Tesis sobre el tema "Medical genetics"
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1
Rodas, Perez M. C. "Medical genetics in Colombia : genetic consultation and counselling in five genetic clinics". Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/46980/.
Resumen
Today genetic services including genetic counselling are widespread across the world. Although developing countries, like Colombia, have started to apply genetic knowledge to the health area, genetic counselling is usually integrated in the routine clinical genetic consultation, however, before this study the process of communication involved in it had not been explored. In collaboration with the Colombian Association of Medical Genetics, the Bogotá Health Service, and the University of Warwick (UK), I observed 25 genetic consultations in five Colombian genetic clinics. I undertook semi-structured interviews with patients / families before and after the consultation. Thematic analysis of the interview transcripts established mismatches between physician perception and patient comprehension. Efficient communication was affected by patient, relatives, practitioner and external factors. Among these environmental factors were excessive administrative procedures, interruptions during the encounter, patients‟ lack of interest to medical terminology, doctors using scientific language, excessive information given in one session, beliefs and education level of the patient and/or relatives, patient distress caused by bad news, unfulfilled expectations and no availability/accessibility of treatment. I also interviewed 20 medical practitioners working in genetics services. There was general agreement that genetic counselling in Colombia was challenging, and that more training in communication skills was required at Medical schools at undergraduate and postgraduate level. Many physicians did not believe that other health professionals should work as genetic counsellors. There was a general recognition of limited genetic knowledge, awareness and understanding in most medical specialities. These results have made a valuable contribution to describe the current situation with genetics consultation and counselling in Colombian genetic clinics, and have already influenced the future development of an effective and robust genetic counselling service in Colombia. They will also be used in the development of the academic curriculum related to basic and clinical genetics at Colombian Universities.
2
Leeming, William J. "Medical specialization and medical genetics in Canada (1947 and after)". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0001/NQ43440.pdf.
3
Martin, Hilary Chenevix. "Genomic approaches to medical and population genetics". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:44fc9605-a2a8-4b91-9ea9-989fb8203d27.
Resumen
Over the last fifteen years, rapid advances in genotyping and DNA sequencing technologies have revolutionised genetic and biomedical research. In this thesis, we present some applications of these technologies in studying rare disease, population genetics and meiotic recombination. We begin by reviewing previous research in these areas in Chapter 1. Then in Chapter 2, we present some case studies of Mendelian neurological disorders that were carried out as part of a large clinical whole-genome sequencing project, WGS500. These led to the discovery of several new genes for a type of severe early-onset epilepsy called Ohtahara Syndrome, and of a particularly interesting mutation that tentatively suggests a role for a glutamate receptor gene, GRIA3, in circadian rhythm control. In Chapter 3, we examine some general lessons learnt from the WGS500 project, including the utility of sequencing family members to reduce the number of candidate pathogenic variants, and the perils of focusing on candidate genes. Chapter 4 describes a population sequencing project on the platypus, in which we sequenced 58 samples from across the whole species range. Our results provide insights into the population structure and history of this fascinating mammal, and also into the ongoing evolution of its remarkable chain of ten sex chromosomes. Finally, in Chapter 5, we describe a study of the effect of maternal age on meiotic recombination, the largest of its kind to date. Our results from multiple cohorts suggest a small but significant positive effect of maternal age on the number of crossovers, but with substantial heterogeneity between cohorts that is likely due to sampling noise, though confounders may also play a role. These studies illustrate the power of genomic approaches for investigating fundamental biological processes at the population, individual and cellular levels.
4
Whitmore, Scott Anthony. "Positional cloning of genes associated with human disease /". Title page, contents and summary only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phw616.pdf.
Resumen
Thesis (Ph.D.) -- University of Adelaide, Dept. of Cytogenetics and Molecular Genetics, 1999.Copies of author's previously published articles inserted. Amendments pasted onto back-end paper. Bibliography: leaves 255-286.
5
Freeze, Samantha. "Genetic Testing and Counseling Practices for Patients with Retinoblastoma at Cincinnati Children’s Hospital Medical Center". University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427813631.
6
Chuang, William 1970. "Design of a genetics database for medical research". Thesis, Massachusetts Institute of Technology, 2000. http://hdl.handle.net/1721.1/86291.
Resumen
Thesis (S.B. and M.Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2000.Includes bibliographical references (leaves 54-57, first group).
by William Chuang.
S.B.and M.Eng.
7
Miller, Fiona Alice. "A blueprint for defining health, making medical genetics in Canada, c. 1935-1975". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ56247.pdf.
8
Ivansson, Emma. "Contribution of Immunogenetic Factors in Susceptibility to Cervical Cancer". Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9552.
Resumen
Cervical cancer is the second most common cancer in women worldwide. Persistent infection by an oncogenic type of human papillomavirus (HPV) is a necessary but not sufficient cause and there is also a genetic component. This thesis aims to identify host genetic risk factors for cervical cancer based on the hypothesis that susceptibility is affected by genetic variation in the immune response towards HPV infection. Paper I analyzed allergy in sons and cervical cancer in their mothers, and revealed an inverse association between cervical cancer and allergy across generations. Mothers of allergic sons have a lower incidence of cervical cancer, supporting the importance of immunogenetic factors. Paper II investigated the HPV type in 1079 women diagnosed 1965-1993. All women were from families with at least two affected. It appeared that HPV 16 was becoming less common with time. There was no evidence that related women were prone to infection by the same type, indicating that the immunogenetic factors act in a general, rather than an HPV type specific, manner. Paper III and IV analysed the association of candidate genes with susceptibility to cervical cancer in 1306 women with cervical cancer in situ and 288 unrelated controls. Paper III showed the association of variation in the two immune response genes chemokine receptor 2 (CCR-2) and interleukin 4 receptor (IL-4R) with cervical cancer. In paper IV variation at several loci in the MHC region was studied and the importance of the HLA class II locus DQB1 emphasized. This thesis work supports the contribution of genes of the immune system to cervical cancer susceptibility. The genetic risk factors so far identified account for only a part of the genetic susceptibility, which implies that other yet undiscovered variants of importance remain to be identified.
9
Andrews, Verity A. "Genetics and genomics in nursing : what are the characteristics of genetic nurse adopters and nurse opinion leaders in genetics and genomics?" Thesis, University of South Wales, 2012. https://pure.southwales.ac.uk/en/studentthesis/genetics-and-genomics-in-nursing(237c7d78-1001-4039-9c54-e694eae69dc9).html.
Resumen
Background. Aspects of genetics/genomics are increasingly being incorporated into medicine. Nurses are crucial in helping transform healthcare through genomic nursing (Loud, 2010). However the integration of genetics/genomics into nursing education has been sporadic (Dodson and Lewallen, 2011). Influencing its uptake into practice may be via nurses who are already utilising genetics/genomics in their practice (adopters) and nurses who may lead the way and encourage others (opinion leaders) to do likewise. Identifying the characteristics of such adopters and opinion leaders within nursing may provide useful information for more wide-scale detection of these individuals to support a strategy for the inclusion of genetics/genomics into nursing practice. Methods. Five change behaviour theories were used to inform the study including the Theory of Planned Behaviour and the Diffusion of Innovations. A mixed methods approach was taken over two phases. In Phase 1 experts in the field of genetics/genomics and nursing were contacted to gain a consensus on four potential genetic indicators of adoption (GIAs), which would identify a nurse who had adopted genetics/genomics. In Phase 2, oncology nurses and practice nurses completed a questionnaire to identify the characteristics and demographic indicators of nurse genetic adopters and opinion leaders. Results. A consensus (>75%) was achieved for all four GIAs to be included as indicators of adoption of genetics/genomics within nursing practice (Phase 1). Individuals identified (in Phase 2) were subcategorised into six different groups, including genetic adopters and opinion leaders. There were 18 identifying features that defined an adopter, with some of the main features being Openness to Experience (p<0.001), seeing the relevance of genetics/genomics to their patient group (p<0.001) and talking to colleagues about genetics/genomics (p<0.001). There were six features that identified an opinion leader, including academic achievement (p=0.007), level of perceived influence over others (p<0.001) and being high on the opinion leadership scale (p<0.001). Two of the biggest barriers to incorporation by nurses were lack of time for adopters and a lack of local study sessions for opinion leaders. Conclusion. It has been identified that nurses can be categorised in terms of their relationship to genetics/genomics, through a number of distinguishing characteristics. It will be important to further identify and clarify these and other characteristics through the development of additional tools. These data can inform approaches to promote a greater integration of genetics/genomics into nursing practice, ultimately improving patient healthcare.
10
Nudel, Ron. "Molecular genetics of language impairment". Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:70249129-ef2e-4508-b8f6-50d6eae8e78b.
Resumen
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.
11
Björck, Hanna. "Vessel wall integrity : influence of genetics and flow". Doctoral thesis, Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-73958.
Resumen
Cardiovascular disease (CVD) is the major cause of death worldwide. Underlying causes, such as atherosclerosis and hypertension, are associated with remodeling of the vessel wall ultimately leading to loss of structural integrity. There are a number of factors that can influence vascular remodeling and hence structural integrity. The overall aim of this thesis was to investigate aortic wall integrity in relation to genetics and blood flow. The influence of SNPs within the currently most robust susceptibility locus identified for CVD (chromosome 9p21.3) on abdominal aortic integrity was studied in elderly individuals. In men, risk-variants were associated with a decreased abdominal aortic stiffness, independent of other factors related to arterial stiffness. Impaired mechanical properties of the abdominal aortic wall may explain the association between chromosome 9p21.3 and vascular disease. Plasminogen activator inhibitor 1 (PAI-1) is the key inhibitor of fibrinolysis, and involved in several processes associated with vascular remodeling. We investigated the impact of the PAI-1 4G/5G polymorphism on central aortic blood pressure as this pressure more strongly relates to cardiovascular morbidity and mortality than the peripheral pressure. Elderly women carrying the 4G/4G genotype had higher central aortic blood pressure than women carrying the 5G/5G genotype. The association was regardless of other risk factors related to hypertension, suggesting that an impaired fibrinolytic potential may play an important role in the development of hypertension in women. Blood flow is a strong determinant of arterial growth and vascular function. We investigated flow-dependent gene expression and vessel wall morphology in the rat aorta under physiological conditions. Microarray analysis revealed a strong differential gene expression between disturbed and uniform flow pattern regions, particularly associated with transcriptional regulation. Moreover, several genes related to Ca2+ signalling were among the most highly differentially expressed. Up-regulation of Ca2+-related genes may be due to endothelial response to disturbed flow and assembly of cilia, consequently leading to functional and structural modifications of the vessel wall. Bicuspid aortic valve (BAV) is a congenital disorder associated with disturbed ascending aortic blood flow. Using a new strategy to dissect flow-mediated gene expression we identified several novel flow-associated genes, particularly related to angiogenesis, wound healing and mechanosensing, showing differential expression in the ascending aorta between BAV and tricuspid aortic valve patients. Fifty-five percent of the identified genes were confirmed to be flowresponsive in the rat aorta. A disturbed flow, and consequently an altered gene expression, may contribute to the increased aneurysm susceptibility associated with BAV morphology.
12
Åberg, Karolina. "Finding genes for schizophrenia /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5894.
13
Huson, Susan Mary. "Clinical and genetic studies of von Recklinghausen neurofibromatosis". Thesis, University of Edinburgh, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236157.
Resumen
A population-based study in South East Wales (population 668,100) identified 69 families with 135 affected members with von Recklinghausen neurofibromatosis (NF-1), giving a disease prevalence of 20/105 of population. In these families penetrance of the NF-1 gene was 100% by the age of five years. 41/135 cases were judged to represent new disease mutations and the mutation rate was estimated to lie between 3.1x10-5 and 10.4x10-5. A parental age effect for new mutations was not demonstrated, nor was a maternal effect on disease severity. The clinical features and natural history of NF-1 in this cohort were used to derive data for genetic counselling and recommendations for the management of affected individuals. For counselling purposes the complications of NF-1 can be usefully divided into 4 categories (the frequency of each, based on this study, are shown in parentheses): intellectual handicap (33% overall, moderate/severe retardation 3.2%, minimal retardation/ learning difficulties 29.8%); complications developing in childhood and causing lifelong morbidity, e. g. facial plexiform neurofibromas, scoliosis, pseudoarthrosis (8.5%); 'treatable' complications which can develop at any age, e. g. benign disorders of the nervous system, visceral and endocrine tumours, renal artery stenosis (15.7%) and malignant or CNS tumours (4.4-5.2%). The study population indicates that sufferers are not being diagnosed sufficiently early, nor receiving appropriate follow-up and counselling. It is recommended that patients with NF-1 have regular clinical assessments to monitor for the development of complications, although none occur often enough to warrant biochemical or radiological screening. As many of the complications develop early in life, children should have biannual review; in adults, unless a particular complication indicates more frequent review,annual clinical examination is sufficient. Alongside the population survey, genetic linkage studies were undertaken in selected large families to determine the chromosomal localisation of the NF-1 gene. At the outset of this work, two families had been reported in which NF-1 and Myotonic Dystrophy (DM) appeared to co-segregate, suggesting that the two genes were closely linked and on chromosome 19. However, linkage studies of 3 chromosome 19 markers linked to DM showed significantly negative lod scores, therefore excluding this possibility. Other chromosomes were then studied using random unique sequence DNA probes and samples from the largest families were made available to collaborators in the USA for linkage studies using possible candidate genes (ß nerve growth factor and oncogenes). No marker studied showed evidence of linkage. The negative data were used to produce an exclusion map for NF-1, using the computer program 'EXCLUDE'. The presentation of this work was one of the factors which precipitated the formation of an international consortium for NF-1 linkage in February 1987; the first task of the consortium was to produce an expanded exclusion map. A small positive lod score for a marker on chromosome 17, taken with the exclusion data, showed that NF-1 was seven times more likely to be on chromosome 17 than any other chromosome; this was rapidly confirmed by two North American groups, one of which was using samples from the 5 largest families presented in the thesis. Subsequent linkage analysis of pericentromeric chromosome 17 markers in the Welsh family panel showed no evidence of non-allelic heterogeneity and identified closely linked flanking markers for the NF-1 gene suitable for prenatal/presymptomatic diagnosis. The chromosomal localisation of NF-1 represents a major step towards the eventual understanding of the disease pathogenesis and the development of possible treatments.
14
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.
Resumen
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.
15
Mulley, John Charles. "Genetic marker studies in humans /". Title page, contents and summary only, 1985. http://web4.library.adelaide.edu.au/theses/09PH/09phm958.pdf.
16
Lundin, Cecilia. "Homologous recombination at replication forks in mammalian cells /". Stockholm : Institutionen för genetik, mikrobiologi och toxikologi, Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-207.
17
Luo, Yuqun. "Incorporation of genetic marker information in estimating model parameters for complex traits with data from large complex pedigrees /". The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486549482668451.
18
Nylander, Per-Olof. "Ethnic heterogeneity of the North-Swedish population : its origin and medical consequences". Doctoral thesis, Umeå universitet, Medicinsk och klinisk genetik, 1992. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-102561.
Resumen
Northern Sweden shows a unique population structure with remarkable geographical variations in the distribution of genetic disorders as well as genetic markers like blood groups, serum groups and red cell enzyme types. The present-day population of northern Sweden is a mixture of people of Finnish, Saamish (Lappish) and Central-Swedish origin. In this thesis the ethnic heterogeneity of the North-Swedish population (counties of Västerbotten and Norrbotten) was studied using genetic blood markers, and the epidemiological impact of the ethnic heterogeneity was exemplified by studying the geographical correlation between Finnish admixture and risk factors for cardiovascular diseases. The following results were found: 1 Two new ethnic marker genes were discovered: the GC*1F allele (GC serum groups) for Saamish influence and the TF*C3 allele (transferrin serum groups) for Finnish influence. 2 Regional gene frequency variations in the A1A2B0 blood groups, 6-phosphogluconate dehydrogenase (6-PGD) types and transferrin and GC serum groups were studied in a sample of 4100-5600 individuals from northern Sweden distributed according to birth place into 23 subpopulations. A significant regional heterogeneity was found in all systems. The ethnic marker genes (AB0*A2, GC*1F, TF*C3, PGD*C) showed clineal variations consistent with the expected patterns of Finnish and Saamish admixture. 3 Finnish and Saamish admixture was estimated in the 23 subpopulations using AB0*A2, GC*1F and PGD*C as Saamish markers and TF*C3, TF*DCHI, TF*B0-1 and SODI*2 as Finnish markers. The Saamish admixture varied between 0 and 34% and was strongest in the northern and northwestern parts of northern Sweden. The Finnish influence varied between 0 and 84% and was strongest in the northern and northeastern parts of the area. The ethnic marker genes showed significant geographical intercorrelations. 4 Hypercholesterolemia showed a significant heterogeneity between the 23 subpopulations, and there was a significant geographical covariation with the degree of Finnish admixture. These results are consistent with the hypothesis that Finnish genetic influence may contribute to the development of hypercholesterolemia and thereby to the increased rate of cardiovascular diseases found in northern Sweden. The results of this study suggest that in addition to the founder effect ethnic heterogeneity is an important determinant of the structure of the North-Swedish population.Diss. (sammanfattning) Umeå : Umeå universitet, 1992, härtill 7 uppsatser.
digitalisering@umu.se
19
Pretorius, Careni Elizabeth. "A clinical and molecular investigation of two families with Simpson-Golabi-Behmel syndrome". Master's thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/6006.
20
Ngongang, Tekendo Cedrik. "Genetic investigation of South Africans with the Noonan Syndrome phenotype using targeted next generation sequencing". Master's thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/27376.
Resumen
Introduction: Noonan Syndrome (NS) is an autosomal dominant multisystem disorder, characterised by short stature, distinctive facial dysmorphism, cardiovascular abnormalities and developmental delay. Its estimated incidence is 1:1000 to 1:2500 live births. NS is caused by germline mutations in more than ten genes encoding proteins integral to the Ras/MAPK signaling pathway. Pathogenic variants in these genes account for 70-80% of NS cases. The clinical diagnosis of NS can be challenging in some cases, even when performed by experienced clinicians. The introduction of Next Generation Sequencing (NGS) technology in clinical practice in the Western world has tremendously facilitated the molecular diagnosis of RASopathies. Molecular testing for NS is not yet available in South Africa, nor has any study investigating NS from clinical and molecular perspectives been conducted in South Africans. Aim: The aim of this study was to investigate selected genes within a group of paediatric and adult patients with a clinical diagnosis of NS. Methods: This study was a cross-sectional descriptive study, including twenty-six familial and isolated NS patients recruited in Cape Town in the period January 2015-January 2017. Thorough phenotyping of each patient according to the international diagnostic criteria for NS was followed by targeted NGS, performed on leucocyte DNA samples from sixteen unrelated patients out of the twenty-six included. Sequencing involved all the exons and intron-exon boundaries of a predesigned panel of 14 genes, including A2ML1, BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1 and SPRED1. Results: Of the 26 patients included, 50% had a family history suggestive of NS. The median age at diagnosis was4.5 years (range: 1month-51years). Individuals of mixed-race ancestry were most represented (53.8%), followed by black Africans (30.8%). The clinical features identified were consistent with those reported in other populations. Compared to other series, our cohort revealed a lower frequency of Pulmonary Valve Stenosis (34.6%) and a less severe developmental phenotype. Variants predicted pathogenic were detected in 7(43.7%) DNA samples out of the 16 analysed. The genes involved were CBL in three cases (42.8%), PTPN11and MAP2K1in two cases (28.6%, for each gene). Surprisingly, the proportion of CBL variants was relatively high compared to those in the literature. Genotype-phenotype correlations showed that clinical features of NS were more typical in patients with pathogenic variants in MAP2K1, and less in those with variants in CBL. Conclusion: This is the first clinical and molecular study in South Africans with the NS phenotype. The phenotype of affected individuals with NS in South Africa is globally similar to that reported in the literature. Therefore, the use of international diagnostic criteria can effectively enable the clinical diagnosis of NS in most South African patients. These preliminary data suggest that the distribution of pathogenic variants in NS genes in South Africans may be different from that reported in other populations. Finally, this study demonstrates that Targeted NGS can be successfully applied to the molecular diagnosis of NS and related conditions in South Africa, and should be implemented in clinical practice.
21
Crous, Ilse. "Craniosynostosis in a South Africa population". Master's thesis, Faculty of Health Sciences, 2021. http://hdl.handle.net/11427/33611.
Resumen
Background: Craniosynostosis refers to the premature fusion of calvarial bones which lead to restricted growth potential. Compensatory growth occurs in the dimensions not restricted by fusion and causes progressive distortion in the skull shape. The majority of craniosynostosis cases occur in isolation and are so called non-syndromic craniosynostosis. In about 30 % of all cases, anomalies are noted along with the craniosynostosis, often defining a described and recognised syndrome. The aim is to delineate the phenotype observed in a South African population. Methods: In this descriptive study, hospital records for the preceding five years were retrospectively reviewed to describe the profile of patients with craniosynostosis seen at the Red Cross War Memorial Children's Hospital in Cape Town. In addition to the retrospective review, a sub cohort of patients were prospectively phenotyped. The patients were subdivided into three groups namely: non-syndromic craniosynostosis, syndromic craniosynostosis and craniosynostosis with additional features. The last group included patients who had additional malformations or clinical findings without a syndromic diagnosis. The prevalence of phenotypic findings, teratogen exposure, birth complications, congenital malformations, surgical interventions and results of genetic testing in this cohort is described. Descriptive statistical analysis was used. Results: A total of 47 children with craniosynostosis were included in this study. Twenty-five individuals of the cohort were male, and one patient has a disorder of sexual development. Eighteen patients had non-syndromic synostosis. Twelve of these had sagittal type synostosis and five had metopic type synostosis with one unspecified. Thirteen had syndromic synostosis. Eight were clinically diagnosed with Crouzon syndrome of which three were molecularly confirmed. Four patients had Apert syndrome and one had Pfeiffer syndrome, these were clinically diagnosed without molecular confirmation. Sixteen patients had craniosynostosis with some additional findings but no syndromic diagnosis. The suture involved in the majority of patients was the sagittal suture. Ten patients had an additional structural brain abnormality and 13 had signs of raised intracranial pressure. The average age at confirmation of diagnosis of craniosynostosis by CT scan was 22.5 months (SD = 31.4, range: 0.1 – 140.9). Thirty of the 47 patients had craniosynostosis surgery. The average age of surgery was 22.4 months (SD = 19; range: 5-79). The anthropometric, phenotype and developmental features indicate that this is a highly heterogenous group of disorders. Conclusion: Craniosynostosis has been widely reported worldwide, especially in individuals of European descent with only a few reports on craniosynostosis in South African or African populations. Knowledge of the phenotypic spectrum will aid in understanding and documenting this group of disorders in our local population. This study also highlights that this is a complex condition best managed by a multidisciplinary team that should include a medical geneticist. The recognition of specific craniosynostosis syndromes together with appropriate molecular testing can be cost effective even in a limited resource setting and aid in accurate prognosis and recurrence risk information for families.
22
Peterson, Kristen N. "Investigating the Role of Bptf in Immunoediting in Breast Cancer and Melanoma". VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3793.
Resumen
In this study, we explore the effects of NURF depletion on the growth of tumors in immune-competent mice. NURF depletion in tumors results in reduced tumor growth in immune-competent mice, suggesting enhanced anti-tumor immunity. Analysis of the tumor microenvironment by flow cytometry revealed a significantly elevated CD8 and progressively elevated activated CD8 phenotype in Bptf KD tumors, possibly contributing to the increase in cell death and decrease in tumor weight observed. Examination of antigen presentation was evaluated using the OT-1 and Pmel-17 models, though no significant difference in cytotoxicity was observed as measured by LDH and/or IFNγ assays. This indicates possible novel antigen presentation mechanisms in tumor cells, and not increased presentation of existing antigens, contributes to the decreased tumor weight observed in Bptf KD tumors.
23
Luedders, Jonathan. "A Review of Common and Rare Genetic Variants in Schizophrenia". VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2540.
Resumen
Genetic epidemiology has shown a large role for genetic influences on schizophrenia. However, the nature of the variants involved is debated. The common disease-common variant (CDCV) hypothesis suggests that schizophrenia is caused by common alleles with small effect sizes. According to the common disease-rare variant (CDRV) hypothesis, schizophrenia is caused by rare variants with large effect sizes. In recent years, evidence has been found for both common and rare variants in schizophrenia. Several SNPs have been associated with schizophrenia through genome-wide association studies (GWAS), supporting the CDCV hypothesis. In support of the CDRV hypothesis, individuals with schizophrenia have been found to have a higher burden of rare copy-number variants (CNVs). Also, several specific rare CNVs have been associated with schizophrenia. The exact mechanisms of these variants are unknown, but common and rare variants appear to affect many of the same pathways in the etiology of schizophrenia.
24
Heilbronn, Leonie Kaye. "Gene/environment interactions in human obesity". Title page, table of contents and summary only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phh466.pdf.
25
Murray, Aoife Maureen. "Investigating the role of ZDHHC9 in intellectual disability". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648223.
26
Wilkinson, Clare Elizabeth. "Multiple experts : scientific, medical, media and lay discourses on 'new genetics'". Thesis, University of Plymouth, 2004. http://hdl.handle.net/10026.1/1629.
Resumen
The significance of public relationships with scientific and medical expertise has increasingly been highlighted as an area of importance in governmental policy formulation and scientific activities. Central to this relationship has been the role of the media, frequently depicted as increasing the strained communications between science, medicine and the public in the present UK 'crisis' of expertise. Sociological research has contributed to our understandings of science, medicine, the media and lay knowledge. The research presented in this thesis correlates these contributions. It focuses on 'new genetics' to elicit the views towards communication and understanding expressed by three groups; media professionals, members of the public and medical and scientific experts. Utilising a range of quantitative and qualitative methods, this research reflects on the relationships and identities created during interactions between these three groups, ignored by prior studies that have frequently focused on one or two participants in such relationships. This thesis contributes to present debates surrounding the role of the media and public, concluding that the present climate for dialogue is a politically motivated, theoretical context, challenged by a lack of practical methods to confront long-held notions of understanding and communication between expertise and lay persons. This offers original insight into the identities members of the media, public and scientific and medical experts create, maintain and displace in their interactions. The 'crisis' in science and trust instead comes 10 represent a manufactured perception of the public and media, which continues to exclude the public from true dialogue with medical and scientific experts and maintains traditional notions of the media as incompetent.
27
Mells, George Frank Gannaway. "Investigation of the genetic basis of primary biliary cirrhosis : the PBC genetics study". Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648610.
28
Schymick, Jennifer. "The genetics of amyotrophic lateral sclerosis". Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:f68f15c2-2875-46ba-bf25-8324c1dead91.
Resumen
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is no cure for ALS and no definitive explanation for the onset and rapid progression of motor neuron degeneration. Genetics is a known risk factor for a portion of familial cases. However, the role of genetics in the commoner sporadic form of the disease is poorly understood, although numerous genes have been implicated. The primary aim of this thesis project is to uncover the genetic causes that underlie ALS. To accomplish this goal, the main focus of this thesis is to perform genome-wide association analysis of sporadic ALS using high density SNP arrays. This thesis describes the first and the largest genome-wide association studies of ALS to date. Results demonstrate that there is no single large effect susceptibility variant underlying a large proportion of ALS, such as ApoE in Alzheimer’s disease. However, the genotyping data has been made publically available and the digital nature of this data means that it is a resource that can grow with future studies. Beyond genome-wide association, this thesis describes work using linkage, haplotype and sequence analysis to investigate the genetic overlap between ALS and frontotemporal dementia. Lastly, this thesis presents a novel method for linkage analysis using high throughput SNP arrays. Ultimately, it is hoped that by uncovering the genes that cause ALS, such knowledge will shed light on the pathogenic mechanisms underlying motor neuron degeneration and potentially lead to new rational therapies effective in slowing or even halting disease progression.
29
Hrabik, Sarah A. "The Clinical Utility of a SNP Microarray in Patients with Epilepsy at a Tertiary Medical Center". University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368024881.
30
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.
Resumen
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.
31
Simmons, Christopher Ryan. "GENOME-WIDE ASSOCIATION STUDIES AT THE INTERFACE OF ALZHEIMER’S DISEASE AND EPIDEMIOLOGICALLY RELATED DISORDERS". UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/824.
Resumen
Genome-wide association studies (GWAS)s provide an unbiased means of exploring the landscape of complex genetic disease. As such, these studies have identified genetic variants that are robustly associated with a multitude of conditions. I hypothesize that these genetic variants serve as excellent tools for evaluation of the genetic interface between epidemiologically related conditions. Herein, I test the association between SNPs associated with either (i) plasma lipids, (ii) rheumatoid arthritis (RA) or (iii) diabetes mellitus (DM) and late-onset Alzheimer’s disease (AD) to identify shared genetic variants. Regarding the most significantly AD-associated variants, I have also attempted to elucidate their molecular function.
Only cholesterol-associated SNPs, as a group, are significantly associated with AD. This association remains after excluding APOE SNPs and suggests that peripheral and or central cholesterol metabolism contribute to AD risk. The general lack of association between RA-associated SNPs and AD is also significant in that these data challenge the hypothesis that genetic variants that increase risk of RA confer protection against AD. Functional studies of variants exhibiting novel associations with AD reveal that the lipid-associated SNP rs3846662 modulates HMGCR exon 13 splicing differentially in different cell types. Although less clear, trends were also observed between the RA-associated rs2837960 and the expression of several BACE2 isoforms, and between the DM-associated rs7804356 and expression of a rare SKAP2 isoform, respectively.
In conclusion, the overlap of lipid-, RA- or DM-associated SNPs with AD is modest but in several instances significant. Continued analysis of the interface between GWAS of separate conditions will likely facilitate novel associations missed by conventional GWAS. Furthermore, the identification of functional variants associated with multiple conditions should provide insight into novel mechanisms of disease and may lead to the identification of new therapeutic targets in an era of personalized genomic medicine.
32
Basu, Saonli. "Allele-sharing methods for linkage detection using extended pedigrees /". Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/8931.
33
Marshall, Jennifer. "The development of contemporary medical genetics research models and the need for scientific responsibility /". Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82289.
Resumen
Current medical genetics research is dominated by a single theory that supports the Human Genome Project rationale. This thesis investigates this and several alternative hypotheses and the ethical context related to their development. Firstly, the hypotheses are discussed in detail followed by a subsection in which research evidence based on each hypothesis is cited. Secondly, these medical genetics hypotheses are situated within the contemporary medical paradigm. To conclude, the thesis examines in depth the ethical and practical implications of medical genetics research. A framework of analysis of scientific responsibility is used to explore these implications. Scientific responsibility, as presented in this thesis, is a process consisting of three steps: (1) scientific discourse; (2) the development of the nature of scientific responsibility; and, (3) effective criticism. Once scientific responsibility is defined, the term is applied specifically to the field of medical genetics research.
34
Dursun, Ahmet. "The molecular pathologies of BRCA1 in ovarian cancer patients from the west of Scotland". Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368585.
35
Martin, Julie Sarah. "In vivo and in vitro analysis of TGF-#beta#1 knockout embryos". Thesis, University of Glasgow, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295325.
36
Gurdasani, Deepti. "Design strategies in the study of genetics of complex disease in diverse populations". Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707908.
37
Pithara, Christalla. "Identifying the benefits and disbenefits of clinical genetics services : a framework for economic evaluation". Thesis, University of South Wales, 2011. https://pure.southwales.ac.uk/en/studentthesis/identifying-the-benefits-and-disbenefits-of-clinical-genetics-services(26dc5692-8d18-4977-99e4-90fd8e76d0fb).html.
Resumen
A number of methodological considerations have been discussed in the area of economic evaluation of Clinical Genetic Services (CGSs) including the limited knowledge of psychosocial consequences of these services. This study aims to address this gap by identifying tangible and intangible benefits and disbenefits of CGSs and presenting these within a framework to assist in the design of a comprehensive welfarist economic evaluation. Mixed methods of data collection were adopted and a UK medical genetics service was used as a case study. Face-to-face interviews with genetic service providers were undertaken in Phase One to explore patient pathways and the perceived role of the service. Focus groups and face-to-face interviews with service users explored the perceived benefits and disbenefits of the CGS in Phase Two. Phase Three comprised a pilot study of using Audience Response Systems (ARSs) for exploring stakeholder preferences and tackled issues of respondent validation and transferability. Both process-related attributes and psychosocial outcomes emerged as utility-bearing for service users. Patient pathways i.e. patient experience, were found to be influenced by factors associated with the genetic condition and with individual patient/family characteristics and needs. The overall (dis)benefits of the service however were found to be common across conditions. The concept of Perceived Familial Control is proposed as a suitable outcome which encompasses the psychosocial dimension of CGSs. This study has demonstrated the use of qualitative methods in the context of health economics and economic evaluation. It has specifically demonstrated the use of various levels of qualitative analysis for obtaining attributes and outcomes of CGSs and has incorporated these within a framework directed towards the design of a welfarist economic evaluation. The use of ARSs was also tested for their usefulness as a method of establishing preferences and exploring the opinions of CGS stakeholders. Further research is required to establish whether the emerging (dis)benefits represent the experiences of users of other UK clinical genetic centres. Subsequently, user preferences for the identified (dis)benefits could be explored as a step towards the design of a welfarist economic evaluation. Further research is also required to develop the concept of Perceived Familial Control into an appropriate outcome measure for CGSs.
38
Phuwadol, Bangrak Lily Eurwilaichitr. "Expression and secretion of giant catfish growth hormone in methylotrophic yeast pichia pastoris /". Abstract, 1999. http://mulinet3.li.mahidol.ac.th/thesis/2542/42E-PhuwadolB.pdf.
39
Glassberg, Andrea E. "Genetic testing for susceptibility to breast and ovarian cancer : a case study of clinical decision-making in medical genetics /". Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/10308.
40
Wilkins, James. "Functional analysis of polymorphisms associated with osteoarthritis susceptibility that affect cis-regulation". Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:cfbed303-bdfd-4bb4-bd8f-a3dcd63167bc.
Resumen
Osteoarthritis (OA) is a common, multifactorial disease that is characterized by focal degeneration of the smooth articular cartilage in any of the synovial joints. Although the underlying molecular mechanisms for OA are still not fully understood, epidemiological studies have evidenced a significant genetic component to OA susceptibility. Genome-wide linkage scans and large-scale association studies have had success in unraveling the genetic architecture underlying OA with the identification of a number of susceptibility genes. In this work, functional analyses are reported of OA associated polymorphisms within two susceptibility genes: BMP5 and GDF5, both members of the TGF-β superfamily of secreted proteins. The extent of differential allelic expression (DAE) of BMP5 in human mesenchymal tissues was first examined with significant differences in BMP5 allelic output observed (allelic ratios exceeding 4:1 in the tissues of some donors). Significant variability in allelic expression within the different tissues of donors was also observed, suggesting that polymorphism in cis-regulation of BMP5 expression is common and that there is a considerable effect of tissue specific elements on BMP5 expression. DAE was then used as a phenotype to map tissue-specific cis-regulatory polymorphisms with the identification of a single nucleotide polymorphism (SNP) located downstream of BMP5 that was significantly associated with DAE as well as OA, suggesting that variability in cis-regulation of BMP5 is important in OA susceptibility. Moreover, the functional effect of a previously identified OA associated microsatellite within intron 1 of BMP5 was investigated using luciferase reporter assays and electrophoretic mobility shift assays (EMSAs) with significant differences observed both in the ability of various microsatellite alleles to modulate BMP5 promoter activity and to bind GATA-3 nuclear proteins, further suggesting a role for variability in BMP5 expression in OA susceptibility that may in part be due to altered GATA-3 binding. Finally, functional characterization of a previously reported OA associated SNP in the 5′ UTR of GDF5 is presented in which EMSAs show differential binding of nuclear factors between the two SNP alleles, strengthening the possible functional contribution of this SNP to OA susceptibility. Overall, this work demonstrates that polymorphism in cis-regulation is likely to play a role in OA susceptibility.
41
Matias, Margret. "Comparison of medical management and genetic counseling options pre- and post-whole exome sequencing for patients with positive and negative results". University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1490352906282189.
42
Melley, Caitlin. "Surgical fetal intervention assessing the current practices of genetic counselors /". Waltham, Mass. : Brandeis University, 2009. http://dcoll.brandeis.edu/handle/10192/23321.
43
Cheng, Timothy. "Genetic susceptibility to endometrial cancer". Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:3a559ae0-156f-48a2-a64e-b03a13c562df.
Resumen
Endometrial cancer (EC) is the fourth most common cancer affecting women in the UK. Those with a family history of EC have an increased risk compared with the general population. Highly penetrant germline mutations in mismatch repair (MMR) genes and DNA polymerases account for only a small proportion of the familial aggregation. The aim of this thesis is to investigate the genetic susceptibility to EC in the general population using cases and controls of European ancestry. A GWAS meta-analysis totalling 7,737 EC cases and 37,144 controls yielded five novel EC risk loci of genome-wide significance (P < 5x10−8). In decreasing order of significance, these were at chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). A second independent EC signal was found in the 8q24 locus. The association found in a previous EC GWAS at HNF1B on chromosome 17 was replicated at a higher significance, with the most significant SNP being rs11263763. CYP19A1 SNPs have previously been associated with EC and higher circulating levels of oestrogen from candidate studies, but I confirmed this locus to be genome-wide significant for the first time. Functional annotation and in vitro studies for the EC risk loci at the intergenic region of chromosome 13q22 suggested that the functional SNP sits within a transcriptional repressor for KLF5, with the higher-risk allele reducing repressor activity. The propensity for germline MMR and DNA polymerase muations to cause both EC and colorectal cancer (CRC) prompted me to search for common variants associated with both cancer phenotypes. An EC CRC GWAS meta-analysis showed little evidence of shared susceptibility loci. However, this meta-analysis revealed a novel genome-wide significant risk locus: rs3184504, a missense SH2B3 SNP that has not previously been associated with either EC or CRC. This thesis has enhanced the understanding of genetic susceptibility to sporadic EC and increased the number of genome-wide EC-associated variants to seven.
44
Davis, Hayley Louise. "Functional analysis of cancer-causing FBXW7 mutations". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:9c1b7f72-0733-439f-919a-6c66f7f44bfc.
Resumen
FBXW7 encodes the substrate recognition component of an SCF E3 ubiquitin ligase complex. This complex regulates the degradation of multiple targets, such as Notch1, c-Jun, c-Myc and cyclin E, that function in critical developmental and cancer pathways. FBXW7 mutations are found in cancers of diverse tissue origins, with one of the highest mutation rates in the colorectrum. FBXW7 mutations are typically missense mutations that disrupt the substrate recognition domain at critical arginine propellor-tips. Mutations are often mono-allelic suggesting that FBXW7 is not a typical tumour supressor gene. Despite this, most of the evidence on FBXW7 function to date comes from null systems. Several Fbxw7 -null mouse models have been generated and suffer homozygous embryonic lethality due to disrupted vascular development. Conditional Fbxw7-null mice have been created but do not in general reflect the mutation spectrum found in human tumours. In order to analyse the functional effects of Fbxw7 propellor-tip missense mutations, mice carrying a commonly-occurring Fbxw7 R482Q mutation were generated. This propellor-tip mutation was knocked-in constitutively and whilst heterozygous mice developed normally in utero, they died perinatally due to defective lung development. Cleft palate and eyelid fusion defects were also observed with incomplete penetrance. Fbxw7 substrates were screened in embryonic lungs and significantly elevated protein levels of Klf5 and Tgif1 were observed. The Fbxw7 R482Q mutation was also conditionally knocked-in in the gut. In the heterozygous state, large adenomas in the small intestine were observed at a low multiplicity, in approximately 30% of mice at an age greater than 300 days. Upregulation of Wnt signalling and Ctnnb1 mutations have been identified in a selection of these tumours. Breeding the Fbxw7R482Q allele onto Apc-mutant backgrounds led to accelerated morbidity, in which compound R482Q/Apc-mutant mice exhibited polyps of increased number and size. Elevated protein levels of Fbxw7 substrates Klf5 and Tgif1 were observed in adenoma and normal intestinal tissue from these mice. In vitro work using epitope-tagged murine wildtype and propellor-tip mutant Fbxw7 proteins showed that they were capable of dimerising, opening the prospect of investigating a dominant negative mechanism of action. To conclude, an Fbxw7 propellor-tip mutation studied in vivo resulted in both disrupted embryonic development and intestinal tumorigenesis and was distinct from Fbxw7 -null alleles.
45
Shipman, Lydia. "The functional consequences of autoimmune variants in the tyrosine kinase 2 gene region". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:d7546fb0-3eb3-459c-867f-6e83d5dc2387.
Resumen
The tyrosine kinase 2 (TYK2) gene was first implicated in autoimmune disease in 2009 when a nonsynonymous single nucleotide polymorphism (nsSNP) in TYK2 was reported to be associated with multiple sclerosis (MS). The immunological function of TYK2, as a kinase involved in signal transduction downstream of numerous different cytokine receptors, further strengthened the candidacy of the gene as an MS-relevant risk factor. More recently, this nsSNP has been associated with several other autoimmune conditions. In addition, another three different SNPs in the region have been found to be associated with a number of autoimmune diseases, sometimes in opposing directions. Considering the complex genetic association pattern that is emerging for the TYK2 region across autoimmune conditions, it was hypothesised that this complexity reflects shared but also distinct pathogenic mechanisms, with the consequences of disease-associated SNPs being unlikely to all be restricted to genotype-dependent effects influencing TYK2. Therefore, the main aim of the work presented in this thesis has been to address this hypothesis by investigating the functional consequences of the disease-associated SNPs in the TYK2 gene region. Using an in vitro cell line system and primary human immune cells, obtained from a genotype-selectable donor cohort, protection at the MS-associated nsSNP was found to correlate with reduced TYK2-mediated signalling downstream of the type I interferon receptor. However, other cytokine signalling pathways were not affected, indicating a greater specificity to the function of TYK2 than has previously been appreciated. For the other SNPs in the region, substantial effects on TYK2 were not observed but immune cell subset-specific correlations with RNA-level expression of other genes in the region were identified. Thus, this is the first study to support the concept that a careful cross-comparative analysis of SNP association patterns in a single genomic region across multiple autoimmune diseases can have significant implications for enabling the delineation of pathways common or specific to different conditions, and this is of particular importance for drug repositioning strategies.
46
Laurell, Henrik. "Hormone-sensitive lipase molecular analyses of the human gene : structural and evolutionary aspects on expression, alternating splicing and cold adaptation /". Lund : Dept. of Cell and Molecular Biology, Section for Molecular Signalling, Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/39056075.html.
47
Verma, Deepti. "Genetic variations in the NALP3 inflammasome: a susceptibility factor for inflammatory diseases". Licentiate thesis, Linköping University, Linköping University, Department of Clinical and Experimental Medicine, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-19144.
Resumen
Innate immunity has received impressive attention in the past decade owing to the discovery of the Toll like receptors (TLRs) and the NOD-like receptors (NLRs). While the TLRs specialize in fighting microbes at the cell surface, the NLRs complement by detecting and responding to intracellular microbes. Recently, the non-microbe sensing NLR called inflammasomes, have been identified, which senses metabolic stress as well as certain pathogenic microbes and elicits host’s inflammatory response.
The NLR, NALP3 (formerly known as cryopyrin) forms a large cytoplasmic complex called the ‘inflammasome’ when NALP3, activated by a stimuli, associates with the adaptor proteins ASC and CARD-8. This interaction leads to the activation of pro-inflammatory caspase-1 which subsequently results in the formation of Interleukin (IL)-1β and IL-18. Mutations in the gene encoding NALP3, termed NLRP3 can lead to its constitutive activation resulting in an uncontrolled production of IL-1β. These mutations have been implicated in hereditary inflammatory diseases, often grouped under cryopyrin associated periodic syndromes (CAPS).
This thesis describes a patient with a long history of arthritis and antibiotic resistant fever, but without the typical symptoms of CAPS. The patient was found to be a heterozygous carrier of two common polymorphisms Q705K in NLRP3 and C10X in the CARD-8. Experimental studies showed elevated levels of caspase-1 and IL-1β in the patient, and a total clinical remission was achieved by IL-1β blockade. These two polymorphisms combined, were found to occur in approximately 4% of the control population, suggesting the possibility of a genetic predisposition for inflammation in these individuals. Therefore, a cohort of rheumatoid arthritis (RA) patients, where elevated IL-1β could be one of the reasons behind chronic inflammation, was investigated. We found that carrying the combined polymorphisms resulted in increased RA susceptibility and a more severe disease course. Hypothetically, this subgroup of patients might benefit from IL-1β blockade. Additional studies are warranted to elucidate the functional effects of the two polymorphisms and to determine whether they identify a subgroup of patients that could benefit from IL-1 targeted therapy. Given the structural similarity of NALP3 to other NALPs, the possibility of involvement of the alternative, homologous genes cannot be eliminated.
48
Wong, Hei Sunny. "Genetic susceptibility to common mycobacterial diseases". Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:cb4dd818-4693-4168-ad8a-cdeb59e2d5f3.
Resumen
Common mycobacterial diseases, including tuberculosis and leprosy, contribute to major mortality and morbidity worldwide. Despite evidence of an important role of host genetic factors in susceptibility to these infections, few compelling genetic associations have been identified with previous candidate gene and linkage approaches. This thesis investigates the genetic factors of human immunity to these mycobacterial diseases using a high-throughput approach of association testing. To assess genetic susceptibility to tuberculosis, I have conducted a genome-wide association study in the Gambian population as part of the Wellcome Trust Case Control Consortium (WTCCC). The study reveals the region flanking CADM1 as a potential susceptibility locus. Combining this study with a Ghanaian cohort further implicates two genetic loci at chromosome 18q11.2 (P = 9.2x10⁻⁹) and PARD3B (P = 1.4x10⁻⁶). For leprosy, I have performed a gene-centric association study in the New Delhi Indian population. Evidence of significant association was observed in the HLA-DRB1/DQA1 (P = 4.9x10⁻14) and TLR1 (P = 1.7x10⁻⁹) loci. These studies identify important genomic regions that may be involved in immunity to tuberculosis and leprosy. Further analysis revealed a significant immunogenetic overlap between tuberculosis and leprosy. This provides proof-of-principle for the subsequent aggregate analysis for mycobacterial susceptibility, which suggests that the steroid biosynthesis pathway may be important in anti-mycobacterial immunity. This thesis represents one of the largest studies to identify the genetic factors for human immunity against mycobacteria. These novel findings will further enhance vaccine and pharmaceutical efforts into prevention and treatment of these mycobacterial diseases.
49
Brohawn, David G. "Investigating the molecular etiologies of sporadic ALS (sALS) using RNA-Sequencing". VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4159.
Resumen
ALS is an often lethal disease involving degeneration of motor neurons in the brain and spinal cord. Current treatments only extend life by several months, and novel therapies are needed. We combined RNA-Sequencing, systems biology analyses, and molecular biology assays to elucidate sporadic ALS group-specific differences in postmortem cervical spinal sections (7 sALS and 8 control samples) that may be relevant to disease pathology. >55 million 2X150 RNA-sequencing reads per sample were generated and processed.
In Chapter 2, we used bioinformatics tools to identify nuclear differentially expressed genes (DEGs) between our two groups. Further, we used Weighted Gene Co-Expression Network Analysis to identify gene co-expression networks associated with disease status. Qiagen’s Ingenuity Pathway Analysis revealed our sALS group-specific DEGs and a sALS group-specific gene co-expression network were associated with inflammatory processes and TNF-α signaling. Further, TNFAIP2 was identified as a sALS group-specific upregulated DEG and a network hub gene within that network. We hypothesized TNFAIP2’s upregulation in our ALS samples reflected increased TNF-α signaling and that TNFAIP2 promoted motor neuron death via TNF superfamily apoptotic pathways. Transient overexpression of TNFAIP2 decreased cell viability in both neural stem cells and induced pluripotent stem cell-derived motor neurons. Further, inhibition of activated caspase 9 (a protein necessary for TNF superfamily mitochondrial-mediated apoptosis) reversed this effect in neural stem cells.
In Chapters 3 and 4, we used bioinformatics tools to identify sALS group-specifc mitochondrial DEGs and differentially used exons (DUEs). Qiagen’s Ingenuity Pathway Analysis revealed our sALS group-specific DUEs were associated with cholesterol biosynthesis.
50
O'Connor, Daniel. "Genetics determinants of vaccine responses". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:6e529d46-4a1a-423e-87e1-eaee8977791d.
Resumen
Vaccines have had a profound influence on human health with no other health intervention rivalling their impact on the morbidity and mortality associated with infectious disease. However, the magnitude and persistence of vaccine immunity varies considerably between individuals, a phenomenon that is not well understood. Recent studies have used contemporary technologies to correlate variations in the genome and transcriptome to complex phenotypic traits, and these approaches have started to provide fresh insight into the intrinsic factors determining the generation and persistence of vaccine-induced immunity. This thesis aimed to describe the relationship between genomic and transcriptomic variations, and the immunogenicity of childhood immunisations. Candidate gene and genome-wide genotyping was conducted to evaluate the influence of genetic variants on vaccine-induced immunity following childhood immunisation. Furthermore, contemporary methodologies were used to assess non-coding and coding gene transcript profiles following vaccination, to further dissect the molecular systems involved in vaccine responses. Key findings from this thesis include the description of the first genome-wide association studies into the persistence of immunity to three routine childhood immunisations: capsular group C meningococcal (MenC) conjugate vaccine, Haemophilus influenzae type b (Hib) conjugate vaccine and tetanus toxoid (TT) vaccine. Genome-wide genotyping was completed on over 2000 participants, with an additional 1000 participants genotyped at selected genetic markers. Genome-wide significant associations (p<5×10−8) were described between single- nucleotide polymorphisms (SNPs) in two genes, CNTN6 and ENKUR, and the persistence of serological immunity to MenC following immunisation of children 6-15 years of age. In addition, genome-wide significant associations were described between SNPs within an intergenic region of chromosome 10 and the persistence of TT-specific IgG concentrations following childhood immunisations. Furthermore, a number of variants in loci with putative involvement in the immune system such as FOXP1, the human leukocyte antigen locus and the lambda light chain immunoglobulin locus, were shown to have suggestive associations (p<1×10−5) with the persistence of vaccine-induced serological immunity. The fundamental challenge will be to describe functional mechanisms associated with these findings, and to translate these into innovative and pragmatic strategies to develop new and more effective vaccines.