genome. In the 1.4 Mb of aligned sequences, mean nucleotide polymorphism and diversity were theta = 0.00890 and pi = 0.00917, respectively. Additionally, the nucleotide diversity in introns was almost three times greater than that in exons, and the frequency of observed InDel was almost 17 times higher in introns than in exons. Information regarding SNPs/InDels obtained here will provide an important resource for genetic studies and breeding programs of B. rapa.

  8. Chemokine receptor CCR5 polymorphisms and Chagas' disease cardiomyopathy.

    PubMed

    Calzada, J E; Nieto, A; Beraún, Y; Martín, J

    2001-09-01

    In this study we investigated the possible role of two CCR5 gene polymorphisms, CCR5Delta32 deletion and CCR5 59029 A-->G promoter point mutation, in determining the susceptibility to Trypanosoma cruzi infection as well as in the development of chagasic heart disease. These CCR5 polymorphisms were assessed in 85 seropositive (asymptomatic, n=53; cardiomyopathic, n=32) and 87 seronegative individuals. The extremely low frequency (0.009) of the CCR5Delta32 allele in our population did not allow us to analyse its possible influence on T. cruzi infection. We found no differences in the distribution of CCR5 59029 promoter genotype or phenotype frequencies between total chagasic patients and controls. However, we observed that the CCR5 59029-A/G genotype was significantly increased in asymptomatic with respect to cardiomyopathic patients (P=0.02; OR=0.33, 95% CI 0.10-0.94). In addition, the presence of the CCR5 59029-G allele was also increased in asymptomatics when compared with cardiomyopathics (P=0.02; OR=0.35, 95% CI 0.12-0.96). Our data suggest that the CCR5 59029 promoter polymorphism may be involved in a differential susceptibility to chagasic cardiomyopathy.

  9. Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells

    PubMed Central

    Tak, Yu Gyoung; Hung, Yuli; Yao, Lijing; Grimmer, Matthew R.; Do, Albert; Bhakta, Mital S.; O'Geen, Henriette; Segal, David J.; Farnham, Peggy J.

    2016-01-01

    Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with increased risk for colorectal cancer (CRC). A molecular understanding of the functional consequences of this genetic variation is complicated because most GWAS SNPs are located in non-coding regions. We used epigenomic information to identify H3K27Ac peaks in HCT116 colon cancer cells that harbor SNPs associated with an increased risk for CRC. Employing CRISPR/Cas9 nucleases, we deleted a CRC risk-associated H3K27Ac peak from HCT116 cells and observed large-scale changes in gene expression, resulting in decreased expression of many nearby genes. As a comparison, we showed that deletion of a robust H3K27Ac peak not associated with CRC had minimal effects on the transcriptome. Interestingly, although there is no H3K27Ac peak in HEK293 cells in the E7 region, deletion of this region in HEK293 cells decreased expression of several of the same genes that were downregulated in HCT116 cells, including the MYC oncogene. Accordingly, deletion of E7 causes changes in cell culture assays in HCT116 and HEK293 cells. In summary, we show that effects on the transcriptome upon deletion of a distal regulatory element cannot be predicted by the size or presence of an H3K27Ac peak. PMID:26743005

  10. 1q25.2-q31.3 Deletion in a female with mental retardation, clinodactyly, minor facial anomalies but no growth retardation

    PubMed Central

    2013-01-01

    The reports of 1q25-32 deletion cases are rare. We reported here an 11-year-old Chinese Han female with an interstitial 1q25 deletion displaying mental retardation, clinodactyly of the 5th finger and minor facial anomalies. Notably, the patient did not present growth retardation which is quite common in patients with 1q25-32 deletion encompassing LHX4. The heterozygous deletion in this patient was characterized as 46,XX,del(1)(q25.2-q31.3) with a length of 20.5 Mb according to SNP-array test results. STRP (Short Tandem Repeat Polymorphism) analysis of the family trio indicated the genomic abnormality was de novo with paternal origin. After a genotype-phenotype analysis, we proposed here the loss of a 3.1 Mb critical region including 24 genes within 1q25.2 (chr1:174.5-177.6 Mb, build 36) may account for the mental retardation in patients with 1q25-32 deletion. PMID:23915434

  11. 78 FR 75912 - Procurement List; Addition and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-13

    ... INFORMATION: Addition On 6/28/2013 (78 FR 38952-38953), the Committee for Purchase From People Who Are Blind... Services Administration, Fort Worth, TX Deletion On 11/1/2013 (78 FR 65618), the Committee for Purchase... is deleted from the Procurement List: Product NSN: 7930-01-367-0989--Cleaner, Water Soluble...

  12. 75 FR 43153 - Procurement List Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-23

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Proposed Additions and Deletions AGENCY... Deletions From the Procurement List. SUMMARY: The Committee is proposing to add products to the Procurement... proposed for addition to the Procurement List. Comments on this certification are invited....

  13. 76 FR 63905 - Procurement List; Proposed Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-14

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Additions and Deletion AGENCY... Deletion from the Procurement List. SUMMARY: The Committee is proposing to add a product and services to the Procurement List that will be furnished by nonprofit agencies employing persons who are blind...

  14. 76 FR 2673 - Procurement List Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-14

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Proposed Additions and Deletions AGENCY... deletions from the procurement list. SUMMARY: The Committee is proposing to add services to the Procurement... addition to the Procurement List. Comments on this certification are invited. Commenters should...

  15. 78 FR 9386 - Procurement List; Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-08

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Additions and Deletions AGENCY... Deletions from the Procurement List. SUMMARY: The Committee is proposing to add products and services to the Procurement List that will be furnished by nonprofit agencies employing persons who are blind or have...

  16. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2014-07-01 2014-07-01 false Adding, deleting, or substituting bases. 2.35 Section 2.35 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK..., deleting, or substituting bases. (a) In an application under section 66(a) of the Act, an applicant may...

  17. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2013-07-01 2013-07-01 false Adding, deleting, or substituting bases. 2.35 Section 2.35 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK..., deleting, or substituting bases. (a) In an application under section 66(a) of the Act, an applicant may...

  18. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2011-07-01 2011-07-01 false Adding, deleting, or substituting bases. 2.35 Section 2.35 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK..., deleting, or substituting bases. (a) In an application under section 66(a) of the Act, an applicant may...

  19. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Adding, deleting, or substituting bases. 2.35 Section 2.35 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK..., deleting, or substituting bases. (a) In an application under section 66(a) of the Act, an applicant may...

  20. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2012-07-01 2012-07-01 false Adding, deleting, or substituting bases. 2.35 Section 2.35 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK..., deleting, or substituting bases. (a) In an application under section 66(a) of the Act, an applicant may...

  1. 16 CFR 312.10 - Data retention and deletion requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Data retention and deletion requirements. 312.10 Section 312.10 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC ACTS OF CONGRESS CHILDREN'S ONLINE PRIVACY PROTECTION RULE § 312.10 Data retention and deletion requirements....

  2. Multivariate Variable Deletion Methods: Don't Do Stepwise

    ERIC Educational Resources Information Center

    Kadhi, TauGamba

    2003-01-01

    This paper explains the theory and methodology behind the use of variable deletion in canonical correlational analysis (CCA). Both the Capraro and Capraro (2002) and the Cantrell (1997) data tables are evaluated and explained in order to clarify strategies utilized. Understanding of variable deletion strategies and their proper usages in a CCA…

  3. 5 CFR 2502.18 - Deletion of exempted information.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... AVAILABILITY OF RECORDS Production or Disclosure of Records Under the Freedom of Information Act, 5 U.S.C. 552 Charges for Search and Reproduction § 2502.18 Deletion of exempted information. Where requested records... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Deletion of exempted information....

  4. 42 CFR 401.118 - Deletion of identifying details.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 2 2010-10-01 2010-10-01 false Deletion of identifying details. 401.118 Section 401.118 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... Deletion of identifying details. When CMS publishes or otherwise makes available an opinion or...

  5. 29 CFR 1610.20 - Deletion of exempted matters.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 4 2011-07-01 2011-07-01 false Deletion of exempted matters. 1610.20 Section 1610.20 Labor... Production or Disclosure Under 5 U.S.C. 552 § 1610.20 Deletion of exempted matters. Where requested records contain matters which are exempted under 5 U.S.C. 552(b) but which matters are reasonably segregable...

  6. 29 CFR 1610.20 - Deletion of exempted matters.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Deletion of exempted matters. 1610.20 Section 1610.20 Labor... Production or Disclosure Under 5 U.S.C. 552 § 1610.20 Deletion of exempted matters. Where requested records contain matters which are exempted under 5 U.S.C. 552(b) but which matters are reasonably segregable...

  7. Linguistic and Psychomotor Development in Children with Chromosome 14 Deletions

    ERIC Educational Resources Information Center

    Zampini, Laura; D'Odorico, Laura; Zanchi, Paola; Zollino, Marcella; Neri, Giovanni

    2012-01-01

    The present study focussed on a specific type of rare genetic condition: chromosome 14 deletions. Children with this genetic condition often show developmental delays and brain and neurological problems, although the type and severity of symptoms varies depending on the size and location of the deleted genetic material. The specific aim of the…

  8. 75 FR 78977 - Procurement List Proposed Addition and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-17

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Proposed Addition and Deletions AGENCY... deletions from the Procurement List. SUMMARY: The Committee is proposing to add a service to the Procurement...) 603-0655, or e-mail CMTEFedReg@AbilityOne.gov . Due to Federal holidays occurring on Friday,...

  9. 75 FR 66741 - Procurement List, Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-29

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List, Additions and Deletions AGENCY: Committee for... Procurement List. SUMMARY: This action adds products and services to the Procurement List that will be... deletes products from the Procurement List previously furnished by such agencies. DATES: Effective...

  10. 76 FR 21335 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-15

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Additions and Deletions AGENCY: Committee for... procurement list. SUMMARY: This action adds products and services to the Procurement List that will be... deletes products and services from the Procurement List previously furnished by such agencies....

  11. 75 FR 78976 - Procurement List Proposed Addition and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-17

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Proposed Addition and Deletions AGENCY... deletions from the Procurement List. SUMMARY: The Committee is proposing to add a service to the Procurement...) 603-0655, or e-mail CMTEFedReg@AbilityOne.gov . Due to Federal holidays occurring on Friday,...

  12. 76 FR 40342 - Procurement List; Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-08

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Additions and Deletions AGENCY... Deletions from the Procurement List. SUMMARY: The Committee is proposing to add products and a service to the Procurement List that will be furnished by nonprofit agencies employing persons who are blind...

  13. 75 FR 56995 - Procurement List Proposed Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Proposed Additions and Deletion AGENCY... Deletion From the Procurement List. SUMMARY: The Committee is proposing to add products to the Procurement...-0655, or e-mail: CMTEFedReg@AbilityOne.gov . SUPPLEMENTARY INFORMATION: This notice is...

  14. 75 FR 56996 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Additions and Deletions AGENCY: Committee for... Procurement List. SUMMARY: This action adds a product and a service to the Procurement List that will be... deletes products and services from the Procurement List previously furnished by such agencies....

  15. 76 FR 21336 - Procurement List; Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-15

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Additions and Deletions AGENCY... Deletions from the Procurement List. SUMMARY: The Committee is proposing to add products and services to the Procurement List that will be furnished by nonprofit agencies employing persons who are blind or have...

  16. 49 CFR 7.6 - Deletion of identifying detail.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Deletion of identifying detail. 7.6 Section 7.6 Transportation Office of the Secretary of Transportation PUBLIC AVAILABILITY OF INFORMATION Information Required To Be Made Public by DOT § 7.6 Deletion of identifying detail. Whenever it is determined to...

  17. 44 CFR 5.27 - Deletion of identifying details.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Deletion of identifying details. 5.27 Section 5.27 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY..., FEMA may delete identifying details when making available or publishing an opinion, statement of...

  18. Polymorphisms in the phosducin (PDC) gene on chromosome 1q25-32

    SciTech Connect

    Humphries, P.; Mansergh, F.C.; Farrar, G.J.

    1994-09-01

    Phosducin (33 kDa protein or MEKA) is a principal water-soluble phosphoprotein in the rod and cone photoreceptor cells and pinealocytes. This protein modulates the phototransduction cascade by binding to the beta and gamma subunit complexes of transducin. The PDC gene has been mapped to 1q25-32, the region of linkage of two hereditary retinal degenerative disorders; autosomal dominant juvenile-onset open-angle glaucoma and one form of autosomal recessive RP. Using previously published sequence data, PCR primers were designed to amplify the coding and 5{prime} flanking regions of the PDC gene. Direct sequencing revealed three polymorphisms in the 5{prime} flanking region, two of which were in regions highly homologous between humans and mice. Analysis of the polymorphisms was then extended to larger population samples using SSCPE and denaturing gel analysis. The first polymorphism PDC1 resulted from an insertion of a G residue at position -653/4. Allele frequencies were determined to be 0.51 (insG) and 0.49 (normal) giving a PIC value of 0.50. A deletion of a T residue at position -488 was the basis of the PDC2 polymorphism with allele frequencies of 0.88 (normal) and 0.12 (delT) and a PIC value of 0.21. Interestingly, the allele with an inserted G residue in PDC1 always segregrated with the deleted T allele in PDC2. The third polymorphism PDC3 was caused by a T or G residue at position -1083. Allele frequencies of 0.26 (G residue) and 0.74 (T residue) were determined from an analysis of 80 individuals with an overall PIC value of 0.39. The identification of these three polymorphisms in the PDC gene will be useful for future genetic linkage studies of chromosome 1q in inherited retinopathies.

  19. Genetic polymorphism in three glutathione s-transferase genes and breast cancer risk

    SciTech Connect

    Woldegiorgis, S.; Ahmed, R.C.; Zhen, Y.; Erdmann, C.A.; Russell, M.L.; Goth-Goldstein, R.

    2002-04-01

    The role of the glutathione S-transferase (GST) enzyme family is to detoxify environmental toxins and carcinogens and to protect organisms from their adverse effects, including cancer. The genes GSTM1, GSTP1, and GSTT1 code for three GSTs involved in the detoxification of carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and benzene. In humans, GSTM1 is deleted in about 50% of the population, GSTT1 is absent in about 20%, whereas the GSTP1 gene has a single base polymorphism resulting in an enzyme with reduced activity. Epidemiological studies indicate that GST polymorphisms increase the level of carcinogen-induced DNA damage and several studies have found a correlation of polymorphisms in one of the GST genes and an increased risk for certain cancers. We examined the role of polymorphisms in genes coding for these three GST enzymes in breast cancer. A breast tissue collection consisting of specimens of breast cancer patients and non-cancer controls was analyzed by polymerase chain reaction (PCR) for the presence or absence of the GSTM1 and GSTT1 genes and for GSTP1 single base polymorphism by PCR/RFLP. We found that GSTM1 and GSTT1 deletions occurred more frequently in cases than in controls, and GSTP1 polymorphism was more frequent in controls. The effective detoxifier (putative low-risk) genotype (defined as presence of both GSTM1 and GSTT1 genes and GSTP1 wild type) was less frequent in cases than controls (16% vs. 23%, respectively). The poor detoxifier (putative high-risk) genotype was more frequent in cases than controls. However, the sample size of this study was too small to provide conclusive results.

  20. Polymorphic Electronic Circuits

    NASA Technical Reports Server (NTRS)

    Stoica, Adrian

    2004-01-01

    Polymorphic electronics is a nascent technological discipline that involves, among other things, designing the same circuit to perform different analog and/or digital functions under different conditions. For example, a circuit can be designed to function as an OR gate or an AND gate, depending on the temperature (see figure). Polymorphic electronics can also be considered a subset of polytronics, which is a broader technological discipline in which optical and possibly other information- processing systems could also be designed to perform multiple functions. Polytronics is an outgrowth of evolvable hardware (EHW). The basic concepts and some specific implementations of EHW were described in a number of previous NASA Tech Briefs articles. To recapitulate: The essence of EHW is to design, construct, and test a sequence of populations of circuits that function as incrementally better solutions of a given design problem through the selective, repetitive connection and/or disconnection of capacitors, transistors, amplifiers, inverters, and/or other circuit building blocks. The evolution is guided by a search-and-optimization algorithm (in particular, a genetic algorithm) that operates in the space of possible circuits to find a circuit that exhibits an acceptably close approximation of the desired functionality. The evolved circuits can be tested by computational simulation (in which case the evolution is said to be extrinsic), tested in real hardware (in which case the evolution is said to be intrinsic), or tested in random sequences of computational simulation and real hardware (in which case the evolution is said to be mixtrinsic).

  1. Role of Metabolic Enzymes P450 (CYP) on Activating Procarcinogen and their Polymorphisms on the Risk of Cancers.

    PubMed

    He, Xin; Feng, Shan

    2015-01-01

    Cytochrome P450 (CYP450) enzymes are the most important metabolizing enzyme family exists among all organs. Apart from their role in the deactivation of most endogenous compounds and xenobiotics, they also mediate most procarcinogens oxidation to ultimate carcinogens. There are several modes of CYP450s activation of procarcinogens. 1) Formation of epoxide and diol-epoxides intermediates, such as CYP1A1 and CYP1B1 mediates PAHs oxidation to epoxide intermediates; 2) Formation of diazonium ions, such as CYP2A6, CYP2A13 and CYP2E1 mediates activation of most nitrosamines to unstable metabolites, which can rearrange to give diazonium ions. 3) Formation of reactive semiquinones and quinines, such as CYP1A1 and CYP1B1 transformation of estradiol to catechol estrogens, subsequently formation semiquinones; 4) Formation of toxic O-esterification, such as CYP1A1 and CYP1A2 metabolizes PhIP to N(2)-acetoxy-PhIP and N(2)-sulfonyloxy-PhIP, which are carcinogenic metabolites. 5) Formation of free radical, such as CYP2E1 is involved in activation tetrachloromethane to free radicals. While for CYP2B6 and CYP2D6, only a minor role has been found in procarcinogens activation. In addition, as the gene polymorphisms reflected, the polymorphisms of CYP1A1 (-3801T/C and -4889A/G), CYP1A2 (- 163C/A and -2467T/delT), CYP1B1 (-48G/C, -119G/T and -432G/C), CYP2E1 (-1293G/C and -1053 C/T) have been associated with an increased risk of lung cancer. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), and CYP2E1 (PstI/Rsa and 9-bp insertion) have an association with higher risk colon cancers, whereas CYP1A2 (-163C/A and -3860G/A) polymorphism is found to be among the protective factors. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), CYP1B1 -432G/C, CYP2B6 (-516G/T and -785A/G) may increase the risk of breast cancer. In conclusion, CYP1A1, CYP1A2, CYP1B1, CYP2A6, and CYP2E1 are responsible for most of the procarcinogens activation, and their gene polymorphisms are associated with the risk of

  2. Attenuation of Monkeypox Virus by Deletion of Genomic Regions

    PubMed Central

    Lopera, Juan G.; Falendysz, Elizabeth A.; Rocke, Tonie E.; Osorio, Jorge E.

    2015-01-01

    Monkeypox virus (MPXV) is an emerging pathogen from Africa that causes disease similar to smallpox. Two clades with different geographic distributions and virulence have been described. Here, we utilized bioinformatic tools to identify genomic regions in MPXV containing multiple virulence genes and explored their roles in pathogenicity; two selected regions were then deleted singularly or in combination. In vitro and in vivo studies indicated that these regions play a significant role in MPXV replication, tissue spread, and mortality in mice. Interestingly, while deletion of either region led to decreased virulence in mice, one region had no effect on in vitro replication. Deletion of both regions simultaneously also reduced cell culture replication and significantly increased the attenuation in vivo over either single deletion. Attenuated MPXV with genomic deletions present a safe and efficacious tool in the study of MPX pathogenesis and in the identification of genetic factors associated with virulence. PMID:25462353

  3. Attenuation of monkeypox virus by deletion of genomic regions

    USGS Publications Warehouse

    Lopera, Juan G.; Falendysz, Elizabeth A.; Rocke, Tonie E.; Osorio, Jorge E.

    2015-01-01

    Monkeypox virus (MPXV) is an emerging pathogen from Africa that causes disease similar to smallpox. Two clades with different geographic distributions and virulence have been described. Here, we utilized bioinformatic tools to identify genomic regions in MPXV containing multiple virulence genes and explored their roles in pathogenicity; two selected regions were then deleted singularly or in combination. In vitro and in vivostudies indicated that these regions play a significant role in MPXV replication, tissue spread, and mortality in mice. Interestingly, while deletion of either region led to decreased virulence in mice, one region had no effect on in vitro replication. Deletion of both regions simultaneously also reduced cell culture replication and significantly increased the attenuation in vivo over either single deletion. Attenuated MPXV with genomic deletions present a safe and efficacious tool in the study of MPX pathogenesis and in the identification of genetic factors associated with virulence.

  4. Growth patterns of patients with 1p36 deletion syndrome.

    PubMed

    Sangu, Noriko; Shimojima, Keiko; Shimada, Shino; Ando, Tomohiro; Yamamoto, Toshiyuki

    2014-05-01

    1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes. Obesity is frequently observed in patients with this syndrome. Thus, it is important to evaluate the growth status of an individual patient. For this purpose, we accumulated recorded growth data from 44 patients with this syndrome and investigated the growth patterns of patients. Most of the patients showed weight parameters within normal limits, whereas a few of these patients showed intrauterine growth delay and microcephaly. The length of the patients after birth was under the 50th centile in most patients. Many patients showed poor weight gain after birth, and only two female patients were overweight. These findings indicate two different phenotypes of the 1p36 deletion syndrome. The overweight patients with 1p36 deletion started excessive weight gain after two years of life. This characteristic of the patients with 1p36 deletion syndrome is similar to Prader-Willi syndrome.

  5. The yeast deletion collection: a decade of functional genomics.

    PubMed

    Giaever, Guri; Nislow, Corey

    2014-06-01

    The yeast deletion collections comprise >21,000 mutant strains that carry precise start-to-stop deletions of ∼6000 open reading frames. This collection includes heterozygous and homozygous diploids, and haploids of both MAT A: and MATα mating types. The yeast deletion collection, or yeast knockout (YKO) set, represents the first and only complete, systematically constructed deletion collection available for any organism. Conceived during the Saccharomyces cerevisiae sequencing project, work on the project began in 1998 and was completed in 2002. The YKO strains have been used in numerous laboratories in >1000 genome-wide screens. This landmark genome project has inspired development of numerous genome-wide technologies in organisms from yeast to man. Notable spinoff technologies include synthetic genetic array and HIPHOP chemogenomics. In this retrospective, we briefly describe the yeast deletion project and some of its most noteworthy biological contributions and the impact that these collections have had on the yeast research community and on genomics in general.

  6. Molecular mimicry and clonal deletion: A fresh look.

    PubMed

    Rose, Noel R

    2015-06-21

    In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and autoimmune disease. Clonal deletion originated as a critical element of the clonal selection theory of antibody formation in order to explain tolerance of self. If we did have complete clonal deletion, there would be major voids, the infamous "black holes", in our immune repertoire. For comprehensive, protective adaptive immunity, full deletion is necessarily a rare event. Molecular mimicry, the sharing of epitopes among self and non-self antigens, is extraordinary common and provides the evidence that complete deletion of self-reactive clones is rare. If molecular mimicry were not common, protective adaptive immunity could not be all-encompassing. By taking a fresh look at these two processes together we can envision their evolutionary basis and understand the need for regulatory devices to prevent molecular mimicry from progressing to autoimmune disease.

  7. Analysis of p16 gene mutation, deletion and methylation in patients with arseniasis produced by indoor unventilated-stove coal usage in Guizhou, China.

    PubMed

    Zhang, Ai-Hua; Bin, Hai-Hua; Pan, Xue-Li; Xi, Xu-Guang

    2007-06-01

    The aim of this study was to determine p16 gene mutation, deletion, and promoter 5' CpG island hypermethylation in peripheral blood mononuclear leukocyte of patients with arseniasis as attributed to exposure to indoor unventilated coal stove. The role of the aberrant change of p16 gene in the induction and development of carcinogenesis in endemic arsenisiasis region in China was also examined. Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP), multiplex PCR (mPCR), methylation-specific PCR (MSP), and sequencing techniques were performed to detect (1) mutation of the p16 gene exon 2, (2) homozygous deletion of the p16 gene exon 1 and exon 2, and (3) hypermethylation of the promoter CpG island in peripheral blood mononuclear leukocyte of patients with arseniasis. Results showed no mutation was found in exon 2 of p16 gene. The homozygous deletion frequency of p16 gene was 5 and 15% in control and arseniasis patients, respectively. The homozygous deletion occurred mainly in exon 2, with significant deletion frequencies of 9, 13, and 20% in mild, intermediate, and severe arseniasis groups. The significant homozygous deletion frequency was 9 and 39% in noncarcinoma and carcinoma individuals. The positive rate of p16 gene promoter CpG island hyermethylation was 42 and 2% in the exposed group and the control group, respectively. The positive rate was 26, 42, and 50% in mild, intermediate, and severe arseniasis. The marked different positive rate was 22 and 56% in noncarcinoma and carcinoma individuals, respectively. In conclusion, homozygous deletion and hypermethylation of p16 gene may play an important role in the initiation and development of manifestations seen in endemic arseniasis including carcinogenesis.

  8. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p.

    PubMed Central

    Reifenberger, J.; Reifenberger, G.; Liu, L.; James, C. D.; Wechsler, W.; Collins, V. P.

    1994-01-01

    The molecular genetic alterations of oligodendroglial tumors and mixed gliomas of the central nervous system were studied in a series of 37 cases (8 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas). A total of 180 polymorphic loci and 5 nonpolymorphic gene loci, distributed over all chromosomes, were examined by restriction fragment length polymorphism analysis. Loss of heterozygosity was most frequently observed for loci on 19q with a commonly deleted region at 19q13.2-q13.4 distal to the CYP2a gene and proximal to the D19S22 locus. The incidence of allelic loss on 19q was particularly high (81%) in oligodendroglial tumors and equal to 31% in mixed gliomas. More than 75% of the tumors with allelic deletions on 19q also showed loss of heterozygosity for loci on 1p with one tumor showing only loss of alleles distal to the NGFB gene (1p13-pter). Seven (19%) tumors had lost alleles from 17p with the deleted region including the TP53 tumor suppressor gene in all cases. Sequencing of the TP53 transcripts from exons 2 to 10, however, did not reveal mutations of the remaining allele in any of these tumors. Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas demonstrated an increased incidence of additional allelic losses involving most frequently chromosomes 9p and 10. Gene amplification was detected in two anaplastic tumors, affecting the epidermal growth factor receptor gene in both cases, with additional amplification of the renin gene at 1q32 in one of these cases. In total our results indicate both differences and similarities between the molecular genetic alterations in tumors with oligodendroglial and astrocytic differentiation. The loss of genetic information from 19q and 1p as well as the rarity of TP53 mutations in oligodendroglial tumors suggests that the early events in their oncogenesis are distinct from those associated with astrocytic tumors. However, similarities are indicated by the

  9. The prion protein gene polymorphisms associated with bovine spongiform encephalopathy susceptibility differ significantly between cattle and buffalo.

    PubMed

    Zhao, Hui; Du, Yanli; Chen, Shunmei; Qing, Lili; Wang, Xiaoyan; Huang, Jingfei; Wu, Dongdong; Zhang, Yaping

    2015-12-01

    Prion protein, encoded by the prion protein gene (PRNP), plays a crucial role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Several polymorphisms within the PRNP are known to be associated with influencing bovine spongiform encephalopathy (BSE) susceptibility in cattle, namely two insertion/deletion (indel) polymorphisms (a 23-bp indel in the putative promoter and a 12-bp indel in intron 1), the number of octapeptide repeats (octarepeats) present in coding sequence (CDS) and amino acid polymorphisms. The domestic buffaloes, Bubalus bubalis, are a ruminant involved in various aspects of agriculture. It is of interest to ask whether the PRNP polymorphisms differ between cattle and buffalo. In this study, we analyzed the previously reported polymorphisms associated with BSE susceptibility in Chinese buffalo breeds, and compared these polymorphisms in cattle with BSE, healthy cattle and buffalo by pooling data from the literature. Our analysis revealed three significant findings in buffalo: 1) extraordinarily low deletion allele frequencies of the 23- and 12-bp indel polymorphisms; 2) significantly low allelic frequencies of six octarepeats in CDS and 3) the presence of S4R, A16V, P54S, G108S, V123M, S154N and F257L substitutions in buffalo CDSs. Sequence alignments comparing the buffalo coding sequence to other species were analyzed using the McDonald-Kreitman test to reveal five groups (Bison bonasus, Bos indicus, Bos gaurus, Boselaphus tragocamelus, Syncerus caffer caffer) with significantly divergent non-synonymous substitutions from buffalo, suggesting potential divergence of buffalo PRNP and others. To the best of our knowledge this is the first study of PRNP polymorphisms associated with BSE susceptibility in Chinese buffalo. Our findings have provided evidence that buffaloes have a unique genetic background in the PRNP gene in comparison with cattle. PMID:26319996

  10. The prion protein gene polymorphisms associated with bovine spongiform encephalopathy susceptibility differ significantly between cattle and buffalo.

    PubMed

    Zhao, Hui; Du, Yanli; Chen, Shunmei; Qing, Lili; Wang, Xiaoyan; Huang, Jingfei; Wu, Dongdong; Zhang, Yaping

    2015-12-01

    Prion protein, encoded by the prion protein gene (PRNP), plays a crucial role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Several polymorphisms within the PRNP are known to be associated with influencing bovine spongiform encephalopathy (BSE) susceptibility in cattle, namely two insertion/deletion (indel) polymorphisms (a 23-bp indel in the putative promoter and a 12-bp indel in intron 1), the number of octapeptide repeats (octarepeats) present in coding sequence (CDS) and amino acid polymorphisms. The domestic buffaloes, Bubalus bubalis, are a ruminant involved in various aspects of agriculture. It is of interest to ask whether the PRNP polymorphisms differ between cattle and buffalo. In this study, we analyzed the previously reported polymorphisms associated with BSE susceptibility in Chinese buffalo breeds, and compared these polymorphisms in cattle with BSE, healthy cattle and buffalo by pooling data from the literature. Our analysis revealed three significant findings in buffalo: 1) extraordinarily low deletion allele frequencies of the 23- and 12-bp indel polymorphisms; 2) significantly low allelic frequencies of six octarepeats in CDS and 3) the presence of S4R, A16V, P54S, G108S, V123M, S154N and F257L substitutions in buffalo CDSs. Sequence alignments comparing the buffalo coding sequence to other species were analyzed using the McDonald-Kreitman test to reveal five groups (Bison bonasus, Bos indicus, Bos gaurus, Boselaphus tragocamelus, Syncerus caffer caffer) with significantly divergent non-synonymous substitutions from buffalo, suggesting potential divergence of buffalo PRNP and others. To the best of our knowledge this is the first study of PRNP polymorphisms associated with BSE susceptibility in Chinese buffalo. Our findings have provided evidence that buffaloes have a unique genetic background in the PRNP gene in comparison with cattle.

  11. hSNF5/INI1 inactivation is mainly associated with homozygous deletions and mitotic recombinations in rhabdoid tumors.

    PubMed

    Rousseau-Merck, M F; Versteege, I; Legrand, I; Couturier, J; Mairal, A; Delattre, O; Aurias, A

    1999-07-01

    The chromatin-remodeling hSNF5/INI1 gene has recently been shown to act as a tumor suppressor gene in rhabdoid tumors (RTs). In an attempt to further characterize the main chromosomal mechanisms involved in hSNF5/INI1 inactivation in RTs, we report here the molecular cytogenetic data obtained in 12 cell lines harboring hSNF5/INI1 mutations and/or deletions in relation to the molecular genetic analysis using polymorphic markers extended to both extremities of chromosome 22q. On the whole, mitotic recombination occurring in the proximal part of chromosome 22q, as demonstrated in five cases, and nondisjunction/duplication, highly suspected in two cases (processes leading respectively to partial or complete isodisomy), appear to be major mechanisms associated with hSNF5/INI1 inactivation. Such isodisomy accompanies each of the RTs exhibiting two cytogenetically normal chromosomes 22. This results in homozygosity for the mutation at the hSNF5/INI1 locus. An alternate mechanism accounting for hSNF5/INI1 inactivation observed in these tumors is homozygous deletion in the rhabdoid consensus region. This was observed in each of the four tumors carrying a chromosome 22q abnormality and, in particular, in the three tumors with chromosomal translocations. Only one case of our series illustrates the mutation/deletion classical model proposed for the double-hit inactivation of a tumor suppressor gene. PMID:10397258

  12. Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene

    PubMed Central

    Baranowska, Izabella; Jäderlund, Karin Hultin; Nennesmo, Inger; Holmqvist, Erik; Heidrich, Nadja; Larsson, Nils-Göran; Andersson, Göran; Wagner, E. Gerhart H.; Hedhammar, Åke; Wibom, Rolf; Andersson, Leif

    2009-01-01

    Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNATyr gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0–11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNATyr had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNATyr gene is the causative mutation for SAN. PMID:19492087

  13. Detection of cryptic chromosomal abnormalities in unexplained mental retardation: a general strategy using hypervariable subtelomeric DNA polymorphisms.

    PubMed Central

    Wilkie, A O

    1993-01-01

    Given the availability of DNA from both parents, unusual segregation of hypervariable DNA polymorphisms (HVPs) in the offspring may be attributable to deletion, unbalanced chromosomal translocation, or uniparental disomy. The telomeric regions of chromosomes are rich in both genes and hypervariable minisatellite sequences and may also be particularly prone to cryptic breakage events. Here I describe and analyze a general approach to the detection of subtelomeric abnormalities and uniparental disomy in patients with unexplained mental retardation. With 29 available polymorphic systems, approximately 50%-70% of these abnormalities could currently be detected. Development of subtelomeric HVPs physically localized with respect to their telomeres should provide a valuable resource in routine diagnostics. PMID:8352277

  14. Polymorphic Evolutionary Games.

    PubMed

    Fishman, Michael A

    2016-06-01

    In this paper, I present an analytical framework for polymorphic evolutionary games suitable for explicitly modeling evolutionary processes in diploid populations with sexual reproduction. The principal aspect of the proposed approach is adding diploid genetics cum sexual recombination to a traditional evolutionary game, and switching from phenotypes to haplotypes as the new game׳s pure strategies. Here, the relevant pure strategy׳s payoffs derived by summing the payoffs of all the phenotypes capable of producing gametes containing that particular haplotype weighted by the pertinent probabilities. The resulting game is structurally identical to the familiar Evolutionary Games with non-linear pure strategy payoffs (Hofbauer and Sigmund, 1998. Cambridge University Press), and can be analyzed in terms of an established analytical framework for such games. And these results can be translated into the terms of genotypic, and whence, phenotypic evolutionary stability pertinent to the original game.

  15. Association between serotonin transporter gene polymorphism and recurrent aphthous stomatitis

    PubMed Central

    Manchanda, Aastha; Iyengar, Asha R.; Patil, Seema

    2016-01-01

    Background: Anxiety-related traits have been attributed to sequence variability in the genes coding for serotonin transmission in  the brain. Two alleles, termed long (L) and short (S) differing by 44 base pairs, are found in a polymorphism identified in the promoter region of serotonin transporter gene. The presence of the short allele  and SS and LS genotypes is found to be associated with the reduced expression of this gene decreasing the uptake of serotonin in the brain leading to various anxiety-related traits. Recurrent aphthous stomatitis (RAS) is an oral mucosal disease with varied etiology including the presence of stress, anxiety, and genetic influences. The present study aimed to determine this serotonin transporter gene polymorphism in patients with RAS and compare it with normal individuals. Materials and Methods: This study included 20 subjects with various forms of RAS and 20 normal healthy age- and gender-matched individuals. Desquamated oral mucosal cells were collected for DNA extraction and subjected to polymerase chain reaction for studying insertion/deletion in the 5-HTT gene-linked polymorphic region. Cross tabulations followed by Chi-square tests were performed to compare the significance of findings, P < 0.05 was considered statistically significant. Results: The LS genotype was the most common genotype found in the subjects with aphthous stomatitis (60%) and controls (40%). The total percentage of LS and SS genotypes and the frequency of S allele were found to be higher in the subjects with aphthous stomatitis as compared to the control group although a statistically significant correlation could not be established, P = 0.144 and 0.371, respectively. Conclusion: Within the limitations of this study, occurrence of RAS was not found to be associated with polymorphic promoter region in serotonin transporter gene. PMID:27274339

  16. Gene Polymorphisms in Chronic Periodontitis

    PubMed Central

    Laine, Marja L.; Loos, Bruno G.; Crielaard, W.

    2010-01-01

    We aimed to conduct a review of the literature for gene polymorphisms associated with chronic periodontitis (CP) susceptibility. A comprehensive search of the literature in English was performed using the keywords: periodontitis, periodontal disease, combined with the words genes, mutation, or polymorphism. Candidate gene polymorphism studies with a case-control design and reported genotype frequencies in CP patients were searched and reviewed. There is growing evidence that polymorphisms in the IL1, IL6, IL10, vitamin D receptor, and CD14 genes may be associated with CP in certain populations. However, carriage rates of the rare (R)-allele of any polymorphism varied considerably among studies and most of the studies appeared under-powered and did not correct for other risk factors. Larger cohorts, well-defined phenotypes, control for other risk factors, and analysis of multiple genes and polymorphisms within the same pathway are needed to get a more comprehensive insight into the contribution of gene polymorphisms in CP. PMID:20339487

  17. Clonal deletion of specific thymocytes by an immunoglobulin idiotype.

    PubMed Central

    Bogen, B; Dembic, Z; Weiss, S

    1993-01-01

    We have investigated whether immunoglobulin can induce clonal deletion of thymocytes by employing two strains of transgenic mice. One strain is transgenic for an alpha/beta T cell receptor (TCR) which recognizes a processed idiotypic peptide of the lambda 2(315) light chain variable region, bound to the I-Ed class II major histocompatibility complex molecule. The other mouse strain is transgenic for the lambda 2(315) gene. Double transgenic offspring from a TCR-transgenic female mated with a lambda 2(315) transgenic male exhibit a pronounced clonal deletion of CD4+CD8+ thymocytes. Analysis of neonates from the reciprocal (lambda 2(315)-transgenic female x TCR-transgenic male) cross suggests that the deletion in double transgenic offspring most likely is caused by lambda 2(315) produced within the thymus rather than by maternally derived IgG, lambda 2(315). Nevertheless, IgG, lambda 2(315) can cause deletion of CD4+CD8+ thymocytes when injected in large amounts intraperitoneally into either adult or neonatal TCR-transgenic mice. Deletion is evident 48 and 72 h after injection, but by day 7 the thymus has already regained its normal appearance. A serum concentration of several hundred microgram/ml is required for deletion to be observed. Therefore, the heterogeneous idiotypes of serum Ig are probably each of too low concentration to cause thymocyte deletion in normal animals. Images PMID:8428591

  18. Two 22q telomere deletions serendipitously detected by FISH.

    PubMed

    Precht, K S; Lese, C M; Spiro, R P; Huttenlocher, P R; Johnston, K M; Baker, J C; Christian, S L; Kittikamron, K; Ledbetter, D H

    1998-11-01

    Cryptic telomere deletions have been proposed to be a significant cause of idiopathic mental retardation. We present two unrelated subjects, with normal G banding analysis, in whom 22q telomere deletions were serendipitously detected at two different institutions using fluorescence in situ hybridisation (FISH). Both probands presented with several of the previously described features associated with 22q deletions, including hypotonia, developmental delay, and absence of speech. Our two cases increase the total number of reported 22q telomere deletions to 19, the majority of which were identified by cytogenetic banding analysis. With the limited sensitivity of routine cytogenetic studies (approximately 2-5 Mb), these two new cases suggest that the actual prevalence of 22q telomere deletions may be higher than currently documented. Of additional interest is the phenotypic overlap with Angelman syndrome (AS) as it raises the possibility of a 22q deletion in patients in whom AS has been ruled out. The use of telomeric probes as diagnostic reagents would be useful in determining an accurate prevalence of chromosome 22q deletions and could result in a significantly higher detection rate of subtelomeric rearrangements.

  19. Do listeners recover "deleted" final /t/ in German?

    PubMed

    Zimmerer, Frank; Reetz, Henning

    2014-01-01

    Reduction and deletion processes occur regularly in conversational speech. A segment that is affected by such reduction and deletion processes in many Germanic languages (e.g., Dutch, English, German) is /t/. There are similarities concerning the factors that influence the likelihood of final /t/ to get deleted, such as segmental context. However, speakers of different languages differ with respect to the acoustic cues they leave in the speech signal when they delete final /t/. German speakers usually lengthen a preceding /s/ when they delete final /t/. This article investigates to what extent German listeners are able to reconstruct /t/ when they are presented with fragments of words where final /t/ has been deleted. It aims also at investigating whether the strategies that are used by German depend on the length of /s/, and therefore whether listeners are using language-specific cues. Results of a forced-choice segment detection task suggest that listeners are able to reconstruct deleted final /t/ in about 45% of the times. The length of /s/ plays some role in the reconstruction, however, it does not explain the behavior of German listeners completely.

  20. Total beta-globin gene deletion has high frequency in Filipinos

    SciTech Connect

    Patrick, N.; Miyakawa, F.; Hunt, J.A.

    1994-09-01

    The distribution of {beta}-thalassemia [{beta}{sup Th}] mutations is unique to each ethnic group. Most mutations affect one or a few bases; large deletions have been rare. Among families screened in Hawaii, [{beta}{sup Th}] heterozygotes were diagnosed by microcytosis, absence of abnormal hemoglobins on isoelectric focusing, and raised Hb A{sub 2} by chromatography. Gene frequency for {beta}{sup Th} was 0.02 in Filipinos. In Filipinos, polymerase chain reaction [PCR] with denaturing gradient gel electrophoresis for {beta}{sup Th} mutations detected a mutation in only 6 of 42 {beta}{sup Th} heterozygotes; an IVS2-666 C/T polymorphism showed non-heterozygosity in 37 and heterozygosity in only 5 of these {beta}{sup Th} heterozygotes. One {beta}{sup Th}/{beta}{sup Th} major patient and his mother had no mutation detected by allele-specific oligomer hybridization; PCR failed to amplify any DNA from his {beta}-globin gene. After a total {beta}-globin gene deletion [{beta}{sup Del}] was found in a Filipino family in Ontario, specific PCR amplification for {beta}{sup Del} detected this in 43 of 53 {beta}{sup Th} Filipino samples tested; the above {beta}{sup Th}/{beta}{sup Th} patient was a ({beta}{sup Del}/{beta}{sup Del}) homozygote. The {beta}{sup Del} may account for over 60% of all {beta}{sup Th} alleles in Filipinos; this is the highest proportion of a deletion {beta}{sup Th} mutation reported from any population. Most but not all {beta}{sup Del} heterozygotes had high Hb F [5.13 {plus_minus} 3.94 mean {plus_minus} 1 s.d.] compared to the codon 41/42 four base deletion common in Chinese [2.30 {plus_minus} 0.86], or to {beta}{sup Th} heterozygotes with normal {alpha}-globin genes [2.23 {plus_minus} 0.80].

  1. Impact of partial DAZ1/2 deletion and partial DAZ3/4 deletion on male infertility.

    PubMed

    Zhang, Yuening; Li, Muyan; Xiao, Feifan; Teng, Ruobing; Zhang, Chengdong; Lan, Aihua; Gu, Kailong; Li, Jiatong; Wang, Di; Li, Hongtao; Jiang, Li; Zeng, Siping; He, Min; Huang, Yi; Guo, Peifen; Zhang, Xinhua; Yang, Xiaoli

    2015-10-15

    This study aims to investigate the effect of the partial DAZ1/2 deletion and partial DAZ3/4 deletion on male infertility through a comprehensive literature search. All case-control studies related to partial DAZ1/2 and DAZ3/4 deletions and male infertility risk were included in our study. Odd ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association and its precision, respectively. Eleven partial DAZ1/2 deletion and nine partial DAZ3/4 deletion studies were included. Partial DAZ1/2 deletion was significantly associated with male infertility risk in the overall analysis (ORs=2.58, 95%CI: 1.60-4.18, I(2)=62.1%). Moreover, in the subgroup analysis stratified by ethnicity, partial DAZ1/2 deletion was significantly associated with male infertility risk in the East Asian populations under the random effect model (ORs=2.96, 95%CI: 1.87-4.71, I(2)=51.3%). Meanwhile, the analysis suggested that partial DAZ3/4 deletion was not associated with male infertility risk in East-Asian ethnicity (ORs=1.02, 95%CI: 0.54-1.92, I(2)=71.3%), but not in Non-East Asian under the random effect model (ORs=3.56, 95%CI: 1.13-11.23, I(2)=0.0%,). More interestingly, partial DAZ1/2 deletion was associated with azoospermia (ORs=2.63, 95%CI: 1.19-5.81, I(2)=64.7%) and oligozoospermia (ORs=2.53, 95%CI: 1.40-4.57, I(2)=51.8%), but partial DAZ3/4 deletion was not associated with azoospermia (ORs=0.71, 95%CI: 0.23-2.22, I(2)=71.7%,) and oligozoospermia (ORs=1.21, 95%CI: 0.65-2.24, I(2)=55.5%). In our meta-analysis, partial DAZ1/2 deletion is a risk factor for male infertility and different ethnicities have different influences, whereas partial DAZ3/4 deletion has no effect on fertility but partial DAZ3/4 deletion might have an impact on Non-East Asian male.

  2. Functional relevance of DNA polymorphisms within the promoter region of the prion protein gene and their association to BSE infection.

    PubMed

    Kashkevich, Kseniya; Humeny, Andreas; Ziegler, Ute; Groschup, Martin H; Nicken, Petra; Leeb, Tosso; Fischer, Christine; Becker, Cord-Michael; Schiebel, Katrin

    2007-05-01

    Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases that can occur spontaneously or can be caused by infection or mutations within the prion protein gene PRNP. Nonsynonymous DNA polymorphisms within the PRNP gene have been shown to influence susceptibility/resistance to infection in sheep and humans. Analysis of DNA polymorphisms within the core promoter region of the PRNP gene in four major German bovine breeds resulted in the identification of both SNPs and insertion/deletion (indel) polymorphisms. Comparative genotyping of both controls and animals that tested positive for bovine spongiform encephalopathy (BSE) revealed a significantly different distribution of two indel polymorphisms and two SNPs within Braunvieh animals, suggesting an association of these polymorphisms with BSE susceptibility. The functional relevance of these polymorphisms was analyzed using reporter gene constructs in neuronal cells. A specific haplotype near exon 1 was identified that exhibited a significantly lower expression level. Genotyping of nine polymorphisms within the promoter region and haplotype calculation revealed that the haplotype associated with the lowest expression level was underrepresented in the BSE group of all breeds compared to control animals, indicating a correlation of reduced PRNP expression and increased resistance to BSE.

  3. Ectrodactyly and proximal/intermediate interstitial deletion 7q

    SciTech Connect

    McElveen, C.; Carvajal, M.V.; Moscatello, D.

    1995-03-13

    We report on an individual with severe mental retardation, seizures, microcephaly, unusual face, scoliosis, and cleft feet and cleft right hand. The chromosomal study showed a proximal interstitial deletion 7q (q11.23q22). From our review of the literature, 11 patients have been reported with ectrodactyly (split hand/split foot malformation) and proximal/intermediate interstitial deletions or rearrangements of 7q. The critical segment for ectrodactyly seems to be located between 7q21.2 and 7q22.1. This malformation is present in 41% of the patients whose deletion involves the critical segment. 37 refs., 3 figs., 1 tab.

  4. Detection of genomic deletions in rice using oligonucleotide microarrays

    PubMed Central

    Bruce, Myron; Hess, Ann; Bai, Jianfa; Mauleon, Ramil; Diaz, M Genaleen; Sugiyama, Nobuko; Bordeos, Alicia; Wang, Guo-Liang; Leung, Hei; Leach, Jan E

    2009-01-01

    Background The induction of genomic deletions by physical- or chemical- agents is an easy and inexpensive means to generate a genome-saturating collection of mutations. Different mutagens can be selected to ensure a mutant collection with a range of deletion sizes. This would allow identification of mutations in single genes or, alternatively, a deleted group of genes that might collectively govern a trait (e.g., quantitative trait loci, QTL). However, deletion mutants have not been widely used in functional genomics, because the mutated genes are not tagged and therefore, difficult to identify. Here, we present a microarray-based approach to identify deleted genomic regions in rice mutants selected from a large collection generated by gamma ray or fast neutron treatment. Our study focuses not only on the utility of this method for forward genetics, but also its potential as a reverse genetics tool through accumulation of hybridization data for a collection of deletion mutants harboring multiple genetic lesions. Results We demonstrate that hybridization of labeled genomic DNA directly onto the Affymetrix Rice GeneChip® allows rapid localization of deleted regions in rice mutants. Deletions ranged in size from one gene model to ~500 kb and were predicted on all 12 rice chromosomes. The utility of the technique as a tool in forward genetics was demonstrated in combination with an allelic series of mutants to rapidly narrow the genomic region, and eventually identify a candidate gene responsible for a lesion mimic phenotype. Finally, the positions of mutations in 14 mutants were aligned onto the rice pseudomolecules in a user-friendly genome browser to allow for rapid identification of untagged mutations . Conclusion We demonstrate the utility of oligonucleotide arrays to discover deleted genes in rice. The density and distribution of deletions suggests the feasibility of a database saturated with deletions across the rice genome. This community resource can continue

  5. A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases

    PubMed Central

    Duno, Morten; Batbayli, Mustafa; Vilhelmsen, Kaj; Rosenberg, Thomas

    2011-01-01

    Purpose The aim of the study was to elucidate the genetic background of retinitis pigmentosa (RP) in a Faroe Islands population, a genetic isolate in the North Atlantic Ocean. Methods Blood samples were collected from subjects diagnosed with RP and their families. DNA from affected individuals underwent single nucleotide polymorphism microarray analysis and homozygosity mapping followed by sequence analysis of candidate genes. Results We identified 25 cases of nonsyndromic RP corresponding to a prevalence of 1 in 1,900. Single nucleotide polymorphism analysis revealed a homozygous region on chromosome 2q, common to patients in four families, which harbored the RP gene MER tyrosine kinase protooncogene (MERTK). A deletion of 91 kb was identified in seven patients, representing 30% of the analyzed Faroese cases of nonsyndromic RP. The clinical course of six patients who were homozygous for the deletion showed onset in the first decade followed by a rapid deterioration of both rod and cone photoreceptor function. Early macular involvement was present, in accordance with that of other reported patients with MERTK mutations. Conclusions Previous studies have shown a frequency of less than 1% of MERTK mutations in RP patients. The 91-kb deletion encompassing exons 1–7 of MERTK is a common founder mutation in the Faroe Islands, responsible for around 30% of RP, and together with mutations in protocadherin 21 (PCDH21) accounts for more than half of the retinal dystrophy cases. PMID:21677792

  6. Genomic Changes in Gliomas Detected Using Single Nucleotide Polymorphism Array in Formalin-Fixed, Paraffin-Embedded Tissue

    PubMed Central

    Harada, Shuko; Henderson, Lindsay B.; Eshleman, James R.; Gocke, Christopher D.; Burger, Peter; Griffin, Constance A.; Batista, Denise A.S.

    2011-01-01

    Deletion or loss of heterozygosity (LOH) in chromosomes 1p and 19q in oligodendrogliomas (ODGs) have diagnostic, prognostic, and therapeutic implications. Current clinical assays are limited because the probes or primers interrogate only limited genomic segments. We investigated the use of single nucleotide polymorphism (SNP) arrays for identifying genomic changes in gliomas from FFPE tissues. DNA was extracted from FFPE tissues of 30 brain tumor cases (15 ODGs and 15 non-ODGs) and assayed on the Illumina array with 300,000 markers. SNP results were compared with standard short tandem repeat (STR) assays of chromosomes 1p and 19q. Fifteen ODGs had LOH by STR and deletion by array on both 1p and 19q. Ten non-ODGs had no evidence of LOH on 1p and 19q by STR, seven of which had no abnormalities for these chromosomes; three had partial deletions by SNP array. Five non-ODG cases had partial LOH or deletion by both assays. No major discordance was found between SNP array and STR results. Advantages of SNP arrays include no need for an accompanying normal sample, the ability to find small segmental deletions, the potential to distinguish between deletions and copy neutral LOH, and whole-genome screening to allow discovery of new, significant loci. Assessment of genomic changes in routine glioma specimens using SNP arrays is feasible and has great potential as an accurate clinical diagnostic test. PMID:21726663

  7. 22q11.2 deletion syndrome

    PubMed Central

    McDonald-McGinn, Donna M.; Sullivan, Kathleen E.; Marino, Bruno; Philip, Nicole; Swillen, Ann; Vorstman, Jacob A. S.; Zackai, Elaine H.; Emanuel, Beverly S.; Vermeesch, Joris R.; Morrow, Bernice E.; Scambler, Peter J.; Bassett, Anne S.

    2016-01-01

    22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population. PMID:27189754

  8. The Prevention of Repeat-Associated Deletions in Saccharomyces Cerevisiae by Mismatch Repair Depends on Size and Origin of Deletions

    PubMed Central

    Tran, H. T.; Gordenin, D. A.; Resnick, M. A.

    1996-01-01

    We have investigated the effects of mismatch repair on 1- to 61-bp deletions in the yeast Saccharomyces cerevisiae. The deletions are likely to involve unpaired loop intermediates resulting from DNA polymerase slippage. The mutator effects of mutations in the DNA polymerase δ (POL3) gene and the recombinational repair RAD52 gene were studied in combination with mismatch repair defects. The pol3-t mutation increased up to 1000-fold the rate of extended (7-61 bp) but not of 1-bp deletions. In a rad52 null mutant only the 1-bp deletions were increased (12-fold). The mismatch repair mutations pms1, msh2 and msh3 did not affect 31- and 61-bp deletions in the pol3-t but increased the rates of 7- and 1-bp deletions. We propose that loops less than or equal to seven bases generated during replication are subject to mismatch repair by the PMS1, MSH2, MSH3 system and that it cannot act on loops >=31 bases. In contrast to the pol3-t, the enhancement of 1-bp deletions in a rad52 mutant is not altered by a pms1 mutation. Thus, mismatch repair appears to be specific to errors of DNA synthesis generated during semiconservative replication. PMID:8844147

  9. AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I.

    PubMed

    Bøe Wolff, A S; Oftedal, B; Johansson, S; Bruland, O; Løvås, K; Meager, A; Pedersen, C; Husebye, E S; Knappskog, P M

    2008-03-01

    Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms or copy number variations in the AIRE gene were associated with AAD and APS II. First, nine SNPs in the AIRE gene were analyzed in 311 patients with AAD and APS II and 521 healthy controls, identifying no associated risk. Second, in a subgroup of 25 of these patients, AIRE sequencing revealed three novel polymorphisms. Finally, the AIRE copy number was determined by duplex quantitative PCR in 14 patients with APS I, 161 patients with AAD and APS II and in 39 healthy subjects. In two Scandinavian APS I patients previously reported to be homozygous for common AIRE mutations, we identified large deletions of the AIRE gene covering at least exon 2 to exon 8. We conclude that polymorphisms in the AIRE gene are not associated with AAD and APS II. We further suggest that DNA analysis of the parents of patients found to be homozygous for mutations in AIRE, always should be performed.

  10. Preferential Nucleation during Polymorphic Transformations

    PubMed Central

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-01-01

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and therefore nucleation more probable - with increasing number of special OR’s. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material. PMID:27484579

  11. Preferential Nucleation during Polymorphic Transformations

    NASA Astrophysics Data System (ADS)

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-08-01

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and therefore nucleation more probable - with increasing number of special OR’s. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.

  12. Preferential Nucleation during Polymorphic Transformations.

    PubMed

    Sharma, H; Sietsma, J; Offerman, S E

    2016-08-03

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR's) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR's with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller - and therefore nucleation more probable - with increasing number of special OR's. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.

  13. Preferential Nucleation during Polymorphic Transformations.

    PubMed

    Sharma, H; Sietsma, J; Offerman, S E

    2016-01-01

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR's) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR's with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller - and therefore nucleation more probable - with increasing number of special OR's. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material. PMID:27484579

  14. Glutathione s-transferase M1 and T1 genetic polymorphisms in Iranian patients with glaucoma

    PubMed Central

    Safa, Fatemeh Kazemi; Shahsavari, Gholamreza; Abyaneh, Reza Zare

    2014-01-01

    Objective(s): Glaucoma is the second leading cause of blindness and it is related to oxidative stress based on numerous studies. Glutathione S-transferases (GSTs) are members of multigenic family, which have important role in cells as an antioxidant. In the present study, we examined the polymorphism of GSTT1 and GSTM1 deletion genotypes (T0M1, T1M0, and T0M0) in 100 Glaucoma patients (41with primary open angle glaucoma (PCAG), and 59 with primary closed angle glaucoma (POAG)) compared to 100 healthy subjects. Materials and Methods: GSTM1and GSTT1 polymorphisms were determined by multiplex polymerase chain reaction. Results: GSTM1 and GSTT1 null deletions genotypes were determined in 22 (53.7%) and 7 (17.1%) patients with PCAG and 34 (34%) and 15 (15%) in healthy subjects. Comparison between patients and healthy subjects regarding GSTM1 and GSTT1 genotypes revealed increase of GSTM1 null deletions genotypes in patients with PCAG (P=0.03). Conclusion: It was concluded that the increased frequencies of GSTM1 null in patients with PCAG could be a risk factor for incidence of PCAG in the Iranian population. PMID:24967061

  15. Deletion of exon 3 of the insulin receptor gene in a kindred with a familial form of insulin resistance

    SciTech Connect

    Wertheimer, E.; Barbetti, F.; Accili, D.; Taylor, S.I.; Litvin, Y.; Ebstein, R.P.; Bennet, E.R.

    1994-05-01

    Molecular scanning techniques, such as denaturing gradient gel electrophoresis (DGGE), greatly facilitate screening candidate genes for mutations. The authors have used DGGE to screen for mutations in the insulin receptor gene in a family in which four of five daughters were affected by type A insulin resistance in association with acanthosis nigricans and hyperandrogenism. DGGE did not detect mutations in any of the 22 exons of the insulin receptor gene. Nevertheless, Southern blot analysis suggested that there was a deletion of exon 3 in the other paternal allele of the insulin receptor gene. Analysis of the father`s cDNA confirmed that exon 3 was deleted from mRNA molecules derived from one of his two alleles of the insulin receptor gene. Furthermore, the father was found to be hemizygous for a polymorphic sequence (GAC{sup Asp} at codon 234) in exon 3 that was not inherited by any of the five daughters. Instead, all five daughters inherited the paternal allele with the deletion mutation. They did not detect mutations in the mother`s insulin receptor gene. Furthermore, the clinical syndrome did not segregate with either of the mother`s two alleles of the insulin receptor gene. Although the youngest daughter inherited the mutant allele from her father, she was not clinically affected. The explanation for the incomplete penetrance is not known. These results emphasize the importance of specifically searching for deletion mutations when screening candidate genes for mutations. Furthermore, the existence of apparently asymptomatic carriers of mutations in the insulin receptor gene, such as the father in the present study, suggests that the prevalence of mutations in the insulin receptor gene may be higher than would be predicted on the basis of the observed prevalence of patients with extreme insulin resistance. 34 refs., 6 figs., 1 tab.

  16. A recombination outside the BB deletion refines the location of the X-linked retinitis pigmentosa locus RP3

    SciTech Connect

    Fujita, R.; Bingham, E.; Forsythe, P.; McHenry, C.

    1996-07-01

    Genetic loci for X-linked retinitis pigmentosa (XLRP) have been mapped between Xp11.22 and Xp22.13 (RP2, RP3, RP6, and RP15). The RP3 gene, which is responsible for the predominant form of XLRP in most Caucasian populations, has been localized to Xp21.1 by linkage analysis and the map positions of chromosomal deletions associated with the disease. Previous linkage studies have suggested that RP3 is flanked by the markers DXS1110 (distal) and OTC (proximal). Patient BB was though to have RP because of a lesion at the RP3 locus, in addition to chronic granulomatous disease, Duchenne muscular dystrophy (DMD), mild mental retardation, and the McLeod phenotype. This patient carried a deletion extending {approximately}3 Mb from DMD in Xp21.3 to Xp21.1, with the proximal breakpoint located {approximately}40 kb centromeric to DXS1110. The RP3 gene, therefore, is believed to reside between DXS1110 and the proximal breakpoint of the BB deletion. In order to refine the location of RP3 and to ascertain patients with RP3, we have been analyzing several XLRP families for linkage to Xp markers. Linkage analysis in an American family of 27 individuals demonstrates segregation of XLRP with markers in Xp21.1, consistent with the RP3 subtype. One affected male shows a recombination event proximal to DXS1110. Additional markers within the DXS1110-OTC interval show that the crossover is between two novel polymorphic markers, DXS8349 and M6, both of which are present in BB DNA and lie centromeric to the proximal breakpoint. This recombination places the XLRP mutation in this family outside the BB deletion and redefines the location of RP3. 22 refs., 3 figs., 2 tabs.

  17. Submicroscopic deletions of 3p sequences in pleomorphic adenomas with t(3;8)(p21;q12).

    PubMed

    Sahlin, P; Mark, J; Stenman, G

    1994-08-01

    A subgroup of benign pleomorphic adenomas of the salivary glands is characterized by translocations, or on rare occasions deletions, with breakpoints at 3p21. We have applied restriction fragment length polymorphism (RFLP) analysis to assess the frequency of allelic losses at four different loci located within 3p21-->p25 in 35 pleomorphic adenomas, 18 of which were also karyotyped. Parallel analysis of constitutional and tumor DNAs in informative tumors revealed that all patients retained heterozygosity in their tumor DNA at the D3S2 and RAF1 loci. Among the 29 tumors informative for THRB three showed loss of heterozygosity (LOH). All three tumors had a t(3;8)(p21;q12). Of the 23 tumors informative for D3F15S2, one showed LOH. This tumor also had a t(3;8)(p21;q12). To further map the deletions in relation to the 3p21 translocation breakpoint, we also sublocalized the THRB locus. Using in situ hybridization we assigned the gene to 3p24.1-3. The fact that none of the tumors with loss of 3p alleles showed cytogenetic evidence of deletions indicates that the losses are submicroscopic, probably interstitial, and in most cases distal to the 3p21 breakpoint. This was confirmed in one case with loss of a THRB allele where both proximal (D3F15S2) and distal (RAF1) markers retained heterozygosity. Our results suggest that deletion of 3p sequences might be of progressional importance in a subset of pleomorphic adenomas with t(3;8)(p21;q12).

  18. Polymorphisms of drug-metabolizing enzymes in healthy nonagenarians and centenarians: difference at GSTT1 locus.

    PubMed

    Taioli, E; Mari, D; Franceschi, C; Bonafè, M; Monti, D; Bertolini, S; Marinelli, D; Garte, S

    2001-02-01

    Drug metabolizing enzymes are involved in the detoxification of several drugs, environmental substances, and carcinogenic compounds, and their polymorphisms have been associated with risk for a variety of cancer. In this paper, we compared the frequency of polymorphisms in cytochrome P450-1A1 gene (CYP1A1), a phase 1 gene (oxidation, activation), and of two polymorphisms of glutathione S-transferase enzymes (GSTM1, GSTT1), two phase 2 genes (conjugation, detoxification). Two groups were studied and compared, i.e., 94 nonagenarians and centenarians and 418 control subjects of younger age. A significant difference in the proportion of nonagenarians and centenarians homozygotes for a GSTT1 deletion (28%) was observed in comparison to control subjects (19%, P = 0.03). The distribution of the other gene polymorphisms did not differ in the two groups. These findings on phase 2 drug-metabolizing enzyme gene polymorphisms may help in disentangling gene-environmental interactions which can have a role in successful aging and longevity, as well as in cancer incidence in the oldest old.

  19. Anthrax Susceptibility: Human Genetic Polymorphisms Modulating ANTXR2 Expression.

    PubMed

    Zhang, Zhang; Zhang, Yan; Shi, Minglei; Ye, Bingyu; Shen, Wenlong; Li, Ping; Xing, Lingyue; Zhang, Xiaopeng; Hou, Lihua; Xu, Junjie; Zhao, Zhihu; Chen, Wei

    2015-12-22

    Anthrax toxin causes anthrax pathogenesis and expression levels of ANTXR2 (anthrax toxin receptor 2) are strongly correlated with anthrax toxin susceptibility. Previous studies found that ANTXR2 transcript abundance varies considerably in individuals of different ethnic/geographical groups, but no eQTLs (expression quantitative trait loci) have been identified. By using 3C (chromatin conformation capture), CRISPR-mediated genomic deletion and dual-luciferase reporter assay, gene loci containing cis-regulatory elements of ANTXR2 were localized. Two SNPs (single nucleotide polymorphism) at the conserved CREB-binding motif, rs13140055 and rs80314910 in the promoter region of the gene, modulating ANTXR2 promoter activity were identified. Combining these two regulatory SNPs with a previously reported SNP, rs12647691, for the first time, a statistically significant correlation between human genetic variations and anthrax toxin sensitivity was observed. These findings further our understanding of human variability in ANTXR2 expression and anthrax toxin susceptibility.

  20. Genetics Home Reference: 19p13.13 deletion syndrome

    MedlinePlus

    ... Resources (1 link) National Human Genome Research Institute: Chromosome Abnormalities Educational Resources (5 links) MalaCards: chromosome 19p13.13 deletion syndrome March of Dimes: Chromosomal ...

  1. 78 FR 57844 - Procurement List; Proposed Addition and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-20

    ... Activity: DEPT OF COMMERCE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, BOULDER, CO. Deletions The... listed: Service Service Type/Location: Janitorial/Custodial Service, National Oceanic & Atmospheric Administration, National Weather Service Office, Except Communication & Electrical Room, 500 Airport Blvd.,...

  2. 76 FR 13362 - Procurement List Proposed Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-11

    ..., Jefferson Plaza 2, Suite 10800, 1421 Jefferson Davis Highway, Arlington, Virginia 22202-3259. For Further... service is proposed for deletion from the Procurement List: Service Service Type/Location:...

  3. Characterization of a lymphoblastoid line deleted for lambda immunoglobulin genes

    SciTech Connect

    Hough, C.A., White, B.N., Holden, J.A.

    1995-04-01

    While characterizing the cat eye syndrome (CES) supernumerary chromosome for the presence of {lambda} immunoglobulin gene region sequences, a lymphoblastoid cell line from one CES patient was identified in which there was selection of cells deleted from some IGLC and IGLV genes. Two distinct deletions, one on each chromosome 22, were identified, presumably arising from independent somatic recombination events occurring during B-lymphocyte differentiation. The extent of the deleted regions was determined using probes from the various IGLV subgroups and they each covered at least 82 kilobases. The precise definition of the deletions was not possible because of conservation of some restriction sites in the IGLV region. The cell line was used to map putative IGLV genes within the recombinant phage {lambda}V{lambda}135 to the distal part of the IGLV gene region. 35 refs., 4 figs.

  4. 78 FR 63967 - Procurement List; Proposed Addition and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-25

    ...: Social Vocational Services, Inc.--Deleted, San Jose, CA Contracting Activity: DEPT OF THE ARMY, W40M NATL... Sustainment Systems, Natick, MA NPA: ReadyOne Industries (ROI), Inc., El Paso, TX Contracting Activity:...

  5. Characteristics of A20 gene polymorphisms in T-cell acute lymphocytic leukemia.

    PubMed

    Zhu, Lihua; Zhang, Fan; Shen, Qi; Chen, Shaohua; Wang, Xu; Wang, Liang; Yang, Lijian; Wu, Xiuli; Huang, Suming; Schmidt, Christian A; Li, Yangqiu

    2014-12-01

    A20 is a repressor of NF-κB and was recently shown to be frequently inactivated by deletions or mutations in several types of lymphomas including T-cell lymphoma. Little is known about the characteristics of A20 mutations in T-cell acute lymphoblastic leukemia (T-ALL). In this study, we analyzed A20 polymorphisms and characterized their features in 11 cases with T-ALL, 30 samples from healthy Chinese individuals, and 3 cells lines including CCRF-CEM, Molt-4, and Toledo cells. Two frequent A20 polymorphisms were found: a CCT deletion at position 12384 and a nucleotide exchange (A to C) at position 13751 (rs2307859 and rs661561). The homozygous form (CC) of rs661561 was detected in all 10 cases with detectable T-ALL, while only 80% (24/30) of the healthy controls had this genotype. We found one T-ALL case without the above frequent single-nucleotide polymorphisms (SNPs) in which a T to G mutation at position 12486 was found, which results in an amino acid exchange (Phe127Cys; rs2230926). Similar results were found in Molt-4 cells, which lack the frequent SNPs but have a heterozygous polymorphism at position 13749 (C > T) (rs5029948). Interestingly, the T-ALL case with the Phe127Cys mutation and Molt-4 cells demonstrated a high A20 copy number as measured by real-time polymerase chain reaction amplification with three primer sets that cover different regions of the A20 gene, corresponding to a high A20 and low NF-κB expression level. In conclusion, we characterized the features of A20 polymorphisms in T-ALL, and found that a low frequency A20 mutation, which was thought to be involved in malignant T-ALL development, might function differently in T cell lymphomas.

  6. Bilateral hand amyotrophy with PMP-22 gene deletion.

    PubMed

    Gochard, A; Guennoc, A M; Praline, J; Malinge, M C; de Toffol, B; Corcia, P

    2007-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) phenotypes are heterogeneous. We report the case of a 52-year-old woman without medical history, who complained of bilateral hand weakness suggestive first of a motor neuron disorder. The presence of a diffuse predominant distal demyelinating neuropathy suggested a deletion of PMP-22 gene, which was confirmed by genetic analysis. This case report underlines a novel phenotype related to the deletion of PMP-22 gene.

  7. Multigenerational autosomal dominant inheritance of 5p chromosomal deletions.

    PubMed

    Zhang, Bin; Willing, Marcia; Grange, Dorothy K; Shinawi, Marwan; Manwaring, Linda; Vineyard, Marisa; Kulkarni, Shashikant; Cottrell, Catherine E

    2016-03-01

    Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations. PMID:26601658

  8. Multigenerational autosomal dominant inheritance of 5p chromosomal deletions.

    PubMed

    Zhang, Bin; Willing, Marcia; Grange, Dorothy K; Shinawi, Marwan; Manwaring, Linda; Vineyard, Marisa; Kulkarni, Shashikant; Cottrell, Catherine E

    2016-03-01

    Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations.

  9. Mitochondrial DNA deletions in patients with chronic suppurative otitis media.

    PubMed

    Tatar, Arzu; Tasdemir, Sener; Sahin, Ibrahim; Bozoglu, Ceyda; Erdem, Haktan Bagis; Yoruk, Ozgur; Tatar, Abdulgani

    2016-09-01

    The aim of this study was to investigate the 4977 and 7400 bp deletions of mitochondrial DNA in patients with chronic suppurative otitis media and to indicate the possible association of mitochondrial DNA deletions with chronic suppurative otitis media. Thirty-six patients with chronic suppurative otitis media were randomly selected to assess the mitochondrial DNA deletions. Tympanomastoidectomy was applied for the treatment of chronic suppurative otitis media, and the curettage materials including middle ear tissues were collected. The 4977 and 7400 bp deletion regions and two control regions of mitochondrial DNA were assessed by using the four pair primers. DNA was extracted from middle ear tissues and peripheral blood samples of the patients, and then polymerase chain reactions (PCRs) were performed. PCR products were separated in 2 % agarose gel. Seventeen of 36 patients had the heterozygote 4977 bp deletion in the middle ear tissue but not in peripheral blood. There wasn't any patient who had the 7400 bp deletion in mtDNA of their middle ear tissue or peripheral blood tissue. The patients with the 4977 bp deletion had a longer duration of chronic suppurative otitis media and a higher level of hearing loss than the others (p < 0.01). Long time chronic suppurative otitis media and the reactive oxygen species can cause the mitochondrial DNA deletions and this may be a predisposing factor to sensorineural hearing loss in chronic suppurative otitis media. An antioxidant drug as a scavenger agent may be used in long-term chronic suppurative otitis media.

  10. Genetic polymorphisms and disease prevention.

    PubMed

    Mahoney, Martin C

    2007-06-15

    Building upon the resources of traditional epidemiology, molecular epidemiology has extended our understanding that disease risk varies based not only upon acquired factors (e.g., exposures, behaviors, demographics), but also as a function of inherited factors (e.g., genetic polymorphisms). Individual susceptibility to cancer is influenced by polymorphisms in phase I enzymes (e.g., activation), phase 2 enzymes (e.g., detoxification), defects in the repair of DNA damage and other cancer susceptibility genes. Because tobacco use and nutrition represent behaviors/exposures which account for a significant number of cancer cases and deaths, these two factors are used to illustrate the relationship between genetic polymorphisms and disease prevention. Susceptibility to the health risks of smoking appears to be influenced by genetic factors that impact initiation, dependence, and nicotine metabolism. Nutrient metabolism also involves polymorphic enzyme pathways and gene-nutrient interactions may influence cancer risk. While the discipline of molecular epidemiology continues to face methodologic challenges related to the need to study large numbers of subjects, current knowledge can be applied to prevention activities. Genetic polymorphisms, and other molecular markers, can be used to develop clinical prevention studies targeted to unique subsets of persons at the highest risk of developing disease. Knowledge about the relationships between polymorphisms and disease outcomes can also be used for reinforcing healthy lifestyles, motivating positive behavior changes, helping to target medical therapy, and aiding in better focusing surveillance activities. PMID:17252563

  11. Xp22. 3 deletions in isolated familial Kallmann's syndrome

    SciTech Connect

    Hardelin, J.P.; Levilliers, J.; Legouis, R.; Petit, C. ); Young, J.; Pholsena, M.; Schaison, G. ); Kirk, J.; Bouloux, P. )

    1993-04-01

    Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been previously shown in patients affected with both X-linked ichthyosis and KS. The authors report here the search for Xp22.3 deletions in 20 unrelated males affected with isolated X-linked KS. Only 2 deletions were found using Southern blot analysis, indicating that large deletions are uncommon in patients affected with KS alone. Both deletions were shown to include the entire KAL gene responsible for X-linked KS. The patients carrying these deletions exhibit additional clinical anomalies, which are discussed: unilateral renal aplasia, unilateral absence of vas deferens, mirror movements, and sensory neural hearing loss. 47 refs., 2 figs., 1 tab.

  12. Clinical and cytogenetic aspects of X-chromosome deletions.

    PubMed

    Goldman, B; Polani, P E; Daker, M G; Angell, R R

    1982-01-01

    Karyotype/phenotype correlations in six non-mosaic patients with dysgenetic ovaries and partial deletions of the X-chromosome (three patients with short arm, and three with long arm deletions) are presented and the pertinent literature is analysed. It would appear that functioning ovarian tissue is present more often in patients with a short arm deletion than in those with a deleted long arm. This may represent a difference in the strength of two sets of controlling factors, but it can also be related to break point position. This in turn may be misinterpreted due to the difficulty in distinguishing between terminal and interstitial deletions in the long arm. Stature may be a heterochromatic effect, but if specific genetic factors influencing stature exist, then they would appear to be situated mostly on the short arm of the X-chromosome, although some 'statural determinants' occur also on the long arm and could be located rather close to the centromere. Deletions of the short arm of the X-chromosome were almost always associated with some features of the Turner phenotype, and could possibly be related to a gene dosage effect.

  13. Fast detection of deletion breakpoints using quantitative PCR

    PubMed Central

    Abildinova, Gulshara; Abdrakhmanova, Zhanara; Tuchinsky, Helena; Nesher, Elimelech; Pinhasov, Albert; Raskin, Leon

    2016-01-01

    Abstract The routine detection of large and medium copy number variants (CNVs) is well established. Hemizygotic deletions or duplications in the large Duchenne muscular dystrophy DMD gene responsible for Duchenne and Becker muscular dystrophies are routinely identified using multiple ligation probe amplification and array-based comparative genomic hybridization. These methods only map deleted or duplicated exons, without providing the exact location of breakpoints. Commonly used methods for the detection of CNV breakpoints include long-range PCR and primer walking, their success being limited by the deletion size, GC content and presence of DNA repeats. Here, we present a strategy for detecting the breakpoints of medium and large CNVs regardless of their size. The hemizygous deletion of exons 45-50 in the DMD gene and the large autosomal heterozygous PARK2 deletion were used to demonstrate the workflow that relies on real-time quantitative PCR to narrow down the deletion region and Sanger sequencing for breakpoint confirmation. The strategy is fast, reliable and cost-efficient, making it amenable to widespread use in genetic laboratories. PMID:27560363

  14. Fast detection of deletion breakpoints using quantitative PCR.

    PubMed

    Abildinova, Gulshara; Abdrakhmanova, Zhanara; Tuchinsky, Helena; Nesher, Elimelech; Pinhasov, Albert; Raskin, Leon

    2016-01-01

    The routine detection of large and medium copy number variants (CNVs) is well established. Hemizygotic deletions or duplications in the large Duchenne muscular dystrophy DMD gene responsible for Duchenne and Becker muscular dystrophies are routinely identified using multiple ligation probe amplification and array-based comparative genomic hybridization. These methods only map deleted or duplicated exons, without providing the exact location of breakpoints. Commonly used methods for the detection of CNV breakpoints include long-range PCR and primer walking, their success being limited by the deletion size, GC content and presence of DNA repeats. Here, we present a strategy for detecting the breakpoints of medium and large CNVs regardless of their size. The hemizygous deletion of exons 45-50 in the DMD gene and the large autosomal heterozygous PARK2 deletion were used to demonstrate the workflow that relies on real-time quantitative PCR to narrow down the deletion region and Sanger sequencing for breakpoint confirmation. The strategy is fast, reliable and cost-efficient, making it amenable to widespread use in genetic laboratories. PMID:27560363

  15. Megabase deletions of gene deserts result in viable mice

    SciTech Connect

    Nobrega, Marcelo A.; Zhu, Yiwen; Plajzer-Frick, Ingrid; Afzal,Veena; Rubin, Edward M.

    2004-05-01

    The functional importance of the approximately 98 percent of mammalian genomes not corresponding to protein coding sequences remain largely un-scrutinized 1. To test experimentally whether some extensive regions of non-coding DNA, referred to as gene deserts 2-4, contain critical functions essential for the viability of the organism, we deleted two large non-coding intervals, 1,511 kb and 845 kb in length, from the mouse genome. Viable mice homozygous for the deletions were generated and were indistinguishable from wild-type litter mates with regards to morphology, reproductive fitness, growth, longevity and a variety of parameters assaying general homeostasis. Further in-depth analysis of the expression of genes bracketing the deletions revealed similar expression characteristics in homozygous deletion and wild-type mice. Together, the two deleted segments harbour 1,243 non-coding sequences conserved between humans and rodents (>100bp, 70 percent identity). These studies demonstrate that some large-scale deletions of non-coding DNA can be well tolerated by an organism, bringing into question the role of many human-mouse conserved sequences 5,6, and further supports the existence of potentially ''disposable DNAi'' in the genomes of mammals.

  16. Interstitial deletion of 13q associated with polymicrogyria.

    PubMed

    Kogan, Jillene M; Egelhoff, John C; Saal, Howard M

    2008-04-01

    Interstitial deletion of the long arm of chromosome 13 is a rare condition characterized by multiple clinical findings. We report a male dizygotic twin with an interstitial deletion of 13q and failure to thrive, hypotonia, polymicrogyria, bilateral foci of retinoblastoma, hearing loss, bilateral inguinal hernias, submucous cleft palate, and dysmorphic features including a triangular shaped face, broad forehead, small chin, prominent eyes, downslanting palpebral fissures, and a downturned mouth. Chromosome analysis showed an interstitial deletion of chromosome 13 which was confirmed by fluorescence in situ hybridization analysis to include the Rb locus, but spare the 13q subtelomeric region. The karyotype was 46,XY,del(13)(q14.1q31.2).ish del(13)(RB1-,D13S327+) de novo. Breakpoints were further characterized by SNP-based microarray. Retinoblastoma tumors are a well-known complication of deletion of the retinoblastoma susceptibility gene, located at chromosome 13q14.2. Growth retardation is another common feature that has been described in other patients with a deletion of 13q. Additionally, this patient had brain findings on MRI consistent with bilateral polymicrogyria with predominance of the frontal lobes, as well as prominent infratentorial and supratentorial vasculature. There are a variety of polymicrogyria syndromes that are distinguished by the cortical location of the abnormal folding. Several of the subtypes have known genetic loci associated with them. To our knowledge, this is the only report of polymicrogyria in association with a deletion of chromosome 13.

  17. Relationship among angiotensin-converting enzyme polymorphism, cardiovascular risk, and osteoporotic fractures

    PubMed Central

    Briongos-Figuero, Laisa Socorro; Cuadrado-Medina, Francisca; Abad-Manteca, Laura; Vega-Tejedor, Gemma; Pineda-Alonso, Mónica; Pérez-Castrillón, José Luis

    2016-01-01

    Objective Angiotensin-converting enzyme (ACE) has been related to cardiovascular physiology and bone remodeling. Our aim was to assess the relationship among ACE polymorphisms, cardiovascular risk, and osteoporotic fractures. Material and Methods We prospectively enrolled 71 patients with hypertension from 2001 to 2014. Sociodemographic and medical data were collected. Comorbidity was evaluated with Charlson index. Densitometric studies on lumbar spine were performed. ACE polymorphism was analyzed by polymerase chain reaction. Data were analyzed using SPSS 15.0 (p value <0.05). Results Homozygous deletion (DD) genotype was described in 32.4% of patients, homozygous insertion (II) in 19.7%, and heterozygous insertion/deletion (ID) in 47.9%. On stratifying data by ACE polymorphism, we observed that DD carriers demonstrated neither greater cardiovascular risk factors (30.4% vs. 33.3%, p=0.4) and higher comorbidity (34.8% vs. 22.9%, p=0.3) nor higher osteoporotic fracture incidence (17.4% vs. 16.8%, p=0.9). In women, no significant differences were observed between DD homozygous individuals and ID+II subjects. Conclusion It is unclear whether DD genotype is an independent risk factor for cardiovascular disease. In contrast to our expectations, we found no relationship among the DD genotype, cardiovascular risk, and osteoporotic fracture incidence.

  18. New polymorphous computing fabric.

    SciTech Connect

    Wolinski, C.; Gokhale, M.; McCabe, K. P.

    2002-01-01

    This paper introduces a new polymorphous computing Fabric well suited to DSP and Image Processing and describes its implementation on a Configurable System on a Chip (CSOC). The architecture is highly parameterized and enables customization of the synthesized Fabric to achieve high performance for a specific class of application. For this reason it can be considered to be a generic model for hardware accelerator synthesis from a high level specification. Another important innovation is the Fabric uses a global memory concept, which gives the host processor random access to all the variables and instructions on the Fabric. The Fabric supports different computing models including MIMD, SPMD and systolic flow and permits dynamic reconfiguration. We present a specific implementation of a bank of FIR filters on a Fabric composed of 52 cells on the Altera Excalibur ARM running at 33 MHz. The theoretical performance of this Fabric is 1.8 GMACh. For the FIR application we obtain 1.6 GMAC/s real performance. Some automatic tools have been developed like the tool to provide a host access utility and assembler.

  19. Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling

    PubMed Central

    de Albuquerque, Felipe Neves; Brandão, Andréa Araujo; da Silva, Dayse Aparecida; Mourilhe-Rocha, Ricardo; Duque, Gustavo Salgado; Gondar, Alyne Freitas Pereira; Neves, Luiza Maceira de Almeida; Bittencourt, Marcelo Imbroinise; Pozzan, Roberto; de Albuquerque, Denilson Campos

    2014-01-01

    Background The role of angiotensin-converting enzyme genetic polymorphisms as a predictor of echocardiographic outcomes on heart failure is yet to be established. The local profile should be identified so that the impact of those genotypes on the Brazilian population could be identified. This is the first study on exclusively non-ischemic heart failure over a follow-up longer than 5 years. Objective To determine the distribution of angiotensin-converting enzyme genetic polymorphism variants and their relation with echocardiographic outcome of patients with non-ischemic heart failure. Methods Secondary analysis of the medical records of 111 patients and identification of the angiotensin-converting enzyme genetic polymorphism variants, classified as DD (Deletion/Deletion), DI (Deletion/Insertion) or II (Insertion/Insertion). Results The cohort means were as follows: follow-up, 64.9 months; age, 59.5 years; male sex, 60.4%; white skin color, 51.4%; use of beta-blockers, 98.2%; and use of angiotensin-converting-enzyme inhibitors or angiotensin receptor blocker, 89.2%. The angiotensin-converting enzyme genetic polymorphism distribution was as follows: DD, 51.4%; DI, 44.1%; and II, 4.5%. No difference regarding the clinical characteristics or treatment was observed between the groups. The final left ventricular systolic diameter was the only isolated echocardiographic variable that significantly differed between the angiotensin-converting enzyme genetic polymorphisms: 59.2 ± 1.8 for DD versus 52.3 ± 1.9 for DI versus 59.2 ± 5.2 for II (p = 0.029). Considering the evolutionary behavior, all echocardiographic variables (difference between the left ventricular ejection fraction at the last and first consultation; difference between the left ventricular systolic diameter at the last and first consultation; and difference between the left ventricular diastolic diameter at the last and first consultation) differed between the genotypes (p = 0.024; p = 0.002; and p = 0

  20. Molecular dissection of a contiguous gene syndrome: Frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated island in the Miller-Dieker chromosome region

    SciTech Connect

    Ledbetter, D.H.; Ledbetter, S.A.; vanTuinen, P.; Summers, K.M.; Robinson, T.J.; Nakamura, Yusuke; Wolff, R.; White, R.; Barker, D.F.; Wallace, M.R.; Collins, F.S.; Dobyns, W.B. )

    1989-07-01

    The Miller-Dieker syndrome (MDS), composed of characteristic facial abnormalities and a severe neuronal migration disorder affecting the cerebral cortex, is caused by visible or submicroscopic deletions of chromosome band 17p13. Twelve anonymous DNA markers were tested against a panel of somatic cell hybrids containing 17p deletions from seven MDS patients. All patients, including three with normal karyotypes, are deleted for a variable set of 5-12 markers. Two highly polymorphic VNTR (variable number of tandem repeats) probes, YNZ22 and YNH37, are codeleted in all patients tested and make molecular diagnosis for this disorder feasible. By pulsed-field gel electrophoresis, YNZ22 and YNH37 were shown to be within 30 kilobases (kb) of each other. Cosmid clones containing both VNTR sequences were identified, and restriction mapping showed them to be <15 kb apart. Three overlapping cosmids spanning >100 kb were completely deleted in all patients, providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region, indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder. The conserved sequences were mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids, extending the remarkable homology between human chromosome 17 and mouse chromosome 11 by 30 centimorgans, into the 17p telomere region.

  1. Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome.

    PubMed

    Francke, U; Ochs, H D; de Martinville, B; Giacalone, J; Lindgren, V; Distèche, C; Pagon, R A; Hofker, M H; van Ommen, G J; Pearson, P L

    1985-03-01

    We are reporting a male patient who suffered from chronic granulomatous disease associated with cytochrome b-245 deficiency and McLeod red cell phenotype, Duchenne muscular dystrophy, and retinitis pigmentosa. On cytogenetic analysis, he seemed to have a very subtle interstitial deletion of part of band Xp21. Since it was impossible to know whether this material was truly deleted or inserted elsewhere in the genome, somatic cell and molecular studies were carried out. In somatic cell hybrids, the deleted X chromosome was isolated on a Chinese hamster background. Southern blot analysis with 20 single-copy probes, that had been mapped to the X short arm, led to the discovery of one (probe 754) that is missing from this patient's X chromosome and also from his total DNA. This proves that he, indeed, has a deletion rather than a balanced insertion. The results provide cytological mapping information for the X-linked phenotypes present in this patient. Furthermore, probe 754 recognizes a restriction fragment length polymorphism of high frequency that makes it the most powerful probe currently available for linkage studies with X-linked muscular dystrophy.

  2. Delineation of a 6 cM commonly deleted region in childhood acute lymphoblastic leukemia on the 6q chromosomal arm.

    PubMed

    Gérard, B; Cavé, H; Guidal, C; Dastugue, N; Vilmer, E; Grandchamp, B

    1997-02-01

    Deletion of the long arm of human chromosome 6 in acute lymphoblastic leukemia (ALL) has been shown by cytogenetic studies in 4-11% of cases. To characterize further the region of deletion and to precisely establish its frequency, we studied loss of heterozygosity (LOH) in 120 children with ALL using polymorphic markers located from the 6q14-15 chromosomal band to the telomere. LOH was detected in eight patients. A single region of LOH, flanked distally by D6S1594 and proximally by D6S301 was detected. These DNA markers are separated by 6 cM and are approximately located at the 6q21-22 band. Our present results delineate a region that is likely to contain a tumor-suppressor gene involved in a subset of childhood ALLs.

  3. The synergy of tobacco and alcohol and glutathione S-transferase θ 1 gene deletion and oral squamous cell carcinoma

    PubMed Central

    D’ Mello, Sarah; Bavle, Radhika Manoj; Paremala, K; Makarla, Soumya; Sudhakara, M; Bhatt, Madhura

    2016-01-01

    Background: Oral squamous cell carcinoma (OSCC) is the leading cancer among males in India. It is related to tobacco habits and alcohol consumption as well as the individual susceptibility for xenobiotic metabolizing enzyme polymorphisms. Glutathione S-transferase θ 1 (GSTT1) is a Phase II metabolic enzyme which is directly involved in catalyzing chemicals to mutagenic intermediates. This gene is characterized by genetic polymorphism resulting in complete gene deletion and subsequent absence of the enzyme, which ultimately dictates the risk of cancer development. Scraping buccal mucosa to obtain DNA from the cells is a simple, readily acceptable and rapid method to detect and assess the gene. Aim: To assess GSTT1 gene deletion in individuals giving a history of tobacco smoking and/or chewing and alcohol consumption and absence of clinically detectable lesions; and in OSCC cases to gauge if GSTT1 gene deletion confers protection to an individual and whether it can be used as a “single” marker to arrive at this conclusion. To validate the use of buccal scrape for determining the genotype of an individual by assessing the polymorphism at GSTT1 gene locus (22q11.2). Materials and Methods: Fifty-two cases were evaluated using buccal mucosal scrapes of tobacco habituates for 8 or more years, without clinically evident lesion (Group I) and from mucosa of tobacco habituates with clinically evident and histopathologically confirmed OSCC (Group II). DNA extraction and genotype at GSTT1 gene locus was determined by polymerase chain reaction assay. Statistical Analysis: The results were statistically analyzed using Chi-square test. Results: 90.66% of subjects had GSTT1 null genotype in Group I subjects. In Group II, subjects with both clinically and histopathologically diagnosed oral cancer, about 76.96% had GSTT1 null genotype. Conclusion: GSTT1 null genotype confers protection to individuals with tobacco habits and alcohol consumption, predominantly to those who used

  4. Deletion of the trichodiene synthase gene of Fusarium venenatum: two systems for repeated gene deletions.

    PubMed

    Royer, J C; Christianson, L M; Yoder, W T; Gambetta, G A; Klotz, A V; Morris, C L; Brody, H; Otani, S

    1999-10-01

    The trichodiene synthase (tri5) gene of Fusarium venenatum was cloned from a genomic library. Vectors were created in which the tri5 coding sequence was replaced with the Neurospora crassa nitrate reductase (nit3) gene and with the Aspergillus nidulans acetamidase (amdS) gene flanked by direct repeats. The first vector was utilized to transform a nitrate reductase (niaD) mutant of F. venenatum to prototrophy, and the second vector was utilized to confer acetamide utilization to the wild-type strain. Several of the transformants lost the capacity to produce the trichothecene diacetoxyscirpenol and were shown by hybridization analysis to have gene replacements at the tri5 locus. The nit3 gene was removed by retransformation with a tri5 deletion fragment and selection on chlorate. The amdS gene was shown to excise spontaneously via the flanking direct repeats when spores were plated onto fluoroacetamide. PMID:10512673

  5. An Indel Polymorphism in the MtnA 3' Untranslated Region Is Associated with Gene Expression Variation and Local Adaptation in Drosophila melanogaster

    PubMed Central

    Glaser-Schmitt, Amanda; Duchen, Pablo; Parsch, John

    2016-01-01

    Insertions and deletions (indels) are a major source of genetic variation within species and may result in functional changes to coding or regulatory sequences. In this study we report that an indel polymorphism in the 3’ untranslated region (UTR) of the metallothionein gene MtnA is associated with gene expression variation in natural populations of Drosophila melanogaster. A derived allele of MtnA with a 49-bp deletion in the 3' UTR segregates at high frequency in populations outside of sub-Saharan Africa. The frequency of the deletion increases with latitude across multiple continents and approaches 100% in northern Europe. Flies with the deletion have more than 4-fold higher MtnA expression than flies with the ancestral sequence. Using reporter gene constructs in transgenic flies, we show that the 3' UTR deletion significantly contributes to the observed expression difference. Population genetic analyses uncovered signatures of a selective sweep in the MtnA region within populations from northern Europe. We also find that the 3’ UTR deletion is associated with increased oxidative stress tolerance. These results suggest that the 3' UTR deletion has been a target of selection for its ability to confer increased levels of MtnA expression in northern European populations, likely due to a local adaptive advantage of increased oxidative stress tolerance. PMID:27120580

  6. Targeted deletion of the 9p21 noncoding coronary artery disease risk interval in mice

    SciTech Connect

    Visel, Axel; Zhu, Yiwen; May, Dalit; Afzal, Veena; Gong, Elaine; Attanasio, Catia; Blow, Matthew J.; Cohen, Jonathan C.; Rubin, Edward M.; Pennacchio, Len A.

    2010-01-01

    Sequence polymorphisms in a 58kb interval on chromosome 9p21 confer a markedly increased risk for coronary artery disease (CAD), the leading cause of death worldwide 1,2. The variants have a substantial impact on the epidemiology of CAD and other life?threatening vascular conditions since nearly a quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein?coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70kb noncoding interval on mouse chromosome 4 affects cardiac expression of neighboring genes, as well as proliferation properties of vascular cells. Chr4delta70kb/delta70kb mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the noncoding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4delta70kb/delta70kb mice, indicating that distant-acting gene regulatory functions are located in the noncoding CAD risk interval. Allelespecific expression of Cdkn2b transcripts in heterozygous mice revealed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4delta70kb/delta70kb aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval plays a pivotal role in regulation of cardiac Cdkn2a/b expression and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.

  7. Hemizygous Deletion on Chromosome 3p26.1 Is Associated with Heavy Smoking among African American Subjects in the COPDGene Study

    PubMed Central

    Ruczinski, Ingo; Hokanson, John E.; Lutz, Sharon M.; Parker, Margaret M.; Cho, Michael H.; Hetmanski, Jacqueline B.; Scharpf, Robert B.; Crapo, James D.; Silverman, Edwin K.; Beaty, Terri H.

    2016-01-01

    Many well-powered genome-wide association studies have identified genetic determinants of self-reported smoking behaviors and measures of nicotine dependence, but most have not considered the role of structural variants, such as copy number variation (CNVs), influencing these phenotypes. Here, we included 2,889 African American and 6,187 non-Hispanic White subjects from the COPDGene cohort (http://www.copdgene.org) to carefully investigate the role of polymorphic CNVs across the genome on various measures of smoking behavior. We identified a CNV component (a hemizygous deletion) on chromosome 3p26.1 associated with two quantitative phenotypes related to smoking behavior among African Americans. This polymorphic hemizygous deletion is significantly associated with pack-years and cigarettes smoked per day among African American subjects in the COPDGene study. We sought evidence of replication in African Americans from the population based Atherosclerosis Risk in Communities (ARIC) study. While we observed similar CNV counts, the extent of exposure to cigarette smoking among ARIC subjects was quite different and the smaller sample size of heavy smokers in ARIC severely limited statistical power, so we were unable to replicate our findings from the COPDGene cohort. But meta-analyses of COPDGene and ARIC study subjects strengthened our association signal. However, a few linkage studies have reported suggestive linkage to the 3p26.1 region, and a few genome-wide association studies (GWAS) have reported markers in the gene (GRM7) nearest to this 3p26.1 area of polymorphic deletions are associated with measures of nicotine dependence among subjects of European ancestry. PMID:27711239

  8. Novel polymorphisms of the IGF1R gene and their association with average daily gain in Egyptian buffalo (Bubalus bubalis).

    PubMed

    El-Magd, M A; Abbas, H E; El-kattawy, A M; Mokhbatly, A

    2013-08-01

    The objective of this study was to detect insulin-like growth factor 1 receptor (IGF1R) polymorphisms, their allele, and genotype frequencies and to determine associations between these polymorphisms and growth traits in Egyptian water buffalo. Three loci of the IGF1R coding region were amplified by RT-PCR and, subsequently, subjected to sequence analysis, followed by single-strand conformation polymorphism to identify different allelic patterns. A total of 11 novel polymorphisms were detected; 6 SNPs among Egyptian water buffaloes and 5 polymorphisms compared with Indian buffalo (Y12700). Three of those polymorphisms; GAG Indel polymorphism, C261G, and G263C SNPs, were nonsynonymous mutations. The GAG Indel polymorphism led to deletion of E (glutamic) amino acid (aa) in the IGF1R of Egyptian water buffaloes compared with Indian buffalo. However, C261G SNP, which replaced A (alanine) by G (glycine) aa, and G263C SNP, which changed A (alanine) to P (proline) aa, were detected among Egyptian water buffaloes. Three different single-strand conformation polymorphism patterns were observed in exon 21: CC/CC, GG/GG, and CG/GC with frequencies of 0.291, 0.253, and 0.556, respectively. The heterozygous animals (CG/GC) had a higher ADG than homozygous animals (CC/CC and GG/GG) from birth to 6 mo of age. We conclude that the heterozygous haplotype, C261G/G263C, in exon 21 of the IGF1R gene is associated with the ADG during the early stages of life (from birth to 6 mo of age) and could be used as a genetic marker for selection of growth traits in Egyptian buffalo.

  9. Bovine and water buffalo Mx2 genes: polymorphism and antiviral activity.

    PubMed

    Babiker, H A E; Nakatsu, Y; Yamada, K; Yoneda, A; Takada, A; Ueda, J; Hata, H; Watanabe, T

    2007-01-01

    Millennia-long selective pressure of single-strand RNA viruses on the bovine Mx locus has increased the advantages of using the bovine Mx protein to evaluate the ultimate significance of the antiviral role of Mx proteins. The conclusions of research based only on the bovine Mx1 protein showed the need for comprehensive studies that demonstrate the role of all isoforms, individually or together, especially in the presence of a second isoform, the bovine Mx2 gene. This study provides information about bovine and water buffalo Mx2 genes, as well as their allelic polymorphism and basic antiviral potential. Observation of an Mx2 cDNA sequence (2,381 bp) obtained from 15 animals from 11 breeds using primers based on a previous sequence (NCBI accession no. AF335147) revealed several nucleotide substitutions, with eight different alleles and two amino acid exchanges: Gly to Ser at position 302 and Ile to Val at position 354, though the latter was found only in the NCBI database. A water buffalo Mx2 cDNA sequence was identified for the first time, revealing 46 nucleotide substitutions with 12 amino acid variations, in addition to a 9-bp insertion in the 5' untranslated region UTR, compared with the bovine Mx2 cDNA. Transfected 3T3 cells expressing bovine Mx2 mRNAs coding Gly or Ser at position 302, water buffalo Mx2 mRNA, positive control bovine Mx1 mRNA-expressing cells, and negative control parental 3T3 were subjected to infection with recombinant vesicular stomatitis virus (VSVDeltaG*-G), as were empty pCI-neo vector-transfected cells. The positive control and all cells expressing Mx2 mRNAs displayed significantly higher levels of antiviral activity against VSVDeltaG*-G (P < 0.01) than did the negative controls.

  10. The phenotype associated with a large deletion on MECP2

    PubMed Central

    Bebbington, Ami; Downs, Jenny; Percy, Alan; Pineda, Mercé; Zeev, Bruria Ben; Bahi-Buisson, Nadia; Leonard, Helen

    2012-01-01

    Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22–0.79, P=0.007) and to be currently walking (OR 0.53, 95% CI: 0.26–1.10, P=0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98–3.48, P=0.057) and epilepsy (OR 2.72, 95% CI: 1.38–5.37, P=0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected. PMID:22473088

  11. Impact of UGT2B17 gene deletion on the steroid profile of an athlete.

    PubMed

    Martín-Escudero, Pilar; Muñoz-Guerra, Jesús; Del Prado, Nayade; Galindo Canales, Mercedes; Fuentes Ferrer, Manuel; Vargas, Soledad; Soldevilla, Ana B; Serrano-Garde, Ester; Miguel-Tobal, Francisco; Maestro de Las Casas, Marisa; Fernandez-Pérez, Cristina

    2015-12-01

    The measurement of the testosterone to epitestosterone ratio (T/E ratio) in urine is often used as a marker for testosterone administration in the doping control field. This study examines the frequencies of the different expression forms of the UGT2B17 gene, and assesses their effects on this marker in volunteer subjects. The sample for this descriptive study was composed of male and female athletes aged between 16 and 55 years old who practiced different sports disciplines. All participants underwent a sports-medical physical examination, and subsequently provided 10 urine samples consecutively over a period of 48 h. The dependent variable examined was T/E and the main independent variable was the UGT2B17 gene polymorphism. During 1 year, 1410 urine samples were obtained from 141 athletes. The frequencies of the three genotypes were as follows: wt homozygotes (ins/ins) 48.2% (n = 68), mutant homozygotes (del/del) 12.1% (n = 17), and heterozygotes (ins/del) 39.7% (n = 56). Genotype distributions varied significantly (P < 0.001) according to ethnicity, 80% of Asian subjects being homozygous for the gene deletion (del/del) compared to 6.9% of Caucasian subjects. A multivariate analysis adjusted for genotype, age, sex, and sports discipline revealed that athletes with the del/del polymorphism showed a significantly lower mean T/E than heterozygotes (ins/del). In contrast, homozygous athletes for the gene insertion (ins/ins) showed higher mean T/E ratios than heterozygotes (ins/del). UGT2B17 gene deletion has a strong influence on the T/E ratio in urine, which is the most efficient indicator of testosterone prohormone misuse. Others factors studied seem not to have such an impact. The genotyping of UGT2B17 is an important source of information for understanding steroid profiling in the doping control field; therefore it is suggested that it be included in the Athletes Biological Passport.

  12. Characterization of the COL2A1 VNTR polymorphism

    SciTech Connect

    Berg, E.S.; Olaisen, B.

    1993-05-01

    The variable number of tandem repeat (VNTR) region 3{prime} to the collagen type II gene (COL2A1) was amplified in vitro by the polymerase chain reaction. Subsequent high-resolution gel electrophoresis showed that the five earlier reported alleles could be further subtyped. A total of 17 allelic variants with a heterozygosity of 73.0% were found in 202 unrelated Norwegians. DNA sequencing of 19 COL2A1 alleles has been performed. The internal organization of the VNTR was common for all alleles, as previously shown for a few alleles. Moreover, the polymorphism in the COL2A1 locus is mainly due to variation in the numbers of copies of two repeat units, containing 34 and 31 bp, respectively, and/or to small deletions in either of the two units. DNA sequencing of alleles with the same electrophoretic size revealed no heterogeneity such as an alternating order of the different units, a feature that might have been expected to be the result of unequal crossing-over events. The observed ordered structure of the VNTR and the possibility of single-stranded DNA from the cores in the VNTR forming hairpins and loops suggest that the COL2A1 polymorphism may have evolved mainly by replication slippage mechanisms. 23 refs., 2 figs., 3 tabs.

  13. ACE and AGTR1 polymorphisms in elite rhythmic gymnastics.

    PubMed

    Di Cagno, Alessandra; Sapere, Nadia; Piazza, Marina; Aquino, Giovanna; Iuliano, Enzo; Intrieri, Mariano; Calcagno, Giuseppe

    2013-02-01

    In the angiotensin-converting enzyme (ACE) gene, Alu deletion, in intron 16, is associated with higher concentrations of ACE serum activity and this may be associated with elite sprint and power performance. The Alu insertion is associated with lower ACE levels and this could lead to endurance performance. Moreover, recent studies have identified a single-nucleotide polymorphism of the angiotensin type 1 receptor gene AGTR1, which seems to be related to ACE activity. The aim of this study was to examine the involvement of the ACE and the AGTR1 gene polymorphisms in 28 Italian elite rhythmic gymnasts (age range 21 ± 7.6 years), and compare them to 23 middle level rhythmic gymnasts (age range 17 ± 10.9 years). The ACE D allele was significantly more frequent in elite athletes than in the control population (χ(2)=4.07, p=0.04). Comparisons between the middle level and elite athletes revealed significant differences (p<0.0001) for the ACE DD genotype (OR=6.48, 95% confidence interval=1.48-28.34), which was more frequent in elite athletes. There were no significant differences in the AGTR1 A/C genotype or allele distributions between the middle level and elite athletes. In conclusion, the ACE D allele genotype could be a contributing factor to high-performance rhythmic gymnastics that should be considered in athlete development and could help to identify which skills should be trained for talent promotion. PMID:23145508

  14. Single Nucleotide Polymorphisms and Linkage Disequilibrium in Sunflower

    PubMed Central

    Kolkman, Judith M.; Berry, Simon T.; Leon, Alberto J.; Slabaugh, Mary B.; Tang, Shunxue; Gao, Wenxiang; Shintani, David K.; Burke, John M.; Knapp, Steven J.

    2007-01-01

    Genetic diversity in modern sunflower (Helianthus annuus L.) cultivars (elite oilseed inbred lines) has been shaped by domestication and breeding bottlenecks and wild and exotic allele introgression−the former narrowing and the latter broadening genetic diversity. To assess single nucleotide polymorphism (SNP) frequencies, nucleotide diversity, and linkage disequilibrium (LD) in modern cultivars, alleles were resequenced from 81 genic loci distributed throughout the sunflower genome. DNA polymorphisms were abundant; 1078 SNPs (1/45.7 bp) and 178 insertions-deletions (INDELs) (1/277.0 bp) were identified in 49.4 kbp of DNA/genotype. SNPs were twofold more frequent in noncoding (1/32.1 bp) than coding (1/62.8 bp) sequences. Nucleotide diversity was only slightly lower in inbred lines (θ = 0.0094) than wild populations (θ = 0.0128). Mean haplotype diversity was 0.74. When extraploted across the genome (∼3500 Mbp), sunflower was predicted to harbor at least 76.4 million common SNPs among modern cultivar alleles. LD decayed more slowly in inbred lines than wild populations (mean LD declined to 0.32 by 5.5 kbp in the former, the maximum physical distance surveyed), a difference attributed to domestication and breeding bottlenecks. SNP frequencies and LD decay are sufficient in modern sunflower cultivars for very high-density genetic mapping and high-resolution association mapping. PMID:17660563

  15. Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis.

    PubMed

    Scheffler, Katja; Krohn, Markus; Dunkelmann, Tina; Stenzel, Jan; Miroux, Bruno; Ibrahim, Saleh; von Bohlen Und Halbach, Oliver; Heinze, Hans-Jochen; Walker, Lary C; Gsponer, Jörg A; Pahnke, Jens

    2012-08-01

    Several lines of evidence link mutations and deletions in mitochondrial DNA (mtDNA) and its maternal inheritance to neurodegenerative diseases in the elderly. Age-related mutations of mtDNA modulate the tricarboxylic cycle enzyme activity, mitochondrial oxidative phosphorylation capacity and oxidative stress response. To investigate the functional relevance of specific mtDNA polymorphisms of inbred mouse strains in the proteostasis regulation of the brain, we established novel mitochondrial congenic mouse lines of Alzheimer's disease (AD). We crossed females from inbred strains (FVB/N, AKR/J, NOD/LtJ) with C57BL/6 males for at least ten generations to gain specific mitochondrial conplastic strains with pure C57BL/6 nuclear backgrounds. We show that specific mtDNA polymorphisms originating from the inbred strains differentially influence mitochondrial energy metabolism, ATP production and ATP-driven microglial activity, resulting in alterations of cerebral β-amyloid (Aβ) accumulation. Our findings demonstrate that mtDNA-related increases in ATP levels and subsequently in microglial activity are directly linked to decreased Aβ accumulation in vivo, implicating reduced mitochondrial function in microglia as a causative factor in the development of age-related cerebral proteopathies such as AD.

  16. Molecular characterization of a Han Chinese family with essential hypertension.

    PubMed

    Zhu, J F; Zhang, X; Ling, L

    2016-01-01

    Mutations in the mitochondrial genome have been found to be associated with essential hypertension. Here, we report the clinical and molecular characterization of a three-generation Han Chinese family with maternally inherited hypertension. Most strikingly, this pedigree exhibited a high penetrance of hypertension. Sequence analysis of the mitochondrial genome showed the presence of a homoplasmic T16189C mutation in the D-loop and the intergenic CO2/tRNA(Lys) 9-bp common deletion, as well as a set of polymorphisms belonging to the East Asia haplogroup B5b1. The well-known T16189C mutation, which is in the first hypervariable segment of the mitochondrial control region, is implicated to be associated with a wide range of clinical disorders. Moreover, the genetic polymorphism 9-bp common deletion is found to be associated with hepatocellular carcinoma in the Han Chinese population. Thus, the combination of T16189C mutation and the 9-bp deletion may have caused mitochondrial dysfunction and contributed to the development of essential hypertension in this Chinese family. PMID:27323027

  17. Genetic map of randomly amplified DNA polymorphisms closely linked to the mating type locus of tetrahymenta thermophila

    SciTech Connect

    Lynch, T.J.; Brickner, J.; Orias, E.; Nakano, K.J.

    1995-12-01

    We have used the PCR-based randomly amplified polymorphic DNA (RAPD) method to efficiently identify and map DNA polymorphisms in the ciliated protozoan Tetrahymena thermophila. The polymorphisms segregate as Mendelian genetic markers. A targeted screen, using DNA from pooled meiotic segregants, yielded the polymorphisms most closely linked to the mat locus. A total of 10 polymorphisms linked to the mat-Pmr segment of the left arm of micronuclear chromosome 2 have been identified. This constitutes the largest linkage group described in T. thermophila. We also provide here the first crude estimate of the frequency of meiotic recombination in the mat region, 20 kb/cM. This frequency is much higher than that observed in most other eukaryotes. Special features of Tetrahymena genetics enhanced the power of the RAPD method: the ability to obtain in a single step meiotic segregants that are whole-genome homozygotes and the availability of nullisomic strains permitting quick deletion mapping of polymorphisms to micronuclear chromosomes or chromosomes segments. The RAPD method appears to provide a practical and relatively inexpensive approach to the construction of a high-resolution map of the Tetrahymena genome. 39 refs., 5 figs., 4 tabs.

  18. Genetic Polymorphisms of the TYMS Gene Are Not Associated with Congenital Cardiac Septal Defects in a Han Chinese Population

    PubMed Central

    Wang, Jue; Wang, Er-Li; Yang, Xue-Yan; Qiao, Bin; Duan, Wen-Yuan; Huang, Guo-Ying; Wang, Hong-Yan

    2012-01-01

    Background Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs). The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS) is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs) risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population. Method Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression. Result We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either. Conclusion Our results show no association between common genetic polymorphisms of the regulatory region of the TYMS gene and CCSDs in the Han Chinese population. PMID:22384047

  19. Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers

    NASA Astrophysics Data System (ADS)

    Husna, M. Z.; Endom, I.; Ibrahim, S.; Selvi, N. Amaramalar; Fakhrurazi, H.; Htwe, R. Ohnmar; Kanehaswari, Y.; Halim, A. R. Abdul; Wong, S. W.; Subashini, K.; Syahira, O. Nur; Aishah, S.

    2013-11-01

    Mechanism underlying the beneficial effect of folic acid supplementation in reducing the risk of neural tube defect is still not well understood. Current evidences show the involvement of folic acid metabolic gene's polymorphism as contributing factors that regulate this pathway. Therefore, the objective of this research was to determine the presence of C677T polymorphism for methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR-19 bp deletion) genes between mother-children pairs of case and control. With the approval of UKMMC ethic committee, genomic DNA was extracted from one hundred and forty consented bloods. Polymerase chain reaction (PCR), PCR-RFLP (Restriction Fragment Length Polymorphism) and sequencing were employed to verify each nucleotide change. Our result shows that mutant MTHFR and DHFR alleles are present in all Malaysian sub-ethnic groups, case and control. Even though mutant MTHFR are found to be slightly higher in the case groups, 75% of the affected child is a non carrier for this allele and 62.5% of the mothers with an affected child are genotypically normal. For DHFR, almost all (87.5-100%) investigated samples are a carrier or having a double DHFR deletion be it a case or control pairs. However, strong maternal inheritance shown by the deleted allele might be due to a cascade effect of lacks of folate consumption or maternal uniparental disomy. In conclusion, the use of MTHFR and DHFR as markers in determining the risk of having spina bifida baby is uninformative and plays a small indirect role as the genetic causes of spina bifida. Therefore, spina bifida remains etiologically unknown polygenic and quantitative developmental trait whereby the searches for positive genetic marker need to be continued.

  20. Frequencies of glutathione s-transferase (GSTM1, GSTM3 AND GSTT1) polymorphisms in a Malaysian population

    PubMed Central

    Alshagga, Mustafa A.; Mohamed, Norazlina; Nazrun Suhid, Ahmad; Abdel Aziz Ibrahim, Ibrahim; Zulkifli Syed Zakaria, Syed

    2011-01-01

    Introduction Glutathione S-transferase (GST) is a xenobiotic metabolising enzyme (XME), which may modify susceptibility in certain ethnic groups, showing ethnic dependent polymorphism. The aim of this study was to determine GSTM1, GSTM3 and GSTT1 gene polymorphisms in a Malaysian population in Kuala Lumpur. Material and methods Blood or buccal swab samples were collected from 137 Form II students from three schools in Wilayah Persekutuan Kuala Lumpur. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results Glutathione-S-transferase GSTM3 gene frequencies were 89% for AA, 10% for AB and 1% for BB. The gene frequencies for deleted GSTM1 and GSTT1 were 66% and 18% respectively. Conclusions This study suggested that the Malay population is at risk for environmental diseases and provides the basis for gene-environment association studies to be carried out. PMID:22291790

  1. Allele-Specific Deletions in Mouse Tumors Identify Fbxw7 as Germline Modifier of Tumor Susceptibility

    PubMed Central

    Perez-Losada, Jesus; Wu, Di; DelRosario, Reyno; Balmain, Allan; Mao, Jian-Hua

    2012-01-01

    Genome-wide association studies (GWAS) have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs) and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5–10%). There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001), but only in animals with a functional p53 gene. These data therefore identify Fbxw7 as a p53-dependent tumor susceptibility gene. Increased p53-dependent tumor susceptibility and allele-specific losses were also seen in a mouse skin model of skin tumor development. We propose that analysis of preferential allelic imbalances in tumors may provide an efficient means of uncovering genetic variants that affect mouse and human tumor susceptibility. PMID:22348067

  2. Dopamine D{sub 3} receptor gene: Organization transcript variants, and polymorphism associated with schizophrenia

    SciTech Connect

    Griffon, N.; Pilon, C.; Martres, M.P.

    1996-02-16

    DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D{sub 3} receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distributions of the Msp I and Bal I genotypes were not independent in 297 individuals ({chi}{sup 2} = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism ({chi}{sup 2} = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls ({chi}{sup 2}= 5.3, df = 1, P = 0.02) and found more important in males than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls ({chi}{sup 2}= 0.06, df = 1, P = 0.80, {chi}{sup 2} = 0.22, df = 1, P = 0.90 and {chi}{sup 2} = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3{prime} part of the gene may explain the discrepant results obtained with the two polymorphisms. 36 refs., 2 figs., 4 tabs.

  3. Association between the TP53 polymorphisms and lung cancer risk: a meta-analysis.

    PubMed

    Ye, Xiang-Hua; Bu, Zhi-Bin; Feng, Jie; Peng, Ling; Liao, Xin-Biao; Zhu, Xin-Li; Sun, Xiao-Li; Yu, Hao-Gang; Yan, Dan-Fang; Yan, Sen-Xiang

    2014-01-01

    The previous published data on the association between TP53 codon 72, intron 6, and intron 3 16 bp polymorphisms and lung cancer risk remained controversial. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. 38 publications with 51 studies were selected for this meta-analysis, including 17,337 cases and 16,127 controls for TP53 codon 72 (from 43 studies), 2,201 cases and 2,399 controls for TP53 intron 6 (from four studies), and 4,322 cases and 4,558 controls for TP53 intron 3 16 bp (from four studies). When all the eligible studies were pooled into the meta-analysis of codon 72 polymorphism, there was significant association between lung cancer risk and codon 72 polymorphism in any genetic model (dominant model: OR = 1.13, 95 % CI 1.05-1.21; recessive model: OR = 1.14, 95 % CI 1.02-1.27; additive model: OR = 1.19, 95 % CI 1.05-1.33). In the subgroup analysis by ethnicity, histological type, source of control, and smoking status, significantly increased risks were observed in subgroups such as Asians, Caucasians, lung squamous cell carcinoma patients for Asians, population-based study, hospital-based study, non-smokers, and smokers. When all the eligible studies were pooled into the meta-analysis of intron 6 polymorphism, there was significant association between lung cancer risk and intron 6 polymorphism in dominant model (OR = 1.27, 95 % CI 1.11-1.44). When all the eligible studies were pooled into the meta-analysis of intron 3 16 bp polymorphism, there was significant association between lung cancer risk and intron 3 16 bp polymorphism in dominant model (OR = 1.12, 95 % CI 1.02-1.23) and additive model (OR = 1.41, 95 % CI 1.04-1.90). Additionally, when one study was deleted in the sensitive analysis, the results of TP53 intron 3 16 bp duplication polymorphism were changed in the dominant model (OR = 1.11, 95 % CI 0.87-1.42) and additive model (OR = 1.01, 95 % CI 0.65-1.56). In summary, this meta

  4. Functional Genomics Using the Saccharomyces cerevisiae Yeast Deletion Collections.

    PubMed

    Nislow, Corey; Wong, Lai Hong; Lee, Amy Huei-Yi; Giaever, Guri

    2016-01-01

    Constructed by a consortium of 16 laboratories, the Saccharomyces genome-wide deletion collections have, for the past decade, provided a powerful, rapid, and inexpensive approach for functional profiling of the yeast genome. Loss-of-function deletion mutants were systematically created using a polymerase chain reaction (PCR)-based gene deletion strategy to generate a start-to-stop codon replacement of each open reading frame by homologous recombination. Each strain carries two molecular barcodes that serve as unique strain identifiers, enabling their growth to be analyzed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays or through the use of next-generation sequencing technologies. Functional profiling of the deletion collections, using either strain-by-strain or parallel assays, provides an unbiased approach to systematically survey the yeast genome. The Saccharomyces yeast deletion collections have proved immensely powerful in contributing to the understanding of gene function, including functional relationships between genes and genetic pathways in response to diverse genetic and environmental perturbations. PMID:27587784

  5. Functional Profiling Using the Saccharomyces Genome Deletion Project Collections.

    PubMed

    Nislow, Corey; Wong, Lai Hong; Lee, Amy Huei-Yi; Giaever, Guri

    2016-01-01

    The ability to measure and quantify the fitness of an entire organism requires considerably more complex approaches than simply using traditional "omic" methods that examine, for example, the abundance of RNA transcripts, proteins, or metabolites. The yeast deletion collections represent the only systematic, comprehensive set of null alleles for any organism in which such fitness measurements can be assayed. Generated by the Saccharomyces Genome Deletion Project, these collections allow the systematic and parallel analysis of gene functions using any measurable phenotype. The unique 20-bp molecular barcodes engineered into the genome of each deletion strain facilitate the massively parallel analysis of individual fitness. Here, we present functional genomic protocols for use with the yeast deletion collections. We describe how to maintain, propagate, and store the deletion collections and how to perform growth fitness assays on single and parallel screening platforms. Phenotypic fitness analyses of the yeast mutants, described in brief here, provide important insights into biological functions, mechanisms of drug action, and response to environmental stresses. It is important to bear in mind that the specific assays described in this protocol represent some of the many ways in which these collections can be assayed, and in this description particular attention is paid to maximizing throughput using growth as the phenotypic measure. PMID:27587776

  6. The yeast deletion collection: a decade of functional genomics.

    PubMed

    Giaever, Guri; Nislow, Corey

    2014-06-01

    The yeast deletion collections comprise >21,000 mutant strains that carry precise start-to-stop deletions of ∼6000 open reading frames. This collection includes heterozygous and homozygous diploids, and haploids of both MAT A: and MATα mating types. The yeast deletion collection, or yeast knockout (YKO) set, represents the first and only complete, systematically constructed deletion collection available for any organism. Conceived during the Saccharomyces cerevisiae sequencing project, work on the project began in 1998 and was completed in 2002. The YKO strains have been used in numerous laboratories in >1000 genome-wide screens. This landmark genome project has inspired development of numerous genome-wide technologies in organisms from yeast to man. Notable spinoff technologies include synthetic genetic array and HIPHOP chemogenomics. In this retrospective, we briefly describe the yeast deletion project and some of its most noteworthy biological contributions and the impact that these collections have had on the yeast research community and on genomics in general. PMID:24939991

  7. The Yeast Deletion Collection: A Decade of Functional Genomics

    PubMed Central

    Giaever, Guri; Nislow, Corey

    2014-01-01

    The yeast deletion collections comprise >21,000 mutant strains that carry precise start-to-stop deletions of ∼6000 open reading frames. This collection includes heterozygous and homozygous diploids, and haploids of both MATa and MATα mating types. The yeast deletion collection, or yeast knockout (YKO) set, represents the first and only complete, systematically constructed deletion collection available for any organism. Conceived during the Saccharomyces cerevisiae sequencing project, work on the project began in 1998 and was completed in 2002. The YKO strains have been used in numerous laboratories in >1000 genome-wide screens. This landmark genome project has inspired development of numerous genome-wide technologies in organisms from yeast to man. Notable spinoff technologies include synthetic genetic array and HIPHOP chemogenomics. In this retrospective, we briefly describe the yeast deletion project and some of its most noteworthy biological contributions and the impact that these collections have had on the yeast research community and on genomics in general. PMID:24939991

  8. Angiotensin converting enzyme gene polymorphism in familial hypertrophic cardiomyopathy patients

    SciTech Connect

    Yu, B; Peric, S.; Ross, D.

    1994-09-01

    An insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene is a useful predictor of human plasma ACE levels. ACE levels tend to be lowest in subjects with ACE genotype DD and intermediate in subjects with ACE genotype ID. Angiotensin II (Ang II) as a product of ACE is a cardiac growth factor and produces a marked hypertrophy of the chick myocyte in cell culture. Rat experiments also suggest that a small dose of ACE inhibitor that does not affect the afterload results in prevention or regression of cardiac hypertrophy. In order to study the relationship of ACE and the severity of hypertrophy, the ACE genotype has been determined in 28 patients with a clinical diagnosis of familial hypertrophic cardiomyopathy (FHC) and 51 normal subjects. The respective frequencies of I and D alleles were: 0.52 and 0.48 (in FHC patients) and 0.44 and 0.56 (in the normal controls). There was no significant difference in the allele frequencies between FHC and normal subjects ({chi}{sup 2}=0.023, p>0.05). The II, ID, and DD genotypes were present in 7, 15, and 6 FHC patients, respectively. The averages of maximal thickness of the interventricular septum measured by echocardiography or at autopsy were 18 {plus_minus}3, 19{plus_minus}4, and 19{plus_minus}3 mm in II, ID and DD genotypes, respectively. The ACE gene polymorphism did not correlate with the severity of left ventricular hypertrophy in FHC patients (r{sub s}=0.231, p>0.05). These results do not necessarily exclude the possible effect of Ang II on the hypertrophy since the latter may be produced through the action of chymase in the human ventricles. However, ACE gene polymorphism is not a useful predictor of the severity of myocardial hypertrophy in FHC patients.

  9. Molecular analysis of Baylisascaris columnaris revealed mitochondrial and nuclear polymorphisms

    PubMed Central

    2013-01-01

    Background Baylisascaris species are intestinal nematodes of skunks, raccoons, badgers, and bears belonging to the genus Ascarididae. Oral uptake of embryonated Baylisascaris sp. eggs by a wide variety of mammals and birds can lead to visceral, ocular and neurological larva migrans. B. procyonis, the raccoon roundworm, is known to cause severe illness in intermediate hosts and in humans, whereas the skunk roundworm B. columnaris is probably less pathogenic. Skunks and raccoons are kept as pets in Europe, sometimes together with cats and dogs, living in close contact with humans. B. procyonis and B. columnaris are difficult to differentiate based on morphological criteria and molecular and phylogenetic information concerning B. columnaris is missing. This is the first study on the genetic characterisation of B. columnaris, based on mitochondrial and nuclear molecular markers. Methods B. columnaris worms were isolated from pet skunks, and used for molecular analysis. PCR primers targeted at mitochondrial cytochrome c oxidase 1 and 2 (CO1 and CO2), ribosomal ITS1-5.8S-ITS2 and ribosomal 28S genes were used. DNA sequences from B. columnaris, B. procyonis and B. transfuga from bears were analysed by cluster analysis. Results Four different multi-locus genotypes were found in B. columnaris, based on 14 single nucleotide polymorphisms (SNPs) and two insertions / deletions in CO1, CO2, ITS1-5.8S-ITS2 and 28S. Conclusions The genetic characteristics of B. columnaris show close resemblance to those of B. procyonis, but in contrast to B. procyonis, show several polymorphisms in both mitochondrial and nuclear markers. These polymorphisms could be used as a tool to differentiate B. columnaris from B. procyonis in molecular diagnostic assays, and to identify B. columnaris by PCR, in addition to or replacing morphometric analysis. This might lead to more insight into the zoonotic relevance of B. columnaris in humans. PMID:23627901

  10. Pepsinogen C gene polymorphisms associated with gastric body ulcer.

    PubMed Central

    Azuma, T; Teramae, N; Hayakumo, T; Yasuda, K; Nakajima, M; Kodama, T; Inokuchi, H; Hayashi, K; Taggart, R T; Kawai, K

    1993-01-01

    This study was aimed to investigate the association of restriction fragment length polymorphisms (RFLPs) for pepsinogen genes with peptic ulcer disease. Eighty unrelated controls, 61 patients with gastric ulcer, and 57 patients with duodenal ulcer were studied. No genetic polymorphisms for pepsinogen A were detected by EcoRI digestion in Japanese subjects but a 100 base pairs insertion-deletion RFLP for the pepsinogen C gene was observed. The allele frequencies of the large (3.6 kilobase EcoRI fragment) and the small fragment (3.5 kilobase EcoRI fragment) were 80.6% and 19.4% respectively in controls, 55.4% and 44.6% in patients with gastric body ulcer, 79.4% and 20.6% in patients with gastric angular ulcer, 71.4% and 28.6% in patients with gastric antral ulcer, and 75.4% and 24.6% in patients with duodenal ulcer. The allele frequency of the small fragment was significantly higher in patients with gastric body ulcer than in controls and in patients with gastric angular or antral ulcer. The genotypes which possessed the small fragment were significantly more frequent in patients with gastric body ulcer (78.4%) than in controls (33.8%) and in patients with gastric angular or antral ulcer (37.5%). These results suggest that there is a significant association between the genetic polymorphism at the pepsinogen C gene locus and gastric body ulcer, and that the pepsinogen C RFLP is a useful marker of the genetic predisposition to this disorder. These results also indicate genetic heterogeneity of gastric ulcer disease, and suggest that the pepsinogen C RFLP may be a useful subclinical marker to explain the differences in genetic aetiologies of gastric body ulcer and gastric angular or antral ulcer. Images Figure 1 Figure 2 PMID:8098309

  11. Deletion 2q37 syndrome: Cognitive-behavioral trajectories and autistic features related to breakpoint and deletion size.

    PubMed

    Fisch, Gene S; Falk, Rena E; Carey, John C; Imitola, Jaime; Sederberg, Maria; Caravalho, Karen S; South, Sarah

    2016-09-01

    Subtelomeric deletions have been reported in ∼2.5% of individuals with developmental disabilities. Subtelomeric deletion 2q37 has been detected in many individuals diagnosed with intellectual disabilities (ID) and autism spectrum disorders (ASD). Previously, genotype-phenotype correspondences were examined for their relationship to breakpoints 37.1, 37.2, or 37.3. Our purpose was to ascertain whether there were phenotypic differences at these breakpoints, elucidate the cognitive-behavioral phenotype in del2q37, and examine the genotype-phenotype association in the deletion with respect to cognitive-behavioral profiles and ASD. We administered a comprehensive cognitive-behavioral battery to nine children diagnosed with del 2q37, ages 3.9-17.75 years. ID for five tested with the Stanford-Binet (4th Edition) (SBFE) ranged from severe to mild [IQ Range: 36-59]. Adaptive behavior scores from the Vineland Adaptive Behavior Scale (VABS) were much below adequate levels (DQ Range: floor value ["19"] to 55). Autism scores from the Child Autism Rating Scale (CARS) ranged from 22 [non-autistic] to 56 [extremely autistic]; 5/8 [63%] children received scores on the autism spectrum. Participants with the largest deletions, 10.1 and 9.5 Mb, attained the highest IQ and DQ scores while those with the smallest deletions, 7.9 and 6.6 Mb, made the lowest IQ and DQ scores. No association between deletion breakpoint and phenotype were found. Assessment of the various deleted regions suggested histone deacetylase 4 gene (HDAC4) was a likely candidate gene for ASD in our sample. However, two earlier reports found no association between HDAC4 haploinsufficiency and ASD. © 2016 Wiley Periodicals, Inc. PMID:27282419

  12. Deletion 2q37 syndrome: Cognitive-behavioral trajectories and autistic features related to breakpoint and deletion size.

    PubMed

    Fisch, Gene S; Falk, Rena E; Carey, John C; Imitola, Jaime; Sederberg, Maria; Caravalho, Karen S; South, Sarah

    2016-09-01

    Subtelomeric deletions have been reported in ∼2.5% of individuals with developmental disabilities. Subtelomeric deletion 2q37 has been detected in many individuals diagnosed with intellectual disabilities (ID) and autism spectrum disorders (ASD). Previously, genotype-phenotype correspondences were examined for their relationship to breakpoints 37.1, 37.2, or 37.3. Our purpose was to ascertain whether there were phenotypic differences at these breakpoints, elucidate the cognitive-behavioral phenotype in del2q37, and examine the genotype-phenotype association in the deletion with respect to cognitive-behavioral profiles and ASD. We administered a comprehensive cognitive-behavioral battery to nine children diagnosed with del 2q37, ages 3.9-17.75 years. ID for five tested with the Stanford-Binet (4th Edition) (SBFE) ranged from severe to mild [IQ Range: 36-59]. Adaptive behavior scores from the Vineland Adaptive Behavior Scale (VABS) were much below adequate levels (DQ Range: floor value ["19"] to 55). Autism scores from the Child Autism Rating Scale (CARS) ranged from 22 [non-autistic] to 56 [extremely autistic]; 5/8 [63%] children received scores on the autism spectrum. Participants with the largest deletions, 10.1 and 9.5 Mb, attained the highest IQ and DQ scores while those with the smallest deletions, 7.9 and 6.6 Mb, made the lowest IQ and DQ scores. No association between deletion breakpoint and phenotype were found. Assessment of the various deleted regions suggested histone deacetylase 4 gene (HDAC4) was a likely candidate gene for ASD in our sample. However, two earlier reports found no association between HDAC4 haploinsufficiency and ASD. © 2016 Wiley Periodicals, Inc.

  13. Comparative Hydrodynamics of Bacterial Polymorphism

    NASA Astrophysics Data System (ADS)

    Spagnolie, Saverio E.; Lauga, Eric

    2011-02-01

    Most bacteria swim through fluids by rotating helical flagella which can take one of 12 distinct polymorphic shapes, the most common of which is the normal form used during forward swimming runs. To shed light on the prevalence of the normal form in locomotion, we gather all available experimental measurements of the various polymorphic forms and compute their intrinsic hydrodynamic efficiencies. The normal helical form is found to be the most efficient of the 12 polymorphic forms by a significant margin—a conclusion valid for both the peritrichous and polar flagellar families, and robust to a change in the effective flagellum diameter or length. Hence, although energetic costs of locomotion are small for bacteria, fluid mechanical forces may have played a significant role in the evolution of the flagellum.

  14. Variation of the Polymorphic Region X of the Protein A Gene during Persistent Airway Infection of Cystic Fibrosis Patients Reflects Two Independent Mechanisms of Genetic Change in Staphylococcus aureus

    PubMed Central

    Kahl, Barbara C.; Mellmann, Alexander; Deiwick, Susanne; Peters, Georg; Harmsen, Dag

    2005-01-01

    Variation of the polymorphic region of the protein A gene (spa) was observed during long-term persistence of Staphylococcus aureus in the airways of 10 cystic fibrosis patients and occurred at a rate of one genetic change every 70 months. Independent mutational events were observed eight times in 142 isolates: four deletions, two duplications of repeats, and two point mutations. PMID:15635028

  15. Rapid detection of mitochondrial sequence polymorphisms using multiplex solid-phase fluorescent minisequencing

    SciTech Connect

    Tully, G.; Sullivan, K.M.; Nixon, P.

    1996-05-15

    This work describes a novel method, multiplex solidphase fluorescent minisequencing, for the simultaneous detection of several point mutations and/or small deletions and insertions. The method is applied to the analysis of mitochondrial DNA polymorphisms for the purposes of individual identification. A database of 152 British Caucasians and 103 British Afro-Caribbeans has been constructed, and the probability of a chance match between two unrelated individuals is calculated as 0.054 for Caucasians and 0.026 for Afro-Caribbeans. 36 refs., 4 figs., 2 tabs.

  16. CYP1A1, GSTM1, GSTT1 and TP53 Polymorphisms and Risk of Gallbladder Cancer in Bolivians.

    PubMed

    Sakai, Kazuaki; Loza, Ernesto; Roig, Guido Villa-Gomez; Nozaki, Ryoko; Asai, Takao; Ikoma, Toshikazu; Tsuchiya, Yasuo; Kiyohara, Chikako; Yamamoto, Masaharu; Nakamura, Kazutoshi

    2016-01-01

    The Plurinational State of Bolivia (Bolivia) has a high incidence rate of gallbladder cancer (GBC). However, the genetic and environmental risk factors for GBC development are not well understood. We aimed to assess whether or not cytochrome P450 (CYP1A1), glutathione S-transferase mu 1 (GSTM1), theta 1 (GSTT1) and tumor suppressor protein p53 (TP53) genetic polymorphisms modulate GBC susceptibility in Bolivians. This case-control study covered 32 patients with GBC and 86 healthy subjects. GBC was diagnosed on the basis of histological analysis of tissues at the Instituto de Gastroenterologia Boliviano-Japones (IGBJ); the healthy subjects were members of the staff at the IGBJ. Distributions of the CYP1A1 rs1048943 and TP53 rs1042522 polymorphisms were assayed using PCR-restriction fragment length polymorphism assay. GSTM1 and GSTT1 deletion polymorphisms were detected by a multiplex PCR assay. The frequency of the GSTM1 null genotype was significantly higher in GBC patients than in the healthy subjects (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.03-5.37; age-adjusted OR, 3.53; 95% CI, 1.29-9.66; age- and sex-adjusted OR, 3.40; 95% CI, 1.24-9.34). No significant differences were observed in the frequencies of CYP1A1, GSTT1, or TP53 polymorphisms between the two groups. The GSTM1 null genotype was associated with increased GBC risk in Bolivians. Additional studies with larger control and case populations are warranted to confirm the association between the GSTM1 deletion polymorphism and GBC risk suggested in the present study.

  17. Genetics Home Reference: catecholaminergic polymorphic ventricular tachycardia

    MedlinePlus

    ... for This Page Cerrone M, Napolitano C, Priori SG. Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand ... on PubMed Central Liu N, Ruan Y, Priori SG. Catecholaminergic polymorphic ventricular tachycardia. Prog Cardiovasc Dis. 2008 ...

  18. Rapid method for growth hormone receptor exon 3 delete (GHRd3) SNP genotyping from archival human placental samples.

    PubMed

    Pelekanos, Rebecca A; Sardesai, Varda S; Dekker Nitert, Marloes; Callaway, Leonie K; Fisk, Nicholas M; Jeffery, Penny L

    2015-08-01

    Analysis of archival samples from cohorts of pregnant women may be key to discovering prognosticators of stillbirth and pregnancy/perinatal complications. Growth hormone (GH) and its receptor (GHR) are pivotal in feto-placental development and pregnancy maintenance. We report a rapid, optimized method for genotyping the GHR full-length versus exon 3-deleted isoform (GHRd3). TaqMan single nucleotide polymorphism (SNP) genotyping proved superior to standard multiplex polymerase chain reaction (PCR) in allele detection and GHR genotyping from archived samples, including those with poor genomic deoxyribonucleic acid quality/quantity such as formalin fixed, paraffin embedded, blood, and serum. Furthermore, this assay is suitable for high through put 96 or 384-well plate quantitative PCR machines with automated genotype calling software. The TaqMan genotyping assay can increase the data obtained from precious archival human samples.

  19. Isochromosome 15q of maternal origin in two Prader-Willi syndrome patients previously diagnosed erroneously as cytogenetic deletions

    SciTech Connect

    Saitoh, Shinji; Niikawa, Norio; Mutirangura, A.; Kuwano, A.; Ledbetter, D.H.

    1994-03-01

    Since a previous report on two Prader-Willi syndrome (PWS) patients with t(15q;15q) was erroneous, the authors report new data and a corrected interpretation. Reexamination of the parental origin of their t(15q;15q) using polymorphic DNA markers that are mapped to various regions of 15q documented no molecular deletions at the 15q11-q13 region in either patient. Both patients were homozygous at all loci examined and their haplotypes on 15q coincided with one of those in their respective mothers. These results indicate that the presumed t(15q;15q) in each patient was actually an isochromosome 15q producing maternal uniparental disomy, consistent with genomic imprinting at the PWS locus. 30 refs., 1 fig., 3 tabs.

  20. Polymorphism in two genes for B2 high sulfur proteins of wool.

    PubMed

    Rogers, G R; Hickford, J G; Bickerstaffe, R

    1994-12-01

    Variation in the nucleotide sequence of the B2 high-sulfur protein genes has not been reported previously. This paper reports 15 nucleotide substitutions in each of the genes for the B2A and B2C proteins and a length of polymorphism in the B2A gene which translates to the insertion/deletion of one 30-nucleotide repeat sequence. Evidence is presented for gene conversion occurring within the B2 high-sulfur multigene family. These DNA polymorphisms may account for some of the microheterogeneity observed in the B2 high-sulfur proteins and may also be useful genetic markers of the B2 high-sulfur protein gene loci for future use in analysing wool fibre characteristics.

  1. Molecular dissection of the 5q deletion in myelodysplastic syndrome

    PubMed Central

    Ebert, Benjamin L.

    2011-01-01

    The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of Chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haploinsufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q- syndrome. The megakaryocytic and platelet phenotype of the 5q- syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of Chromosome 5q is due to haploinsufficiency of multiple genes. PMID:21943668

  2. Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms.

    PubMed

    Wang, Qi; Yu, Wan-Ni; Chen, Xinyu; Peng, Xiao-Ding; Jeon, Sang-Min; Birnbaum, Morris J; Guzman, Grace; Hay, Nissim

    2016-04-11

    Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality. Akt2(-/-) mice survived hepatic Akt1 deletion but all developed spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC-bearing livers is similar to aggressive human HCC. Consistently, neither Akt1(-/-) nor Akt2(-/-) mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2(-/-) mice display a high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC. PMID:26996309

  3. Crystal Polymorphs of Barbital: News about a Classic Polymorphic System

    PubMed Central

    2013-01-01

    Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I0, III, IV, and V) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications I0, III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I0/III, I0/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I0 > III > V > IV. The metastable modification III is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N–H···O=C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV. PMID:24283960

  4. Inversion of the Williams syndrome region is a common polymorphism found more frequently in parents of children with Williams syndrome.

    PubMed

    Hobart, Holly H; Morris, Colleen A; Mervis, Carolyn B; Pani, Ariel M; Kistler, Doris J; Rios, Cecilia M; Kimberley, Kendra W; Gregg, Ronald G; Bray-Ward, Patricia

    2010-05-15

    Williams syndrome (WS) is a multisystem disorder caused by deletion of about 1.55 Mb of DNA (including 26 genes) on chromosome 7q11.23, a region predisposed to recombination due to its genomic structure. Deletion of the Williams syndrome chromosome region (WSCR) occurs sporadically. To better define chance for familial recurrence and to investigate the prevalence of genomic rearrangements of the region, 257 children with WS and their parents were studied. We determined deletion size in probands by metaphase FISH, parent-of-origin of the deleted chromosome by molecular genetic methods, and inversion status of the WSCR in both parents by interphase FISH. The frequency of WSCR inversion in the transmitting parent group was 24.9%. In contrast, the rate of inversion in the non-transmitting parent group (a reasonable estimate of the rate in the general population) was 5.8%. There were no significant gender differences with respect to parent-of-origin for the deleted chromosome or the incidence of the inversion polymorphism. There was no difference in the rate of spontaneous abortion for mothers heterozygous for the WSCR inversion relative to mothers without the inversion. We calculate that for a parent heterozygous for a WSCR inversion, the chance to have a child with WS is about 1 in 1,750, in contrast to the 1 in 9,500 chance for a parent without an inversion.

  5. Dissecting the phenotypes of Dravet syndrome by gene deletion

    PubMed Central

    Rubinstein, Moran; Han, Sung; Tai, Chao; Westenbroek, Ruth E.; Hunker, Avery; Scheuer, Todd

    2015-01-01

    Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Nav1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Nav1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Nav1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Nav1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Nav1.1 in parvalbumin-expressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types. PMID:26017580

  6. Internal deletion mutants of Xenopus transcription factor IIIA.

    PubMed Central

    Hanas, J S; Littell, R M; Gaskins, C J; Zebrowski, R

    1989-01-01

    Xenopus transcription factor IIIA (TFIIIA) or TFIIIA mutants with internal deletions were expressed in E. coli utilizing a bacteriophage T7 RNA polymerase system. TFIIIA or deletion mutant TFIIIAs, isolated from E.coli cell extracts, were identified by SDS PAGE and immunoblotting with rabbit antiserum against native TFIIIA purified from Xenopus immature oocytes. Specific DNA binding of intact or internally deleted TFIIIA was compared by analyzing their abilities to protect the internal control gene (ICR) of the Xenopus 5S RNA gene from DNase I digestion. Intact protein, synthesized from a full-length TFIIIA cDNA, bound specifically to the entire ICR (+96 to +43) and promoted 5S RNA gene transcription in vitro. One TFIIIA deletion mutant, expressed from cDNA lacking the coding sequence for the putative fourth zinc finger (designated from the N-terminus, amino acids 103-132) protected the ICR from DNase I digestion from nucleotide positions +96 to +78. A second TFIIIA mutant resulting from fusion of putative zinc fingers 7 and 8 (deletion of amino acids 200-224) protected the 5S gene ICR from positions +96 to +63. The DNase I protection patterns of these mutant proteins are consistent with the formation of strong ICR contacts by those regions of the protein on the N-terminal side of the mutation but not by those regions on the C-terminal side of the mutation. The regions of the protein comprising the N-terminal 3 fingers and N-terminal six fingers appear to be in contact with approximately 18 and 33 bp of DNA respectively on the 3' side of the 5S gene ICR. These internal deletion mutants promoted 5S RNA synthesis in vitro and DNA renaturation. Images PMID:2690011

  7. Interstitial deletion of long arm of chromosome 13.

    PubMed

    Carnevale, A; Frias, S; Alcantar, R

    1984-01-01

    The case is presented of a patient with the karyotype 46,XX,del(13q)(pter----q22::q32----qter) confirmed by densitometry and a phenotype of mental and growth deficiency, hypotonia, hypertelorism, ptosis, broad nasal bridge, protruding upper incisors, short neck, dislocation of the hip, hypoplasia of the thumbs, fusion of fourth and fifth metacarpal bones and syndactyly of toes. The findings are compared with those of well documented cases with a similar deleted segment of the long arm of chromosome 13. Although it seems obvious that a clinical syndrome for the distal deletion 13q appears to exist more studies with banded chromosomes are needed. PMID:6609673

  8. Serine Racemase Deletion Protects Against Cerebral Ischemia And Excitotoxicity

    PubMed Central

    Mustafa, Asif K.; Ahmad, Abdullah S.; Zeynalov, Emil; Gazi, Sadia K.; Sikka, Gautam; Ehmsen, Jeffrey T.; Barrow, Roxanne K.; Coyle, Joseph T.; Snyder, Solomon H.; Doré, Sylvain

    2010-01-01

    D-serine, formed from L-serine by serine racemase (SR), is a physiologic co-agonist at NMDA receptors. Using mice with targeted deletion of SR, we demonstrate a role for D-serine in NMDA receptor mediated neurotoxicity and stroke. Brain cultures of SR deleted mice display markedly diminished nitric oxide (NO) formation and neurotoxicity. In intact SR knockout mice NO formation and nitrosylation of NO targets are substantially reduced. Infarct volume following middle cerebral artery occlusion is dramatically diminished in several regions of the brains of SR mutant mice despite evidence of increased NMDA receptor number and sensitivity. PMID:20107067

  9. A large TAT deletion in a tyrosinaemia type II patient.

    PubMed

    Legarda, Maria; Wlodarczyk, Katarzyna; Lage, Sergio; Andrade, Fernando; Kim, Gwang-Jin; Bausch, Elke; Scherer, Gerd; Aldamiz-Echevarria, Luis Jose

    2011-11-01

    A girl, born to unrelated Spanish parents, presented at 6 months of age with photophobia, keratitis, palmar hyperkeratosis and high plasma tyrosine levels, indicative of tyrosinaemia type II. Analysis of the tyrosine aminotransferase (TAT) gene revealed a paternally inherited frameshift mutation c.1213delCinsAG at codon 405 causing a premature stop codon, and a maternally inherited deletion of 193kb encompassing the complete TAT gene and three neighbouring genes. This is the first complete TAT deletion in tyrosinaemia type II described so far.

  10. Elevated polymorphism and divergence in the class C scavenger receptors of Drosophila melanogaster and D. simulans.

    PubMed

    Lazzaro, Brian P

    2005-04-01

    Scavenger receptor proteins are involved in the cellular internalization of a broad variety of foreign material, including pathogenic bacteria during phagocytosis. I find here that nonsynonymous divergence in three class C scavenger receptors (Sr-C's) between Drosophila melanogaster and D. simulans and between each of these species and D. yakuba is approximately four times the typical genome average. These genes also exhibit unusually high levels of segregating nonsynonymous polymorphism in D. melanogaster and D. simulans populations. A fourth Sr-C is comparatively conserved. McDonald-Kreitman tests reveal a significant excess of replacement fixations between D. melanogaster and D. simulans in the Sr-C's, but tests of polymorphic site frequency spectra do not support models of directional selection. It is possible that the molecular functions of SR-C proteins are sufficiently robust to allow exceptionally high amino acid substitution rates without compromising organismal fitness. Alternatively, SR-Cs may evolve under diversifying selection, perhaps as a result of pressure from pathogens. Interestingly, Sr-CIII and Sr-CIV are polymorphic for premature stop codons. Sr-CIV is also polymorphic for an in-frame 101-codon deletion and for the absence of one intron.

  11. Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms.

    PubMed

    Oliveira-Paula, Gustavo H; Lacchini, Riccardo; Tanus-Santos, Jose E

    2016-01-10

    Nitric oxide (NO) is an important vasodilator with a well-established role in cardiovascular homeostasis. While mediator is synthesized from L-arginine by neuronal, endothelial, and inducible nitric oxide synthases (NOS1,NOS3 and NOS2 respectively), NOS3 is the most important isoform for NO formation in the cardiovascular system. NOS3 is a dimeric enzyme whose expression and activity are regulated at transcriptional, posttranscriptional,and posttranslational levels. The NOS3 gene, which encodes NOS3, exhibits a number of polymorphic sites including single nucleotide polymorphisms (SNPs), variable number of tandem repeats (VNTRs), microsatellites, and insertions/deletions. Some NOS3 polymorphisms show functional effects on NOS3 expression or activity, thereby affecting NO formation. Interestingly, many studies have evaluated the effects of functional NOS3 polymorphisms on disease susceptibility and drug responses. Moreover, some studies have investigated how NOS3 haplotypes may impact endogenous NO formation and disease susceptibility. In this article,we carried out a comprehensive review to provide a basic understanding of biochemical mechanisms involved in NOS3 regulation and how genetic variations in NOS3 may translate into relevant clinical and pharmacogenetic implications. PMID:26428312

  12. Meta-analytical association between angiotensin-converting enzyme gene polymorphisms and sarcoidosis risk.

    PubMed

    Zhu, R; Bi, L Q; Kong, H; Tilley, S L; Wang, H; Xie, W P

    2015-01-01

    Previous reports identified an association between sarcoidosis and an insertion/deletion (I/D) polymorphism in angiotensin-converting enzyme. Our meta-analysis of articles published between March 1996 and June 2013 identified studies in the PubMed, EMBASE, and the China National Knowledge Infrastructure databases. We examined whether angiotensin-converting enzyme polymorphisms influence sarcoidosis susceptibility. The strength of the association between I/D polymorphisms and sarcoidosis risk was measured based on the odds ratio and 95% confidence interval. Analysis was based on recessive and dominant models. Ethnic subgroup analysis from 18 articles (1882 cases and 3066 controls) showed that DD homozygote carriers were at a slightly increased risk of sarcoidosis compared with II homozygotes and DI heterozygotes (P = 0.03). Comparison of DD plus DI vs II revealed no significant association with sarcoidosis in group and ethnic subgroup analysis. We found that the I/D polymorphism in the angiotensin-converting enzyme gene was not associated with a major risk of sarcoidosis. PMID:25966127

  13. Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms.

    PubMed

    Oliveira-Paula, Gustavo H; Lacchini, Riccardo; Tanus-Santos, Jose E

    2016-01-10

    Nitric oxide (NO) is an important vasodilator with a well-established role in cardiovascular homeostasis. While mediator is synthesized from L-arginine by neuronal, endothelial, and inducible nitric oxide synthases (NOS1,NOS3 and NOS2 respectively), NOS3 is the most important isoform for NO formation in the cardiovascular system. NOS3 is a dimeric enzyme whose expression and activity are regulated at transcriptional, posttranscriptional,and posttranslational levels. The NOS3 gene, which encodes NOS3, exhibits a number of polymorphic sites including single nucleotide polymorphisms (SNPs), variable number of tandem repeats (VNTRs), microsatellites, and insertions/deletions. Some NOS3 polymorphisms show functional effects on NOS3 expression or activity, thereby affecting NO formation. Interestingly, many studies have evaluated the effects of functional NOS3 polymorphisms on disease susceptibility and drug responses. Moreover, some studies have investigated how NOS3 haplotypes may impact endogenous NO formation and disease susceptibility. In this article,we carried out a comprehensive review to provide a basic understanding of biochemical mechanisms involved in NOS3 regulation and how genetic variations in NOS3 may translate into relevant clinical and pharmacogenetic implications.

  14. The frequency of CCR5 promoter polymorphisms and CCR5 Δ 32 mutation in Iranian populations.

    PubMed

    Zare-Bidaki, Mohammad; Karimi-Googheri, Masoud; Hassanshahi, Gholamhossein; Zainodini, Nahid; Arababadi, Mohammad Kazemi

    2015-04-01

    Evidence showed that chemokines serve as pro-migratory factors for immune cells. CCL3, CCL4 and CCL5, as the main CC chemokines subfamily members, activate immune cells through binding to CC chemokine receptor 5 or CCR5. Macrophages, NK cells and T lymphocytes express CCR5 and thus, affected CCR5 expression or functions could be associated with altered immune responses. Deletion of 32 base pairs (Δ 32) in the exon 1 of the CCR5 gene, which is known as CCR5 Δ 32 mutation causes down regulation and malfunction of the molecule. Furthermore, it has been evidenced that three polymorphisms in the promoter region of CCR5 modulate its expression. Altered CCR5 expression in microbial infection and immune related diseases have been reported by several researchers but the role of CCR5 promoter polymorphisms and CCR5 Δ 32 mutation in Iranian patients suffering from these diseases are controversial. Due to the fact that Iranian people have different genetic backgrounds compared to other ethnics, hence, CCR5 promoter polymorphisms and CCR5 32 mutation association with the diseases may be different in Iranian patients. Therefore, this review addresses the most recent information regarding the prevalence as well as association of the mutation and polymorphisms in Iranian patients with microbial infection and immune related diseases as along with normal population.

  15. eQTL mapping identify insertion and deletion specific eQTLs in multiple tissues

    PubMed Central

    Huang, Jinyan; Chen, Jun; Esparza, Jorge; Ding, Jun; Elder, James; Abecasis, Goncalo R; Lee, Young-Ae; Lathrop, G. Mark; Moffatt, Miriam F; Cookson, William O C; Liang, Liming

    2016-01-01

    GenomeC wide gene expression quantitative trait loci (eQTL) mapping have been focused on single nucleotide polymorphisms and have helped interpret findings from diseases mapping studies. The functional effect of structure variants, especially short insertions and deletions (indel) has not been well investigated. Here we imputed 1,380,133 indels based on the latest 1000 Genomes Project panel into 3 eQTL datasets from multiple tissues. Imputation of indels increased 9.9% power and identified indel specific eQTLs for 325 genes. We found introns and vicinities of UTRs were more enriched of indel eQTLs and 3.6 (singleC tissue)C 9.2%(multiC tissue) of previous identified eSNPs were taggers of eindels. Functional analyses identified epigenetics marks, gene ontology categories and disease GWAS loci affected by SNPs and indels eQTLs showing tissueC consistent or tissueC specific effects. This study provides new insights into the underlying genetic architecture of gene expression across tissues and new resource to interpret function of diseases and traits associated structure variants. PMID:25951796

  16. A deletion mutation in GDF9 in sisters with spontaneous DZ twins.

    PubMed

    Montgomery, Grant W; Zhao, Zhen Zhen; Marsh, Anna J; Mayne, Renee; Treloar, Susan A; James, Michael; Martin, Nicholas G; Boomsma, Dorret I; Duffy, David L

    2004-12-01

    A loss of function mutation in growth differentiation factor 9 (GDF9) in sheep causes increased ovulation rate and infertility in a dosage-sensitive manner. Spontaneous dizygotic (DZ) twinning in the human is under genetic control and women with a history of DZ twinning have an increased incidence of multiple follicle growth and multiple ovulation. We sequenced the GDF9 coding region in DNA samples from 20 women with DZ twins and identified a four-base pair deletion in GDF9 in two sisters with twins from one family. We screened a further 429 families and did not find the loss of function mutation in any other families. We genotyped eight single nucleotide polymorphisms across the GDF9 locus in 379 families with two sisters who have both given birth to spontaneous DZ twins (1527 individuals) and 226 triad families with mothers of twins and their parents (723 individuals). Using case control analysis and the transmission disequilibrium test we found no evidence for association between common variants in GDF9 and twinning in the families. We conclude that rare mutations in GDF9 may influence twinning, but twinning frequency is not associated with common variation in GDF9.

  17. Deletion and deletion/insertion mutations in the juxtamembrane domain of the FLT3 gene in adult acute myeloid leukemia

    PubMed Central

    Deeb, Kristin K.; Smonskey, Matthew T.; DeFedericis, HanChun; Deeb, George; Sait, Sheila N.J.; Wetzler, Meir; Wang, Eunice S.; Starostik, Petr

    2014-01-01

    In contrast to FLT3 ITD mutations, in-frame deletions in the FLT3 gene have rarely been described in adult acute leukemia. We report two cases of AML with uncommon in-frame mutations in the juxtamembrane domain of the FLT3 gene: a 3-bp (c.1770_1774delCTACGinsGT; p.F590_V592delinsLF) deletion/insertion and a 12-bp (c.1780_1791delTTCAGAGAATAT; p.F594_Y597del) deletion. We verified by sequencing that the reading frame of the FLT3 gene was preserved and by cDNA analysis that the mRNA of the mutant allele was expressed in both cases. Given the recent development of FLT3 inhibitors, our findings may be of therapeutic value for AML patients harboring similar FLT3 mutations. PMID:25379410

  18. Tandem duplication/deletion in a maternally derived chromosome 9 supernumerary derivative resulting in 9p trisomy and partial 9q tetrasomy.

    PubMed

    Wyandt, H E; Lebo, R V; Fenerci, E Y; Sadhu, D N; Milunsky, J M

    2000-08-14

    A 19-week stillborn female fetus with bilateral cleft palate, horseshoe kidney, bicornuate uterus, low-set ears, and intrauterine growth retardation (IUGR) was found to have a supernumerary derivative chromosome 9 (der(9)) with an apparent tandem duplication in the long arm. PCR analysis at five polymorphic loci confirmed the duplication and showed an adjacent deletion, while whole chromosome FISH demonstrated only chromosome 9 to be involved. Further FISH studies of der(9) found the 9qh region to be duplicated, telomeric sequences to be intact, and subtelomeric sequences to be absent. Thus, the fetus was determined to be trisomic for 9pter-->9q12 and 9q34.3-->9qter, tetrasomic for 9q12--> 9q33, and disomic for 9q33-->9q34.3. These results are consistent with a tandem duplication of 9q12-->9q33 and adjacent distal deletion as designated by the karyotype, 47,XX,+der(9)dup(9) (q12q33)del(9) (q33q34.3).ish der(9)(WCP9+,D9Z1x2,STP9q-, AHT+) de novo. In addition to characterizing der(9), the combined PCR and cytogenetic studies refined the Genome Database Map of three loci (D9S907, D9S155, and D9S302) approximately to the distal 9q33 region. Without the attempt to refine breakpoints by PCR analysis, the deletion in distal 9q would not have been detected. Tandem direct duplication/deletion chromosomes have been reported in fewer cases than inverted duplication/deletions. We propose mechanisms of origin, consistent with those for recurrent inter stitial microdeletion and microduplication syndromes, shown to arise by recombination at homologous, flanking DNA sequences. PMID:10946358

  19. Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148

    PubMed Central

    Dharmadhikari, Avinash V.; Kang, Sung-Hae L.; Szafranski, Przemyslaw; Person, Richard E.; Sampath, Srirangan; Prakash, Siddharth K.; Bader, Patricia I.; Phillips, John A.; Hannig, Vickie; Williams, Misti; Vinson, Sherry S.; Wilfong, Angus A.; Reimschisel, Tyler E.; Craigen, William J.; Patel, Ankita; Bi, Weimin; Lupski, James R.; Belmont, John; Cheung, Sau Wai; Stankiewicz, Pawel

    2012-01-01

    We have identified a rare small (∼450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER (http://decipher.sanger.ac.uk) patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ∼109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses. PMID:22543972

  20. Paracentric inversion of chromosome 2 associated with cryptic duplication of 2q14 and deletion of 2q37 in a patient with autism.

    PubMed

    Devillard, Françoise; Guinchat, Vincent; Moreno-De-Luca, Daniel; Tabet, Anne-Claude; Gruchy, Nicolas; Guillem, Pascale; Nguyen Morel, Marie-Ange; Leporrier, Nathalie; Leboyer, Marion; Jouk, Pierre-Simon; Lespinasse, James; Betancur, Catalina

    2010-09-01

    We describe a patient with autism and a paracentric inversion of chromosome 2q14.2q37.3, with a concurrent duplication of the proximal breakpoint at 2q14.1q14.2 and a deletion of the distal breakpoint at 2q37.3. The abnormality was derived from his mother with a balanced paracentric inversion. The inversion in the child appeared to be cytogenetically balanced but subtelomere FISH revealed a cryptic deletion at the 2q37.3 breakpoint. High-resolution single nucleotide polymorphism array confirmed the presence of a 3.5 Mb deletion that extended to the telomere, and showed a 4.2 Mb duplication at 2q14.1q14.2. FISH studies using a 2q14.2 probe showed that the duplicated segment was located at the telomeric end of chromosome 2q. This recombinant probably resulted from breakage of a dicentric chromosome. The child had autism, mental retardation, speech and language delay, hyperactivity, growth retardation with growth hormone deficiency, insulin-dependent diabetes, and mild facial dysmorphism. Most of these features have been previously described in individuals with simple terminal deletion of 2q37. Pure duplications of the proximal chromosome 2q are rare and no specific syndrome has been defined yet, so the contribution of the 2q14.1q14.2 duplication to the phenotype of the patient is unknown. These findings underscore the need to explore apparently balanced chromosomal rearrangements inherited from a phenotypically normal parent in subjects with autism and/or developmental delay. In addition, they provide further evidence indicating that chromosome 2q terminal deletions are among the most frequently reported cytogenetic abnormalities in individuals with autism.

  1. Polymorphism in pleistocene land snails.

    PubMed

    Owen, D F

    1966-04-01

    Under suitable conditions the colors and patterns of the shells of land snails may be preserved for thousands of years. In a late Pleistocene population of Limicolaria martensiana all the major color forms that occur in modern living snails may be distinguished, and the basic polymorphism is at least 8,000 to 10,000 year old. PMID:17830234

  2. Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia.

    PubMed

    Tsai, Ellen A; Grochowski, Christopher M; Falsey, Alexandra M; Rajagopalan, Ramakrishnan; Wendel, Danielle; Devoto, Marcella; Krantz, Ian D; Loomes, Kathleen M; Spinner, Nancy B

    2015-06-01

    Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. PMID:25765999

  3. Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene.

    PubMed

    Ianakiev, P; van Baren MJ; Daly, M J; Toledo, S P; Cavalcanti, M G; Neto, J C; Silveira, E L; Freire-Maia, A; Heutink, P; Kilpatrick, M W; Tsipouras, P

    2001-01-01

    Acheiropodia is an autosomal recessive developmental disorder presenting with bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. This severely handicapping condition appears to affect only the extremities, with no other systemic manifestations reported. Recently, a locus for acheiropodia was mapped on chromosome 7q36. Herein we report the narrowing of the critical region for the acheiropodia gene and the subsequent identification of a common mutation in C7orf2-the human orthologue of the mouse Lmbr1 gene-that is responsible for the disease. Analysis of five families with acheiropodia, by means of 15 polymorphic markers, narrowed the critical region to 1.3 cM, on the basis of identity by descent, and to <0.5 Mb, on the basis of physical mapping. Analysis of C7orf2, the human orthologue of the mouse Lmbr1 gene, identified a deletion in all five families, thus identifying a common acheiropodia mutation. The deletion was identified at both the genomic-DNA and mRNA level. It leads to the production of a C7orf2 transcript lacking exon 4 and introduces a premature stop codon downstream of exon 3. Given the nature of the acheiropodia phenotype, it appears likely that the Lmbr1 gene plays an important role in limb development.

  4. Heterozygous Deletion of FOXA2 Segregates with Disease in a Family with Heterotaxy, Panhypopituitarism, and Biliary Atresia

    PubMed Central

    Tsai, Ellen A.; Grochowski, Christopher M.; Falsey, Alexandra M.; Rajagopalan, Ramakrishnan; Wendel, Danielle; Devoto, Marcella; Krantz, Ian D.; Loomes, Kathleen M.; Spinner, Nancy B.

    2015-01-01

    Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277kb heterozygous deletion on chromosome 20 which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. PMID:25765999

  5. Polymorphisms of glutathione S-transferase and methylenetetrahydrofolate reductase genes in Moldavian patients with ulcerative colitis: Genotype-phenotype correlation

    PubMed Central

    Varzari, Alexander; Deyneko, Igor V.; Tudor, Elena; Turcan, Svetlana

    2015-01-01

    Background Glutathione S-transferases (GSTM1, GSTT1, and GSTP1) and methylenetetrahydrofolate reductase (MTHFR) are important enzymes for protection against oxidative stress. In addition, MTHFR has an essential role in DNA synthesis, repair, and methylation. Their polymorphisms have been implicated in the pathogenesis of ulcerative colitis (UC). The aim of the present study was to investigate the role of selected polymorphisms in these genes in the development of UC in the Moldavian population. Methods In a case-control study including 128 UC patients and 136 healthy individuals, GSTM1 and GSTT1 genotypes (polymorphic deletions) were determined using multiplex polymerase chain reaction (PCR). The GSTP1 rs1695 (Ile105Val), MTHFR rs1801133 (C677T), and MTHFR rs1801131 (A1298C) polymorphisms were studied with restriction fragment length polymorphism (RFLP) analysis. Genotype–phenotype correlations were examined using logistic regression analysis. Results None of the genotypes, either alone or in combination, showed a strong association with UC. The case-only sub-phenotypic association analysis showed an association of the MTHFR rs1801133 polymorphism with the extent of UC under co-dominant (p corrected = 0.040) and recessive (p corrected = 0.020; OR = 0.15; CI = 0.04–0.63) genetic models. Also, an association between the MTHFR rs1801131 polymorphism and the severity of UC was reported for the over-dominant model (p corrected = 0.023; coefficient = 0.32; 95% CI = 0.10–0.54). Conclusion The GST and MTHFR genotypes do not seem to be a relevant risk factor for UC in our sample. There was, however, evidence that variants in MTHFR may influence the clinical features in UC patients. Additional larger studies investigating the relationship between GST and MTHFR polymorphisms and UC are required. PMID:26862484

  6. A simple repeat polymorphism in the MITF-M promoter is a key regulator of white spotting in dogs.

    PubMed

    Baranowska Körberg, Izabella; Sundström, Elisabeth; Meadows, Jennifer R S; Rosengren Pielberg, Gerli; Gustafson, Ulla; Hedhammar, Åke; Karlsson, Elinor K; Seddon, Jennifer; Söderberg, Arne; Vilà, Carles; Zhang, Xiaolan; Åkesson, Mikael; Lindblad-Toh, Kerstin; Andersson, Göran; Andersson, Leif

    2014-01-01

    The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (s(w)). We have investigated four candidate mutations associated with the s(w) allele, a SINE insertion, a SNP at a conserved site and a simple repeat polymorphism all associated with the MITF-M promoter as well as a 12 base pair deletion in exon 1B. The variants associated with white spotting at all four loci were also found among wolves and we conclude that none of these could be a sole causal mutation, at least not for extreme white spotting. We propose that the three canine white spotting alleles are not caused by three independent mutations but represent haplotype effects due to different combinations of causal polymorphisms. The simple repeat polymorphism showed extensive diversity both in dogs and wolves, and allele-sharing was common between wolves and white spotted dogs but was non-existent between solid and spotted dogs as well as between wolves and solid dogs. This finding was unexpected as Solid is assumed to be the wild-type allele. The data indicate that the simple repeat polymorphism has been a target for selection during dog domestication and breed formation. We also evaluated the significance of the three MITF-M associated polymorphisms with a Luciferase assay, and found conclusive evidence that the simple repeat polymorphism affects promoter activity. Three alleles associated with white spotting gave consistently lower promoter activity compared with the allele associated with solid colour. We propose that the simple repeat polymorphism affects cooperativity between transcription factors binding on either flanking sides of the repeat. Thus, both genetic and functional evidence show that the simple repeat polymorphism is a key regulator of white spotting in dogs. PMID:25116146

  7. Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals

    SciTech Connect

    Goodrich, Jaclyn M.; Wang, Yi; Gillespie, Brenda; Werner, Robert; Franzblau, Alfred; Basu, Niladri

    2011-12-15

    Mercury is a potent toxicant of concern to both the general public and occupationally exposed workers (e.g., dentists). Recent studies suggest that several genes mediating the toxicokinetics of mercury are polymorphic in humans and may influence inter-individual variability in mercury accumulation. This work hypothesizes that polymorphisms in key glutathione synthesizing enzyme, glutathione s-transferase, and selenoprotein genes underlie inter-individual differences in mercury body burden as assessed by analytical mercury measurement in urine and hair, biomarkers of elemental mercury and methylmercury, respectively. Urine and hair samples were collected from a population of dental professionals (n = 515), and total mercury content was measured. Average urine (1.06 {+-} 1.24 ug/L) and hair mercury levels (0.49 {+-} 0.63 ug/g) were similar to national U.S. population averages. Taqman assays were used to genotype DNA from buccal swab samples at 15 polymorphic sites in genes implicated in mercury metabolism. Linear regression modeling assessed the ability of polymorphisms to modify the relationship between mercury biomarker levels and exposure sources (e.g., amalgams, fish consumption). Five polymorphisms were significantly associated with urine mercury levels (GSTT1 deletion), hair mercury levels (GSTP1-105, GSTP1-114, GSS 5 Prime ), or both (SEPP1 3 Prime UTR). Overall, this study suggests that polymorphisms in selenoproteins and glutathione-related genes may influence elimination of mercury in the urine and hair or mercury retention following exposures to elemental mercury (via dental amalgams) and methylmercury (via fish consumption). -- Highlights: Black-Right-Pointing-Pointer We explore the influence of 15 polymorphisms on urine and hair Hg levels. Black-Right-Pointing-Pointer Urine and hair Hg levels in dental professionals were similar to the US population. Black-Right-Pointing-Pointer GSTT1 and SEPP1 polymorphisms associated with urine Hg levels. Black

  8. Interleukin gene polymorphisms in pneumoconiosis.

    PubMed

    Helmig, Simone; Grossmann, Martin; Wübbeling, Jelena; Schneider, Joachim

    2012-08-01

    Inhaled asbestos fibres are known to cause inflammation processes with the result of lung or pleural fibrosis and malignancies. Interleukins (IL), such as IL-1β, IL-6 and IL-10, have various functions in the regulation of the inflammatory response and in proliferative processes after inhalation of silica dust and can, therefore, influence the pathogenesis of asbestos-induced fibrosis and carcinogenesis. Polymorphisms within these genes may be associated with susceptibility to silica and asbestos-induced lung diseases. Thus, IL-1β, IL-6 and IL-10 polymorphisms were examined to determine an association with asbestos or silica-induced fibrosis or malignancies. Association studies were performed in 1180 individuals, using control subjects (n=177), fibrosis patients (n=605), lung cancer (LC) patients (n=364) and malignant mesothelioma (MM) patients (n=34). IL-1β (C-511T; C+3954T), IL-6 (G-174C) as well as IL-10 (G-1082A) polymorphisms were investigated. Compared to a healthy (control) group, a higher risk was seen for malignant mesothelioma patients in all investigated polymorphisms. The IL-6 -174C allele showed a tendency towards a higher risk for fibrosis or asbestos-induced lung cancer (ORasbestosis, 1.338; 95% CI, 0.71-2.53; ORsilicosis, 1.226; 95% CI, 0.54-2.81; ORfibrosis other aetiology, 1.313; 95% CI, 0.58-2.98 and ORLC asbestos, 2.112; 95% CI, 0.75-5.92). The IL-10 -1082A carrier seemed to be at higher risk for silicosis (ORsilicosis, 2.064; 95% CI, 0.78-5.49) but not for asbestosis. In summary, this study did not reveal sufficient evidence for a significant association of the investigated interleukin polymorphisms with asbestos or silica-induced diseases in the population studied.

  9. Characterization of polymorphic ampicillin forms.

    PubMed

    Baraldi, C; Tinti, A; Ottani, S; Gamberini, M C

    2014-11-01

    In this work polymorphs of α-aminobenzylpenicillin (ampicillin), a β-lactamic antibiotic, were prepared and investigated by several experimental and theoretical methods. Amorphous monohydrate and three crystalline forms, the trihydrate, the crystal form I and the crystal form II, were investigated by FT-IR and micro-Raman. Also data obtained by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD) and hot-stage Raman spectroscopy are reported. Finally, quantum mechanical calculations were performed by density functional theory (DFT) to assist the assignment of spectroscopic experimental bands. For the first time, the ampicillin molecule in its zwitterionic form was studied at the B3LYP/aug-cc-pVDZ level and the corresponding theoretical vibrational spectra were computed. In fact, ampicillin in the crystal is in zwitterionic form and concentrations of this same form are quite relevant in solutions at physiological pH. Experimental and theoretical results allowed identification of specific features for polymorph characterization. Bands typical of the different polymorphs are identified both in IR and Raman spectra: in particular in the NH stretching region (IR), in the amide I+δNH region (both techniques), in the 1520-1490cm(-1) region (IR), in the 1320-1300cm(-1) and 1280-1220cm(-1) (IR), in the 1200-1170cm(-1) (Raman), in the amide V region (IR), and, finally, in the 715-640cm(-1) and 220-200cm(-1) (Raman). Interconversion among different polymorphs was investigated by hot-stage Raman spectroscopy and thermal analysis, clarifying the complex pattern of transformations undergone as a function of temperature and heating rate. In particular, DSC scans show how the trihydrate crystals transform into anhydrous forms on heating. Finally, stability tests demonstrated, after a two years period, that no transformation or degradation of the polymorphs occurred.

  10. 23 CFR 658.11 - Additions, deletions, exceptions, and restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... AND TRAFFIC OPERATIONS TRUCK SIZE AND WEIGHT, ROUTE DESIGNATIONS-LENGTH, WIDTH AND WEIGHT LIMITATIONS § 658.11 Additions, deletions, exceptions, and restrictions. To ensure that the National Network remains... National Network as well as requests for the imposition of certain restrictions. FHWA approval...

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    Code of Federal Regulations, 2011 CFR

    2011-04-01

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  12. 76 FR 51954 - Procurement List Additions And Deletions

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  16. Schizophrenia in an Adult With 6p25 Deletion Syndrome

    PubMed Central

    Caluseriu, O.; Mirza, G.; Ragoussis, J.; Chow, E.W.C.; MacCrimmon, D.; Bassett, A.S.

    2011-01-01

    Chromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld–Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. There was no family history of intellectual deficits or psychosis. Karyotyping revealed a 6p25 deletion, and detailed fluorescence in situ hybridization (FISH) analyses using 23 probes confirmed a 6.7 Mb 6p25-pter deletion. The breakpoint is near a possible 6p25-p24 locus for schizophrenia. Psychotic illness may be part of the neurodevelopmental abnormalities and long-term outcome of patients with 6p terminal deletions. Other similarly affected patients likely remain to be diagnosed in adult populations of schizophrenia and/or mental retardation. PMID:16642507

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    ... . SUPPLEMENTARY INFORMATION: Additions On 3/15/2013 (78 FR 16475-16476) and 3/22/2013 (78 FR 17641-17642), the...: Washington Headquarters Services (WHS), Acquisition Directorate, Washington, DC. Deletion On 4/5/2013 (78 FR... Rice Center, Walla Walla, WA. ] Contracting Activity: Dept of the Army, W071 Endist Walla Walla,...

  1. 78 FR 53733 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-30

    ... . SUPPLEMENTARY INFORMATION: Additions On 7/8/2013 (78 FR 40727-40728) and 7/12/2013 (78 FR 41915-41916), the... Regional Fleet Mgt Office, Fort Worth, TX ] Deletions On 7/19/2013 (78 FR 43180), the Committee for... following products and services are added to the Procurement List: Products NSN: MR 546--Sponge,...

  2. Multigene deletions in lung adenocarcinomas from irradiated and control mice

    SciTech Connect

    Zhang, Y.; Woloschak, G.E.

    1996-06-01

    K-ras codon 12 point mutations mRb and p53 gene deletions were examined in tissues from 120 normal lungs and lung adenocarcinomas that were Formalin-treated and paraffin-embedded 25 years ago. The results showed that 12 of 60 (20%) lung adenocarcinomas had mRb deletions. All lung adenocarcinomas that were initially found bearing deleted mRb had p53 deletions (15 of 15; 100%). A significantly higher mutation frequency for K-ras codon 12 point mutations was also found in the lung adenocarcinomas from mice exposed to 24 once-weekly neutron irradiation (10 of 10; 100%) compared with those exposed to 24 or 60 once-weekly {gamma}-ray doses (5 of 10; 50%). The data suggested that p53 and K-ras gene alterations were two contributory factors responsible for the increased incidence of lung adenocarcinoma in B6CF{sub 1} male mice exposed to protracted neutron radiation.

  3. 76 FR 27999 - Procurement List; Addition and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... . SUPPLEMENTARY INFORMATION: Addition On 3/11/2011 (76 FR 13362-13363), the Committee for Purchase From People Who.... ] Deletion On 3/11/2011 (76 FR 13362-13363), the Committee for Purchase From People Who Are Blind or Severely... business the opportunity to compete for these projects in the future. The Javits-Wagner-O'Day Act and...

  4. 76 FR 3880 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-21

    ...@AbilityOne.gov . SUPPLEMENTARY INFORMATION: Additions On 9/10/2010 (75 FR 55309-55310); 11/15/2010 (75 FR 69639-69640); and 11/19/2010 (75 FR 70909-70910), the Committee for Purchase From People Who Are Blind... Interior, National Park Service, Midwest Region, Omaha, NE. Deletions On 10/22/2010 (FR 65305) and...

  5. 75 FR 76960 - Procurement List; Additions And Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-10

    ...@AbilityOne.gov . SUPPLEMENTARY INFORMATION: Additions On 10/15/2010 (75 FR 63446-63447), the Committee for..., LA. Deletions On 10/15/2010 (75 FR 63446-63447), the Committee for Purchase From People Who Are Blind...-Wagner-O'Day Act (41 U.S.C. 46- 48c) in connection with the product and service proposed for addition...

  6. 76 FR 51955 - Procurement List Proposed Addition and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-19

    ... the objectives of the Javits-Wagner-O'Day Act (41 U.S.C. 46- 48c) in connection with the service... the Javits-Wagner-O'Day Act (41 U.S.C. 46- 48c) in connection with the services proposed for deletion... e-mail CMTEFedReg@AbilityOne.gov . SUPPLEMENTARY INFORMATION: This notice is published pursuant...

  7. 76 FR 50184 - Procurement List, Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-12

    ...@AbilityOne.gov . SUPPLEMENTARY INFORMATION: Additions On 5/20/2011 (76 FR 29210-29211) and 6/17/2011 (76 FR 35415-35417), the Committee for Purchase From People Who Are Blind or Severely Disabled published...: Department of Veterans Affairs, VISN 11, Indianapolis, IN Deletions On 4/8/2011 (76 FR 19750-19751),...

  8. Remarks on Causative Verbs and Object Deletion in English

    ERIC Educational Resources Information Center

    Onozuka, Hiromi

    2007-01-01

    Rappaport Hovav and Levin [Rappaport Hovav, M., Levin, B., 1998. "Building verb meanings." In: Butt, M., Geuder, W. (Eds.), "The Projection of Arguments: Lexical and Compositional Factors." CSLI Publications, Stanford, pp. 97-134] contend that result verbs disallow object deletion because of their lexical semantic properties. Their point is that…

  9. 36 CFR 1275.58 - Deletion of restricted portions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Deletion of restricted portions. 1275.58 Section 1275.58 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION NIXON PRESIDENTIAL MATERIALS PRESERVATION AND PROTECTION OF AND ACCESS TO THE...

  10. 36 CFR 1275.58 - Deletion of restricted portions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Deletion of restricted portions. 1275.58 Section 1275.58 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION NIXON PRESIDENTIAL MATERIALS PRESERVATION AND PROTECTION OF AND ACCESS TO THE...

  11. 36 CFR 1275.58 - Deletion of restricted portions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Deletion of restricted portions. 1275.58 Section 1275.58 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION NIXON PRESIDENTIAL MATERIALS PRESERVATION AND PROTECTION OF AND ACCESS TO THE...

  12. 36 CFR 1275.58 - Deletion of restricted portions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Deletion of restricted portions. 1275.58 Section 1275.58 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION NIXON PRESIDENTIAL MATERIALS PRESERVATION AND PROTECTION OF AND ACCESS TO THE...

  13. 36 CFR 1275.58 - Deletion of restricted portions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Deletion of restricted portions. 1275.58 Section 1275.58 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION NIXON PRESIDENTIAL MATERIALS PRESERVATION AND PROTECTION OF AND ACCESS TO THE...

  14. 78 FR 20620 - Procurement List; Additions to and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-05

    ... . SUPPLEMENTARY INFORMATION: Additions On 2/1/2013 (78 FR 7412-7413) and 2/8/2013 (78 FR 9386-9387), the Committee... impact on a substantial number of small entities. The major factors considered for this certification... SERVICE, GSA/PBS/R03 SOUTH SERVICE CENTER, PHILADELPHIA, PA Deletions On 3/23/2012 (77 FR 17035),...

  15. 75 FR 16755 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-02

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Additions and Deletions AGENCY: Committee for... Procurement List. SUMMARY: This action adds to the Procurement List a product and services to be furnished by... Procurement List products previously furnished by such agencies. DATES: Effective Date: May 3, 2010....

  16. 78 FR 71581 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-29

    ... Prime Vendor Supply Chain Management Service [to support production, assembly, receipt, storage...-APG Natick, Natick, MA. Service Type/Location: Integrated Prime Vendor, Supply Chain Management... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Additions and Deletions AGENCY: Committee...

  17. 78 FR 38952 - Procurement List; Proposed Additions to and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-28

    ..., W7NX USPFO ACTIVITY PA ARNG, ANNVILLE, PA. Service Type/Location: Integrated Prime Vendor Supply Chain... Type/Location: Integrated Prime Vendor Supply Chain Management Service, U.S. Navy, Naval Surface... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Additions to and Deletions...

  18. Deletion Mutations Keep Kinase Inhibitors in the Loop

    PubMed Central

    Freed, Daniel M.; Park, Jin H.; Radhakrishnan, Ravi; Lemmon, Mark A.

    2016-01-01

    Effective clinical application of conformationally selective kinase inhibitors requires tailoring drug choice to the tumor's activating mutation(s). In this issue of Cancer Cell, Foster et al. (2016) describe how activating deletions in BRAF, EGFR, and HER2 cause primary resistance to common inhibitors, suggesting strategies for improved inhibitor selection. PMID:27070691

  19. 76 FR 6452 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-04

    ...@AbilityOne.gov . SUPPLEMENTARY INFORMATION: Additions On 9/24/2010 (75 FR 58367); 10/22/2010 (75 FR 65305); and 12/10/ 2010 (75 FR 76961-76962), the Committee for Purchase From People Who Are Blind or Severely.... Deletions On 12/10/2010 (75 FR 76961-76962), the Committee for Purchase From People Who Are Blind...

  20. Genetic Counseling for the 22q11.2 Deletion

    ERIC Educational Resources Information Center

    McDonald-McGinn, Donna M.; Zackai, Elaine H.

    2008-01-01

    Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to…

  1. 75 FR 13262 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-19

    ... . SUPPLEMENTARY INFORMATION: Additions On 1/11/2010 (75 FR 1354-1355) and 1/15/2010 (75 FR 2510), the Committee.... Deletions On 1/11/2010 (75 FR 1354-1355), the Committee for Purchase From People Who Are Blind or Severely... Logistics Agency, DLA Support Services--DSS, Fort Belvoir, VA. Patricia Briscoe, Deputy Director,...

  2. Automatic Element Addition and Deletion in Lens Optimization

    NASA Astrophysics Data System (ADS)

    Cheng, Xuemin; Wang, Yongtian; Hao, Qun; Sasian, Jose

    2003-03-01

    A mechanism is established for the automatic addition and deletion of optical elements during the course of lens optimization. Two lens-form parameters, quantifying the symmetry of the optical system and the optical-power distribution among the individual lens elements, are used as criteria in this automatic procedure. Design examples are provided that demonstrate the practicability of the scheme.

  3. On Making a Distinguished Vertex Minimum Degree by Vertex Deletion

    NASA Astrophysics Data System (ADS)

    Betzler, Nadja; Bredereck, Robert; Niedermeier, Rolf; Uhlmann, Johannes

    For directed and undirected graphs, we study the problem to make a distinguished vertex the unique minimum-(in)degree vertex through deletion of a minimum number of vertices. The corresponding NP-hard optimization problems are motivated by applications concerning control in elections and social network analysis. Continuing previous work for the directed case, we show that the problem is W[2]-hard when parameterized by the graph's feedback arc set number, whereas it becomes fixed-parameter tractable when combining the parameters "feedback vertex set number" and "number of vertices to delete". For the so far unstudied undirected case, we show that the problem is NP-hard and W[1]-hard when parameterized by the "number of vertices to delete". On the positive side, we show fixed-parameter tractability for several parameterizations measuring tree-likeness, including a vertex-linear problem kernel with respect to the parameter "feedback edge set number". On the contrary, we show a non-existence result concerning polynomial-size problem kernels for the combined parameter "vertex cover number and number of vertices to delete", implying corresponding nonexistence results when replacing vertex cover number by treewidth or feedback vertex set number.

  4. Deletion and Interallelic Complementation Analysis of Steel Mutant Mice

    PubMed Central

    Bedell, M. A.; Cleveland, L. S.; O'Sullivan, T. N.; Copeland, N. G.; Jenkins, N. A.

    1996-01-01

    Mutations at the Steel (St) locus produce pleiotropic effects on viability as well as hematopoiesis, pigmentation and fertility. Several homozygous viable Sl alleles have previously been shown to contain either structural alterations in mast cell growth factor (Mgf) or regulatory mutations that affect expression of the Mgf gene. More severe Sl alleles cause lethality to homozygous embryos and all lethal Sl alleles examined to data contain deletions that remove the entire Mgf coding region. As the timing of the lethality varies from early to late in gestation, it is possible that some deletions may affect other closely linked genes in addition to Mgf. We have analyzed the extent of deleted sequences in seven homozygous lethal Sl alleles. The results of this analysis suggest that late gestation lethality represents the Sl null phenotype and that peri-implantation lethality results from the deletion of at least one essential gene that maps proximal to Sl. We have also examined gene dosage effects of Sl by comparing the phenotypes of mice homozygous and hemizygous for each of four viable Sl alleles. Lastly, we show that certain combinations of the viable Sl alleles exhibit interallelic complementation. Possible mechanisms by which such complementation could occur are discussed. PMID:8849899

  5. 78 FR 54870 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-06

    ... Vendor, Supply Chain Management Service(inventory control, obsolescence identification, engineering...: Additions On 6/28/2013 (78 FR 38952-38953) and 7/19/2013 (78 FR 43180), the Committee for Purchase From...: Dept of the Navy, NSWC Crane, Crane, IN Deletions On 7/26/2013 (78 FR45183) and 8/2/2013 (78 FR...

  6. Minimum prevalence of chromosome 22q11 deletions

    SciTech Connect

    Wilson, D.I.; Cross, I.E.; Burn, J.

    1994-09-01

    Submicroscopic deletions from within chromosome 22q11 are associated with DiGeorge (DGS), velocardiofacial (VCFS) and conotruncal anomaly syndromes and isolated congenital heart defects. In 1993 our pediatric cardiologists clinically referred all children in whom a chromosome 22q11 deletion was suspected for fluorescent in situ hybridization studies using probes from the DGS critical region. 10 affected individuals have been identified to date from the children born in 1993 in the Northern Region served exclusively by our center. A further case, the subsequent pregnancy in one of these families was affected and terminated on the basis of a major heart malformation. In the years 1988-92, for which we have complete ascertainment, there were 1009 heart defects among 191,700 births (mean 202 per annum). Thus we estimate that chromosome 22q11 deletions were the cause of at least 5% of congenital heart disease. As not all children with chromosome 22q11 deletions have a heart defect, this gives an estimated minimum prevalence of 1/4000 live births.

  7. 75 FR 44940 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-30

    ...@AbilityOne.gov . SUPPLEMENTARY INFORMATION: Additions On 6/4/2010 (75 FR 31768-31769), the Committee for... Administration, Hdqtrs-- Office of Acquisition & Grants, Baltimore, MD. Deletions On 5/21/2010 (75 FR 28589-28590); 6/4/2010 (75 FR 31768-31769); and 6/11/2010 (75 FR 33270-33271), the Committee for Purchase...

  8. 42 CFR 401.118 - Deletion of identifying details.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 2 2014-10-01 2014-10-01 false Deletion of identifying details. 401.118 Section 401.118 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN..., statement of policy, or other record which relates to a private party or parties, the name or names or...

  9. [Multiplex PCR for detecting genotypes of deletional alpha-thalassemia].

    PubMed

    Wu, Jie-Ying; Liao, Can; Li, Jian; Huang, Yi-Ning

    2004-08-01

    To investigate the clinical application of multiplex PCR in detecting genotypes of deletional alpha-thalassemia in South China and observe the distribution frequency of alpha-globin gene deletion, 145 patients with silent carrier, alpha thalassemia trait or HbH were identified by M-PCR and 1.2% agarose gel electrophoresis. There are 1.3, 1.6, 1.8 and 2.0 kb bands which indicate --(SEA), -alpha(4.2), alphaalpha and -alpha(3.7), respectively. The results showed that among 145 patients, 100 patients with --(SEA)/alphaalpha (68.9%), 15 with -alpha(3.7)/alphaalpha (10.3%), 8 with -alpha(4.2)/alphaalpha (5.52%), 2 with -alpha(3.7)/-alpha(4.2) (1.38%), 1 with -alpha(3.7)/-alpha(3.7) (0.69%), 1 with -alpha(4.2)/-alpha(4.2) (0.69%), 14 with --(SEA)/-alpha(3.7) (9.65%), 2 with --(SEA)/-alpha(4.2) (1.38%) were found. Two patients prenatal diagnosed were confirmed with Bart's hydrops fetuses. In conclusion, M-PCR analysis is a simple, rapid and accurate method for detection of alpha-thalassemia gene deletion. This technique is helpful in screening, carrier identification and prenatal diagnosis of deletional alpha-thalassemia.

  10. 77 FR 40344 - Procurement List; Proposed Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-09

    ... Resource Center, Alexandria, VA (CONUS). Contracting Activity: Defense Human Resource Center, Alexandria... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Additions and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed Additions to...

  11. Neutral behavior of shared polymorphism

    PubMed Central

    Clark, Andrew G.

    1997-01-01

    Several cases have been described in the literature where genetic polymorphism appears to be shared between a pair of species. Here we examine the distribution of times to random loss of shared polymorphism in the context of the neutral Wright–Fisher model. Order statistics are used to obtain the distribution of times to loss of a shared polymorphism based on Kimura’s solution to the diffusion approximation of the Wright–Fisher model. In a single species, the expected absorption time for a neutral allele having an initial allele frequency of ½ is 2.77 N generations. If two species initially share a polymorphism, that shared polymorphism is lost as soon as either of two species undergoes fixation. The loss of a shared polymorphism thus occurs sooner than loss of polymorphism in a single species and has an expected time of 1.7 N generations. Molecular sequences of genes with shared polymorphism may be characterized by the count of the number of sites that segregate in both species for the same nucleotides (or amino acids). The distribution of the expected numbers of these shared polymorphic sites also is obtained. Shared polymorphism appears to be more likely at genetic loci that have an unusually large number of segregating alleles, and the neutral coalescent proves to be very useful in determining the probability of shared allelic lineages expected by chance. These results are related to examples of shared polymorphism in the literature. PMID:9223256

  12. Lack of Association between the Serotonin Transporter (5-HTT) and Serotonin Receptor (5-HT2A) Gene Polymorphisms with Smoking Behavior among Malaysian Malays

    PubMed Central

    Rozak, Nur Iwani A; Ahmad, Imran; Gan, Siew Hua; Abu Bakar, Ruzilawati

    2014-01-01

    Abstract An insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and a polymorphism (rs6313) in the serotonin 2A receptor gene (5-HT2A) have previously been linked to smoking behavior. The objective of this study was to determine the possible association of the 5-HTTLPR and 5-HT2A gene polymorphisms with smoking behavior within a population of Malaysian male smokers (n=248) and non-smokers (n=248). The 5-HTTLPR genotypes were determined using the polymerase chain reaction (PCR) and were classified as short (S) alleles or long (L) alleles. The 5HT2A genotypes were determined using PCR-restriction fragment length polymorphisms (PCR-RFLP). No significant differences in the distribution frequencies of the alleles were found between the smokers and the non-smokers for the 5-HTTLPR polymorphism (x2 = 0.72, P>0.05) or the 5HT2A polymorphism (x2 = 0.73, P>0.05). This is the first study conducted on Malaysian Malay males regarding the association of 5-HTTLPR and 5HT2A polymorphisms and smoking behavior. However, the genes were not found to be associated with smoking behavior in our population. PMID:25853073

  13. Crystallization and transitions of sulfamerazine polymorphs.

    PubMed

    Zhang, Geoff G Z; Gu, Chonghui; Zell, Mark T; Burkhardt, R Todd; Munson, Eric J; Grant, David J W

    2002-04-01

    A bulk powder of sulfamerazine polymorph II in a narrow distribution of particle size was prepared for the first time. The two known sulfamerazine polymorphs, I and II, were physically characterized by optical microscopy, powder X-ray diffractometry, differential scanning calorimetry, carbon-13 solid-state nuclear magnetic resonance spectroscopy, and measurements of aqueous solubility and density. The thermodynamics and kinetics of the transition between the polymorphs was examined under various pharmaceutically relevant conditions, such as heating, cooling, milling, compaction, and contact with solvents. The two polymorphs were found to be enantiotropes with slow kinetics of interconversion. The thermodynamic transition temperature lies between 51 and 54 degrees C, with polymorph II stable at lower temperatures. Ostwald's Rule of Stages explains the crystallization of the polymorphs from various solvents and may account for the delay in the discovery of polymorph II. PMID:11948548

  14. Further delineation of the chromosome 14q terminal deletion syndrome.

    PubMed

    van Karnebeek, Clara D M; Quik, Safira; Sluijter, Sigrid; Hulsbeek, Miriam M F; Hoovers, Jan M N; Hennekam, Raoul C M

    2002-06-01

    A patient with hypotonia, blepharophimosis, ptosis, a bulbous nose, a long philtrum, upturned corners of the mouth, and mild developmental delay was found to have a small subtelomeric deletion of the long arm of chromosome 14 (q32.31-qter). In comparing her phenotype with previously reported patients with similar 14q deletions, due to either a linear deletion or to a ring chromosome 14, a clinically recognizable terminal 14q microdeletion syndrome was evident. Due to the limited number of cases reported, it was not possible to assign specific features to specific regions of terminal 14q. The comparison of features in cases with a linear deletion of 14qter (n = 19) to those in cases with a deletion due to a ring chromosome 14 (n = 23), both with the same breakpoint in 14q, showed that seizures and retinitis pigmentosa have been found only in patients with ring chromosomes. Several hypotheses are put forward to explain this difference: mitotic instability of ring chromosomes; a telomere position effect in ring chromosomes in which the 14p telomere silences nearby gene(s) on the q-arm; and dose-dependent gene(s) involved in seizures and retinitis pigmentosa located on the short arm of chromosome 14. In our opinion, only seizures may be explained by the mitotic instability of ring chromosomes, while both seizures and retinitis pigmentosa may be explained by silencing of gene(s) on 14q by the 14p telomere; the third hypothesis seems unlikely to explain either symptom.

  15. Deletion affecting band 7q36 not associated with holoprosencephaly

    SciTech Connect

    Ebrahim, S.A.D.; Krivchenia, E.; Mohamed, A.N.

    1994-09-01

    Although the appearance of 7q36 aberrations have been postulated to be responsible for holoprosencephaly (HPE), the presence of a de novo 7q36 deletion in fetus without HPE has not been reported. We report the first case of a fetus with 7q36 deletion but lacking HPE. Ultrasound examination of a 25-year-old G3P1 Caucasian female showed small head circumference with microcephaly at 28 weeks. Decreased amniotic fluid volume, bilateral renal dilatation and abnormal facial features were also noted. Chromosome analysis after cordocentesis showed an abnormal female karyotype with a deletion involving the chromosome band 7q36, 46,XX,del(7)(q36). Chromosome studies on the biological parents were normal. In view of the chromosome finding and after extensive counseling, the couple elected to terminate the pregnancy. The chromosome findings were confirmed by fetal blood chromosome analysis at termination. Post-mortem examination confirmed dysmorphic features including a depressed nasal bridge and large flat ears with no lobules, but no cleft lip or palate was noted. Internal abnormalities included a bicuspid pulmonary valve and abnormally located lungs. The brain weighed 190g (249 {plus_minus} 64g expected) and had symmetric cerebral hemispheres without evidence of HPE or other gross or microscopic malformation, except focal cerebellar cortical dysplasia. In summary, our patient showed a deletion of the same chromosomal band implicated in HPE but lacked HPE. This finding indicates that 7q36 deletion may be seen in the absence of HPE and suggests that other genetic mechanisms may be responsible for HPE in this setting.

  16. Rare Copy Number Deletions Predict Individual Variation in Intelligence

    PubMed Central

    Yeo, Ronald A.; Gangestad, Steven W.; Liu, Jingyu; Calhoun, Vince D.; Hutchison, Kent E.

    2011-01-01

    Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in “mutation load” emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent) copy number variations (CNVs), and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77) had been administered the Wechsler Abbreviated Scale of Intelligence (WASI). After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = −.30, p = .01). As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES), we also examined the impact of ethnicity (Anglo/White vs. Other), as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less) adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed. PMID:21298096

  17. Mutation and deletion analysis of GFRα-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours

    PubMed Central

    Gimm, O; Gössling, A; Marsh, D J; Dahia, P L M; Mulligan, L M; Deimling, A von; Eng, C

    1999-01-01

    Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRα-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRα-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRα-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRα-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRα-1 and/or nearby genes may contribute to the pathogenesis of these tumours. © 1999 Cancer Research Campaign PMID:10408842

  18. Clinical experience with single‐nucleotide polymorphism‐based non‐invasive prenatal screening for 22q11.2 deletion syndrome

    PubMed Central

    Gross, S. J.; Stosic, M.; McDonald‐McGinn, D. M.; Bassett, A. S.; Norvez, A.; Dhamankar, R.; Kobara, K.; Kirkizlar, E.; Zimmermann, B.; Wayham, N.; Babiarz, J. E.; Ryan, A.; Jinnett, K. N.; Demko, Z.

    2016-01-01

    ABSTRACT Objectives To evaluate the performance of a single‐nucleotide polymorphism (SNP)‐based non‐invasive prenatal test (NIPT) for the detection of fetal 22q11.2 deletion syndrome in clinical practice, assess clinical follow‐up and review patient choices for women with high‐risk results. Methods In this study, 21 948 samples were submitted for screening for 22q11.2 deletion syndrome using a SNP‐based NIPT and subsequently evaluated. Follow‐up was conducted for all cases with a high‐risk result. Results Ninety‐five cases were reported as high risk for fetal 22q11.2 deletion. Diagnostic testing results were available for 61 (64.2%) cases, which confirmed 11 (18.0%) true positives and identified 50 (82.0%) false positives, resulting in a positive predictive value (PPV) of 18.0%. Information regarding invasive testing was available for 84 (88.4%) high‐risk cases: 57.1% (48/84) had invasive testing and 42.9% (36/84) did not. Ultrasound anomalies were present in 81.8% of true‐positive and 18.0% of false‐positive cases. Two additional cases were high risk for a maternal 22q11.2 deletion; one was confirmed by diagnostic testing and one had a positive family history. There were three pregnancy terminations related to screening results of 22q11.2 deletion, two of which were confirmed as true positive by invasive testing. Conclusions Clinical experience with this SNP‐based non‐invasive screening test for 22q11.2 deletion syndrome indicates that these deletions have a frequency of approximately 1 in 1000 in the referral population with most identifiable through this test. Use of this screening method requires the availability of counseling and other management resources for high‐risk pregnancies. © 2015 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd. on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID:26396068

  19. A HindIII polymorphism detected by cDMD 4-5a at the DMD locus in a family with Becker muscular dystrophy

    SciTech Connect

    Gibb, M.F.; Greenberg, C.R.; Carson, N.L.

    1994-09-01

    Deletions within the dystrophin gene can be detected by hybridizing a series of cDNA probes to HindIII-digested DNA, with the absence of one or more fragments indicating the presence of a deletion. However, incorrect interpretations can be made if the absence of a fragment is due to a polymorphism rather than a deletion. Otto and Rothbery reported that the 5.2 kb fragment detected by cM 4-5a could be resolved, with extended electrophoresis, into two fragments estimated to be 5.2 and 5.15 kb in size. They concluded that the extra fragment of this doublet appears to be polymorphic, inherited in a Mendelian dominant fashion. The mother, who is an obligate carrier of BMD, does not have the upper fragment as is the case for her normal and affected sons. The father, who clinically has no evidence of neuromuscular disease, does have the upper fragment as do all their daughters. Given a dominant pattern of inheritance, the daughters should be heterozygous. Analysis of one grandson, who was predicted to have inherited the grandpaternal dystrophin gene, showed that he did have the upper fragment, consistent with our conclusions. To date, we have been unable to analyze a grandson that has inherited the grandmaternal allele; however, presuably he would not have the upper fragment of this doublet. We conclude that there likely is a dominant HindIII polymorphism detected with the cDMD 4-5a probe at the DMD locus. Population studies will be required to determine the frequency of this polymorphism; however, it should be noted that absence of the upper fragment of this doublet in a male with BMD/DMD does not necessarily correspond to the presence of a deletion.

  20. Association between DAZL polymorphisms and susceptibility to male infertility: systematic review with meta-analysis and trial sequential analysis.

    PubMed

    Zhang, Simin; Tang, Qiuqin; Wu, Wei; Yuan, Beilei; Lu, Chuncheng; Xia, Yankai; Ding, Hongjuan; Hu, Lingqing; Chen, Daozhen; Sha, Jiahao; Wang, Xinru

    2014-04-10

    Several studies have investigated the association between polymorphisms in the Deleted in AZoospermia-Like (DAZL) gene and male infertility risk, but with inconsistent results. We aimed to derive a more precise estimation of the relationship, therefore a meta-analysis was performed. A total of 13 case-control studies, including 2556 cases and 1997 controls, were selected. Two polymorphisms in DAZL were investigated, namely T12A (Thr12 → Ala) and T54A (Thr54 → Ala). Our meta-analysis showed that A > G is a risk factor for male infertility (P = 0.047, OR = 1.262, 95%CI = 1.003-1.587). However, when using trial sequential analysis (TSA) to confirm, we found that A > G risk effect turned out to be false positive. In addition, significant association was found between the T54A polymorphism and male infertility under co-dominant model (AG vs. AA: OR = 4.364, 95%CI = 2.207-8.630, P < 0.001) and dominant model (OR = 4.584, 95%CI = 2.320-9.058, P < 0.001). Stratified analysis showed that significantly strong association between T54A polymorphism and male infertility was present only in Asians, but not in Caucasians. Further studies of T12A and T54A with their biological functions are needed to understand the role of these polymorphisms in the development of male infertility.

  1. Association of the Serotonin Transporter Gene Promoter Region (5-HTTLPR) Polymorphism with Biased Attention for Emotional Stimuli

    PubMed Central

    Beevers, Christopher G.; Wells, Tony T.; Ellis, Alissa J.; McGeary, John E.

    2010-01-01

    A deletion polymorphism in the serotonin transporter-linked polymorphic region (5-HTTLPR) has been associated with vulnerability to affective disorders, yet the mechanism by which this gene confers vulnerability remains unclear. Two studies examined associations between the 5-HTTLPR polymorphism and attentional bias for emotional stimuli among non-depressed adults. Biased attention, attention engagement, and difficulty with attention disengagement were assessed with a spatial cueing task using emotional stimuli. Results from Study 1 (N = 38) indicated that short 5-HTTLPR allele carriers experienced greater difficulty disengaging their attention from sad and happy stimuli compared to long allele homozygotes. Study 2 participants (N = 144) were genotyped for the 5-HTTLPR polymorphism, including single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5-HTTLPR. Consistent with Study 1, individuals homozygous for the low expressing 5-HTTLPR alleles (i.e., S and LG) experienced greater difficulty disengaging attention from sad, happy, and fear stimuli than high expressing 5-HTTLPR homozygotes. Since this association exists in healthy adults, it may represent a susceptibility factor for affective disorders that becomes problematic during stressful life experiences. PMID:19685963

  2. Ancestral major histocompatibility complex DRB genes beget conserved patterns of localized polymorphisms.

    PubMed Central

    Gaur, L K; Nepom, G T

    1996-01-01

    Genes within the major histocompatibility complex (MHC) are characterized by extensive polymorphism within species and also by a remarkable conservation of contemporary human allelic sequences in evolutionarily distant primates. Mechanisms proposed to account for strict nucleotide conservation in the context of highly variable genes include the suggestion that intergenic exchange generates repeated sets of MHC DRB polymorphisms [Gyllensten, U. B., Sundvall, M. & Erlich, H. A. (1991) Proc. Natl. Acad. Sci. USA 88, 3686-3690; Lundberg, A. S. & McDevitt, H. 0. (1992) Proc. Natl. Acad. Sci. USA 89, 6545-6549]. We analyzed over 50 primate MHC DRB sequences, and identified nucleotide elements within macaque and baboon DRB6-like sequences with deletions corresponding to specific exon 2 hypervariable regions, which encode a discrete alpha helical segment of the MHC antigen combining site. This precisely localized deletion provides direct evidence implicating segmental exchange of MHC-encoded DRB gene fragments as one of the evolutionary mechanisms both generating and maintaining MHC diversity. Intergenic exchange at this site may be fundamental to the diversification of immune protection in populations by permitting alteration in the specificity of the MHC that determines the repertoire of antigens bound. Images Fig. 2 PMID:8643583

  3. Lysis Delay and Burst Shrinkage of Coliphage T7 by Deletion of Terminator Tφ Reversed by Deletion of Early Genes

    PubMed Central

    Nguyen, Huong Minh

    2014-01-01

    ABSTRACT Bacteriophage T7 terminator Tφ is a class I intrinsic terminator coding for an RNA hairpin structure immediately followed by oligo(U), which has been extensively studied in terms of its transcription termination mechanism, but little is known about its physiological or regulatory functions. In this study, using a T7 mutant phage, where a 31-bp segment of Tφ was deleted from the genome, we discovered that deletion of Tφ from T7 reduces the phage burst size but delays lysis timing, both of which are disadvantageous for the phage. The burst downsizing could directly result from Tφ deletion-caused upregulation of gene 17.5, coding for holin, among other Tφ downstream genes, because infection of gp17.5-overproducing Escherichia coli by wild-type T7 phage showed similar burst downsizing. However, the lysis delay was not associated with cellular levels of holin or lysozyme or with rates of phage adsorption. Instead, when allowed to evolve spontaneously in five independent adaptation experiments, the Tφ-lacking mutant phage, after 27 or 29 passages, recovered both burst size and lysis time reproducibly by deleting early genes 0.5, 0.6, and 0.7 of class I, among other mutations. Deletion of genes 0.5 to 0.7 from the Tφ-lacking mutant phage decreased expression of several Tφ downstream genes to levels similar to that of the wild-type phage. Accordingly, phage T7 lysis timing is associated with cellular levels of Tφ downstream gene products. This suggests the involvement of unknown factor(s) besides the known lysis proteins, lysozyme and holin, and that Tφ plays a role of optimizing burst size and lysis time during T7 infection. IMPORTANCE E. coli PMID:24335287

  4. Transmitted deletions of medial 5p and learning difficulties; does the cadherin cluster only become penetrant when flanking genes are deleted?

    PubMed

    Barber, John C K; Huang, Shuwen; Bateman, Mark S; Collins, Amanda L

    2011-11-01

    The central portion of the short arm of chromosome 5 is unusual in that large, cytogenetically visible interstitial deletions segregate in families with and without phenotypic consequences. Here we present a family in which a transmitted interstitial deletion of 5p13.3 to 5p14.3 co-segregated with learning and/or behavioral difficulties in six family members. Facial dysmorphism was not striking but a father and daughter both had lacrimal fistulae. The deletion was 12.23 Mb in size (chr5:20,352,535-32,825,775) and contained fifteen known protein coding genes. Five of these (GOLPH3; MTMR12; ZFR; SUB1; and NPR3) and an ultra-conserved microRNA (hsa-miR-579) were present in an 883 kb candidate gene region in 5p13.3 that was deleted in the present family but not in previously reported overlapping benign deletions. Members of the cadherin precursor gene cluster, with brain specific expression, were deleted in both affected and benign deletion families. The candidate genes in 5p13.3 may be sufficient to account for the consistent presence or absence of phenotype in medial 5p deletions. However, we consider the possibility of position effects in which CDH6, and/or other cadherin genes, become penetrant when adjacent genes, or modifiers of gene expression, are also deleted. This could account for the absence of intellectual disability in benign deletions of the cadherin cluster, the cognitive phenotype in medial 5p deletion syndrome and the greater severity of intellectual disability in patients with cri-du-chat syndrome and deletions of 5p15 that extend into the region deleted in the present family. PMID:21965044

  5. Superhard Monoclinic Polymorph of Carbon

    SciTech Connect

    Li, Quan; Ma, Yanming; Oganov, Artem R.; Wang, Hongbo; Wang, Hui; Xu, Ying; Cui, Tian; Mao, Ho-Kwang; Zou, Guangtian; Jilin; SBU; CIW

    2009-05-08

    We report a novel phase of carbon possessing a monoclinic C2/m structure (8 atoms/cell) identified using an ab initio evolutionary structural search. This polymorph, which we call M-carbon, is related to the (2x1) reconstruction of the (111) surface of diamond and can also be viewed as a distorted (through sliding and buckling of the sheets) form of graphite. It is stable over cold-compressed graphite above 13.4 GPa. The simulated x-ray diffraction pattern and near K-edge spectroscopy are in satisfactory agreement with the experimental data [W.L. Mao et al., Science 302, 425 (2003)] on overcompressed graphite. The hardness and bulk modulus of this new carbon polymorph are calculated to be 83.1 and 431.2 GPa, respectively, which are comparable to those of diamond.

  6. A 63bp deletion in the promoter of rage correlates with a decreased risk for nephropathy in patients with type 2 diabetes.

    PubMed

    Rudofsky, G; Isermann, B; Schilling, T; Schiekofer, S; Andrassy, M; Schneider, J G; Morcos, M; Humpert, P M; Sayed, A A R; Witte, S; Renn, W; Pfohl, M; Hamann, A; Nosikov, V; Schleicher, E; Häring, H-U; Rudofsky, G; Ritz, E; Nawroth, P P; Bierhaus, A

    2004-03-01

    Several polymorphisms have been identified in the RAGE-promoter region that might modulate the outcome of disease. Here we analyse the association of a 63bp deletion (delta63) spanning from bp - 407 to bp - 345 with diabetic nephropathy. The deletion was determined using the polymerase chain reaction (PCR) in a cross-sectional study with 1087 patients with type 1 diabetes (n = 559) and type 2 diabetes (n = 528). 475 patients with osteoporosis served as disease independent control. The prevalence of the heterozygous genotype did not significantly differ between the three groups (type 1: 2.15 %, type 2: 2.27 %, controls: 1.47 %), indicating that heterozygous delta63 is not related to the manifestation of diabetes. Homozygous carriers were not identified in this study. The heterozygous delta63 genotype, was associated with a reduced prevalence of diabetic nephropathy in patients with type 2 diabetes (OR = 0.06; 95 % CI: [0.05, 0.07]), but not in patients with type 1 (OR = 1.49; 95 % CI: [1.14, 1.94]). We conclude, that patients with type 2 diabetes and the 63bp deletion in the promoter of RAGE seem to be protected from diabetic nephropathy. The observed difference between type 1 and type 2 diabetes might point to diverse pathomechanisms of nephropathy in both types of diabetes.

  7. Milk casein polymorphism in man.

    PubMed

    Ponzone, A; Voglino, G F

    1976-06-01

    Urea-starch-gel electrophoresis was used to examine 175 casein samples, 130 collected at random from women from the urban area of Turin, and 45 from women resident in villages in the Sardinian hinterland. Two polymorphic systems controlling alpha- and beta-casein were demonstrated in both groups, together with similar gene frequencies for individual alleles. In addition, a rare variant was discovered in the Sardinian group.

  8. The Single Nucleotide Polymorphism Consortium

    NASA Technical Reports Server (NTRS)

    Morgan, Michael

    2003-01-01

    I want to discuss both the Single Nucleotide Polymorphism (SNP) Consortium and the Human Genome Project. I am afraid most of my presentation will be thin on law and possibly too high on rhetoric. Having been engaged in a personal and direct way with these issues as a trained scientist, I find it quite difficult to be always as objective as I ought to be.

  9. A genome-wide survey reveals a deletion polymorphism associated with resistance to gastrointestinal nematodes in Angus cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gastrointestinal (GI) nematode infections are a worldwide threat to animal health and production. In this study, we performed a genome-wide association study between copy number variations (CNV) and resistance to GI nematodes in an Angus cattle population. Using a linear regression analysis, we iden...

  10. Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia

    PubMed Central

    Thiart, R.; Scholtz, C.; Vergotine, J.; Hoogendijk, C.; de Villiers, J N. P; Nissen, H.; Brusgaard, K.; Gaffney, D.; Hoffs, M.; Vermaak, W; Kotze, M.

    2000-01-01

    In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in striking contrast to its reported virtual absence in the black population in general. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three screening methods resulted in the identification of seven different mutations in the coding region of the low density lipoprotein (LDLR) gene in 10 of the patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W, R385Q, E387K, P678L, and R793Q) detected in single families. The Sotho patient with missense mutation R232W was also heterozygous for a de novo splicing defect 313+1G→A. Several silent mutations/polymorphisms were detected in the LDLR and apolipoprotein B genes, including a base change (g→t) at nucleotide position −175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compared to controls and occurred in cis with mutation E387K in one family. Analysis of four intragenic LDLR gene polymorphisms showed that the same chromosomal background was identified at this locus in the four FH patients with the 6 bp deletion. Detection of the 6 bp deletion in Xhosa, Pedi, and Tswana FH patients suggests that it is an ancient mutation predating tribal separation approximately 3000 years ago.


Keywords: apolipoprotein B; hypercholesterolaemia; low density lipoprotein receptor; mutation PMID:10882754

  11. SSCP analysis and sequencing of the human prion protein gene (PRNP) detects two different 24 bp deletions in an atypical Alzheimer`s disease family

    SciTech Connect

    Perry, R.T.; Go, R.C.P.; Harrell, L.E.; Acton, R.T.

    1995-02-27

    Alzheimer`s disease (AD) is a progressive, degenerative neurological disorder of the central nervous system. AD is the fourth leading cause of death in elderly persons 65 years or older in Western industrialized societies. The etiology of AD is unknown, but clinical, pathological, epidemiological, and molecular investigations suggest it is etiologically heterogeneous. Mutations in the amyloid protein are rare and segregate with the disease in a few early-onset familial AD (FAD) families. Similarities between AD and the unconventional viral (UCV) diseases, and between the amyloid and prion proteins, implicate the human prion protein gene (PRNP) as another candidate gene. Single strand conformation polymorphism (SSCP) analysis was used to screen for mutations at this locus in 82 AD patients from 54 families (30 FAD), vs. 39 age-matched controls. A 24-bp deletion around codon 68 that codes for one of five Gly-Pro rich octarepeats was identified in two affected sibs and one offspring of one late-onset FAD family. Two other affected sibs, three unaffected sibs, and three offspring from this family, in addition to one sporadic AD patient and three age-matched controls, were heterozygous for another octarepeat deletion located around codon 82. Two of the four affected sibs had features of PD, including one who was autopsy-verified AD and PD. Although these deletions were found infrequently in other AD patients and controls, they appear to be a rare polymorphism that is segregating in this FAD family. It does not appear that mutations at the PRNP locus are frequently associated with AD in this population. 54 refs., 4 figs.

  12. Development of TaqMan allelic discrimination based genotyping of large DNA deletions.

    PubMed

    Fedick, Anastasia; Su, Jing; Treff, Nathan R

    2012-03-01

    The high prevalence of genetic diseases resulting from gross deletions has highlighted a need for a quick, simple, and reliable method of genotyping these mutations. Here, we developed a novel strategy for applying TaqMan allelic discrimination to accurately genotype 3 different large deletions in a high-throughput manner. Allelic discrimination has previously been used to genotype frame shift and point mutations, and small insertions or deletions six base pairs in length, but not large deletions. The assays designed here recognize a 2502 base pair deletion in the Nebulin (NEB) gene that results in Nemaline Myopathy, a 308,769 base pair deletion in the Gap Junction Protein, beta 6 (GJB6) gene that causes Hearing Loss, and a 6433 base pair deletion in the Mucolipin 1 (MCOLN1) gene responsible for causing Mucolipidosis IV Disease. This methodology may also be successfully applied to high throughput genotyping of other large deletions. PMID:22281206

  13. Restoration of half the normal dystrophin sequence in a double-deletion Duchenne muscular dystrophy family

    SciTech Connect

    Hoop, R.C.; Schwartz, L.S.; Hoffman, E.P.; Russo, L.S.; Riconda, D.L.

    1994-02-01

    Two male cousins with Duchenne muscular dystrophy were found to have different maternal dystrophin gene haplotypes and different deletion mutations. One propositus showed two noncontiguous deletions-one in the 5{prime}, proximal deletional hotspot region, and the other in the 3{prime}, more distal deletional hotspot region. The second propositus showed only the 5{prime} deletion. Using multiple fluorescent exon dosage and fluorescent multiplex CA repeat linkage analyses, the authors show that the mother of each propositus carries both deletions on the same grandmaternal X chromosome. This paradox is explained by a single recombinational event between the 2 deleted regions of one of the carrier`s dystrophin genes, giving rise to a son with a partially {open_quotes}repaired{close_quotes} gene retaining only the 5{prime} deletion. 20 refs., 4 figs.

  14. Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions

    SciTech Connect

    Lindsay, E.A.; Goldberg, R.; Jurecic, V.

    1995-07-03

    Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). In 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. 22 refs., 2 figs., 1 tab.

  15. Short, direct repeats at the breakpoints of deletions of the retinoblastoma gene

    SciTech Connect

    Canning, S.; Dryja, T.P. )

    1989-07-01

    The authors found deletions involving the retinoblastoma gene in 12 of 49 tumors from patients with retinoblastoma or osteosarcoma. After mapping the deletion breakpoints, they found that no two breakpoints coincided. Thus, the data do not support the conclusions of others regarding the existence of a hotspot for deletion breakpoints in this gene. In 4 of the tumors, they sequenced 200 base pairs surrounding each deletion breakpoint. Three deletions had termini within pairs of short, direct repeats ranging in size from 4 to 7 base pairs. These results indicate that the slipped mispairing mechanism may predominate in the generation of deletions at this locus. The review of deletion breakpoints at other genetic loci reveals that the nature of the sequences present at deletion breakpoints (short, direct repeats versus middle repetitive elements) varies according to the genetic locus under study.

  16. Neuropathology of 16p13.11 Deletion in Epilepsy

    PubMed Central

    Liu, Joan Y. W.; Kasperavičiūtė, Dalia; Martinian, Lillian; Thom, Maria; Sisodiya, Sanjay M.

    2012-01-01

    16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets

  17. Hypertension-associated C825T polymorphism impairs the function of Gβ3 to target GRK2 ubiquitination

    PubMed Central

    Zha, Zhengyu; Han, Xiao-Ran; Smith, Matthew D; Lei, Qun-Ying; Guan, Kun-Liang; Xiong, Yue

    2016-01-01

    Population-based and case–control studies in different ethnicities have linked a polymorphism, C825T, in exon 10 of GNB3 gene to hypertension and several additional diseases. The 825T allele is associated with alternative splicing and results in a shortened Gβ3 protein, referred to as Gβ3s, which loses 41 amino acids encompassing one WD40 repeat domain. The mechanism of how Gβ3 C825T polymorphism is associated with hypertension has remained unclear, but an impairment of its canonical function in G-protein-coupled receptor signaling has been ruled out. Here, we report that Gβ3, like other Gβ proteins, binds to DDB1 and assembles a DDB1-CUL4A-ROC1 E3 ubiquitin ligase (CRL4AGβ3) to target GRK2 ubiquitination. The loss of the 41 amino-acid residues disrupts the Gβ3-DDB1 binding and impairs the function of Gβ3s to ubiquitinate GRK2. GRK2 ubiquitination levels were decreased and protein levels were accumulated in the blood samples of Gβ3 825T allele carriers. Deletion of Cul4a in mice resulted in systolic pressure increased and weakened heart function in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a mechanism explaining the link between Gβ3 C825T polymorphism and hypertension. PMID:27462452

  18. Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes

    PubMed Central

    Sadikovic, Bekim; Wang, Jing; El-Hattab, Ayman; Landsverk, Megan; Douglas, Ganka; Brundage, Ellen K.; Craigen, William J.; Schmitt, Eric S.; Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and

  19. Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis

    SciTech Connect

    Villard, E.; Soubrier, F.; Tiret, L.; Rakotovao, R. Cambien, F.; Visvikis, S.

    1996-06-01

    Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage disequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms could be divided into two groups: five polymorphisms in the 5{prime} region and three in the coding sequence and the 3{prime} UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5{prime} group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT){sub 2/3} polymorphism. The second QTL would have a frequency of {approximately}.20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants. 30 refs., 1 fig., 6 tabs.

  20. Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Park, Seo Yeon; Kim, Eun Joo

    2015-01-01

    Abstract Objectives: The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. Results: There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). Conclusions: The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting. PMID:26402385

  1. Glutathione S-transferase T1, M1 and P1 Genetic Polymorphisms and Susceptibility to Colorectal Cancer in Turkey.

    PubMed

    Gorukmez, Ozlem; Yakut, Tahsin; Gorukmez, Orhan; Sag, Sebnem Ozemri; Topak, Ali; Sahinturk, Serdar; Kanat, Ozkan

    2016-01-01

    Colorectal cancer (CRC) is reported to be the third most common cancer worldwide and the fourth most common cause of cancer related deaths. CRC is considered to be a multifactorial disease whose risk varies due to the complex interaction between individual genetic basis and exposure to multiple endogenous factors. Glutathione S-transferases are pro-carcinogenic in CRC and are required for the conjugation between chemotherapeutics and broad spectrum xenobiotics. One hundred and eleven patients with CRC and 128 control subjects without any cancer history were enrolled in this study. Multiplex PCR was applied to determine polymorphisms for the GSTT1 and M1 genes, and PCR-RFLP was applied for the GSTP1 (Ile105Val) gene polymorphism. Values <0.05 were defined as statistically significant. We detected a significant high correlation between predisposition for CRC and presence of the Ile/Ile genotype of the GSTP1 (IIe105Val) gene polymorphism, but we did not find a significant relationship between predisposition for CRC and GSTT1 and M1 deletion polymorphisms. In addition, we did not determine a relationship between GSTT1, M1 and P1 gene polymorphisms and any clinicopathological features of CRC. GSTT1 null/GSTM1 positive and GSTT1 null/GSTM1 positive/GSTP1 Ile/ Ile genotypes were significantly higher in the patient group. Our results revealed that there is no relationship among CRC, its clinicopathologic features, and GSTT1 M1 gene polymorphisms. However, there was a significant correlation between CRC and the GSTP1 Ile/Ile genotype. Further studies with larger patient groups are required to delineate the relationships between GST gene polymorphisms and the clinicopathologic features of CRC in Turkey. PMID:27644629

  2. 47 CFR 1.229 - Motions to enlarge, change, or delete issues.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

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  3. 5p deletions: Current knowledge and future directions.

    PubMed

    Nguyen, Joanne M; Qualmann, Krista J; Okashah, Rebecca; Reilly, AmySue; Alexeyev, Mikhail F; Campbell, Dennis J

    2015-09-01

    Disorders resulting from 5p deletions (5p-) were first recognized by Lejeune et al. in 1963 [Lejeune et al. (1963); C R Hebd Seances Acad Sci 257:3098-3102]. 5p- is caused by partial or total deletion of the short arm of chromosome 5. The most recognizable phenotype is characterized by a high-pitched cry, dysmorphic features, poor growth, and developmental delay. This report reviews 5p- disorders and their molecular basis. Hemizygosity for genes located within this region have been implicated in contributing to the phenotype. A review of the genes on 5p which may be dosage sensitive is summarized. Because of the growing knowledge of these specific genes, future directions to explore potential targeted therapies for individuals with 5p- are discussed. © 2015 Wiley Periodicals, Inc. PMID:26235846

  4. Bayesian Case-deletion Model Complexity and Information Criterion

    PubMed Central

    Zhu, Hongtu; Ibrahim, Joseph G.; Chen, Qingxia

    2015-01-01

    We establish a connection between Bayesian case influence measures for assessing the influence of individual observations and Bayesian predictive methods for evaluating the predictive performance of a model and comparing different models fitted to the same dataset. Based on such a connection, we formally propose a new set of Bayesian case-deletion model complexity (BCMC) measures for quantifying the effective number of parameters in a given statistical model. Its properties in linear models are explored. Adding some functions of BCMC to a conditional deviance function leads to a Bayesian case-deletion information criterion (BCIC) for comparing models. We systematically investigate some properties of BCIC and its connection with other information criteria, such as the Deviance Information Criterion (DIC). We illustrate the proposed methodology on linear mixed models with simulations and a real data example. PMID:26180578

  5. 5p Deletions: Current Knowledge and Future Directions

    PubMed Central

    Nguyen, Joanne M.; Qualmann, Krista J.; Okashah, Rebecca; Reilly, Amysue; Alexeyev, Mikhail F.; Campbell, Dennis J.

    2016-01-01

    Disorders resulting from 5p deletions (5p–) were first recognized by Lejeune et al. in 1963 [Lejeune et al. (1963); C R Hebd Seances Acad Sci 257:3098-3102]. 5p– is caused by partial or total deletion of the short arm of chromosome 5. The most recognizable phenotype is characterized by a high-pitched cry, dysmorphic features, poor growth, and developmental delay. This report reviews 5p– disorders and their molecular basis. Hemizygosity for genes located within this region have been implicated in contributing to the phenotype. A review of the genes on 5p which may be dosage sensitive is summarized. Because of the growing knowledge of these specific genes, future directions to explore potential targeted therapies for individuals with 5p– are discussed. PMID:26235846

  6. Uncoupling Protein 2 Polymorphisms as Risk Factors for Neural Tube Defects

    PubMed Central

    Mitchell, Adam; Pangilinan, Faith; VanderMeer, Julie; Molloy, Anne M.; Troendle, James; Conley, Mary; Kirke, Peadar N.; Scott, John M.; Brody, Lawrence C.; Mills, James L.

    2008-01-01

    BACKGROUND: Both environmental and genetic factors are involved in the etiology of neural tube defects (NTDs). Inadequate folate intake and obesity are important environmental risk factors. Several folate-related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type-2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk. METHODS: We evaluated three polymorphisms, −866G>A, A55V, and the 3′UTR 45bp insertion/deletion, as risk factors for NTDs in Irish NTD cases (N=169), their mothers (N=163), their fathers (N=167) and normal control subjects (N=332). RESULTS: Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3′UTR 45bp deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls. CONCLUSIONS: In our Irish study population, UCP2 polymorphisms do not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample. PMID:19137581

  7. Promoter polymorphism in the matrix metalloproteinase-1 and risk of cervical cancer in Korean women.

    PubMed

    Ju, Woong; Kang, Sokbom; Kim, Jae Weon; Park, Noh Hyun; Song, Yong Sang; Kang, Soon Beom; Lee, Hyo Pyo

    2005-01-20

    The aim of this investigation was to analyze the association between a single nucleotide polymorphism (SNP) in the matrix metalloproteinase (MMP)-1 promoter gene -1607 bp region and cervical cancer risk in Korean women. The blood samples of 232 cervical cancer patients and 332 non-cancer control subjects who managed at Seoul National University Hospital from 1999 to 2002 were collected. Polymorphism in MMP-1 promoter -1607 region was determined using TaqMan method. Allele frequency and genotype distribution in the cervical cancer group were compared with those of the control group to determine whether this polymorphism elevates the susceptibility of Korean women to cervical cancer. The relationship between this SNP and cancer invasiveness was also evaluated by collating clinicopathologic data of those in the cancer group, such as FIGO stage, lymph node status, histologic type and parametrial invasion. In the cervical cancer group, the allele frequency of 2G was 66.1%, in the control group 68.2%, showing no significant difference (P=0.41). Similarly the genotypes with insertion (2G/2G) or deletion (1G/1G) polymorphism showed no increased risk for cervical cancer susceptibility compared with 1G/2G genotype. A subgroup analysis of the clinicopathologic parameters in cancer group also showed no significant difference suggesting the lack of an association between SNP of the MMP-1 promoter -1607 bp region and cervical cancer invasiveness. In conclusion, this study shows that Korean with specific polymorphism in MMP-1 are neither more susceptible to develop cervical cancer nor more vulnerable for cancer progression.

  8. SSRs and INDELs mined from the sunflower EST database: abundance, polymorphisms, and cross-taxa utility.

    PubMed

    Heesacker, Adam; Kishore, Venkata K; Gao, Wenxiang; Tang, Shunxue; Kolkman, Judith M; Gingle, Alan; Matvienko, Marta; Kozik, Alexander; Michelmore, Richard M; Lai, Zhao; Rieseberg, Loren H; Knapp, Steven J

    2008-11-01

    Simple sequence repeats (SSRs) are abundant and frequently highly polymorphic in transcribed sequences and widely targeted for marker development in eukaryotes. Sunflower (Helianthus annuus) transcript assemblies were built and mined to identify SSRs and insertions-deletions (INDELs) for marker development, comparative mapping, and other genomics applications in sunflower. We describe the spectrum and frequency of SSRs identified in the sunflower EST database, a catalog of 16,643 EST-SSRs, a collection of 484 EST-SSR and 43 EST-INDEL markers developed from common sunflower ESTs, polymorphisms of the markers among the parents of several intraspecific and interspecific mapping populations, and the transferability of the markers to closely and distantly related species in the Compositae. Of 17,904 unigenes in the transcript assembly, 1,956 (10.9%) harbored one or more SSRs with repeat counts of n > or = 5. EST-SSR markers were 1.6-fold more polymorphic among exotic than elite genotypes and 0.7-fold less polymorphic than non-genic SSR markers. Of 466 EST-SSR or INDEL markers screened for cross-species amplification and polymorphisms, 413 (88.6%) amplified alleles from one or more wild species (H. argophyllus, H. tuberosus, H. anomalus, H. paradoxus, and H. deserticola), whereas 69 (14.8%) amplified alleles from safflower (Carthamus tinctorius) and 67 (14.4%) amplified alleles from lettuce (Lactuca sativa); hence, only a fraction were transferable to distantly related genera in the Compositae, whereas most were transferable to wild relatives of H. annuus. Several thousand additional SSRs were identified in the EST database and supply a wealth of templates for EST-SSR marker development in sunflower.

  9. 75 FR 19945 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-16

    ... INFORMATION: Additions On 2/12/2010 (75 FR 6869-6870) and 2/19/2010 (75 FR 7450-7451), the Committee for..., FORT CARSON, CO. Deletions On 2/12/2010 (75 FR 6869-6870 and 2/19/2010 (75 FR 7450-7451), the Committee..., Internal Revenue Services, 5100 River Road, Schiller Park, IL. NPAs: ServiceSource, Inc., Alexandria,...

  10. Learning About Gene Regulatory Networks From Gene Deletion Experiments

    PubMed Central

    Brazma, Alvis

    2002-01-01

    Gene regulatory networks are a major focus of interest in molecular biology. A crucial question is how complex regulatory systems are encoded and controlled by the genome. Three recent publications have raised the question of what can be learned about gene regulatory networks from microarray experiments on gene deletion mutants. Using this indirect approach, topological features such as connectivity and modularity have been studied. PMID:18629255

  11. 78 FR 21916 - Procurement List; Addition And Deletions

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    2013-04-12

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  12. 75 FR 34703 - Procurement List; Additions and Deletions

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    2010-06-18

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    2011-06-03

    ...@AbilityOne.gov . SUPPLEMENTARY INFORMATION: Additions On 3/11/2011 (76 FR 13362-13363); 3/25/2011 (76 FR 16733-16734); 4/ 1/2011 (76 FR 18188-18189); and 4/8/2011 (76 FR 19750-19751), the Committee for...: Dept of the Army, ] W6QM Ft Sam Houston Contr Ctr, Fort Sam Houston, TX. Deletions On 3/25/2011 (76...

  14. Deletion (11)(q14.1q21)

    SciTech Connect

    Stratton, R.F.; Lazarus, K.H.; Ritchie, E.J.L.; Bell, A.M.

    1994-02-01

    The authors report on a 4-year-old girl with moderate development delay, horseshoe kidney, bilateral duplication of the ureters with right upper pole obstruction, hydronephrosis and nonfunction, and subsequent Wilms tumor of the right lower pole. She had an interstitial deletion of the long arm of chromosome 11 involving the region 11(q14.1q21). 22 refs., 2 figs., 1 tab.

  15. 76 FR 30924 - Procurement List Additions and Deletions

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    2011-05-27

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  16. 76 FR 38640 - Procurement List; Additions and Deletions

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    2011-07-01

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  19. 75 FR 49481 - Procurement List; Additions and Deletion

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    2010-08-13

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  1. 75 FR 60739 - Procurement List; Additions and Deletions

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    2010-10-01

    ...@AbilityOne.gov . SUPPLEMENTARY INFORMATION: Additions On 6/4/2010 (75 FR 31768-31769); 6/25/2010 (75 FR 36363-36371); 8/ 6/2010 (75 FR 47551); and 8/27/2010 (75 FR 52723-52724), the Committee for Purchase.... Deletions On 7/23/2010 (75 FR 43153-43155), the Committee for Purchase From People Who Are Blind or...

  2. 78 FR 46926 - Procurement List Additions and Deletions

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    2013-08-02

    ... . SUPPLEMENTARY INFORMATION: Additions On 5/31/2013 (78 FR 32631-32632); 6/7/2013 (78 FR 34350-34351); and 6/21/2013 (78 FR 37524-37525), the Committee for Purchase From People Who Are Blind or Severely Disabled... Contracting Activity: Dept of the Army, W071 ENDIST Kansas City, Kansas City, MO Deletions On 5/31/2013 (78...

  3. 75 FR 27313 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-14

    ... INFORMATION: Additions On 3/12/2010 (75 FR 11863-11864) and 3/26/2010 (75 FR 14575-14576), the Committee for..., PA. ] Deletions On 3/5/2010 (75 FR 10223-10224) and 3/12/2010 (75 FR 11863-11864), the Committee for... Protection NSN: 7045-01-558-4983--512MB. NSN: 7045-01-558-4984--USB Flash Drive. USB Flash Drive with...

  4. Gene Copy-Number Polymorphism Caused by Retrotransposition in Humans

    PubMed Central

    Galante, Pedro A. F.; Parmigiani, Raphael B.; Camargo, Anamaria A.; Hahn, Matthew W.; de Souza, Sandro J.

    2013-01-01

    The era of whole-genome sequencing has revealed that gene copy-number changes caused by duplication and deletion events have important evolutionary, functional, and phenotypic consequences. Recent studies have therefore focused on revealing the extent of variation in copy-number within natural populations of humans and other species. These studies have found a large number of copy-number variants (CNVs) in humans, many of which have been shown to have clinical or evolutionary importance. For the most part, these studies have failed to detect an important class of gene copy-number polymorphism: gene duplications caused by retrotransposition, which result in a new intron-less copy of the parental gene being inserted into a random location in the genome. Here we describe a computational approach leveraging next-generation sequence data to detect gene copy-number variants caused by retrotransposition (retroCNVs), and we report the first genome-wide analysis of these variants in humans. We find that retroCNVs account for a substantial fraction of gene copy-number differences between any two individuals. Moreover, we show that these variants may often result in expressed chimeric transcripts, underscoring their potential for the evolution of novel gene functions. By locating the insertion sites of these duplicates, we are able to show that retroCNVs have had an important role in recent human adaptation, and we also uncover evidence that positive selection may currently be driving multiple retroCNVs toward fixation. Together these findings imply that retroCNVs are an especially important class of polymorphism, and that future studies of copy-number variation should search for these variants in order to illuminate their potential evolutionary and functional relevance. PMID:23359205

  5. Functional characterization of CYP2D6 enhancer polymorphisms

    PubMed Central

    Wang, Danxin; Papp, Audrey C.; Sun, Xiaochun

    2015-01-01

    CYP2D6 metabolizes nearly 25% of clinically used drugs. Genetic polymorphisms cause large inter-individual variability in CYP2D6 enzyme activity and are currently used as biomarker to predict CYP2D6 metabolizer phenotype. Previously, we had identified a region 115 kb downstream of CYP2D6 as enhancer for CYP2D6, containing two completely linked single nucleotide polymorphisms (SNPs), rs133333 and rs5758550, associated with enhanced transcription. However, the enhancer effect on CYP2D6 expression, and the causative variant, remained to be ascertained. To characterize the CYP2D6 enhancer element, we applied chromatin conformation capture combined with the next-generation sequencing (4C assays) and chromatin immunoprecipitation with P300 antibody, in HepG2 and human primary culture hepatocytes. The results confirmed the role of the previously identified enhancer region in CYP2D6 expression, expanding the number of candidate variants to three highly linked SNPs (rs133333, rs5758550 and rs4822082). Among these, only rs5758550 demonstrated regulating enhancer activity in a reporter gene assay. Use of clustered regularly interspaced short palindromic repeats mediated genome editing in HepG2 cells targeting suspected enhancer regions decreased CYP2D6 mRNA expression by 70%, only upon deletion of the rs5758550 region. These results demonstrate robust effects of both the enhancer element and SNP rs5758550 on CYP2D6 expression, supporting consideration of rs5758550 for CYP2D6 genotyping panels to yield more accurate phenotype prediction. PMID:25381333

  6. Distinct phenotype of PHF6 deletions in females.

    PubMed

    Di Donato, N; Isidor, B; Lopez Cazaux, S; Le Caignec, C; Klink, B; Kraus, C; Schrock, E; Hackmann, K

    2014-02-01

    We report on two female patients carrying small overlapping Xq26.2 deletions of 100 kb and 270 kb involving the PHF6 gene. Mutations in PHF6 have been reported in individuals with Borjeson-Forssman-Lehmann syndrome, a condition present almost exclusively in males. Two very recent papers revealed de novo PHF6 defects in seven female patients with intellectual disability and a phenotype resembling Coffin-Siris syndrome (sparse hair, bitemporal narrowing, arched eyebrows, synophrys, high nasal root, bulbous nasal tip, marked clinodactyly with the hypoplastic terminal phalanges of the fifth fingers and cutaneous syndactyly of the toes, Blaschkoid linear skin hyperpigmentation, dental anomalies and occasional major malformations). The clinical presentation of these patients overlaps completely with our first patient, who carries a germline deletion involving PHF6. The second patient has a mosaic deletion and presented with a very mild phenotype of PHF6 loss in females. Our report confirms that PHF6 loss in females results in a recognizable phenotype overlapping with Coffin-Siris syndrome and distinct from Borjeson-Forssman-Lehmann syndrome. We expand the clinical spectrum and provide the first summary of the recommended medical evaluation.

  7. Targeted deletion of Vegfa in adult mice induces vision loss.

    PubMed

    Kurihara, Toshihide; Westenskow, Peter D; Bravo, Stephen; Aguilar, Edith; Friedlander, Martin

    2012-11-01

    Current therapies directed at controlling vascular abnormalities in cancers and neovascular eye diseases target VEGF and can slow the progression of these diseases. While the critical role of VEGF in development has been well described, the function of locally synthesized VEGF in the adult eye is incompletely understood. Here, we show that conditionally knocking out Vegfa in adult mouse retinal pigmented epithelial (RPE) cells, which regulate retinal homeostasis, rapidly leads to vision loss and ablation of the choriocapillaris, the major blood supply for the outer retina and photoreceptor cells. This deletion also caused rapid dysfunction of cone photoreceptors, the cells responsible for fine visual acuity and color vision. Furthermore, Vegfa deletion showed significant downregulation of multiple angiogenic genes in both physiological and pathological states, whereas the deletion of the upstream regulatory transcriptional factors HIFs did not affect the physiological expressions of angiogenic genes. These results suggest that endogenous VEGF provides critical trophic support necessary for retinal function. Targeting factors upstream of VEGF, such as HIFs, may be therapeutically advantageous compared with more potent and selective VEGF antagonists, which may have more off-target inhibitory trophic effects. PMID:23093773

  8. Mitochondrial DNA exhibits resistance to induced point and deletion mutations

    PubMed Central

    Valente, William J.; Ericson, Nolan G.; Long, Alexandra S.; White, Paul A.; Marchetti, Francesco; Bielas, Jason H.

    2016-01-01

    The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaTMMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure. PMID:27550180

  9. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta.

    PubMed

    Poulter, James A; Murillo, Gina; Brookes, Steven J; Smith, Claire E L; Parry, David A; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2014-10-15

    Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid.

  10. Insertion and deletion mutagenesis of the human cytomegalovirus genome

    SciTech Connect

    Spaete, R.R.; Mocarski, E.S.

    1987-10-01

    Studies on human cytomegalovirus (CMV) have been limited by a paucity of molecular genetic techniques available for manipulating the viral genome. The authors have developed methods for site-specific insertion and deletion mutagenesis of CMV utilizing a modified Escherichia coli lacZ gene as a genetic marker. The lacZ gene was placed under the control of the major ..beta.. gene regulatory signals and inserted into the viral genome by homologous recombination, disrupting one of two copies of this ..beta.. gene within the L-component repeats of CMV DNA. They observed high-level expression of ..beta..-galactosidase by the recombinant in a temporally authentic manner, with levels of this enzyme approaching 1% of total protein in infected cells. Thus, CMV is an efficient vector for high-level expression of foreign gene products in human cells. Using back selection of lacZ-deficient virus in the presence of the chromogenic substrate 5-bromo-4-chloro-3-indolyl ..beta..-D-galactoside, they generated random endpoint deletion mutants. Analysis of these mutant revealed that CMV DNA sequences flanking the insert had been removed, thereby establishing this approach as a means of determining whether sequences flanking a lacZ insertion are dispensable for viral growth. In an initial test of the methods, they have shown that 7800 base pairs of one copy of L-component repeat sequences can be deleted without affecting viral growth in human fibroblasts.

  11. Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice

    PubMed Central

    Lone, Anna Mari; Leidl, Mathias; McFedries, Amanda K.; Horner, James W.; Creemers, John; Saghatelian, Alan

    2014-01-01

    Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL) is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS). HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL−/−) mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL−/− mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL+/+) counterparts. A righting assay revealed that PREPL−/− pups took significantly longer than PREPL+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL−/− mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical, cellular and physiological pathways that link PREPL to HCS, and this may eventually lead to new insights in the treatment of this disease. PMID:24586561

  12. Accelerated speciation in colour-polymorphic birds.

    PubMed

    Hugall, Andrew F; Stuart-Fox, Devi

    2012-05-09

    Colour polymorphism exemplifies extreme morphological diversity within populations. It is taxonomically widespread but generally rare. Theory suggests that where colour polymorphism does occur, processes generating and maintaining it can promote speciation but the generality of this claim is unclear. Here we confirm, using species-level molecular phylogenies for five families of non-passerine birds, that colour polymorphism is associated with accelerated speciation rates in the three groups in which polymorphism is most prevalent. In all five groups, colour polymorphism is lost at a significantly greater rate than it is gained. Thus, the general rarity and phylogenetic dispersion of colour polymorphism is accounted for by a combination of higher speciation rate and higher transition rate from polymorphism to monomorphism, consistent with theoretical models where speciation is driven by fixation of one or more morphs. This is corroborated by evidence from a species-level molecular phylogeny of passerines, incorporating 4,128 (66.5%) extant species, that polymorphic species tend to be younger than monomorphic species. Our results provide empirical support for the general proposition, dating from classical evolutionary theory, that colour polymorphism can increase speciation rates.

  13. Novel genetic polymorphisms that further delineate the phylogeny of the Mycobacterium tuberculosis complex.

    PubMed

    Huard, Richard C; Fabre, Michel; de Haas, Petra; Lazzarini, Luiz Claudio Oliveira; van Soolingen, Dick; Cousins, Debby; Ho, John L

    2006-06-01

    In a previous report, we described a PCR protocol for the differentiation of the various species of the Mycobacterium tuberculosis complex (MTC) on the basis of genomic deletions (R. C. Huard, L. C. de Oliveira Lazzarini, W. R. Butler, D. van Soolingen, and J. L. Ho, J. Clin. Microbiol. 41:1637-1650, 2003). That report also provided a broad cross-comparison of several previously identified, phylogenetically relevant, long-sequence and single-nucleotide polymorphisms (LSPs and SNPs, respectively). In the present companion report, we expand upon the previous work (i) by continuing the evaluation of known MTC phylogenetic markers in a larger collection of tubercle bacilli (n = 125), (ii) by evaluating additional recently reported MTC species-specific and interspecific polymorphisms, and (iii) by describing the identification and distribution of a number of novel LSPs and SNPs. Notably, new genomic deletions were found in various Mycobacterium tuberculosis strains, new species-specific SNPs were identified for "Mycobacterium canettii," Mycobacterium microti, and Mycobacterium pinnipedii, and, for the first time, intraspecific single-nucleotide DNA differences were discovered for the dassie bacillus, the oryx bacillus, and the two Mycobacterium africanum subtype I variants. Surprisingly, coincident polymorphisms linked one M. africanum subtype I genotype with the dassie bacillus and M. microti with M. pinnipedii, thereby suggesting closer evolutionary ties within each pair of species than had been previously thought. Overall, the presented data add to the genetic definitions of several MTC organisms as well as fine-tune current models for the evolutionary history of the MTC. PMID:16740934

  14. Identification of unbalanced genome copy number abnormalities in patients with multiple myeloma by single-nucleotide polymorphism genotyping microarray analysis.

    PubMed

    Kamada, Yuhei; Sakata-Yanagimoto, Mamiko; Sanada, Masashi; Sato-Otsubo, Aiko; Enami, Terukazu; Suzukawa, Kazumi; Kurita, Naoki; Nishikii, Hidekazu; Yokoyama, Yasuhisa; Okoshi, Yasushi; Hasegawa, Yuichi; Ogawa, Seishi; Chiba, Shigeru

    2012-10-01

    Single-nucleotide polymorphism genotyping microarray (SNP array) analysis provides detailed information on chromosomal copy number aberrations. To obtain detailed information on genomic abnormalities related to pathogenesis or prognosis of multiple myeloma (MM), we performed 250K SNP array analysis in 39 MM patients and 11 cell lines. We identified an accumulation of deletions and uniparental disomies at 22q12.1. Among the hyperdiploid MM cases, chromosomal imbalance at this locus was associated with poor prognosis. On sequencing, we also found a mutation in the seizure-related 6 homolog (mouse)-like (SEZ6L) gene located at ch.22q12.1 in an MM cell line, NOP1. We further found isolated deletions in 17 genes, five of which are known tumor suppressor genes. Of these, deletion of protein tyrosine phosphatase, receptor type D (PTPRD) was found in three samples, including two patients. Consistent with previous reports, non-hyperdiploid MM, deletion of 13q (del13q) and gain of 1q in non-hyperdiploid MMs were predictive of poor prognosis (p = 0.039, p = 0.049, and p = 0.013, respectively). However, our analysis revealed that unless accompanied by gain of 1q, the prognosis of non-hyperdiploid MM was as good as that of hyperdiploid MM. Thus, SNP array analysis provides significant information useful to understanding the pathogenesis and prognosis of MM.

  15. Novel mutations associated with resistance to Bacillus sphaericus in a polymorphic region of the Culex quinquefasciatus cqm1 gene.

    PubMed

    Chalegre, Karlos Diogo de Melo; Romão, Tatiany Patrícia; Tavares, Daniella Aliny; Santos, Eloína Mendonça; Ferreira, Lígia Maria; Oliveira, Cláudia Maria Fontes; de-Melo-Neto, Osvaldo Pompílio; Silva-Filha, Maria Helena Neves Lobo

    2012-09-01

    Bin toxin from Bacillus sphaericus acts on Culex quinquefasciatus larvae by binding to Cqm1 midgut-bound receptors, and disruption of the cqm1 gene is the major cause of resistance. The goal of this work was to screen for a laboratory-selected resistance cqm1(REC) allele in field populations in the city of Recife, Brazil, and to describe other resistance-associated polymorphisms in the cqm1 gene. The cqm1(REC) allele was detected in the four nontreated populations surveyed at frequencies from 0.001 to 0.017, and sequence analysis from these samples revealed a novel resistant allele (cqm1(REC-D16)) displaying a 16-nucletotide (nt) deletion which is distinct from the 19-nt deletion associated with cqm1(REC). Yet a third resistant allele (cqm1(REC-D25)), displaying a 25-nt deletion, was identified in samples from a treated area exposed to B. sphaericus. A comparison of the three deletion events revealed that all are located within the same 208-nt region amplified during the screening procedure. They also introduce equivalent frameshifts in the sequence and generate the same premature stop codon, leading to putative transcripts encoding truncated proteins which are unable to locate to the midgut epithelium. The populations analyzed in this study contained a variety of alleles with mutations disrupting the function of the corresponding Bin toxin receptor. Their locations reveal a hot spot that can be exploited to assess the resistance risk through DNA screening. PMID:22773633

  16. Copy-Number Variations Measured by Single-Nucleotide–Polymorphism Oligonucleotide Arrays in Patients with Mental Retardation

    PubMed Central

    Wagenstaller, Janine ; Spranger, Stephanie ; Lorenz-Depiereux, Bettina ; Kazmierczak, Bernd ; Nathrath, Michaela ; Wahl, Dagmar ; Heye, Babett ; Gläser, Dieter ; Liebscher, Volkmar ; Meitinger, Thomas ; Strom, Tim M. 

    2007-01-01

    Whole-genome analysis using high-density single-nucleotide–polymorphism oligonucleotide arrays allows identification of microdeletions, microduplications, and uniparental disomies. We studied 67 children with unexplained mental retardation with normal karyotypes, as assessed by G-banded chromosome analyses. Their DNAs were analyzed with Affymetrix 100K arrays. We detected 11 copy-number variations that most likely are causative of mental retardation, because they either arose de novo (9 cases) and/or overlapped with known microdeletions (2 cases). The eight deletions and three duplications varied in size from 200 kb to 7.5 Mb. Of the 11 copy-number variations, 5 were flanked by low-copy repeats. Two of those, on chromosomes 15q25.2 and Xp22.31, have not been described before and have a high probability of being causative of new deletion and duplication syndromes, respectively. In one patient, we found a deletion affecting only a single gene, MBD5, which codes for the methyl-CpG-binding domain protein 5. In addition to the 67 children, we investigated 4 mentally retarded children with apparent balanced translocations and detected four deletions at breakpoint regions ranging in size from 1.1 to 14 Mb. PMID:17847001

  17. Determination of gene dosage by a quantitative adaptation of the polymerase chain reaction (gd-PCR): Rapid detection of deletions and duplications of gene sequences

    SciTech Connect

    Celi, F.S.; Roth, J.; Schuldiner, A.R. Johns Hopkins Univ. School of Medicine, Baltimore, MD ); Cohen, M.M. ); Antonarakis, S.E. ); Wertheimer, E. )

    1994-05-15

    Screening methods based on the polymerase chain reaction (PCR), such as denaturing gradient gel electrophoresis, single-stranded conformational polymorphism, and heteroduplex analysis, are powerful tools for the detection of point mutations as well as small deletions and insertions, but are unable to detect heterozygous deletions or duplications of exons, genes, or chromosomes. The authors now report a PCR-based approach, designated gene dosage-PCR (gd-PCR), that allows rapid screening for heterozygous deletions and duplications of genes or exons. Gene dosage-PCR is a quantitative method in which two in vitro-synthesized DNA internal standards are coamplified with the genomic DNA sample, one corresponding to the gene of interest (test sequence) and the other to a reference (disomic) gene (reference sequence). Both internal standards are designed to be amplified with the same primer pairs and with efficiencies similar to those of their genomic DNA counterparts, yielding PCR products slightly smaller than those derived from genomic DNA. Amplification of approximately equimolar amounts of the two internal standards and genomic DNA, in the presence of [[sup 32]P]dCTP, results in four radiolabeled PCR products; after electrophoresis and quantification of the products, gene dosage is easily calculated. For validation, genomic DNA from 56 subjects, 28 with cytogenetically documented Down syndrome (trisomy 21) and 28 controls that were disomic for chromosome 21, was assayed. Using the [beta]-amyloid precursor protein gene (APP: Chromosome 21q21) as the test sequence, control subjects had an adjusted mean gene dose of 2.00 [+-] 0.29, while subjects with Down syndrome had a mean gene dose of 3.05 [+-] 0.27. There was a clear separation of all of the samples between the two groups. The authors also successfully used gd-PCR to detect allelic deletions by screening pertinent regions of the insulin receptor gene. 48 refs., 5 figs., 2 tabs.

  18. Array-CGH in patients with Kabuki-like phenotype: Identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration

    PubMed Central

    Cuscó, Ivon; del Campo, Miguel; Vilardell, Mireia; González, Eva; Gener, Blanca; Galán, Enrique; Toledo, Laura; Pérez-Jurado, Luis A

    2008-01-01

    Background Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by specific facial features, mild to moderate mental retardation, postnatal growth delay, skeletal abnormalities, and unusual dermatoglyphic patterns with prominent fingertip pads. A 3.5 Mb duplication at 8p23.1-p22 was once reported as a specific alteration in KS but has not been confirmed in other patients. The molecular basis of KS remains unknown. Methods We have studied 16 Spanish patients with a clinical diagnosis of KS or KS-like to search for genomic imbalances using genome-wide array technologies. All putative rearrangements were confirmed by FISH, microsatellite markers and/or MLPA assays, which also determined whether the imbalance was de novo or inherited. Results No duplication at 8p23.1-p22 was observed in our patients. We detected complex rearrangements involving 2q in two patients with Kabuki-like features: 1) a de novo inverted duplication of 11 Mb with a 4.5 Mb terminal deletion, and 2) a de novo 7.2 Mb-terminal deletion in a patient with an additional de novo 0.5 Mb interstitial deletion in 16p. Additional copy number variations (CNV), either inherited or reported in normal controls, were identified and interpreted as polymorphic variants. No specific CNV was significantly increased in the KS group. Conclusion Our results further confirmed that genomic duplications of 8p23 region are not a common cause of KS and failed to detect other recurrent rearrangement causing this disorder. The detection of two patients with 2q37 deletions suggests that there is a phenotypic overlap between the two conditions, and screening this region in the Kabuki-like patients should be considered. PMID:18405349

  19. Interstitial deletion 5p accompanied by dicentric ring formation of the deleted segment resulting in trisomy 5p13-cen

    SciTech Connect

    Schuffenhauer, S.; Daumer-Haas, C.; Murken, J.

    1996-10-02

    Karyotypes with an interstitial deletion and a marker chromosome formed from the deleted segment are rare. We identified such a rearrangement in a newborn infant, who presented with macrocephaly, asymmetric square skull, minor facial anomalies, omphalocele, inguinal hernias, hypospadias, and club feet. The karyotype 46,XY,del(5)(pter{r_arrow}p13::cen{r_arrow}qter)/47,XY,+dicr(5)(:p13{r_arrow}cen::p13{r_arrow}cen),del(5)(pter{r_arrow}p13::cen{r_arrow}qter) was identified by banding studies and FISH analysis in the peripheral lymphocytes. One breakpoint on the del(5) maps distal to GDNF, and FISH analysis using an {alpha}-satellite probe suggests that the proximal breakpoint maps within the centromere. The dicentric r(5) consists of two copies of the segment deleted in the del(5), resulting in trisomy of proximal 5p (5p13-cen). The phenotype of the propositus is compared with other trisomy 5p cases and possible mechanisms for the generation of this unique chromosomal rearrangement are discussed. 27 refs., 3 figs.

  20. Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin

    SciTech Connect

    Thanh, L.T.; Man, Nguyen Thi; Morris, G.E.

    1995-08-28

    We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying {open_quotes}revertant{close_quotes} fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene. 27 refs., 7 figs., 3 tabs.