Dissertations / Theses: 'Allele variances'

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Hummel, Matthew Aaron. "Dapsone activation of CYP2C9 allelic variants." Morgantown, W. Va. : [West Virginia University Libraries], 2003. http://etd.wvu.edu/templates/showETD.cfm?recnum=2767.

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Thesis (M.S.)--West Virginia University, 2003.
Title from document title page. Document formatted into pages; contains vi, 42 p. : ill. Includes abstract. Includes bibliographical references (p. 35-42).

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2

Milani, Lili. "Gene Expression in Cancer Cells : Detection of Splice Variants, Allele-specific Expression and DNA Methylation." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-99067.

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Makambwa, Edson. "The role of warfarin pharmacogenomics on the time it takes to reach stable therapeutic International Normalized Ratio (INR) and on warfarin dose required to maintain stable therapeutic INR in Black African and Mixed Ancestry South Africans: a focus on CYP2C9 and VKORC1." Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31178.

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Warfarin, the most commonly prescribed anticoagulant, is principally metabolized by cytochrome P450 2C9 which functions by inhibiting the Vitamin K epoxide reductase. Genes CYP2C9 and VKORC1 code for these two proteins, respectively. CYP2C9 and VKORC1 exhibit genetic polymorphisms that have been shown to affect warfarin response and favorably facilitate warfarin dosing and improve clinical outcomes. However, none of these studies have involved populations from sub-Saharan Africa where the potential benefit of optimal dosing and reduced complications is greatest. Therefore, the thesis describes a study designed to investigate the role of genetic variations in CYP2C9 and VKORC1 on the time taken to reach a stable therapeutic international normalized ratio (INR) and warfarin dose required to maintain a therapeutic INR. This was a cross-sectional study of patients on warfarin to determine the relationship between genetic polymorphism in CYP2C9 and VKORC1 amongst black and mixed ancestry South Africans and clinical surrogates of warfarin metabolism. Medical records were accessed to determine time to INR and warfarin doses. DNA was extracted from blood samples, and genotyping for polymorphism in CYP2C9 (*2,*3,*8,*11) and VKORC1 (1173C>T, 1639G>A, 3730G>A) was accomplished by PCR-RFLP, Sanger sequencing and iPlex Mass Sequencing. Our results show that the genetic profile of CYP2C9 and VKORC1 differs between Black Africans (BA) and their Mixed Ancestry (MA) counterparts. VKORC1-1639AA genotype was observed at frequencies of 0.11 and 0.01 in the MA and BA, respectively. Time to stable INR was not influenced by CYP2C9 and VKORC1. Furthermore, compared to known genetic polymorphisms in these genes from population out of Africa, both qualitative and quantitative differences were observed. Finally, we found that VKORC1 genetic variation significantly affected the doses of warfarin in MA but had no effect in BA. These results suggest that further research in this area is warranted, and that it will be important to include populations from sub-Saharan Africa in future if the potential to develop personalized algorithms which integrate pharmacogenomics to assist with effective warfarin dosing and prevention of warfarin related complications is to be realized.

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Cid, Nuria Alonso Lopez. "AVALIAÇÃO DE POLIMORFISMOS DA CYP3A5 EM INDIVÍDUOS DA REGIÃO CENTRO-OESTE DO BRASIL." Pontifícia Universidade Católica de Goiás, 2016. http://localhost:8080/tede/handle/tede/2410.

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Made available in DSpace on 2016-08-10T10:39:16Z (GMT). No. of bitstreams: 1 NURIA ALONSO LOPEZ CID.pdf: 1461437 bytes, checksum: 7aabd2e9fb0164bdf7480906eadb35b7 (MD5) Previous issue date: 2016-04-14
The advances in Anesthesiology took place at the same time as the development of drugs that ensured greater control over pain, patient comfort, and safety during surgical anesthetic procedures. Pharmacogenetics is the science that enables enhanced healthcare, by understanding the genetic variations that may affect the different responses to treatments. CYP3A are the most important enzymes involved in the metabolism of drugs prescribed in clinical practice, showing extensive genetic variability in their expression. CYP3A5 presents the highest number of functional variants, with significant differences in the frequencies observed among different population groups around the world and in Brazil. This study aimed and at assessing the frequency of CYP3A5*3 and CYP3A5*6 genotypic and allelic variants and to estimate the metabolizing profile according to these variants, as well as any potential implications on adverse events with drugs used in anesthesia. The sample used for this study included 166 subjects users of the Laboratório da Área de Saúde da PUCGoiás (PUC Healthcare Laboratory city of Goiás). They were all born in the Brazilian Midwest, over 18 years of age, and from both genders. The blood samples were obtained from each individual and genotyped for CYP3A5*3, A>G (rs 776746) and CYP3A5*6, G>A (rs 10264272) by real time Polymerase Chain Reaction using TaqMan assays. Data analysis of the allelic frequency was conducted by calculating the percentage for the established groups, according to color or race, compared to the total sample. In individuals from the Brazilian Midwest, assessed in this study, the frequency of the allelic variant CYP3A5*3 was 40% and 2% for CYP3A5*6. The frequency observed for the CYP3A5*3 allelic variant in subjects from the Midwest was lower than that from other Brazilian studies and also lower than the frequencies observed in Europeans and Asians, however, they were similar to the frequency seen in populations from East and West Africa. The frequency of the CYP3A5*6 allelic variant, in this study, was higher than that found in European studies and similar of the subjects in the North of Africa. Based on the results, one may infer that 72% would be poor metabolizers. The higher frequency of the poor metabolizer profile shows that there is potential for a greater occurrence of adverse events when using drugs metabolized by CYP3A5 in this population from the Brazilian Midwest.
O progresso da Anestesiologia junto com o desenvolvimento de drogas garantiram maior controle da dor, conforto ao paciente e segurança durante o ato anestésicocirúrgico. A Farmacogenética é uma ciência que permite a melhora da assistência à saúde, por meio do conhecimento das variações genéticas que podem estar envolvidas com as diferenças na resposta terapêutica. As CYP3A são as enzimas mais importantes envolvidas com o metabolismo de drogas prescritas na prática clínica, apresentando grande variabilidade genética na sua expressão. A CYP3A5 é a forma que apresenta mais variantes funcionais e com diferenças expressivas nas frequências observadas em diferentes grupos populacionais do mundo. Este estudo teve como objetivo avaliar a frequência das variantes genotípicas e alélicas do CYP3A5*3 e CYP3A5*6 e inferir sobre o perfil metabolizador dos indivíduos em função destas variantes em relação a drogas usadas em anestesia. O grupo avaliado incluiu 166 indivíduos usuários do Laboratório da Área de Saúde da PUCGoiás, nascidos na região Centro-Oeste do Brasil, maiores de 18 anos e de ambos os sexos. As amostras de sangue foram obtidas de cada indivíduo e genotipados para CYP3A5*3, A>G (rs 776746) and CYP3A5*6, G>A (rs 10264272) por Reação em Cadeia de Polimerase usando sondas TaqMan. A análise dos dados das frequências alélicas foi realizada através do cálculo das porcentagens para os grupos estabelecidos, segundo a cor ou raça, em relação a amostra total. Nos indivíduos da região Centro-Oeste do Brasil avaliados neste estudo, a frequência da variante alélica CYP3A5*3 foi de 40% e da CYP3A5*6 foi de 2%. A frequência observada para a variante alélica CYP3A5*3 em indivíduos da região Centro-Oeste foi menor que a de outros estudos brasileiros e também menor que as frequências verificadas em europeus e asiáticos, porém similar à observada na população do leste e oeste da África. A frequência da variante alélica CYP3A5*6, neste estudo, foi maior que a encontrada em estudos europeus e com valores mais próximos daqueles observados no norte da África. Com base nos resultados obtidos da amostra pode-se inferir que 72% dos indivíduos seriam fracos metabolizadores. A maior frequência do perfil de fraco metabolizador mostra que existe potencial de maior ocorrência de eventos adversos no uso de fármacos metabolizados pela CYP3A5 nesta população da região Centro-Oeste do Brasil.

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Yang, Su jeong. "Biochemical and biophysical characterisation of allelic variants of ovine prion protein." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611255.

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Walton, Esther, Daniel Geisler, Johannes Hass, Jingyu Liu, Jessica Turner, Anastasia Yendiki, Michael N. Smolka, et al. "The Impact of Genome-Wide Supported Schizophrenia Risk Variants in the Neurogranin Gene on Brain Structure and Function." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-132122.

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The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two common NRGN risk single nucleotide polymorphisms (SNPs) with functional and structural brain-based intermediate phenotypes for schizophrenia. We obtained structural, functional MRI and genotype data of 92 schizophrenia patients and 114 healthy volunteers from the multisite Mind Clinical Imaging Consortium study. Two schizophrenia-associated NRGN SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. NRGN rs12541 risk allele homozygotes (TT) displayed increased working memory-related activity in several brain regions, including the left DLPFC, left insula, left somatosensory cortex and the cingulate cortex, when compared to non-risk allele carriers. NRGN rs12807809 non-risk allele (C) carriers showed reduced cortical gray matter thickness compared to risk allele homozygotes (TT) in an area comprising the right pericalcarine gyrus, the right cuneus, and the right lingual gyrus. Our study highlights the effects of schizophrenia risk variants in the NRGN gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate NRGN in the pathophysiology of schizophrenia by suggesting that genetic NRGN risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.

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Jin, Huilin. "Mechanisms of osteoporosis associated with common allelic variants of the COL1A1 gene." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/29182.

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Three single nucleotide polymorphisms (SNP) have been identified in the 5’ flank of the COLIA1 gene (-1997G/T; -1663IndelT and +1245G/T) which have been associated with osteoporosis in various populations. The individual polymorphisms were all associated with BMD, but the haplotypes defined by all three SNP showed a stronger association with BMD, biomechanical strength of bone and hip fracture. Two haplotypes increased in frequency with age suggesting an effect on survival. However these haplotypes were particularly enriched in hip fracture patients. Biomechanical testing showed that all three SNPs were strongly associated with reduced bone strength, independently of BMD. Gel shift assays showed that the region surrounding the -1663insdeIT polymorphism recognised the nuclear binding proteins NMP4 and Osterix and the -1663deIT allele had greater binding affinity than -1663insT allele. the region surrounding the -1997 G/T polymorphism also recognised DNA binding proteins but the polymorphism did not have affect DNA protein binding significantly. Reporter assays showed significant differences between the ability of different haplotypes to drive gene expression and constructs containing haplotype (G-delT-T) had the highest transcriptional activity (p<0.001). Transgenic constructs containing different 5’ COL1A1 haplotypes were completed and transformed into mouse embryonic stem cells by electroporation in an attempt to generate a disease model of osteoporosis associated with common variants in the COLIA1 gene. The studies suggest that haplotypes, rather than individual polymorphisms in the 5’ flank of COL1A1 predispose to osteoporosis, by affecting DNA protein interactions and gene expression.

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Albers, Patrick K. "Rare and low-frequency variants and predisposition to complex disease." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:2d569297-5d2a-49c8-a1ca-32a978aec49d.

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Advances in high-throughput genomic technologies have facilitated the collection of DNA information for thousands of individuals, providing unprecedented opportunities to explore the genetic architecture of complex disease. One important finding has been that the majority of variants in the human genome are low in frequency or rare. It has been hypothesised that recent explosive growth of the human population afforded unexpectedly large amounts of rare variants with potentially deleterious effects, suggesting that rare variants may play a role in disease predisposition. But, importantly, rare variants embody a source of information through which we may learn more about our recent evolutionary history. In this thesis, I developed several statistical and computational methods to address problems associated with the analysis of rare variants and, foremost, to leverage the genealogical information they encode. First, one constraint in genome-wide association studies is that lower-frequency variants are not well captured by genotyping methods, but instead are predicted through imputation from a reference dataset. I developed the meta-imputation method to improve imputation accuracy by integrating genotype data from multiple, independent reference panels, which outperformed imputations from separate references in almost all comparisons (mean correlation with masked genotypes r²>0.9). I further demonstrated in simulated case-control studies that meta-imputation increased the statistical power to identify low-frequency variants of intermediate or high penetrance by 2.2-3.6%. Second, rare variants are likely to have originated recently through mutation and thereby sit on relatively long haplotype regions identical by descent (IBD). I developed a method that exploits rare variants as identifiers for shared haplotype segments around which the breakpoints of recombination are detected using non-probabilistic approaches. In coalescent simulations, I show that such breakpoints can be inferred with high accuracy (r²>0.99) around rare variants at frequencies <0.05%, using either haplotype or genotype data. Third, I show that technical error poses a major problem for the analysis of whole-genome sequencing or genotyping data, particularly for alleles below 0.05% frequency (false positive rate, FPR=0.1). I therefore propose a novel approach to infer IBD segments using a Hidden Markov Model (HMM) which operates on genotype data alone. I incorporated an empirical error model constructed from error rates I estimated in publicly available sequencing and genotyping datasets. The HMM was robust in presence of error in simulated data (r²>0.98) while nonprobabilistic methods failed (r²<0.02). Lastly, the age of an allele (the time since its creation through mutation) may provide clues about demographic processes that resulted in its observed frequency. I present a novel method to estimate (rare) allele age based on the inferred shared haplotype structure of the sample. The method operates in a Bayesian framework to infer pairwise coalescent times from which the age is estimated using a composite posterior approach. I show in simulated data that coalescent time can be inferred with high accuracy (rank correlation >0.91) which resulted in a likewise high accuracy for estimated age (>0.94). When applied to data from the 1000 Genomes Project, I show that estimated age distributions were overall conform with frequency-dependent expectations under neutrality, but where patterns of low frequency and old age may hint at signatures of selection at certain sites. Thus, this method may prove useful in the analysis of large cohorts when linked to biomedical phenotype data.

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Gréard, Camille. "La détection des variants alléliques comme voie d'amélioration génétique des plantes fourragères : exemple de la luzerne." Thesis, Poitiers, 2019. http://www.theses.fr/2019POIT2261.

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L’amélioration génétique de la luzerne (Medicago sativa), une légumineuse fourragère autotétraploïde, pourrait bénéficier de l’allele mining. Cette méthode consiste à rechercher, dans la diversité naturelle, des allèles ayant potentiellement un effet sur le phénotype. Pour évaluer l’intérêt de cette stratégie qui exploite la diversité naturelle, cinq gènes impliqués dans des caractères sélectionnés ont été retenus : CAD1 et CCoaOMT (digestibilité), CONSTANS-like (rendement fourrager), NHX1 (tolérance à la salinité) et WXP1 (tolérance à la sécheresse). La diversité de ces gènes a été étudiée en séquençant 387 génotypes cultivés et 20 génotypes sauvages. L’analyse des données confirme la présence d’un goulot d’étranglement durant la domestication et la sélection de la luzerne. CONSTANS-like et WXP1 révèlent de nombreux variants alors que CAD1, CCoaOMT et NHX1 sont très peu variables. Des variants ayant un effet potentiel sur le phénotype ont été identifiés dans les zones de la séquence protéique qui sont conservées au sein des Faboideae. L’impact sur le phénotype de deux variants du gène CONSTANS-like a été étudié : Constans-634, à l’origine d’un codon stop prématuré et Constans-4111, situé dans une région conservée du gène. Pour cela des croisements ont été réalisés afin d’obtenir une descendance avec toutes les doses possibles (AAAA, AAAB, AABB, ABBB and BBBB) pour chaque mutation étudiée. Des marqueurs KASPar ont été développés afin de déterminer les doses de mutations chez les descendants. Aucun génotype homozygote muté pour Constans-634 n’a été détecté parmi les 1505 descendants. Ce variant a induit une floraison plus précoce de trois jours pour les génotypes portant trois doses d’allèle muté. Le variant Constans-4111 a induit un effet additif sur la hauteur de tige. Les génotypes homozygotes de type sauvage étaient en moyenne 11,8 cm plus petits que les génotypes homozygotes portant trois ou quatre doses du variant. L’intégration de la stratégie allele mining dans les schémas de sélection des espèces végétales autotétraploïdes hétérozygotes a été discutée
Lucerne (Medicago sativa) is an autotetraploid forage legume, whose breeding could beneficiate from allele mining. This strategy is based on the natural diversity and consists in seeking alleles with a potential effect on the phenotype. The interest of this approach was evaluated by studying five genes of agronomic interest: CAD1 and CCoaOMT (digestibility), CONSTANS-like (forage yield), NHX1 (salt tolerance) and WXP1 (drought tolerance). The diversity of these five genes was evaluated by sequencing 387 genotypes of cultivated accessions and 20 genotypes of wild accessions. The results confirmed a bottleneck during lucerne domestication and selection. CONSTANS-like and WXP1 were very variable whereas CAD1, CCoaOMT and NHX1 contained very few variants. Variants with a potential strong impact on the phenotype were identified in conserved parts of protein sequence within the Faboideae. The impact on phenotype was studied for two mutations of the CONSTANS-like gene: constans-634, causing a premature stop codon and constans-4111, located in a conserved region of the gene. Genotypes carrying one to three doses of the mutations (AAAB, AABB and ABBB) were polycrossed in order to obtain offsprings with every allele combination (AAAA, AAAB, AABB, ABBB and BBBB). KASPar markers were developed to determine the mutation doses in offspring progeny. No homozygous genotype was found for constans-634 in the 1505 offspring progeny. This mutation induced a premature flowering of three days for the genotypes carrying three doses of the mutation. The mutation constans-4111 induced an additive effect on stem height and the homozygous genotypes without the variant where on average 11.8 cm shorter than homozygous genotypes carrying three or four doses of the variant. The application of allele mining strategy in plant schemes of heterozygous autotetraploid species was discussed

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Johnson, Andrew Danner. "Search for functional alleles in the human genome with focus on cardiovascular disease candidate genes." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1187018497.

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Walton, Esther, Daniel Geisler, Johannes Hass, Jingyu Liu, Jessica Turner, Anastasia Yendiki, Michael N. Smolka, et al. "The Impact of Genome-Wide Supported Schizophrenia Risk Variants in the Neurogranin Gene on Brain Structure and Function." Public Library of Science, 2013. https://tud.qucosa.de/id/qucosa%3A27422.

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The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two common NRGN risk single nucleotide polymorphisms (SNPs) with functional and structural brain-based intermediate phenotypes for schizophrenia. We obtained structural, functional MRI and genotype data of 92 schizophrenia patients and 114 healthy volunteers from the multisite Mind Clinical Imaging Consortium study. Two schizophrenia-associated NRGN SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. NRGN rs12541 risk allele homozygotes (TT) displayed increased working memory-related activity in several brain regions, including the left DLPFC, left insula, left somatosensory cortex and the cingulate cortex, when compared to non-risk allele carriers. NRGN rs12807809 non-risk allele (C) carriers showed reduced cortical gray matter thickness compared to risk allele homozygotes (TT) in an area comprising the right pericalcarine gyrus, the right cuneus, and the right lingual gyrus. Our study highlights the effects of schizophrenia risk variants in the NRGN gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate NRGN in the pathophysiology of schizophrenia by suggesting that genetic NRGN risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.

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Panicco, Paola. "Protein engineering of human cytochromes P450 and their allelic variants for nanobiotechnological applications." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/11739.

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Human cytochromes P450 (CYP) constitute one of the most important and studied classes of phase I drug metabolizing enzymes. A small group of 6-7 isoforms of the 57 identified until now accounts for 90-95% of the metabolism of clinically used drugs and can contain mutations (single nucleotide polymorphisms) that, when located in the coding regions, can lead to absent, deficient or enhanced enzyme activity. Thanks to the development of pharmacogenetics and later on pharmacogenomics, the presence of these single nucleotide polymorphisms (SNP) has been associated to inter-individual and inter-ethnic variability in the response to several important therapeutic agents. Due to this direct correlation between polymorphism and efficacy of drug treatment, the pharmaceutical industry is particularly interested in developing new analytical tools for the determination of the cytochrome P450 in vitro metabolism to correlate to the in vivo situation. The use of amperometric sensing systems represents an interesting alternative to the traditional methods. In the present study an electrochemical characterisation of the human cytochrome P450 2C9 and its two main allelic variants the CYP2C9*2 and CYP2C9*3 have been performed. Different methods of immobilisation and electrodes have been used to investigate the conditions that are more suitable to maintain and guarantee the active state and biocatalytic response of an immobilised cytochrome P450. The CYP2C9 and its two main allelic variants CYP2C9*2 and CYP2C9*3 have been inserted into engineered constructs where the human cytochrome P450 gene is linked to artificial redox chains to regulate the electron flow from the electrode surface to the haem. All the constructs have been successfully expressed and purified in heterologous E.Coli cells, with the CYP2C9FLD chimeras showing higher yields. Preliminary spectroelectrochemical studies on semi-conductive and optically transparent tin-dioxide allowed the combination of absorption spectroscopy and electrochemistry (cyclic voltammetry) to ascertain the native state of these P450 enzymes once immobilised. The results showed how the conversion from the active P450 form to the inactive P420 one can be achieved by modifying the surface with polycations with slightly different chemical properties. A proper characterisation of the two species was performed for the first time and, under certain conditions, the inactive P420 species appeared to dominate the cyclic voltammogram (CV). Similar findings have been observed when the CYP2C9 wild type have been electrochemically characterised on DDAB and PDDA modified glassy carbon electrodes. Electrocatalysis in presence of S-warfarin and FT-IR spectra of the CYP2C9/DDAB/GC electrodes revealed higher catalytic activity and maintenance of the native secondary structure of the enzyme. Immobilisation of the CYP2C9FLD, CYP2C9*2FLD and CYP2C9*3FLD on DDAB modified glassy carbon electrodes showed well defined redox couples on the oxygen-free cyclic voltammograms (CVs) and mid point potentials of all enzymes were calculated. Electrocatalysis in presence of substrate and quantification of the product formed showed lower catalytic activities for the CYP2C9*3FLD and CYP2C9*2FLD compared to the wild type CYP2C9FLD as it was expected from literature data. When the CYP2C9FLD, CYP2C9*2FLD and CYP2C9*3FLD were immobilised on alkanethiol modified gold electrodes, the system was tested as both amperometric sensor and catalyser. Parameters such as the apparent Michaelis– Menten constant Km and the Vmax were determined and the metabolic profile of S-warfarin was confirmed to be in line with literature findings. The fundamental knowledge acquired was then transferred to a commercial prototype sensor for testing the metabolic profile of known drugs. Encouraging results in line with the previous findings were achieved.

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Kalita, Ann Marie. "Comparison of the activities of two allelic variants of the human wildtype p53 protein." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq29729.pdf.

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Johansson, Ann-Sofie. "Exploring the Functional Plasticity of Human Glutathione Transferases : Allelic Variants, Novel Isoenzyme and Enzyme Redesign." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5270-1/.

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Zhang, Xiaolu. "Cis-acting Genetic Variants that Alter ERCC5 Regulation as a Prototype to Characterize cis-regulation of Key Protective Genes in Normal Bronchial Epithelial Cells." University of Toledo Health Science Campus / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1461321386.

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Lu, Tonghua. "Characterization and strain distribution of multicopy allelic variants of the M. fermentans membrane lipoprotein gene, p57." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9901259.

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Inagaki(Kawata), Yukiko. "Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263544.

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Galbiati, Federica. "Functional characterization of allelic variants of pulmonary adenoma susceptibility 1 (Pas1) genes for their cancer modifier activity." Thesis, Open University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446307.

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Blomquist, Thomas M. "Development of Bimodal Gene Expression Analysis and Allele-Specific Competitive PCR for Investigation of Complex Genetic Traits, Lung Cancer Risk." University of Toledo Health Science Campus / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1277151230.

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Yeung, Catherine K. "Structure and function of the human FMOs : tissue localization, comparative modeling, and kinetic parameters of FMO3 allelic variants /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/8151.

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Imsland, Freyja. "Monogenic Traits Associated with Structural Variants in Chicken and Horse : Allelic and Phenotypic Diversity of Visually Appealing Traits." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-259621.

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Domestic animals have rich phenotypic diversity that can be explored to advance our understanding of the relationship between molecular genetics and phenotypic variation. Since the advent of second generation sequencing, it has become easier to identify structural variants and associate them with phenotypic outcomes. This thesis details studies on three such variants associated with monogenic traits. The first studies on Rose-comb in the chicken were published over a century ago, seminally describing Mendelian inheritance and epistatic interaction in animals. Homozygosity for the otherwise dominant Rose-comb allele was later associated with reduced rooster fertility. We show that a 7.38 Mb inversion is causal for Rose-comb, and that two alleles exist for Rose-comb, R1 and R2. A novel genomic context for the gene MNR2 is causative for the comb phenotype, and the bisection of the gene CCDC108 is associated with fertility issues. The recombined R2 allele has intact CCDC108, and normal fertility. The dominant phenotype Greying with Age in horses was previously associated with an intronic duplication in STX17. By utilising second generation sequencing we have examined the genomic region surrounding the duplication in detail, and excluded all other discovered variants as causative for Grey. Dun is the ancestral coat colour of equids, where the individual is mostly pale in colour, but carries intensely pigmented primitive markings, most notably a dorsal stripe. Dun is a dominant trait, and yet most domestic horses are non-dun in colour and intensely pigmented. We show that Dun colour is established by radially asymmetric expression of the transcription factor TBX3 in hair follicles. This results in a microscopic spotting phenotype on the level of the individual hair, giving the impression of pigment dilution. Non-dun colour is caused by two different alleles, non-dun1 and non-dun2, both of which disrupt the TBX3-mediated regulation of pigmentation. Non-dun1 is associated with a SNP variant 5 kb downstream of TBX3, and non-dun2 with a 1.6 kb deletion that overlaps the non-dun1 SNP. Homozygotes for non-dun2 show a more intensely pigmented appearance than horses with one or two non-dun1 alleles. We have also shown by genotyping of ancient DNA that non-dun1 predates domestication.

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Sekar, Aswin. "A natural allelic series of complex structural variants and its influence on the risk of lupus and schizophrenia." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070061.

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The human genome's strongest influences on two common diseases, systemic lupus erythematosus (SLE) and schizophrenia, arise from genetic variation in the Human Leukocyte Antigen (HLA) locus. However, the genes and functional alleles driving these genetic relationships have remained unknown. We hypothesized that a complex, multi-allelic form of structural variation in the Complement component 4 (C4) gene, within the HLA locus, underlies these relationships. Loci that exist in many structural forms and vary widely in copy number have been difficult to analyze molecularly. As a result, we know little about their population genetic properties or their influence on phenotypes. In this work, we developed molecular and statistical methods to characterize such loci and to evaluate their contribution to phenotypes. Applying these methods to the C4 locus, we found that C4 segregates in four common and at least eleven low-frequency structural forms in human populations. Although there was only partial correlation between C4 structural variation and individual single nucleotide polymorphisms (SNPs), we developed an imputation approach to enable statistical prediction of C4 structural states from flanking SNP haplotypes. C4 structural variation associated to gene expression in lymphoblastoid cell lines and human brain tissue. Applying our imputation strategy to SLE and schizophrenia case-control cohorts totaling > 75,000 individuals, we found that structural variation in C4 contributes to risk of both phenotypes in a manner predicted by its effect on gene expression in relevant tissues, and with largely opposite directions of effect - alleles that were protective for schizophrenia increased risk for SLE, and vice versa. Leveraging a natural allelic series of C4 structural forms, we developed a novel form of association testing and showed that the association to C4 is unlikely to be caused by correlation with HLA SNPs. C4 was expressed in human neurons, whereas other upstream complement pathway genes were expressed primarily by microglia. Mice lacking C4 showed a deficit in synaptic pruning that was rescued by human C4. The methods developed in this thesis enable analysis of complex structural variation, and our results identify a novel form of genome variation as making a strong contribution to phenotypes.

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Soltys, Daniela Tathiana. "Análise da natureza genotípica de pacientes Xeroderma pigmentosum brasileiros." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/42/42132/tde-05082010-114429/.

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O NER é uma via de reparo de DNA capaz de lidar com uma ampla variedade de lesões. Participam do NER diversas proteínas, entre elas a endonuclease XPG. Pacientes que possuem mutações no gene XPG apresentam a síndrome XP, e em alguns casos XP/CS. Investigamos a natureza genética de dois pacientes XP-G, que são irmãos e apresentam fenótipo moderado. As células destes pacientes demonstraram alta sensibilidade à luz UVC. Quando expostas a um agente oxidativo, apenas células XP-G/CS exibiram sensibilidade. Identificamos duas mutações missense no gene XPG desses pacientes, e comparamos com outras mutações existentes. Observamos que as mutações possuem um impacto negativo na funcionalidade de XPG. A proteína com a mutação p.Ala28Asp exibiu uma atividade residual em testes de complementação. Os resultados indicam que o fenótipo XP-G desses pacientes é causado por duas mutações missense em heterozigose composta, e que células portadoras dessas alterações exibem respostas diferenciadas frente aos estresses genotóxicos causados pela luz UV e pelo agente oxidativo utilizado.
NER is the most flexible of all known DNA repair mechanisms. XPG is an endonuclease that participates in the final steps of NER. Mutations in this gene may result in the human syndrome XP and, in some cases, in the XP/CS. We investigated the genetic nature in two XP-G patients, siblings and mildly affected. The cells from these patients demonstrated the high UV sensitivity typical of this syndrome. When exposed to an oxidative agent, only XP-G/CS cells exhibited sensitivity. We identified two missense mutations in the XPG gene of these patients, and a comparison with other known mutations is presented. These mutations have a negative impact in the function of XPG. The protein harboring the mutation p.Ala28Asp exhibited residual activity in complementation tests. These results indicate that the phenotype of XP-G patients is caused by two missense mutations in a compound heterozygous manner, and that the cells carrying these alterations exhibit different responses against genotoxic stress caused by the UV light and by the oxidative agent used.

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Lim, Jeong-Eun. "Regulatory genetic variants in mental illness focus on serotonin-related genes /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1196198735.

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25

Tervasmäki, A. (Anna). "Hereditary predisposition to breast cancer:evaluating the role of rare copy number variant, protein-truncating and missense candidate alleles." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220826.

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Abstract Breast cancer is the most common cancer among women, and inherited predisposition is one of the major recognized causes of increased breast cancer risk. Only about half of the hereditary cases are explained by mutations in the known susceptibility genes, including the DNA damage response genes BRCA1, BRCA2 and PALB2, leaving the majority still uncovered. Identification of the missing genetic predisposing factors is important for more effective diagnostics and counseling of the risk families, and also for better understanding of the etiology and cellular characteristics of breast cancer. The first aim of this study was to investigate the cancer associations of six rare germline copy number variant (CNV) deletions, which were previously identified in breast cancer patients by a genome-wide microarray approach. The second aim was to identify novel susceptibility alleles, both protein-truncating variants and missense mutations, by next-generation sequencing (NGS) of nearly 800 DNA damage response genes in 189 hereditary breast cancer patients. The cancer-associations of all selected candidate alleles (6 CNVs, 39 protein-truncating variants and 35 missense mutations) were studied by case-control approach using DNA samples from several hundred breast cancer patients and healthy controls. The prevalence of the studied CNVs did not significantly differ between the cases and controls, but when studying the associations with specific clinical parameters, deletion in the CYP2C19 gene showed enrichment in the breast cancer patients with hormonally triple-negative tumors (p=0.021). As CYP2C19 functions in estrogen metabolism, the results indicate that disturbance of hormonal balance due to enzyme defects may predispose specifically to the estrogen receptor-negative subtype of breast cancer. Two protein truncating-variants, TEX15 c.7253dupT and FANCD2 c.2715+1G>A showed significant breast cancer association in the Northern Finnish cohort (p=0.018 and p=0.036, respectively). Similarly, two of the studied missense variants, RECQL p.Ile156Met (p=0.043) and POLG p.Leu392Val (p=0.010), were enriched in the breast cancer cases. Thus, this study provided novel connections between increased breast cancer risk and inherited mutations in TEX15, FANCD2 and POLG genes, and further supported the recently established role of RECQL as a breast cancer susceptibility gene
Tiivistelmä Rintasyöpä on naisten yleisin syöpä, ja perinnöllinen alttius on yksi merkittävimmistä sairastumisriskiin vaikuttavista tekijöistä. Tunnetuimpia alttiustekijöitä ovat mutaatiot BRCA1-, BRCA2- ja PALB2-DNA-vauriovastegeeneissä, mutta ne yhdessä muiden altistavien geenimutaatioiden kanssa selittävät kuitenkin vain noin puolet perinnöllisistä rintasyöpätapauksista. Uusien alttiusgeenien löytäminen mahdollistaa tehokkaamman diagnostiikan ja korkeassa syöpäriskissä olevien sukujen perinnöllisyysneuvonnan, sekä auttaa ymmärtämään syvemmin rintasyövän etiologiaa ja syntymekanismeja solutasolla. Tämän väitöskirjan ensimmäisenä päämääränä oli tutkia tarkemmin aiemmin genominlaajuisella mikrosirumenetelmällä rintasyöpäpotilailta tunnistettujen harvinaisten perinnöllisten DNA-kopiolukuvariaatioiden (CNV) yhteyttä rintasyöpäriskiin. Toisena tavoitteena oli tunnistaa uusia rintasyöpäalttiusalleeleja, sekä proteiinitrunkaatioita että missense-mutaatioita, hyödyntämällä uuden sukupolven sekvensointitekniikkaa, jonka avulla tutkittiin mutaatioita lähes 800 DNA-vauriovastegeenistä 189 pohjoissuomalaiselta rintasyöpäpotilaalta. Valittujen kandidaattialleelien (6 deleetion aiheuttavaa CNV:tä, 39 proteiinitrunkaatiota ja 35 missense-mutaatiota) yhteyttä rintasyöpään tutkittiin tapaus-verrokkimenetelmällä käyttäen DNA-näytteitä usealta sadalta rintasyöpäpotilaalta ja terveeltä kontrollihenkilöltä. Tutkittujen CNV:iden esiintyvyydessä ei ollut merkitseviä eroja potilaiden ja kontrollien välillä, mutta tarkasteltaessa yhteyttä potilaiden kasvaimista saatuihin kliinisiin parametreihin, deleetio CYP2C19-geenissä oli yleisempi hormonaalisesti kolmoisnegatiivisissa rintatuumoreissa kuin muissa tuumorityypeissä (p=0.021). Koska CYP2C19 on estrogeenimetaboliaan osallistuva entsyymi, sen viallinen toiminta voi mahdollisesti altistaa erityisesti estrogeenireseptorinegatiiviselle rintasyövälle. Kaksi tutkituista proteiinitrunkaatioista, TEX15 c.7253dupT ja FANCD2 c.2715+1G>A, olivat rikastuneet perinnöllisessä rintasyöpäpotilasaineistossa verrattuna kontrolleihin (p=0.018 ja p=0.036). Myös kaksi missense-alleelia, RECQL p.Ile156Met (p=0.043) ja POLG p.Leu392Val (p=0.010), olivat yleisempiä rintasyöpäpotilailla. Tulokset osoittivat uuden yhteyden kohonneen rintasyöpäriskin ja perinnöllisten muutosten TEX15-, FANCD2- ja POLG-geenien välillä, sekä tukivat aiempia tutkimustuloksia, joiden mukaan RECQL on kohtalaisen riskin rintasyöpäalttiusgeeni

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26

Zhang, Ying. "Exploring functional genetic variants in genes involved in mental disorders." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1186433668.

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27

Zuchowska, Magdalena Anna [Verfasser]. "Bedeutung von allelen Varianten des Hexose-Transporters Hxt3p und der Hexokinasen Hxk1p und Hxk2p für Aufnahme und Verwertung von Glucose und Fructose durch Weinhefen / Magdalena Anna Zuchowska." Mainz : Universitätsbibliothek Mainz, 2015. http://d-nb.info/1077801629/34.

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Grievink, Hilbert. "Malignant hyperthermia: allele specific expression and mutation screening of the ryanodine receptor 1 : a dissertation presented to Massey University in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry." Massey University, 2009. http://hdl.handle.net/10179/1051.

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Malignant hyperthermia (MH) is a dominant skeletal muscle disorder caused by mutations in the ryanodine receptor skeletal muscle calcium release channel (RyR1). Allele-specific differences in RyR1 expression levels might provide insight into the observed incomplete penetrance and variations in MH phenotypes between individuals. Firstly, an H4833Y allele-specific PCR (AS-PCR) assay was designed that allowed for the relative quantification of the two RYR1 mRNA alleles in heterozygous samples. In four MHS skeletal muscle samples and two lymphoblastoid cell lines (LCLs), the wild type allele was found to be expressed at higher levels than the mutant RyR1 allele. These differences were not caused by variations in RYR1 mRNA stabilities. Secondly, high-throughput amplicon sequencing was employed for the quantification of both the T4826I and H4833Y causative MH mutations in heterozygous MHS samples. With the exception of one, all detected H4833Y and T4826I mutation frequencies were about 50%. This included a control, which was constructed and proven to have a 3:1 ratio of the wild type (H4833) versus the mutant (Y4833) RYR1 allele. This suggested that that the high-throughput amplicon sequencing approach as used here, was not suitable for accurate quantification of the two RyR1 alleles in heterozygous H4833Y MHS samples. To detect possible variations in RyR1 alleles at the protein level, the RyR1 was to be isolated from microsomes prepared from a H4833Y MHS frozen skeletal muscle tissue. Microsomes isolated from MHS skeletal muscle tissues lacked the immunoreactive band that was believed to be the full length RyR1. Poor muscle quality, due to long term storage was believed to be the main cause of RyR1 depletion. Faster and less expensive screening methodologies are required for the identification of genetic variants in MH research. Thus, in an additional project inexpensive and high-throughput high-resolution melting (HRM) assays were developed to allow screening of the RYR1 gene, for mutations associated with MH and/or central core disease (CCD).

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Rivas, Cruz Manuel A. "Medical relevance and functional consequences of protein truncating variants." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:a042ca18-7b35-4a62-aef0-e3ba2e8795f7.

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Genome-wide association studies have greatly improved our understanding of the contribution of common variants to the genetic architecture of complex traits. However, two major limitations have been highlighted. First, common variant associations typically do not identify the causal variant and/or the gene that it is exerting its effect on to influence a trait. Second, common variant associations usually consist of variants with small effects. As a consequence, it is more challenging to harness their translational impact. Association studies of rare variants and complex traits may be able to help address these limitations. Empirical population genetic data shows that deleterious variants are rare. More specifically, there is a very strong depletion of common protein truncating variants (PTVs, commonly referred to as loss-of-function variants) in the genome, a group of variants that have been shown to have large effect on gene function, are enriched for severe disease-causing mutations, but in other instances may actually be protective against disease. This thesis is divided into three parts dedicated to the study of protein truncating variants, their medical relevance, and their functional consequences. First, I present statistical, bioinformatic, and computational methods developed for the study of protein truncating variants and their association to complex traits, and their functional consequences. Second, I present application of the methods to a number of case-control and quantitative trait studies discovering new variants and genes associated to breast and ovarian cancer, type 1 diabetes, lipids, and metabolic traits measured with NMR spectroscopy. Third, I present work on improving annotation of protein truncating variants by studying their functional consequences. Taken together, these results highlight the utility of interrogating protein truncating variants in medical and functional genomic studies.

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Taerk, Evan. "Modulation of executive function in children with Attention DeficitHyperactivity Disorder by allelic variants of the catechol-O-methyltransferase gene and three varying doses of methylphenidate." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84079.

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An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children. Furthermore, since methylphenidate (MPH), the primary pharmacological drug in ADHD, may exert its effects, at least in part, through PFC dopaminergic pathways, we investigated the relationship between the COMT polymorphism and acute neuropsychological and behavioural response to three varying doses of MPH. Children with ADHD showed improvement on measures of both cognitive and motor behaviours under MPH, although improvement within each functional domain appeared to follow distinctive dose-response patterns possibly reflecting different neurobiological pathways. No genotype effects were observed on any measures of cognitive or motor behaviour or on the response of cognitive or motor behaviours to MPH.

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Raud, Loann. "De la variabilité génétique à l’expression phénotypique des groupes sanguins : exemple du système Rh From genetic variability to phenotypic expression of blood group systems, in Transfusion Clinique et biologique 24(4), November 2017 Functional analysis of novel RHD variants: splicing disruption is likely to be a common mechanism of variant D phenotype, in Transfusion 59(4), April 2019 Weak D type 1, 2 and 3 subtype alleles are rare in the Western French population, in Transfusion medicine 29(3), June 2019." Thesis, Brest, 2020. http://www.theses.fr/2020BRES0012.

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Le système Rh est le système sanguin érythrocytaire le plus complexe et le plus poly morphe. Il est sous le contrôle de deux gènes homo logues RHD et RHCE et comporte 55 antigènes, parmi lesquels l’antigène D, porté par la protéine RhD, est le plus immunogène et présente un intérêt majeur en terme de Santé Publique. Actuellement, plusieurs centaines d’allèles variants sont répertoriés dans le gène RHD, qui se traduisent par une grande variabilité phénotypique de l’expression de l’antigène D. La plupart du temps, le typage sanguin des individus porteurs d’un variant de l’antigène D n’est souvent pas réalisable par des approches sérologiques, il faut alors avoir recours à des analyses moléculaires pour identifier les anomalies potentielles et déduire le phénotype correspondant. Néanmoins, l’interprétation de ces variants rares et de leurs conséquences sur l’expression de l’antigène demeurent souvent difficiles. Dans ce travail, nous nous sommes intéressés, plus spécifiquement à trois catégories de variants : les variants d’épissage, les variants synonymes et les variants faux-sens. Nous avons étudié l’impact moléculaire et cellulaire de ces variants en développant des approches de génétiques fonctionnelles et observé leurs effets respectifs sur l’altération de l’épissage et/ou sur l’expression de l’antigène D. Ces travaux ont per mis d’avoir une vision globale des différents mécanismes moléculaires impliqués dans la variabilité génétique du système Rh, en particulier sur l’interprétation des variants rares affectant les sites canoniques et les éléments régulateurs de l’épissage, par une approche minigène développée dans notre laboratoire. Puis, au-delà de l’intérêt fondamental de la caractérisation fonctionnelle de ces variants, en association avec les analyses sérologiques, elle présente un intérêt diagnostique dans l’interprétation fonctionnelle de certains phénotypes ambigus et ainsi guider le biologiste dans la prise en charge de la transfusion et de la grossesse
Rh system is the most complex and polymorphic blood group system. It’s driven by two homologous genes RHD and RHCE and contains 55 antigens, including the D antigen, carried by the RhD protein, is the most immunogenic and has a major interest in terms of public health. Currently, several hundred variants alleles are listed in the RHD gene, resulting in high phenotypic variability of the D antigen expression. In most cases, blood typing of individuals with a D variant is often not available by serological approaches, so molecular analyses should be used to identify potential defects and deduce the corresponding phenotype. Nevertheless, the interpretation of these rare variants and their consequences on the antigen expression often remain difficult. In this work, we are more specifically interested in three categories of variants: splicing variants, synonymous variants and missense variants. We studied the molecular and cellular impact of these variants by developing functional genetic approaches and observed their respective effects on the splicing alteration and/or on the D antigen expression. This work has provided an overview of the different molecular mechanisms involved in the genetic variability of the Rh system, in particular the interpretation of rare variants affecting the canonical splice sites and the splicing regulatory elements, using a minigene splicing assay developed in our laboratory. Then, beyond the fundamental interest of the functional characterization of these variants, in association with serological analyses, it presents a diagnostic interest in the functional interpretation of certain ambiguous phenotypes. Then, beyond the fundamental interest of the functional characterization of these variants, in association with serological analyses, it presents a diagnostic interest in the functional interpretation of certain ambiguous phenotypes and thus guide the biologist in the management of transfusion and pregnancy

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Modén, Olof. "Mutational Analysis and Redesign of Alpha-class Glutathione Transferases for Enhanced Azathioprine Activity." Doctoral thesis, Uppsala universitet, Biokemi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-167332.

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Glutathione transferase (GST) A2-2 is the human enzyme most efficient in catalyzing azathioprine activation. Structure-function relationships were sought explaining the higher catalytic efficiency compared to other alpha class GSTs. By screening a DNA shuffling library, five recombined segments were identified that were conserved among the most active mutants. Mutational analysis confirmed the importance of these short segments as their insertion into low-active GSTs introduced higher azathioprine activity. Besides, H-site mutagenesis led to decreased azathioprine activity when the targeted positions belonged to these conserved segments and mainly enhanced activity when other positions were targeted. Hydrophobic residues were preferred in positions 208 and 213. The prodrug azathioprine is today primarily used for maintaining remission in inflammatory bowel disease. Therapy leads to adverse effects for 30 % of the patients and genotyping of the metabolic genes involved can explain some of these incidences. Five genotypes of human A2-2 were characterized and variant A2*E had 3–4-fold higher catalytic efficiency with azathioprine, due to a proline mutated close to the H-site. Faster activation might lead to different metabolite distributions and possibly more adverse effects. Genotyping of GSTs is recommended for further studies. Molecular docking of azathioprine into a modeled structure of A2*E suggested three positions for mutagenesis. The most active mutants had small or polar residues in the mutated positions. Mutant L107G/L108D/F222H displayed a 70-fold improved catalytic efficiency with azathioprine. Determination of its structure by X-ray crystallography showed a widened H-site, suggesting that the transition state could be accommodated in a mode better suited for catalysis. The mutational analysis increased our understanding of the azathioprine activation in alpha class GSTs and highlighted A2*E as one factor possibly behind the adverse drug-effects. A successfully redesigned GST, with 200-fold enhanced catalytic efficiency towards azathioprine compared to the starting point A2*C, might find use in targeted enzyme-prodrug therapies.

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(13991187), Joseph W. Daley. "Mixed model methods for quantitative trait loci estimation in crosses between outbred lines." Thesis, 2003. https://figshare.com/articles/thesis/Mixed_model_methods_for_quantitative_trait_loci_estimation_in_crosses_between_outbred_lines/21376767.

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Methodology is developed for Quantitative Trait Loci (QTL) analysis in F₂ and backcross designed experiments between outbred lines using a mixed model framework through the modification of segment mapping techniques. Alleles are modelled in the F₁ and parental generations allowing the estimation of individual additive allele effects while accounting for QTL segregation within lines as well as differences in mean QTL effects between lines.

Initially the theory, called F₁ origin mapping, is developed for a single trait scenario involving possible multiple QTL and polygenic variation. Additive genetic variances are estimated via Restricted Maximum Likelihood (REML) and allele effects are modelled using Best Linear Unbiased Prediction (BLUP). Simulation studies are carried out comparing F₁ origin mapping with existing segment mapping methods in a number of genetic scenarios. While there was no significant difference in the estimation of effects between the two methods the average CPU time of one hundred replicates was 0.26 seconds for F₁ origin mapping and 3.77 seconds for the segment mapping method. This improvement in computation efficiency is due to the restructuring of IBD matrices which result in the inversion and REML iteration over much smaller matrices.

Further theory is developed which extends F₁ origin mapping from single to multiple trait scenarios for F₂crosses between outbred lines. A bivariate trait is simulated using a single QTL with and without a polygenic component. A single trait and bivariate trait analysis are performed to compare the two approaches. There was no significant difference in the estimation of QTL effects between the two approaches. However, there was a slight improvement in the accuracy of QTL position estimates in the multiple trait approach. The advantage of F₁ origin mapping with regard to computational efficiency becomes even more important with multiple trait analysis and allows the investigation of interesting biological models of gene expression.

F₁ origin mapping is developed further to model the correlation structure inherent in repeated measures data collected on F₂ crosses between outbred lines. A study was conducted to show that repeated measures F₁ origin mapping and multiple trait F₁ origin mapping give similar results in certain circumstances. Another simulation study was also conducted in which five regular repeated measures where simulated with allele breed difference effects and allele variances increasing linearly over time. Various polynomial orders of fit where investigated with the linear order of fit most parsimoniously modelling the data. The linear order of fit correctly identified the increasing trend in both the additive allele difference and allele variance. Repeated measures F₁ origin mapping possesses the benefits of using the correlated nature of repeated measures while increasing the efficiency of QTL parameter estimation. Hence, it would be useful for QTL studies on measurements such as milk yield or live weights when collected at irregular intervals.

Theory is developed to combine the data from QTL studies involving F₂ and backcross designed experiments. Genetic covariance matrices are developed for random QTL effects by modelling allele variation in the parental generation instead of the offspring generation for an F₂and backcross between outbred lines. The result is a general QTL estimation method called parental origin mapping. Phenotypes and genotypes from such a study involving Romney and Merino sheep are analysed providing evidence for a QTL affecting adult and hogget fibre diameter.

By coupling these new methods with computer software programs such as ASREML, F₁ origin mapping and parental origin mapping provide powerful and flexible tools for QTL studies with the ability to efficiently handle single traits, multiple traits and repeated measures.

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Alsaedi, Sakhaa. "Evaluating the Application of Allele Frequency in the Saudi Population Variant Detection." Thesis, 2020. http://hdl.handle.net/10754/662641.

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Human Mendelian disease in Saudi Arabia is both significant and challenging. Next-generation sequencing (NGS) has resulted in important discoveries of the genetic variants responsible for inherited disease. However, the success of clinical genomics using NGS requires accurate and consistent identification of rare genome variants. Rarity is one very important criterion for pathogenicity. Here we describe a model to detect variants by analyzing allele frequencies of a Saudi population. This work will enhance the opportunity to improve variant calling workflow to gain robust frequency estimates in order to better detect rare and unusual variants which are frequently associated with inherited disease.

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Rosli, Nordiana. "Functional characterisation of putative Cis-Regulatory Risk Loci for breast cancer." Master's thesis, 2015. http://hdl.handle.net/10400.1/8544.

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Dissertação de Mestrado, Qualidade em Análises - Erasmus Mundus, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2015
At present, 94 breast cancer susceptibility loci have been discovered from genome-wide association studies (GWAS). The next step is to identify the causal risk variant, the target gene and to understand the underlying disease mechanism. Studies revealed that most of the variants discovered by GWAS are cis-acting regulatory. Cis-acting regulatory variants can be identified most efficiently by differential allelic expression (DAE) analysis. A DAE genome-wide mapping was done in normal breast tissue, which was cross-compared with GWAS breast cancer data. 19 loci associated with risk and with evidence of cis-regulation were identified, including the 5q14.2 locus that has one SNP associated with risk - rs7707921, and five SNPs displaying DAE across three genes: ATG10, RPS23 and ATP6AP1L. The aim of this thesis is to set out to map the regulatory variants responsible for the DAE signals in the 5q14.2 locus and to determine which one(s) is (are) associated with risk for breast cancer. We performed in silico analysis using data obtained through publically accessible databases, to identify candidate regulatory SNPs (rSNPs) that could be responsible for the DAE and determine if they may be associated with risk to breast cancer. Experimental in vitro analysis by EMSA and analysis of available ChIP-seq data was also conducted in order to investigate possible interactions between candidate rSNPs and transcription factors (TFs). In this study, three SNPs rs226198, rs6880209 and rs17247678 were identified as potential cis-acting regulators of ATG10, RPS23 and ATP6AP1L. Henceforth, we propose a risk model based on our findings: Binding of c-Myc and POL2 to the common allele of rs226198 and rs6880209 lead to over expression of RPS23 and under expression of ATG10, respectively, whereas, binding of STAT3 and c-FOS to rs17247678 lead to under expression of ATP6AP1L, increasing the risk for breast cancer.
Erasmus Mundus

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Fiala, Ondřej. "Genetika a fenotypová charakteristika Parkinsonovy nemoci s časným začátkem." Doctoral thesis, 2014. http://www.nusl.cz/ntk/nusl-332551.

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Objective: Mutations in the parkin (PARK2) gene have been associated with autosomal recessive early-onset Parkinson's disease (EOPD) with various frequencies in different populations. The aim of the study is to describe phenotypic characteristics of Czech EOPD patients, to evaluate the influence of environmental risk factors, and to determine the frequency of parkin allelic variants in patients and healthy controls. Methods: A total of 70 EOPD patients (age at onset ≤ 40 years) and 75 controls were phenotyped and screened for the sequence variants and exon rearrangements in the parkin gene. Results: The main features in the phenotype of the patients' sample were: the absence of cognitive deficit, high occurrence of dystonia, depression, hyperhidrosis, an excellent response to dopaminergic therapy, early onset of dyskinesia and motor fluctuation. Patients with mutations in the parkin gene had significantly lower age at onset. The agricultural occupation and work with chemicals increased the risk of EOPD, however the coffee drinking appeared to be a protective factor. Parkin mutations were identified in five patients (7.1%): the p.R334C point mutation was present in one patient, four patients had exon deletions. The detected mutations were observed in the heterozygous state except one homozygous...

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Dissertations / Theses on the topic 'Allele variances'

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