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1
Bruiners, Natalie. "Molecular genetic analysis of preterm labour." Thesis, Stellenbosch : Stellenbosch University, 2007. http://hdl.handle.net/10019.1/17741.
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Thesis (MSc)--University of Stellenbosch, 2007.ENGLISH ABSTRACT: The World Health Organisation (WHO) has defined preterm labour as the onset of labour before 37 completed weeks of gestation with an incidence ranging between 5-10%. Although patient care has improved, the rate of preterm birth has slowly been increasing and currently impacts significantly on maternal and fetal mortality and morbidity. The complex condition of preterm labour involves multiple etiologies and risk factors, which complicates the search for candidate markers and / or biomarkers. The aim of this prospective study was to investigate potential genetic associations with preterm labour. The study cohort consisted of consecutive first-time booking, low-risk primigravid pregnant women from a restricted geographical region. The study cohort comprised 421 [306 Coloured and 115 Black] pregnant women presenting at the Paarl Hospital Obstetric clinic. Subsequently, DNA was extracted from whole blood and investigated for a range of known polymorphisms in pro-inflammatory and anti-inflammatory cytokines, as well as the novel LGALS13 gene, for potential variants that may impact on pregnancy outcome. Screening techniques involve combinations of allele-specific PCR amplification, Multiphor SSCP/HD analysis, restriction enzyme analyses and DNA sequencing. A significant association was demonstrated between the IL-1RN*2-allele and adverse pregnancy outcome, mainly in the preterm labour and hypertension group. The presence TNFα-308 A-allele was associated with overall adverse pregnancy outcome and preterm labour. In addition to this, a novel IL-1RN allele was identified in the control group. Mutation screening and subsequent statistical methods revealed an association between a novel LGALS13 exonic variant, 221delT, and preterm labour in Coloured women. Two previouslydocumented intronic variants (IVS2-22A/G and IVS3+72T/A) demonstrated linkage disequilibrium, signifying evolutionary conservation of exon three. Additionally, two novel intronic variants, IVS2-36 G/A and IVS2-15 G/A, demonstrated no association with adverse pregnancy outcome. In this study we identified rare novel exonic variants; two non-synonymous variants in exon three (M44V, [N=2] and K87R, [N=1]) and a silent variant in exon four (P117P, [N=1]) - all identified in individuals from the control cohort. Within coding exon three, an interesting variant [“hotspot”] was identified, which represents six polymorphic bases within an 11bp stretch. No associations were demonstrated with these variants and pregnancy outcome. Furthermore, a previously documented 5' “‘promoter” variant, -98 A/C, was identified and demonstrated no association with adverse pregnancy outcome. However, subdivision of lateonset pre-eclamptic cases revealed a significant association with the A-allele and late-onset preeclampsia. Genotype-phenotype investigation demonstrated association between the IL-10 -1082 A/G, IL-4 C/T and 221delT loci and poor pregnancy progress which manifested as (i) delivery of infants weighing <2000g, (ii) before 37 weeks of gestation. The findings of this study will strengthen our understanding of the pathophysiology underlying pregnancy complications and facilitate the further development of effective treatment strategies to reduce maternal and fetal morbidity and mortality.
AFRIKAANSE OPSOMMING: Die Wêreld Gesondheid Organisasie (WHO) klassifiseer voortydse kraam as kontraksie voor 37 volledige weke, met ‘n insidensie tussen 5-10%. Alhoewel pasiënte-sorg verbeter het, neem die tempo van voortydse geboorte steeds toe, wat ‘n groot impak het op moederstrefte en fetale mortaliteit en morbiditeit. Die komplekse kondisie van voortydse kraam sluit veelvoudige oorsake en risiko faktore in, wat die navorsing van kandidaat en / of biologiese merkers kompliseer. Die doel van hierdie prospektiewe studie, was die potensiële navorsing van genetiese assosiasies met voortydse kraam. Die studie kohort bevat opeenvolgende eerste bespreking van lae risiko primigravida swanger vrouens vanaf ‘n beperkte geografiese omgewing. Die studie kohort beslaan 421 [306 Kleurling en 115 Swart] swanger vrouens teenwoordig by die Paarl Hospitaal Verloskunde kliniek. Vervolgens was DNS geëkstraeer van bloedmonsters en geondersoek vir ‘n verskeidenheid van bekende polimorfismes in pro-inflammatoriese en antiinflammatoriese sitokiene, insluitend die nuwe sifting van die LGALS13 geen potensiaal vir variante wat ‘n impak op swangerskap uitkomste sal hê. Die siftings tegnieke toegepas, sluit in ‘n kombinasie van alleel-spesifieke amplifikasie, Multiphor enkelstring konformasie polimorfisme / heterodupleks analise, restriksie ensiem verterings en volgorde bepalings tegnieke. ‘n Betekenisvolle assosiasie was gedemonstreer tussen die IL-1RN*2-alleel en nadelige swangerskap, beperk tot voortydse kraam en die hipertensie groep. Die teenwoordigheid van die TNFα-308 A-alleel was geassosieer met algehele nadelige uitkomste en voortydse kraam. Daarby, was ‘n nuwe IL-1RN alleel geïdentifiseer in die kontrole groep. Mutasie sifting en opeenvolgende statistiese metodes, het ‘n assosiasie getoon tussen ‘n nuwe LGALS13 koderende variant, 221delT, en voortydse kraam in Kleurling vrouens. Twee voorafbeskryfde introniese variante (IVS2-22 A/G en IVS3+72 T/A), het ‘n betekenisvolle bewys opgelewer dat daar koppelings-onewewig bestaan tussen hierdie variante, en toon evolusionêre konservasie van ekson drie. Addisioneel was twee nuwe introniese variante ontdek, IVS2-36 G/A en IVS2-15 G/A, wat geen assosiasie getoon nie. In hierdie studie het ons ‘n nuwe seldsame koderende variante geïdentifiseer in die kontrole groep, waarvan twee nie-sinonieme variante was in ekson drie (M44V, N=2 en K87R, N=1) en ‘n stil variasie in ekson vier (P117P, N=1). Geleë in die koderende area van ekson drie, was ’n interessante variant [“hotspot’] ontdek, waarvan ses basisse in ‘n 11 basis paar area polimorfies is. Geen assosiasie was getoon met hierdie variante en swangerskap uitkomste nie. Verder was ‘n voorafbeskryfde 5' ‘promotor’ variant, -98 A/C, geïdentifiseer wat geen assosiasie getoon met nadelige swangerskap uitkomste nie. Onderverdeling van laat-aanvangs preeklampsie, het getoon dat die A-alleel ‘n betekenisvolle assosiasie getoon het met die ontwikkeling van laat pre-eklampsie. Genotipe-fenotipe interaksies het ’n assosiasie getoon tussen die IL-10 -1082 A/G, IL-4 C/T en 221delT lokusse en nadelige swangerskap uitkomste, wat manifesteer as (i) kraam van suigelinge wat <2000g weeg, (ii) geboorte voor 37 weke. Die bevindings van hierdie studie sal ons basiese kennis verbeter oor die patologie beskrywend aan swangerskap komplikasies, asook die fasilitering en ontwikkeling van effektiewe behandelings strategieë, om moederstrefte en fetale mortaliteit en morbiditeit te verminder.
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Fourie, Mariesa. "Molecular characterization and further shortening of recombinant forms of the Lr19 translocation." Thesis, Link to the online version, 2005. http://hdl.handle.net/10019/189.
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Hedmark, Eva. "Conservation Genetics of Scandinavian Wolverines." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6636.
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Howell, Viive Maarika. "Molecular Genetics of Hyperparathyroidism." University of Sydney, 2005. http://hdl.handle.net/2123/6022.
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Doctor of Philosophy(PhD)Hyperparathyroidism, a disease of the parathyroid glands, is one of the most common endocrinopathies, having a prevalence of 1 – 3 per 1000 individuals. It is characterised by calcium insensitive hypersecretion of parathyroid hormone, and increased cell proliferation. While the treatment for familial as well as many sporadic tumours associated with hyperparathyroidism includes parathyroidectomy, the extent of surgery and the follow-up monitoring regime, are dependent on accurate clinical and histopathological classification of the lesion. However, overlaps in histopathological and morphological features confound distinctions between the three main classifications of adenoma, hyperplasia and carcinoma and differential diagnosis of these lesions remains challenging. At the start of this candidature in January 2002, the genes associated with two familial syndromes in which hyperparathyroidism may feature, Multiple Endocrine Neoplasia (MEN) 1 and 2 had been identified, respectively MEN1 and RET. In addition, overexpression or translocation of cyclin D1 had been identified in both benign and malignant sporadic lesions, indicating a role for cyclin D1 in parathyroid tumorigenesis. However, the underlying events leading either directly, or indirectly, to the development of a large proportion of parathyroid lesions are still largely unknown. The work described in this thesis has contributed to the understanding of parathyroid lesions and the diagnosis and prognosis of affected individuals. During this candidature, constitutive mutation of HRPT2 was associated with Hyperparathyroidism–Jaw Tumour syndrome (HPT-JT). HRPT2 mutation analysis and loss of heterozygosity studies at 1q24-32 in parathyroid tumours presented in this thesis identified the strong association of HRPT2 mutation with sporadic parathyroid malignancy. In addition, 2-hits affecting HRPT2 were identified in several tumours suggestive of a role for HRPT2 as a tumour suppressor gene in sporadic parathyroid tumorigenesis. Microarray analysis of parathyroid tumours presented in this thesis identified three broad clusters of tumours. Cluster 1 comprised predominantly hyperplastic specimens and also included the normal tissue. Cluster 2, the most robust of the clusters, consisted of tumours harbouring HRPT2 mutations. The HPT-JT-associated tumours, both benign and malignant, and sporadic carcinomas, comprised this cluster. Cluster 3 contained the majority of the sporadic adenoma specimens, some hyperplasia, as well as all of the MEN 1-associated tumours. The cluster data is strongly suggestive that parathyroid tumours with somatic HRPT2 mutation, or tumours developing on a background of germline HRPT2 mutation, follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumours. The results of this work provide strong evidence for an adenoma to carcinoma progression model for parathyroid tumorigenesis in the presence of a germline HRPT2 mutation. With the knowledge that both HRPT2 and MEN1 have significant roles in familial as well as sporadic parathyroid tumorigenesis, assays for mutation screening of these two genes have been developed as part of this thesis. These assays will facilitate a rapid molecular diagnosis for patients with one of these familial syndromes. Furthermore, novel putative biomarkers for different parathyroid tumour subtypes have also been identified. VCAM1 and UCHL1 (PGP9.5) were found to be significantly overexpressed in tumours harbouring an HRPT2 mutation at both the transcript and protein level. These two molecules are suggested as putative biomarkers for the discrimination of sporadic carcinoma or HPT-JT-associated tumours. RALDH2 transcript and protein were highly significantly overexpressed in the hyperplasia class relative to the adenoma class, and this molecule is suggested as a putative biomarker for discrimination of these classes of parathyroid tumours. These biomarkers may assist in the accurate diagnosis and prognosis of hyperparathyroidism. Large cohort studies of these putative biomarkers will be required to determine their robustness in discriminating parathyroid tumour subtypes. Further studies of their putative role in parathyroid tumorigenesis may identify them as novel molecular targets for future therapeutics to treat both hyperplastic and neoplastic parathyroid lesions.
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Wallace, Robyn. "Molecular genetics of epilepsy /." Title page, contents and summary only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phw193.pdf.
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Thesis (Ph. D.)--University of Adelaide, Dept. of Paediatrics, 1997.Errata pasted onto back end-paper. Copies of author's previously published articles inserted. Includes bibliographical references (leaves 157-176).
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Busfield, Frances. "Molecular genetics of dementia." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336329.
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Hill, Margaret J. "Molecular genetics of tabtoxin." Thesis, University of East Anglia, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292600.
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Asumalahti, Kati. "Molecular genetics of psoriasis." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/asumalahti/.
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Law, Bic-fai Fian, and 羅璧輝. "Molecular genetics of esophageal squamous cell carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B3660446X.
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Sjödin, Per. "Effects of Selection and Demography on DNA Polymorphism in Black Mustard (Brassica nigra)." Doctoral thesis, Uppsala universitet, Evolutionär funktionsgenomik, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6633.
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The evolution of three genes from the CONSTANS-LIKE gene family is studied in Brassica nigra. We use a combination of population genetic and phylogenetic techniques in order to assess the relative importance of selection and demography on the pattern of DNA variation. The analysis is complicated by the fact that they are recent duplicates of each other and hence there is a potential redundancy factor that has to be considered. The relationship between two of the genes, COa and COb, is however much closer than between any relationship to the third gene, COL1. The three genes are all suspected to play a part in the natural variation of flowering time of B. nigra. The thesis consists of four papers. The first paper is a technical paper concerning when and if the existence of an effective population size can be assumed. More specifically, the impact of population structure and a fluctuating (census) population size on the standard coalescent is studied. The second paper is a population genetic study of B. nigra using micro-satellites and RFLP. The resulting population genetic structure is argued to reflect the early spread of agriculture in Europe. In the third paper the general evolution of the three genes is studied. We find that not all aspects of the data could be accounted for by demography or redundancy effects, but that selection most likely played a part in the evolution of these genes. The fourth paper concerns the functional status of COb, whether it is a pseudogene or not. The most likely scenario is that COb recently became non-functional due to the fixation of a deleterious mutation during a recent bottleneck.
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Bitalo, Daphne Nyachaki. "Implementation of molecular markers for triticale cultivar identification and marker-assisted selection." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/71670.
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Thesis (MSc)--Stellenbosch University, 2012.Triticale is an amphidiploid that consists of wheat (A and B) and rye (R) genomes. This cereal is fast becoming important on a commercial basis and warrants further assessment for the better management and breeding of the hybrid. The assessment of the genetic diversity among the wheat and rye genomes within triticale can be obtained by using molecular markers developed in both donor genomes. Simple sequence repeats markers (SSRs) and amplified fragment length markers (AFLPs) have been previously used to assess the genetic diversity among triticale lines. SSRs are highly polymorphic markers that are abundant and which have been shown to be highly transferable between species in previous studies while AFLP markers are known to generate plenty of data as they cover so many loci. Thus, the aim of this study was to develop a marker system suitable to assess the genetic diversity and relationships of advanced breeding material (and cultivars) of the Stellenbosch University’s Plant Breeding Laboratory (SU-PBL). Therefore, both AFLP and SSR markers were initially analysed using eight triticale cultivars (with known pedigrees) to facilitate cultivar identification. Fourty-two AFLP primer combinations and 86 SSR markers were used to assess the genetic diversity among the Elite triticale cultivars. The AFLP primer combinations generated under average polymorphism information content (PIC) values. Furthermore, these markers generated neighbour-joining (NJ) and unweighted pair group method with arithmetic average (UPGMA) dendograms that displayed relationships that did not correspond with the available pedigree information. Therefore, this marker system was found not to be suitable. A set of 86 SSRs previously identified in both wheat and rye, was used to test the genetic diversity among the eight cultivars. The markers developed in wheat achieved 84% transferability while those developed in rye achieved 79.3% transferability. A subset of SSR markers was able to distinguish the cultivars, and correctly identify them by generating NJ and UPGMA dendograms that exhibited relationships that corroborated the available pedigree data. This panel of markers was therefore chosen as the most suitable for the assessment of the advanced breeding material. The panel of seven SSR markers was optimised for semi-automated analysis and was used to screen and detect the genetic diversity among 306 triticale entries in the F6, Senior and Elite phases of the SU-PBL triticale breeding programme. An average PIC value of 0.65 was detected and moderate genetic variation was observed. NJ and UPGMA dendograms generated showed no clear groupings. However, the panel of markers managed to accurately identify all cultivars within the breeding program. The marker panel developed in this study is being used to routinely distinguish among the advanced breeding material within the SU-PBL triticale breeding programme and as a tool in molecular-assisted backcross.
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Soler, del Monte Marçal. "Molecular genetics of cork formation." Doctoral thesis, Universitat de Girona, 2008. http://hdl.handle.net/10803/7629.
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La peridermis és una estructura complexa que protegeix els òrgans vegetals madurs (secundaris) i les zones que han sofert ferides de la pèrdua d'aigua i dels patògens. Aquesta funció barrera és deguda al fel·lema o súber, un teixit format per cèl·lules suberificades. Tant el fel·lema com la suberina són crucials per la vida de les plantes terrestres, però pràcticament no es coneix res dels processos moleculars que regulen la seva formació, probablement degut a la manca de models adequats. En aquesta tesi s'han identificat i caracteritzat gens induïts al fel·lema mitjançant la combinació de dues plantes models. L'escorça d'alzina surera (Quercus suber) s'ha utilitzat per aïllar gens candidats de la formació del fel·lema i per investigar el comportament d'alguns d'aquests gens durant l'estació de creixement, mentre que la pela de la patata (Solanum tuberosum) s'ha utilitzat en estudis de genètica reversa per demostrar la funció d'alguns gens reguladors al fel·lema.The periderm is a complex structure that protects plant mature (secondary) organs and wounded tissues from water loss, injuries and pathogens. This barrier capacity is accomplished by the cork layer of the periderm, a tissue made of dead cells with suberin deposited into cell walls. Although cork and suberin are critical for the survival of land plants, very few is known about the molecular processes involved in their biosynthesis and differentiation, probably due to the lack of appropriate plant models. Here we developed a strategy to identify and characterize cork candidate genes using a combination of two model plants for periderm studies. The bark of cork oak (Quercus suber) was used to identify candidate genes and to analyze the seasonal behaviour of some of these genes. The potato (Solanum tuberosum) tuber was used to demonstrate the role of some selected candidates in the regulation of cork by reverse genetic analyses.
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Cox, Joanne Mary. "Molecular genetics of Campylobacter species." Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29782.
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Campylobacter species are becoming increasingly significant to the health of humans. Campylobacters are notably difficult to isolate, maintain and manipulate and the use of molecular biology techniques is very limited. As a result few genes have been identified from this bacterium and little is known of its association with humans or animal disease in comparison to other enteric pathogens. A specifically targeted strategy employing the polymerase chain reaction with degenerate oligonucleotide primers (PCRDOP) was used to successfully clone portions of the C. upsaliensis flagellin genes, fla1 and fla2. Sequence analysis showed that the C. upsaliensis flagellin gene fragments were highly similar to the flagellin genes of C. jejuni and C. coli, although it contained a region of DNA extra to that of the other species. An alternative strategy was attempted to identify genes encoding potentially exported proteins using the transposon, TnPhoA. This technique resulted in the cloning of portions of the gene homologues of the a subunit of ATP synthase (uncB), an ATP-dependent protease (sms), two cytochromes (clpA and clpB), a cytochrome oxidase bd (cydA) and polyphosphate kinase (ppK). This is the first report of the identification of cytochrome bd in a campylobacter species. Campylobacters were previously thought to possess cytochromes of the b and c types only, and not the a or d types. The cytochrome bd is often hidden in other species when using traditional methods for identification of bacterial cytochromes involving spectrophotometry. A defined mutant in the putative cydA gene was engineered using a novel strategy for the transformation of campylobacters. The phenotype was investigated and revealed severe growth restrictions at low oxygen tensions.
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Wilson, Peter John. "Molecular genetics of Hunter syndrome /." Title page, contents and summary only, 1992. http://web4.library.adelaide.edu.au/theses/09PH/09phw7521.pdf.
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Scrable, Heidi. "Molecular genetics of childhood rhabdomyosarcoma." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74265.
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Rhabdomyosarcoma is a class of malignant neoplasms composed of cells histologically resembling fetal striated muscle. It is the most common soft tissue tumor of children, adolescents, and young adults. In this Thesis, I demonstrate that the rhabdomyosarcoma tumor class is delimited in molecular genetic terms by the expression of the MyoD gene, and that loss of alleles on chromosome 11 distinguishes between the embryonal and alveolar subtypes. The elucidation of this genotypic distinction resolved the paradox between phenotypic variation and an apparent histogenetic relatedness between and among rhabodmyosarcomas. It also allowed for the construction of a two-tiered scheme for the unequivocal differential diagnosis of rhabdomyosarcoma and its subtypes. MyoD is syntenic to but distinct from Rd, a locus consistently involved in the etiology of the embryonal subtype. Abnormal segregation of alleles on chromosome 11p in both familial and sporadic embryonal rhabdomyosarcoma results in retention of only paternal alleles in tumors and supports a model of tumorigenesis involving unlinked modifier loci which inactivate Rd, perhaps by genome imprinting. Uniform loss of heterozygosity at loci on chromosome 11 in phenotypic variants of embryonal rhabdomyosarcoma that show simultaneous differentiation into another neoplastic tissue type implies that mutation at Rd is one of the earliest somatic events.
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Barnby, Gabrielle. "The molecular genetics of autism." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289350.
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MacPhie, Ian Laurence. "The molecular genetics of dyslexia." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400145.
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Bowl, Michael Richard. "Molecular genetics of hypoparathyroid disorders." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275359.
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Chapman, Jade. "Molecular genetics of developmental dyslexia." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/55076/.
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Developmental Dyslexia (DD) is a complex, cognitive disorder which is characterised by an impairment in reading despite adequate educational, motivational and intellectual opportunities. Family and twin studies have shown that this common neurodevelopmental disorder has a highly heritable component. The aim of this thesis was to identify novel susceptibility variants for DD using several approaches. A candidate gene study was conducted, testing variants within the genes CDC42, PRTG, KIAA0319L, DCDC2b and RIOK3 for association with DD in the Cardiff case-control sample. None of the variants within these genes showed a significant association withDD. A genome-wide association study (GWAS) was conducted in collaboration with other groups as part of the NeuroDys consortium, using DD cases from Europe and population controls. 27 of the most significant SNPs identified were selected and genotyped in a larger replication sample. 8 of these showed a significant association with DD, with the most interesting SNPs within the gene SNX29. An additional GWAS was conducted by the NeuroDys consortium in the form of a pooling study using a larger array. 38 of the most significant SNPs identified were selected for individual genotyping after which 14 remained significant, with the most interesting within the genes TMC1 and WDR78. Another GWAS was conducted in the form of a pooling study using the Cardiff cases and screened controls only. 57 of the most significant SNPs identified were selected for individual genotyping of which 54 remained significant. This study highlighted a number of interesting genes and demonstrated the effect of using a homogeneous case-control sample when conducting pooling studies. Analysis of copy number variants (CNVs) was also conducted using data from the initial NeuroDys GWAS. This study highlighted the technical issues that can affect the outcome of such studies. As such, the CNVs in this study need to be validated before these results can be relied upon. To conclude, some interesting variants have been identified in this thesis but further work is required to confirm these findings.
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Shearman, Jeremy David. "The molecular genetics of haemochromatosis." Thesis, University of Oxford, 1996. http://ora.ox.ac.uk/objects/uuid:ecb03d17-3cbf-4147-91aa-f252a2e5137e.
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Haemochromatosis is the most common single gene disorder to afflict North- West European populations. It is probably the most common genetic disorder of iron metabolism worldwide. As many as 1 in 250 people in the UK are affected and although the phenotype causes only a mild increase in gastrointestinal iron absorption a proportion of affected individuals will accumulate sufficient iron over their life-time to cause cirrhosis and hepatocellular carcinoma. Venesection treatment instituted before cirrhosis has established ensures a normal life expectancy, but clinical presentation is often late in life after irreversible organ injury has occurred. Identification of people at risk in the early, asymptomatic stage by measurements of iron status is unreliable. The genetic defect responsible for haemochromatosis has been sought in the hope that its identification might facilitate early diagnosis and that studies on the gene product would lead to a greater understanding of the mechanisms of mammalian iron absorption. Genetic linkage to HLA-A3 placed the gene responsible for haemchromatosis in, or close to, the major histocompatibilty complex (MHC) on the short arm of chromosome 6 and a positional cloning strategy has been adopted. This thesis describes work directed to the identification of the haemochromatosis gene by positional cloning. The region telomeric to the MHC was mapped using yeast artificial chromosomes, from which new microsatellites were isolated. These markers were used in linkage disequilibrium analyses and the mapping of a recombination breakpoint that defined a haemochromatosis gene region. This region was physically mapped in fine detail and positional candidates sought by EST database analysis. Before a systematic search for genes in the region began a strong positional candidate was reported (Feder et al 1996). Analysis of this mutation in patients from the UK confirmed this to be the ancestral haemochromatosis mutation.
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Dobson-Stone, Carol N. M. "Molecular genetics of chorea-acanthocytosis." Thesis, University of Oxford, 2004. http://ora.ox.ac.uk/objects/uuid:3992386d-7d0d-4b88-bcf6-7170e2ba98cc.
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Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. The disorder shares features with Huntington's disease and McLeod syndrome (MLS), and can sometimes be difficult to distinguish clinically from the latter. In 1997, ChAc was linked to a 6-cM region on chromosome 9q21-22. A novel gene, >em>CHAC, was identified in the critical region. CHAC (now renamed VPS13A) encodes a large protein called chorein, with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in VPS13A were screened for mutations in 83 unrelated ChAc patients. We identified 88 different VPS13A mutations in 72 probands, comprising six deletions of entire exons, 22 nonsense, 36 frameshift, 19 splice-site and five missense mutations. This disorder therefore shows substantial allelic heterogeneity: however, evidence for common inheritance of the EX70_73del mutation in four French Canadian pedigrees indicates a possible founder effect in this population. Expression of VPS13A appears to be ubiquitous, as determined by tissue-specific analysis of mRNA and chorein distribution. However, chorein expression was markedly reduced or undetectable in lymphoblasts, fibroblasts and erythrocyte membranes from 14 ChAc patients. In contrast, MLS cells showed chorein expression similar to control levels, suggesting that loss of chorein expression is a diagnostic feature of ChAc. Yeast two-hybrid analysis of six different -600 amino-acid chorein fragments was used to screen a human brain cDNA library for proteins that may interact with chorein. One fragment interacted weakly with constructs derived from transcription factor NF-κB, putative protein phosphatase PP2Cη and TAB2, a protein implicated in the mitogen-activated kinase cascade. Although exogenously expressed chorein and TAB2 did not appear to colocalise, co-immunoprecipitation experiments supported an interaction between the two proteins, suggesting an avenue for future research into chorein function.
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Porter, Timothy Robin. "Molecular genetics of gastrointestinal cancer." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273741.
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Irving, Michael Richard. "Molecular genetics of vestibular schwannoma." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338957.
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Nash, Edmund Augustine. "Molecular genetics of dinoflagellate mitochondria." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612522.
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Kandaswamy, R. "Molecular genetics of bipolar disorder." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1370613/.
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Bipolar affective disorder has a strong genetic heritability. In the UCL laboratory, a locus on chromosome 1p36 was found to be linked to bipolar and related unipolar affective disorders with a log of the odds score above 3.00. This region was subjected to fine mapping using tests of allelic association in a case-control sample as part of this thesis in order to identify the genes involved in bipolar disorder. In addition, a GWAS was also employed to fine map other bipolar affective disorder susceptibility genes. The tests of allelic association found evidence for the involvement of the PRKCZ gene. Markers D1S243 and rs3128396 at the PRKCZ gene were significantly associated with bipolar disorder with empirical P = 0.037 and P = 0.040, respectively. Other loci encoding brain expressed proteins found to be associated in the UCL GWAS sample were the genes - GRM3 and GRM7. Therefore, these genes were sequenced using PCR-based genomic sequencing. A 3'-UTR base pair change (rs56173829) in the GRM7 gene was found to be significantly associated with the disorder, although the minor allele was more frequent in controls. A base pair mutation (rs148754219) was found in the GRM3 exon 1 two bases before the translation start codon (forming part of Kozak sequence) of a GRM3 receptor isoform. The mutation was associated with bipolar disorder (P = 0.0046, odds ratio 4.2 (95% CI 1.42-12.37)). Transcription factor binding assays and cloning experiments comparing the gene expression activity of wild-type and mutant alleles showed that the mutant allele strongly affected the reporter gene activity in SH-SY5Y and HEK293 cells. If the GRM3 Kozak sequence mutation is confirmed as an important mutation in the aetiology of bipolar disorder, then it could be used as a marker for personalised treatment for a genetic subtype of affective disorders.
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Gaw, Allan. "Molecular genetics of lipoprotein(a)." Thesis, University of Glasgow, 1995. http://theses.gla.ac.uk/4015/.
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The work presented in this thesis aims to extend our understanding of controlling mechanisms that influence the plasma concentration of lipoprotein(a) [LP(a)]. The techniques of apo(a) genotyping and apo(a) phenotyping are used to study Lp(a) in different ethnic and genetic groups to achieve this end. In chapter 3 the effective use of a commercially available monoclonal antibody is demonstrated. Two primary antibodies were compared and apo(a) isoform analysis was performed using an immunoblotting method. With both monoclonals it was possible to detect 0.05mg. dL-1 Lp(a). Distributions of plasma Lp(a) concentrations exhibit marked inter-racial differences. Apo(a), the unique constituent of Lp(a), is highly polymorphic in length due to allelic variations in the number of kringle 4 (K-4)-encoding sequences. Plasma Lp(a) concentrations are inversely related to the number of K-4 repeats in the apo(a) alleles. To determine the contribution of this length variation to the inter-racial variation in plasma Lp(a) levels, the APO(a) allele size, glycoprotein size, and plasma Lp(a) concentrations in Caucasians, Chinese and African-Americans were compared in chapter 4. Caucasians and African-Americans had very different distributions of plasma Lp(a) concentrations yet there was no significant difference in the overall frequency distributions of their APO(a) alleles. Over the entire size spectrum of apo(a) alleles, the plasma Lp(a) levels were higher in African-Americans that in Caucasians. Conversely, Caucasians and Chinese had similar plasma Lp(a) concentrations, but significantly different APO(a) allele size distributions. Therefore, inter-racial differences in plasma concentrations of Lp(a) are not due to differences in the frequency distributions of APO(a) alleles. The relationship between APO(a) allele size and the presence of detectable plasma apo(a) protein in plasma were also examined. APO(a) alleles associated with no detectable plasma protein were not of uniformly large size, as had been expected, but were distributed over the entire size spectrum. From this analysis, it was concluded that there is no common "null" allele at the APO(a) locus.
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Nudel, Ron. "Molecular genetics of language impairment." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:70249129-ef2e-4508-b8f6-50d6eae8e78b.
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Developmental language impairments are neurodevelopmental disorders in which the acquisition of language, a task which children typically perform with ease, is hindered or fraught with difficulty. This work focuses on specific language impairment (SLI), a common and highly heritable language impairment in which language development is abnormal while other developmental domains are normal. Additionally, a case-study of a child with a broader linguistic and behavioural phenotype is also presented. The work described in this thesis includes both genetic and functional investigations which were aimed at identifying candidate genes for language impairment and provide insight into the genetic mechanisms that underlie language development. I performed a genome-wide association study of SLI which included child genotype effects, maternal genotype effects, parent-of-origin effects, and maternal-foetal interaction effects. This study found significant paternal parent-of-origin effects with the gene NOP9 on chromosome 14, and suggestive maternal parent-of-origin effects with a region on chromosome 5 which had previously been implicated in autism and ADHD. Case-control and quantitative association analyses of HLA genes and SLI identified several risk alleles and protective alleles. A case-control association analysis for related individuals which used an isolated population affected by SLI identified a non-synonymous coding variant in the gene NFXL1 which was significantly more frequent in affected individuals than in unaffected individuals. High-throughput sequencing of the coding regions of NFXL1 and LD blocks surrounding associated variants in ATP2C2, CMIP and CNTNAP2 (as reported in previous studies) identified novel or rare non-synonymous coding variants in NFXL1 and ATP2C2 in SLI families as well as intronic variants in all four genes that were significantly more frequent in SLI probands than in population controls. I describe a functional study of NFXL1 examining its expression in various brain regions, the presence of different splice variants across several tissues, its effect on genes it potentially interacts with, and the subcellular localisation of the protein. Finally, I present the case-study of a child with language impairment who had chromosomal rearrangements which spanned the location of FOXP2. I examine the potential influence the chromosomal rearrangements had on FOXP2 expression and describe a lincRNA gene which was disrupted by the chromosomal inversion. In conclusion, this work identified new candidate genes for language impairment, provided further support for the involvement of previously-identified candidate genes in SLI and contributed to the understanding of the molecular function of a newly-identified candidate gene for SLI.
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Edghill, E. L. "Molecular genetics of monogenic diabetes." Thesis, Exeter and Plymouth Peninsula Medical School, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700493.
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Liu, Shaolin 1968. "Oligonucleotides applied in genomics, bioinformatics and development of molecular markers for rice and barley." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85569.
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A genome sequence can be conceptualized as a 'book' written with four nucleotide 'letters' in oligonucleotide (oligo) 'words'. These words can be used in genomics, bioinformatics and the development of molecular markers. The whole-genome sequence for rice (Oryza sativa L.) is almost finished and has been assembled into pseudomolecules. For barley ( Hordeum vulgare L.) expressed sequence tags (ESTs) have been assembled into 21,981 tentative consensus sequences (TCs). The availability of such sequence information provides opportunities to investigate oligo usage within and between genomes. For the first of three studies reported in this thesis, a C++ program was written to automatically design oligos that are conserved between two sets of sequence information. In silico mapping between rice coding sequences (CDS) and barley TCs indicated that oligos between 18 and 24 bp provide good specificity and sensitivity (83% and 86%, respectively, for 20mers). Conserved oligos used as PCR primers had a high (91%) success rate on barley lines. Sequencing of PCR products revealed conservation in exon sequence, size and order between barley and rice. Introns were not conserved in sequence but were relatively stable in size. Map locations of eight new markers in barley revealed both genome colinearity and rearrangements between barley and rice. The second study reported in this thesis examined word frequency within the rice genome. A non-random landscape composed of high-frequency and low-frequency zones was observed. Interestingly, high-frequency words seemed to be rice specific while single-copy words were gene specific and conserved across species. As in the first study, oligos of 12 bp or less were not specific, and 18 bp seemed to be a critical length for the specificity of oligos. The third study reported in this thesis involved the development of molecular markers for known genes using public sequence information. Six new polymorphic markers were d
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Alonso, Diego Peres [UNESP]. "Utilização de marcadores moleculares no estudo populacional de Leishmania infantum chagasi no Brasil." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/102700.
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A leishmaniose é uma doença parasitária causada por protozoários do gênero Leishmania, e transmitida através da picada de fêmeas de mosquitos da família Plebotomidae. As formas clínicas da leishmaniose são particularmente variadas tendo como forma mais grave a leishmaniose visceral (LV) ou calazar. No Brasil a LV é causada pelo protozoário L.infantum chagasi e transmitida pelo flebotomíneo Lutzomyia longipalpis, os principais reservatórios que participam do ciclo zoonótico são canídeos selvagens e cães domésticos. O fato de as leishmanioses, de uma maneira geral, apresentarem um amplo espectro no que diz respeito à sintomatologia da doença, aliado a grande diversidade das espécies de hospedeiros infectados, sugere a presença de variantes genéticas do parasita. No caso da leishmaniose visceral, por exemplo, variantes genotípicas de L.infantum chagasi interagindo com diferentes espécies de hospedeiros podem ter papel fundamental na dinâmica de transmissão e virulência de possíveis epidemias. O presente estudo teve como meta identificar possíveis variantes genotípicas de L. infantum chagasi presentes na área endêmica de Teresina no Estado do Piauí, e comparar com os genótipos encontrados em Campo Grande no Estado de Mato Grosso do Sul e Bauru no Estado de São Paulo, visto que a história natural da doença nessas regiões é muito mais recente do que no Estado do Piauí. O estudo utilizou marcadores microssatélites já descritos na literatura, seqüenciamento de regiões gênicas codificantes e não-codificantes e também a técnica de PCR-RFLP do DNA do cinetoplasto (kDNA) do parasita, para a obtenção de perfis genéticos que possibilitem relacionar as diferenças genotípicas com as diferentes origens geográficas dos parasitas isolados como um primeiro passo para a eleição e aplicação de um marcador molecular robusto para o estudo populacional...
Leishmaniasis is a parasitary disease caused by Leishmania protozoans and transmitted by female Phebotomidae sandflies. Clinical manifestations are particularly diverse, being visceral leishmaniasis (VL) the most severe form. In Brazil VL is caused by Leishmania infantum chagasi and transmitted by Lutzomyia longipalpis sandfly; the main zoonotic reservoirs are dogs and wild canids. Due to a broad range of disease manifestations and great variety of host species infected, Leishmania parasites are thought to possess great genotypic variability. This is of major significance in epidemiological features and in disease transmission. The aim of this study is to identify different genotypic strains of L. infantum chagasi in endemic areas of Teresina, Piauí State; Campo Grande, Mato Grosso do Sul State and Bauru, São Paulo State, and after that, select an appropriate molecular marker in order to study population genetics of L. infantum chagasi in Brazil. Microsatellites markers, sequencing of DNA coding and non-coding regions and PCR-RFLP of kinetoplast DNA (kDNA) were used in order to compare genetic profiles in parasites from different geographical origins. Among all this techniques, kDNA PCRRFLP has shown greater performance, and was able to detect a clear distinction in Teresina isolates when compared to Campo Grande and Bauru isolates
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Sene, Viviani França [UNESP]. "Citogenética molecular e caracterização cromossômica no gênero Eigenmannia (Teleostei, Gymnotiformes, Sternopygidae)." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/99394.
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Foram analisadas seis espécies/citótipos de peixes do gênero Eigenmannia, Eigenmannia sp1, Eigenmannia sp2, E. cf. trilineata, Eigenmannia sp e dois citótipos de E. virescens de diferentes bacias hidrográficas brasileiras, com o uso de técnicas citogenéticas básicas (coloração com Giemsa, localização das RONs pela marcação com nitrato de Prata e bandamento C) e moleculares (hibridação fluorescente in situ com sondas de DNAr 18S e 5S, com sondas teloméricas (TTAGGG)n, com sondas para elementos retrotransponíveis Rex 1 e Rex 3 e também por microdissecção, amplificação e hibridação in situ fluorescente com sonda produzida a partir do cromossomo sexual Y de Eigenmannia sp2). As espécies/citótipos analisados apresentaram intensa variação em seus números diploides, de 2n=28 cromossomos em Eigenmannia sp1, 2n=31/32 em Eigenmannia sp2, 2n=34 em E. cf. trilineata, 2n=36 em Eigenmannia sp e 2n=38 em E. virescens, além da ocorrência de sistema sexual XX-XY no citótipo de E. virescens do rio Ribeirão Claro (chamado de E. virescens-XY) e ausência desse sistema no citótipo do rio Mogi-Guaçu (chamado de E. virescens), bem como a ocorrência de sistema múltiplo do tipo X1X1X2X2-X1X2Y em Eigenmannia sp2 do rio Araquá. O DNAr 5S está organizado em duas classes distintas e foi localizado em diferentes cromossomos entre estas espécies/citótipos, mas sempre em posição terminal dos cromossomos, com exceção apenas do par cromossômico 7 de Eigenmannia sp1, que possui DNAr 5S em posição intersticial. Ainda, sequências de DNAr 5S foram localizadas no par sexual XY do citótipo de E. virescens-XY, evidenciando uma nova característica dos cromossomos sexuais deste grupo. As RONs, identificadas pelo tratamento com nitrato de Prata e pela sonda de DNAr 18S, foram sempre localizadas em compartimentos cromossômicos distintos do DNAr 5S e, apesar de serem localizadas...
Conventional (Giemsa, Ag-NOR, C-banding) and molecular (Fluorescent in situ hybridization with 18S and 5S rDNA probes, telomeric repeats (TTAGGG)n, Rex1 and Rex3 retrotransposable elements and microdissection, amplification and fluorescent in situ hybridization with probes produced from the Y sex chromosome of Eigenmannia sp2.) cytogenetic studies were carried out in six fish species/cytotypes of the genus Eigenmannia from different Brazilian hydrographic basins. The analyzed species/cytotypes presented an intense variation in diploid number, ranging from 2n=28 chromosomes in Eigenmannia sp1, 2n=31/32 in Eigenmannia sp2, 2n=34 in Eigenmannia cf. trilineata, 2n=36 in Eigenmannia sp to 2n=38 in E. virescens, besides the occurrence of a sex chromosome system XX-XY in the cytotypes of E. virescens from Ribeirão Claro river (named as E. virescens-XY) and absence of this sex chromosome system in the cytotypes of Mogi-Guaçu river (named E. virescens), as well as the occurrence of a multiple sex chromosome system X1X1X2X2-X1X2Y in Eigenmannia sp2 from Araquá river. The 5S rDNA is organized in two distinct classes and was located in different chromosomes between these species/cytotypes; on the other hand, the location in the terminal position of chromosomes was a conserved feature, with exception of chromosome pair 7 in Eigenmannia sp1, which had 5S rDNA sites in an interstitial position. Yet, 5S rDNA signals were detected on the XY sex chromosome of E. virescens-XY, showing some new characteristics of sex chromosomes in this group. The NORs, identified by silver nitrate staining and 18S rDNA probes, were always located in distinct chromosome compartments of 5S rDNA and besides located in different chromosomes in all analyzed samples, they remained conserved through the karyotypic differentiation process in this group. The analysis of constitutive heterochromatin... (Complete abstract click electronic access below)
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Chen, Lei. "Molecular Tools for Biomarker Detection." Doctoral thesis, Uppsala universitet, Molekylära verktyg, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-331745.
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The advance of biological research promotes the emerging of new methods and solutions to answer the biological questions. This thesis describes several new molecular tools and their applications for the detection of genomic and proteomic information with extremely high sensitivity and specificity or simplify such detection procedures without compromising the performance. In paper I, we described a general method namely super RCA, for highly specific counting of single DNA molecules. Individual products of a range of molecular detection reactions are magnified to Giga-Dalton levels that are easily detected for counting one by one, using methods such as low-magnification microscopy, flow cytometry, or using a mobile phone camera. The sRCA-flow cytometry readout presents extremely high counting precision and the assay’s coefficient of variation can be as low as 0.5%. sRCA-flow cytometry readout can be applied to detect the tumor mutations down to 1/100,000 in the circulating tumor cell-free DNA. In paper II, we applied the super RCA method into the in situ sequencing protocol to enhance the amplified mRNA detection tags for better signal-to-noise ratios. The sRCA products co-localize with primary RCA products generated from the gene specific padlock probes and remain as a single individual object in during the sequencing step. The enhanced sRCA products is 100% brighter than regular RCA products and the detection efficiency at least doubled with preserved specificity using sRCA compared to standard RCA. In paper III, we described a highly specific and efficient molecular switch mechanism namely RCA reporter. The switch will initiate the rolling circle amplification only in the presence of correct target sequences. The RCA reporter mechanism can be applied to recognize single stranded DNA sequences, mRNA sequences and sequences embedded in the RCA products. In paper IV, we established the solid phase Proximity Ligation Assay against the SOX10 protein using poly clonal antibodies. Using this assay, we found elevated SOX10 in serum at high frequency among vitiligo and melanoma patients. While the healthy donors below the threshold.
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Meredith, Christopher. "Molecular genetic investigation of autosomal dominant muscular dystrophy." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2001. https://ro.ecu.edu.au/theses/1509.
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This thesis contributes to the Human Genome Project by adding detail to the physical and genetic maps of the human genome, and by identifying a strong candidate gene for a form of distal myopathy. Genomic clones for the human skeletal muscle genes slow troponin (TNN/1), alpha actin (ACTA1), and (3-tropomyosin (TPM2) were isolated for use in the fluorescent in situ hybridisation localisation of these genes on the cytogenetic map of the human genome. The localisation of these genes made them potential candidates for inherited skeletal muscle diseases, including the muscular dystrophies investigated here. Microsatellite, VNTR and RFLP markers were used in a search for linkage to a novel form of distal myopathy segregating in a Western Australian family. The decadic logarithm of the likelihood ratio, or 'lod score' method, was used to determine linkage between markers and this distal myopathy gene. A 22.4 cM candidate region was identified at 14q11.2. This was the first localisation of a distal myopathy gene. The Human Genome Organisation Nomenclature Committee reserved MPD1, 'myopathy, distal 1 ', for this form of distal myopathy, now known as Laing myopathy. The MPD1 candidate region was excluded as the disease gene location for two other forms of distal myopathy. Silburn myopathy in 1994, which established the genetic heterogeneity of distal myopathy, and Felice myopathy in 1996. The exclusion of the MPD1 and French-Canadian OPMD candidate regions as disease gene locations for a putative-OPMD segregating in a Western Australian family, proved that this disease gene did not lie at 14q11.2. Testing an MPD1 muscle-specific candidate gene for the Laing myopathy mutation, the myosin heavy polypeptide 7 gene (MYH7), identified seven base changes between the MPD1 proband sequence and the published MYH7 eDNA sequence. All of these base changes were found in eight unrelated, unaffected Western Australians, therefore none of them were the Laing myopathy mutation. Two further differences to the published MYH7 sequence segregated exclusively with the MPD1 proband. One of these, the MYH7 G5073C (cDNA)/G23628C (gDNA) base change, caused a critical change to the MYH7 13-myosin heavy chain polypeptide product (13-MyHC). An A 1663P 13-MyHC substitution. G23628/C 23628 segregated with Laing myopathy in the Western Australian distal myopathy family. This segregation was confirmed by a single-strand conformation polymorphism test, then used to test 256 unaffected chromosomes. None possessed MYH7C23628. Two patients from European distal myopathy families phenotypically similar to Laing myopathy, the Voit and Scoppetta families, were tested for the presence of MYH7 gDNA G23628/C23628 heterozygosity. Both were homozygous MYH7 G23628. One of these patients (Voit) was also tested for MYH7 eDNA G5073/C5073 heterozygosity. She was homozygous MYH7 G5073. An analysis of the effect of the 13-MyHC A 1663P substitution at various levels of protein structure strengthened the candidature of MYH7 G5073C as the Laing myopathy mutation. It demonstrated the extreme rarity of the 13-MyHC A 1663P substitution; it showed that this substitution did have a detrimental effect on coiled-coil formation; and it identified ways in which the 13-MyHC A 1663P substitution could disrupt myofibrillogenesis or contractility. Future research directions are identified and the contribution of this work to evolving concepts in muscular dystrophy is evaluated.
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Katzer, Frank. "Molecular genetic and functional analyses of surface molecules of Theileria annulata sporozoites." Thesis, University of York, 1995. http://etheses.whiterose.ac.uk/9778/.
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Zhou, Gaoying, and 周高英. "Molecular characterization of chicken SOCS2 gene." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31480263.
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Li, Luosheng. "Molecular genetics of type 2 diabetes /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-194-2/.
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Eskandarpour, Malihe. "Molecular genetics of cutaneous malignant melanoma /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-277-4/.
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Léon, Del Rio Alfonso. "Molecular genetics of holocarboxylase synthetase deficiency." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29074.
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The objective of this thesis was to determine the molecular basis of neonatal multiple carboxylase deficiency (MCD) produced by an impairment in holocarboxylase synthetase (HCS) activity and the origin of the biotin-responsiveness that characterizes this disease. To determine HCS activity, I developed a peptide substrate and used the biotinylation system of E: coli to determine its properties. C-terminal fragments of the $ alpha$ subunit of human propionyl-CoA carboxylase (PCC-$ alpha$) were expressed in E. coli and site-directed mutagenesis was used to define the residues required for biotinylation by the bacterial biotin ligase, BirA. These experiments showed that the biotin region of PCC-$ alpha$ can act as an autonomous domain for biotinylation and suggested its use as substrate for human HCS. For the molecular characterization of MCD, I isolated several cDNA clones encoding human HCS by functional complementation of an E. coli mutant with a temperature-sensitive BirA. Comparison of the predicted amino acid sequence of HCS with bacterial biotin ligases allowed the identification of the putative biotin-binding domain of this protein. Mutation analysis of DNA from HCS deficient patients showed that most of the changes in the HCS sequence are clustered in the biotin-binding domain. All the patients tested in this study showed deficiency of HCS activity as determined using the PCC-$ alpha$ peptide as substrate for biotinylation. The biotin-responsiveness was demonstrated by obtaining a stimulation of HCS activity of MCD cells at high biotin concentrations while remaining unstimulated in extracts of normal cells. Together with the mutation studies, these results showed that neonatal MCD is caused by mutations in the biotin binding domain of HCS which reduce the affinity of the enzyme towards biotin. This change in the kinetic properties of HCS results in the inefficient biotinylation of carboxylases at physiological concentrations of biotin. The defect can be over
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Matthews, Deborah Anne. "The molecular genetics of familial psoriasis." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266107.
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Gloyn, Anna Louise. "Molecular genetics of type 2 diabetes." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343364.
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Zhang, Yun. "Molecular genetics of type 2 diabetes." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298425.
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Owen, Nicholas. "Molecular genetics of spinal muscular atrophy." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342635.
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Lok, Chun Yu. "Understanding the molecular genetics of haemochromatosis." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526485.
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Murphy, Morna J. "Molecular genetics of human ovarian cancer." Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317465.
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Ellis, David. "The molecular genetics of myelin genes." Thesis, Institute of Cancer Research (University Of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481211.
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Raeder, U. "Molecular genetics of lignin degrading fungi." Thesis, University of Manchester, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379725.
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Davies, Joanna Pauline. "The molecular genetics of Fabry disease." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281738.
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Bitner-Glindzicz, Maria Aniela Katarzyna. "Molecular genetics of X-linked deafness." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362334.
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McGregor, Lesley Karen. "The molecular genetics of Fraser syndrome." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407507.
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Kelberman, Daniel. "Molecular genetics of complex craniofacial disorders." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250201.
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