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1
Hu, Xianghong. "Statistical methods for Mendelian randomization using GWAS summary data." HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/639.
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Mendelian Randomization (MR) is a powerful tool for accessing causality of exposure on an outcome using genetic variants as the instrumental variables. Much of the recent developments is propelled by the increasing availability of GWAS summary data. However, the accuracy of the MR causal effect estimates could be challenged in case of the MR assumptions are violated. The source of biases could attribute to the weak effects arising because of polygenicity, the presentence of horizontal pleiotropy and other biases, e.g., selection bias. In this thesis, we proposed two works, expecting to deal with these issues.In the first part, we proposed a method named 'Bayesian Weighted Mendelian Randomization (BMWR)' for causal inference using summary statistics from GWAS. In BWMR, we not only take into account the uncertainty of weak effects owning to polygenicity of human genomics but also models the weak horizontal pleiotropic effects. Moreover, BWMR adopts a Bayesian reweighting strategy for detection of large pleiotropic outliers. An efficient algorithm based on variational inference was developed to make BWMR computationally efficient and stable. Considering the underestimated variance provided by variational inference, we further derived a closed form variance estimator inspired by a linear response method. We conducted several simulations to evaluate the performance of BWMR, demonstrating the advantage of BWMR over other methods. Then, we applied BWMR to access causality between 126 metabolites and 90 complex traits, revealing novel causal relationships. In the second part, we further developed BWMR-C: Statistical correction of selection bias for Mendelian Randomization based on a Bayesian weighted method. Based on the framework of BWMR, the probability model in BWMR-C is built conditional on the IV selection criteria. In such way, BWMR-C delicated to reduce the influence of the selection process on the causal effect estimates and also preserve the good properties of BWMR. To make the causal inference computationally stable and efficient, we developed a variational EM algorithm. We conducted several comprehensive simulations to evaluate the performance of BWMR-C for correction of selection bias. Then, we applied BWMR-C on seven body fat distribution related traits and 140 UK Biobank traits. Our results show that BWMR-C achieves satisfactory performance for correcting selection bias. Keywords: Mendelian Randomization, polygenicity, horizontal pleiotropy, selection bias, variation inference.
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Lalonde, Emilie. "The application of next-generation sequencing technologies: from Mendelian diseases to cancer." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104572.
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The field of medical informatics has been primarily driven by advances in technology. In recent years, “next-generation sequencing” (NGS) has emerged as an affordable and quick means for accurate, large-scale sequencing at a single-base resolution, generating many gigabases of data per sequencing run. As with all new technological innovations, considerable development and improvements of analysis software is required, specifically to accurately extract relevant information from these large datasets. In this thesis, we explore two applications of next-generation sequencing to human health: sequencing of all protein coding exons (i.e. exome sequencing) of patients with Fowler Syndrome, a rare, prenatally lethal Mendelian disease, and sequencing of mRNA (i.e. RNA-Seq) of breast cancer cell lines and tumors from BRCA1 germline mutation carriers. We focus on both the bioinformatics developments and the application to human health in a “simple” Mendelian disease and in a genetically complex cancer. Indeed, in both these studies, we aim to find genetic events which may improve patient care. The discovery of the gene causing Fowler Syndrome will lead to improved genetic counseling for affected families and may influence choices such as family planning or preventive measures (e.g. prenatal or preimplantation genetic diagnosis). Delineation of transcripts which unambiguously characterize or contribute to BRCA1-related breast cancers could lead to new biomarkers or therapeutic options. In the first study, we develop a bioinformatics pipeline capable of identifying Mendelian disease genes from exome sequencing data. These diseases are typically caused by a single mutation which affects the protein coding sequence; thus, exome sequencing can be used to detect all coding variants in an individual which are then filtered to identify the most likely causative mutation. The successful application of this pipeline is demonstrated in Fowler Syndrome. We found that mutations in the gene FLVCR2 are responsible for this recessive disease using only two affected individuals. Next, we use mRNA sequencing to identify alternative splice isoforms which may contribute to tumorigenesis in breast cancers caused by BRCA1 germline mutations. This subtype of breast cancer accounts for a large proportion of familial breast cancers and is associated with a poorer than expected prognosis. These breast cancers are characterized by several dysregulated cellular processes but the role of alternative splicing in tumorigenesis has not been investigated in BRCA1-related breast cancers. We find several highly recurrent splice junctions that are more abundant in BRCA1-related breast cancers than in controls but none which clearly contribute to breast cancer tumorigenesis. This study illustrates the heterogeneity of BRCA1-related breast cancers at the level of RNA splicing. In summary, in this thesis we show that NGS is an effective tool for global identification and analysis of genetic events in an individual and will thus enable the transition to personalized-medicine.<br>Le domaine d'informatique médicale avance primordialement grâce aux développements technologiques. Durant les années récentes, le « séquençage de nouvelle-génération » (SNG) a émergé comme un moyen abordable et rapide pour le séquençage à grande échelle. Cette technologie possède une grande précision, avec une résolution au niveau d'une seule base d'ADN, générant plusieurs gigabases d'information. Comme toutes innovations technologiques, des développements et améliorations des logiciels analytiques sont essentiels, en particulier pour extraire avec précision les informations pertinentes à partir de ces grands ensembles de données. Dans cette thèse, nous explorons deux applications de SNG à la santé humaine: le séquençage de tous les exons codant les protéines (i.e. séquençage d'exome) des patients avec le Syndrome Fowler, une maladie Mendélienne rare et létale, et le séquençage des ARNm (i.e. ARN-Seq) des lignées cellulaires et tumeurs des patients du cancer de sein portant une mutation germinale de BRCA1. Nous nous concentrons sur les développements bioinformatiques et les applications pour la santé humaine dans une maladie Mendélienne « simple » et dans un cancer génétiquement complexe. En effet, dans les deux études, nous essayons de trouver des événements génétiques qui pourraient améliorer le soin des patients. La découverte du gène qui cause le Syndrome Fowler rendra les conseils génétiques plus complets pour les familles atteintes par cette maladie et pourrait influencer les choix de planification familiale ou de mesure préventive (par exemple, le diagnostic génétique prénatal ou préimplantatoire). La découverte des isoformes qui caractérisent ou contribuent sans ambigüité au cancer de sein relié à BRCA1 pourrait mener à des nouveaux biomarqueurs et traitements. Dans la première étude, nous développons une approche bioinformatique capable d'identifier les gènes causant les maladies Mendéliennes à partir des données du séquençage d'exome. Ces maladies sont généralement causées par une seule mutation qui change la séquence des protéines; ainsi, le séquençage d'exome peut être utilisé pour identifier toutes les variations dans l'exome d'un individu qui sont ensuite filtrées pour trouver la mutation causative la plus probable. Nous démontrons notre succès avec l'application de cette approche dans le Syndrome Fowler. Nous avons trouvé que des mutations dans le gène FLVCR2 causent cette maladie récessive, en utilisant seulement deux individus. Ensuite, nous utilisons le séquençage des ARNm pour identifier des isoformes alternatifs qui pourraient contribuer à la tumorigenèse dans les cancers de sein causé par des mutations de BRCA1. Ce type de cancer de sein représente une grande proportion des cancers de sein familiale et est associé avec une prognose moins favorable. Ces cancers de sein sont caractérisés par des processus cellulaires dérégulés; pourtant, le rôle de l'épissage alternatif dans la tumorigène n'a jamais été exploré dans les cancers de sein relié à BRCA1. Nous trouvons plusieurs jonctions d'épissages très récurrents qui sont plus abondantes dans les cancers de sein relié à BRCA1, par rapport aux autres cancers de sein, mais aucune contribuant clairement à la tumorigène du cancer de sein. Cette étude démontre le hétérogénéité des cancers de relié à BRCA1au niveau de l'épissage alternatif. En bref, dans cette thèse nous montrons que le SNG est un outil effectif pour l'identification et l'analyse globale des événements génétiques dans un individu, permettant ainsi la transition vers la médicine personnalisée.
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Deans, Natalie Christine. "Molecular mechanisms that underlie non-Mendelian inheritance patterns in Zea mays." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu159541311114259.
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Assimes, Themistocles L., and Robert Roberts. "Genetics: Implications for Prevention and Management of Coronary Artery Disease." ELSEVIER SCIENCE INC, 2016. http://hdl.handle.net/10150/623131.
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An exciting new era has dawned for the prevention and management of CAD utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for coronary artery disease (CAD) confirm not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis
of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Lastly, genetic risk scores of CAD may serve not only as prognostic, but also as
predictive markers and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications.
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Chen, Anlu. "Applying Forward Genetic Approaches to Rare Mendelian Disorders and Complex Traits." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1532522241487661.
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O'Neill, Eric Michael. "Evolutionary Consequences of the Introduction of Eleutherodactylus Coqui to Hawaii." DigitalCommons@USU, 2009. https://digitalcommons.usu.edu/etd/305.
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The introduction of a species to areas outside its native range can result in ecological and genetic changes of evolutionary significance. The frog Eleutherodactylus coqui was introduced to Hawaii, from Puerto Rico, in the late 1980s and has lost genetic variation in mitochondrial DNA. The extent to which founder effects have influenced phenotypic variation in the introduced range is unknown. In this study I compared phenotypic variation in life-history traits, advertisement calls, and stripe patterns among introduced and native populations of the frog Eleutherodactylus coqui. I also conducted laboratory experiments to determine the influence of genetics and temperature on trait variation. Body size in wild populations was positively correlated with elevation in both ranges, but the slope of elevation on body size was greater in Puerto Rico than in Hawaii. Advertisement call frequencies and rates were negatively correlated with elevation but duration was positively correlated with elevation. Frequencies were correlated with body size, but rate, duration, and intensity were not. Color patterns are more variable in Puerto Rico than Hawaii and appear to be maintained by balancing selection in Puerto Rico. Lab results indicate that body size is negatively correlated with temperature, which may explain Bergmann's rule in the field, but patterns of intrinsic growth rate may explain differences in the effect of elevation between Hawaii and Puerto Rico. Body size appears to explain most of the variation in call frequencies, whereas temperature explained most of the variation in rate and duration. Color patterns appear to be determined by a single locus with five alleles. Founder effects appear to explain the difference between Hawaii and Puerto Rico in color pattern variation and in clinal variation in body size and call frequencies. The loss of genetic variation in these traits is likely to have evolutionary consequences for this species in Hawaii.
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Moore, John M. "Using human examples to teach Mendelian genetic concepts : assessing acquisition and retention." Virtual Press, 1989. http://liblink.bsu.edu/uhtbin/catkey/558371.
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This study was designed to investigate whether or not Mendelian genetics instruction using human examples, in contrast to traditional genetic examples, would facilitate the acquisition and retention of four genetic concepts: (1) complete dominance, (2) incomplete dominance, (3) law of segregation, and (4) law of independent assortment. A pre/post/delayed-posttest was designed to assess the acquisition and retention of the concepts and the formation of misconceptions of genetic concepts. A written Piagetian Task Instrument (PTI) was employed to detect cognitive growth toward the formal operational level of thought.Eighty ninth-grade biology students from Marion High School, Marion, Indiana were used in the study. The students were assigned randomly to two control and two treatment groups. Students in the control groups. were instructed in Mendelian genetics using traditional genetic examples to explain the concepts. Students in the treatment groups were instructed in Mendelian genetics using only human examples to explain the concepts.Students who were instructed in Mendelian genetics using human examples acquired and retained those concepts better and acquired fewer misconceptions than students who were instructed using traditional examples.Students who were instructed in Mendelian genetics using human examples did not differ from those instructed via traditional examples with respect to their movement from concrete operational toward formal operational thought.<br>Department of Biology
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Schilling, Taylor. "Non-Mendelian Inheritance in C. elegans: A Violation of The Law of Independent Assortment." Cleveland State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=csu1611776149127827.
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Lin, Michelle [Verfasser], and Jobst [Akademischer Betreuer] Meyer. "Genetics of common psychiatric disorders: A Mendelian perspective based on genetic analyses of large pedigrees / Michelle Lin ; Betreuer: Jobst Meyer." Trier : Universität Trier, 2012. http://d-nb.info/1197698183/34.
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Raykova, Doroteya. "Genetics of Two Mendelian Traits and Validation of Induced Pluripotent Stem Cell (iPSC) Technology for Disease Modeling." Doctoral thesis, Uppsala universitet, Medicinsk genetik och genomik, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-246228.
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Novel technologies for genome analysis have provided almost unlimited opportunities to uncover structural gene variants behind human disorders. Whole exome sequencing (WES) is especially useful for understanding rare Mendelian conditions, because it reduces the requirements for a priori clinical data, and can be applied on a small number of patients. However, supporting functional data on the effect of specific gene variants are often required to power these findings. A variety of methods and biological model systems exists for this purpose. Among those, induced pluripotent stem cells (iPSCs), which are capable of self-renewal and differentiation, stand out as an alternative to animal models. In papers I and II we took advantage of WES to identify gene variants underlying autosomal recessive pure hair and nail ectodermal dysplasia (AR PHNED) as well as autosomal dominant familial visceral myopathy (FVM). We identified a homozygous variant c.821T>C (p.Phe274Ser) in the KRT74 gene as the causative mutation in AR PHNED, supported by the fact that Keratin-74 was undetectable in hair follicles of an affected family member. In a family segregating FVM we found a heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in the ACTG2 gene in the affected members. This novel variant is associated with a broad range of visceral symptoms and a variable age of onset. In Paper III we explored the similarity between clonally derived iPSC lines originating from a single parental fibroblast line and we highlighted the necessity to use lines originating from various donors in disease modeling because of biological variation. Paper IV focused on how the genomic integrity of iPSCs is affected by the choice of reprogramming methods. We described several novel cytogenetic rearrangements in iPSCs and we identified a chromosome 5q duplication as a candidate aberration for growth advantage. In summary, this doctoral thesis brings novel findings on unreported disease-causing variants, as supported by extensive genetic analysis and functional data. A novel molecular mechanism behind AR PHNED is presented and the phenotypic spectrum associated with FVM is expanded. In addition, the thesis brings novel understanding of benefits and limitations of the iPSC technology to be considered for disease modeling.
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Bryen, Samantha Jane. "Identification and molecular mechanisms of pathogenic splicing variants in neuromuscular disorders." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/26955.
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Background
For families with rare Mendelian disorders, obtaining a precise genetic diagnosis is essential to enable personalised and preventative medicine. However, only ∼50% of families receive a genetic diagnosis following genetic testing, as there are still many challenges in the clinical interpretation of genetic variation. One such challenge is the identification and classification of variants that disrupt precursor messenger RNA (pre-mRNA) splicing, hereafter termed splicing variants. Even though splicing variants are well recognised as a common cause of Mendelian disorders, they are regularly classified as Variants of Uncertain Significance (VUS) rendering them clinically unactionable. It is our inability to accurately predict if and how a variant disrupts pre-mRNA splicing that prevents definitive classification of putative splicing variants.
Aims
To explore the molecular mechanisms by which variants disrupt pre-mRNA splicing, thereby improving our ability to detect and accurately assign pathogenicity to splicing variants in the context of genetically diagnosing individuals with neuromuscular disorders.
Methods
We have a cohort of 214 families with neuromuscular disorders for whom we have iteratively applied exomic, genomic and transcriptomic diagnostic sequencing approaches. Putative splicing variants were identified within this cohort or referred to us as VUSs from collaborators. Functional studies were performed to assess variant effect on pre-mRNA splicing. Analysis of datasets derived from variant databases and the human reference genome provided additional insights.
Results
Numerous complex splicing variants were investigated and established as pathogenic for a variety of neuromuscular conditions. Splicing variants analysed included intronic deletions, deep intronic variants, coding variants, structural rearrangements, and extended splice site variants. The mechanistic basis of aberrant pre-mRNA splicing arising from these variants were explored, revealing novel or under-recognised disease mechanisms.
Conclusions
We reveal important mechanistic insights behind pre-mRNA splicing that can be incorporated into diagnostic pipelines and used to inform new splicing prediction algorithms. The discoveries and lessons learned within this thesis are applicable to all rare Mendelian disorders and cancer genomics.
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Elliott, Mats. "The evolution of biological theories: explaining the success of Mendelian genetics, Darwin’s Theory of natural selection and their synthesis." Master's thesis, Faculty of Humanities, 2019. http://hdl.handle.net/11427/31420.
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Darwin’s theory of natural selection was not widely accepted in the biological community until its synthesis with Mendelian genetics. I investigate the history of both sciences, with the aim discovering why Mendelian genetics and the synthesis were scientifically successful. One possible explanation for this is given by constructivism, the view that developments in science are decided not by rational reasons, but by contingent factors. A sophisticated version of this view is defended by Gregory Radick, who argues that Weldonian biometry, a rival theory of inheritance, could have supplanted Mendelism. For Radick, the success of Mendelism and the corresponding decline of biometry can be explained by historical circumstances, such as Weldon’s untimely death and his inability to recruit talented students. Another popular philosophical explanation of scientific developments is scientific realism, whose proponents argue that scientific success can be explained by the truth of scientific theories. More sophisticated versions of realism, such as Weisberg’s, take the routine scientific distortion of truth (idealization) into account. I argue from the history of genetics that neither constructivism nor realism, sophisticated or otherwise, can help us understand the success of Mendelian genetics. Instead, I argue that there were rational reasons in favor of Mendelian genetics, even if it was not a true theory of inheritance. I further conclude that the synthesis was successful because Mendelian genetics theoretically enriched Darwin’s theory of natural selection. This enrichment solved serious empirical and conceptual problems for Darwin’s theory, showing that we can also understand the success of the synthesis without appeal to broad realist or constructivist views.
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Lieber, Daniel Solomon. "Computational and Experimental Approaches For Evaluating the Genetic Basis of Mitochondrial Disorders." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10830.
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Mitochondria are responsible for many fundamental biological pathways and metabolic processes, including aerobic ATP production by the mitochondrial respiratory chain. In humans, mitochondrial dysfunction can lead to severe disorders of energy metabolism, which are collectively referred to as mitochondrial disorders and affect approximately 1:5,000 individuals. These disorders are clinically heterogeneous and can affect multiple organ systems, often within a single individual. Symptoms can include myopathy, exercise intolerance, hearing loss, blindness, stroke, seizures, diabetes, and GI dysmotility. Mutations in over 150 genes in the mitochondrial DNA (mtDNA) and nuclear genome are known to cause mitochondrial diseases and an additional ~1,000 nuclear-encoded mitochondrial proteins have the potential to underlie mitochondrial disorders but have not yet been linked to human disease. As a result, determining a molecular diagnosis for patients with suspected mitochondrial disorders remains a challenge.
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Thörne, Karin. "Teaching genetics - a linguistic challenge : A classroom study of secondary teachers' talk about genes, traits and proteins." Licentiate thesis, Karlstads universitet, Avdelningen för biologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-15311.
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The overall aim of this thesis is to investigate how teachers talk about genetics in actual classroom situations. An understanding of how language is used in action can give detailed information about how the subject matter is presented to the students as well as insights in linguistic challenges. From the viewpoint of seeing language to be at the very core of teaching and learning, this study investigates teachers’ spoken language in the classroom in topics within genetics that are known to be both crucial and problematic. Four lower secondary school teachers in compulsory school grade 9 (15-16 years old) were observed and recorded through a whole sequence of genetic teaching. The empirical data consisted of 45 recorded lessons. The teachers’ verbal communication was analyzed using thematic pattern analysis, which is based on the framework of systemic functional linguistics (SFL). The focus of the thesis is to determine how teachers talk about the relationships between the concepts of gene, protein and trait, i.e. the functional aspects of genetics. Prior research suggests that this is a central aspect of genetics education, but at the same time it is problematic for students to understand because the concepts belong to different organizational levels. In the first study I investigated how the concepts of gene and trait were related in the context of Mendelian genetics. My results revealed that the teachers’ way of talking resulted in different meanings regarding the relationship between gene and trait: 1) the gene as an active entity causing the trait 2) the gene as a passive entity identified by the trait 3) the gene as having the trait, and 4) the gene as being the trait. Moreover it was found that the old term anlag was regularly used by the teachers as synonym for both gene and trait. In the second study I examined how teachers included proteins in their lessons, and if and how they discussed proteins as a link between different organizational levels. This study showed that teachers commonly did not emphasize the many functions of proteins in our body. The main message of all teachers was that proteins are built. Two of the teachers used proteins as a link between gene and trait, whereas two of them did not. None of the teachers talked explicitly about genes as exclusively coding for proteins, which implies that the gene codes for both proteins and traits. The linguistic analysis of teachers’ talk in action revealed that small nuances in language used by the teachers resulted in different meanings of the spoken language. Thus, my work identifies several linguistic challenges in the teaching of genetics.<br><p>This thesis is written within the framework of the Hasselblad Foundation Graduate School, a four-year programme financed by the Hasselblad Foundation.</p>
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Racacho, Lemuel Jean. "The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32187.
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Brachydactyly type A1 (BDA1) is a rare autosomal dominant trait characterized by the shortening of the middle phalanges of digits 2-5 and of the proximal phalange of digit 1 in both hands and feet. Many of the brachymesophalangies including BDA1 have been associated with genetic perturbations along the BMP-SMAD signaling pathway. The goal of this thesis is to identify the molecular pathways that are associated with the BDA1 phenotype through the genetic assessment of BDA1-affected families. We identified four missense mutations that are clustered with other reported BDA1 mutations in the central region of the N-terminal signaling peptide of IHH. We also identified a missense mutation in GDF5 cosegregating with a semi-dominant form of BDA1. In two families we reported two novel BDA1-associated sequence variants in BMPR1B, the gene which codes for the receptor of GDF5. In 2002, we reported a BDA1 trait linked to chromosome 5p13.3 in a Canadian kindred (BDA1B; MIM %607004) but we did not discover a BDA1-causal variant in any of the protein coding genes within the 2.8 Mb critical region. To provide a higher sensitivity of detection, we performed a targeted enrichment of the BDA1B locus followed by high-throughput sequencing. We report the identification of a novel 9.5 Kb intergenic tandem duplication in two unrelated BDA1-affected families. In-vitro and in-vivo reporter assays demonstrated the enhancer activity of noncoding conserved sequence elements found within the microduplication. We also show an upregulation of the neighboring genes, NPR3 and PDZD2, in the patients' fibroblasts that suggests a gain-of-function through the duplication of cis-regulatory elements on dose sensitive genes. By expanding the repertoire of BDA1-causing mutations in IHH, GDF5, BMPR1B and at the BDA1B locus, we have begun to elucidate a common genetic pathway underlying phalangeal formation and elongation.
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Harshfield, Eric Leigh. "Genomics of lipid metabolism : identification of genetic determinants of lipid metabolites and the effect of perturbations of lipid levels on coronary heart disease risk factors." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277818.
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Background: Coronary heart disease (CHD) is one of the leading causes of death worldwide, and global mortality rates are expected to continue to rise over the coming decades. In Pakistan in particular, chronic diseases are responsible for 50% of the total disease burden. Circulating lipids are strongly and linearly associated with risk of CHD; however, despite considerable efforts to demonstrate causality, available evidence is conflicting and insufficient. Study of the underlying metabolic pathways implicated in the association between lipids and CHD would help to disentangle and elucidate these complex relationships. Objectives: The primary objectives of this dissertation were to (1) identify the genetic determinants of lipid metabolites and (2) advance understanding of the effect of perturbations in lipid metabolite levels on CHD and its risk factors. Methods: Direct infusion high-resolution mass spectrometry was performed on 5662 participants from the Pakistan Risk of Myocardial Infarction Study to obtain signals for 444 known lipid metabolites. Correlations and associations of the lipids with smoking, physical activity, circulating biomarkers, and other CHD risk factors were assessed. Genome-wide analyses were conducted to analyse the association of each lipid with over 6.7 million imputed single nucleotide polymorphisms. Functional annotation and Gaussian Graphical Modelling were used to link the variants associated with each lipid to the most likely mediating gene, discern the underlying metabolic pathways, and provide a visual representation of the genetic determinants of human metabolism. Mendelian randomisation was also implemented to examine the causal effect of lipids on risk of CHD. Results: The lipids were highly correlated with each other and with levels of major circulating lipids, and they exhibited significant associations with several CHD risk factors. There were 254 lipids that had significant associations with one or more genetic variants and 355 associations between lipids and variants, with a total of 89 sentinel variants from 23 independent loci. The analyses described in this dissertation resulted in the discovery of four novel loci, identified novel relationships between genetic variants and lipids, and revealed new biological insights into lipid metabolism. Conclusion: Analyses of lipid metabolites in large epidemiological studies can contribute to enhanced understanding of mechanisms for CHD development and identification of novel causal pathways and new therapeutic targets.
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Sliz, E. (Eeva). "Genetics and molecular epidemiology of metabolic syndrome-related traits:focus on metabolic profiling of lipid-lowering therapies and fatty liver, and the role of genetic factors in inflammatory load." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526222554.
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Abstract Metabolic syndrome is a constellation of metabolic abnormalities predisposing to cardiovascular diseases (CVD), type 2 diabetes, and increased mortality. Due to the high prevalence and severe co-morbidities, metabolic syndrome constitutes a major burden for both public health and the global economy. Improved understanding of the detailed molecular mechanisms could provide novel strategies for the treatment and preferably prevention of the metabolic syndrome-related health issues. Recent advancements in ‘omics’ technologies have facilitated the development of novel tools to examine the links between genetic variation and human health. The new techniques allow determination of millions of genotypes or quantification of hundreds of metabolic measures from a single blood sample. In this thesis, genomics and metabolomics approaches are coupled to improve our understanding of the metabolic syndrome-related health issues. More precisely, my projects evaluate the metabolic effects of two lipid-lowering therapies and non-alcoholic fatty liver, as well as assess genetic determinants of chronic inflammation. The present results indicate generally consistent metabolic effects of statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) genetic inhibition. The subtle discrepancies observed could potentially contribute to differences in the efficacy to lower CVD risk between statins and PCSK9 inhibitors. The dissimilar metabolic effects of the four genetic variants that increase the risk of non-alcoholic fatty liver disease (NAFLD) highlight the heterogeneity of the molecular mechanisms involved in NAFLD pathogenesis. The results further suggest that fatty liver by itself might not promote unfavourable metabolic aberrations associated with fatty liver on a population level. The newly identified loci associating with inflammatory phenotypes elucidate the genetic mechanisms contributing to the inflammatory load. In particular, the present results suggest the important role of the locus determining the ABO blood types in the regulation of the soluble adhesion molecule levels. To conclude, this thesis successfully complements the knowledge of the molecular mechanisms involved in metabolic syndrome-related traits and provides examples of how to couple omics technologies in the study of complex traits or in the evaluation of drug effects<br>Tiivistelmä Metabolinen oireyhtymä on tila, jossa useiden aineenvaihdunnallisten riskitekijöiden kasautuminen suurentaa riskiä sairastua tyypin 2 diabetekseen ja sydän- ja verisuonitauteihin sekä lisää kokonaiskuolleisuutta. Vakavista liitännäissairauksista ja suuresta esiintyvyydestä johtuen metabolinen oireyhtymä kuormittaa merkittävästi sekä terveydenhuoltoa että kansantaloutta. Jotta metabolisen oireyhtymän hoitoon ja ennaltaehkäisyyn voitaisiin kehittää uusia keinoja, on tärkeää ymmärtää paremmin oireyhtymän syntyyn vaikuttavat täsmälliset molekyylimekanismit. Niin sanottujen ’omiikka-tekniikoiden’ viimeaikainen kehitys tarjoaa uusia mahdollisuuksia tutkia geenimuutosten vaikutuksia terveyteen. Uusien tekniikoiden avulla voidaan määrittää miljoonia genotyyppejä tai satoja aineenvaihdunnan merkkiaineita yhdestä verinäytteestä. Tässä väitöskirjatyössä yhdistetään genomiikan ja metabolomiikan menetelmiä metaboliseen oireyhtymään liittyvien terveysongelmien tutkimiseksi. Väitöskirjani osatöissä arvioin kahden lipidilääkkeen sekä ei-alkoholiperäisen rasvamaksan aineenvaihdunnallisia vaikutuksia sekä pyrin tunnistamaan krooniseen tulehdukseen vaikuttavia geneettisiä tekijöitä. Tulosten mukaan statiinien ja PCSK9:n (engl. proprotein convertase subtilisin/kexin type 9) geneettisen eston aineenvaihduntavaikutukset ovat hyvin samankaltaiset. Kuitenkin havaitut pienet poikkeavuudet tietyissä merkkiaineissa voivat vaikuttaa eroavaisuuksiin siinä, kuinka tehokkaasti lääkeaineet alentavat sydäntautiriskiä. Suuret erot rasvamaksan riskiä lisäävien geenimuutosten vaikutuksissa aineenvaihduntaan korostavat rasvamaksaan liittyvien molekyylimekanismien monimuotoisuutta. Tulosten perusteella vaikuttaa siltä, että rasvan kertyminen maksaan ei luultavasti itsessään aiheuta suuria muutoksia verenkierron aineenvaihduntatuotteiden pitoisuuksiin. Tulehdusmerkkiaineisiin assosioituvat uudet geenialueet täydentävät tulehduksen molekyylimekanismeihin liittyvää tietoa. Tulokset korostavat ABO-veriryhmän määräävän geenin vaikutusta liukoisten adheesiomolekyylien pitoisuuksiin. Kaiken kaikkiaan väitöskirjan osatyöt tuovat uutta tietoa metaboliseen oireyhtymään liittyvien terveysongelmien molekyylimekanismeihin. Projektit havainnollistavat, miten omiikka-tekniikoita voidaan hyödyntää monitekijäisten fenotyyppien tutkimuksessa sekä lääkeaineiden aineenvaihduntavaikutusten arvioinnissa
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Spataro, Nino 1984. "Human genetic disorders: Mendelian and complex diseases." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/482220.
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From Darwin’s “On the Origin of Species”, many years elapsed before human diseases were considered in an evolutionary framework. Besides theoretical and empirical advances, we are far from the complete understanding of disease aetiology. Highly penetrant disorders with Mendelian inheritance are mostly explained by the mutation-selection balance model, which is insufficient to describe the selective pressures acting on the full set of alleles related to diseases. We show in the first two papers that Next Generation Sequencing (NGS) technologies provide a unique opportunity to investigate variation and contribute to the understanding of the genetic architecture of disease. Besides exploring the role of rare and copy number variants in Parkinson’s disease (PD), we demonstrate the functional relation between Mendelian and idiopathic PD. In the last paper, we report that variation in genes previously related to Mendelian disorders has a more important role in driving complex disease susceptibility than genes associated only to complex diseases.<br>Des de l'Origen de les Espècies de Darwin van passar molts anys abans que les malalties humanes fossin considerades sota un marc evolutiu. Tanmateix, tot i els darrers avenços teòrics i empírics, estem molt lluny de tenir una comprensió completa de l'etiologia de les malalties humanes. Mentre els trastorns altament penetrants amb herència mendeliana poden explicar-se sota un model d’equilibri mutació-selecció, aquest és insuficient per descriure les pressions selectives que actuen sobre tot el conjunt d'al·lels associats a malalties. Mostrem en els dos primers treballs que les noves tecnologies de seqüenciació proporcionen una oportunitat única per investigar la variació i contribuir a la comprensió de l'arquitectura genètica de la malaltia. A més d'explorar el paper de les variants rares i en el nombre de còpies en la malaltia de Parkinson (PD), demostrem la relació funcional entre les formes mendelianes i idiopàtiques d’aquesta malaltia. En el darrer treball, mostrem sota una perspectiva evolutiva i funcional que, en comparació amb la variació genètica en gens associats només a malalties complexes, la variació en gens prèviament relacionats amb trastorns Mendelians sembla tenir un paper clarament més important en la susceptibilitat a la malaltia complexa.
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Dofash, Lein. "Investigating Genetic Causes of Mendelian Congenital Myopathies." Thesis, Curtin University, 2022. http://hdl.handle.net/20.500.11937/88348.
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This thesis investigates the genetic aetiology of congenital myopathy in families with an unresolved genetic diagnosis. In two families, massively parallel sequencing and functional analyses identified two genetic candidates: a regulatory variant (c.*152G>T) and multi-exon deletion in a known disease gene (KLHL40), and a homozygous missense variant (c.1339T>C) in HMGCS1, a novel disease gene. This work supports the further investigation of regulatory variants for congenital myopathy screening and highlights the mevalonate pathway in muscle function.
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Huang, Xiufeng. "Immunogenetics of acute anterior uveitis and comparison to ankylosing spondylitis." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/213839/1/Xiufeng_Huang_Thesis.pdf.
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This thesis comprehensively applies genome-wide association study, Mendelian randomization analyses, and cytokine proteomics to investigate the genetic basis and immunopathogenic mechanisms of acute anterior uveitis (AAU). Multiple susceptibility loci, environmental risk factors, and potential biomarkers are identified, and a polygenic risk score for AAU developed. These findings provide novel insights into the immunogenetics in AAU, and contribute to clinical translational studies.
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Lao, Grueso Oscar 1976. "Història natural de les malalties genètiques mendelianes i complexes." Doctoral thesis, Universitat Pompeu Fabra, 2004. http://hdl.handle.net/10803/7210.
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Las enfermedades genéticas se clasifican típicamente en dos grandes grupos: las enfermedades mendelianas y las enfermedades complejas. Mientras que las enfermedades mendelianas se caracterizan por ser de baja frecuencia en la población y estar causadas por mutaciones en un gen particular, las enfermedades complejas son el principal problema sanitario en los países desarrollados y se encuentran producidas por la interacción de factores ambientales y factores genéticos. En este caso no se puede hablar de mutación en un determinado gen, sino de polimorfismo que incrementa en una pequeña fracción el riesgo a padecer la enfermedad. En la presente tesis se ha estudiado la distribución espacial de la variabilidad genética tanto en enfermedades mendelianas (en concreto la fibrosis quística, la fenilcetonuria y la b-talasemia) como en una enfermedad compleja (la enfermedad coronaria) en poblaciones europeas y de todo el mundo. Los resultados obtenidos sugieren que la distribución geográfica de la variabilidad genética de las enfermedades mendelianas depende principalmente de factores demográficos y de la historia de las poblaciones. Ahora bien, este efecto no es independiente de factores selectivos. En particular, fenómenos de selección equilibradora pueden incrementar o disminuir la variabilidad genética en una población dependiendo de el momento en el que se dio el evento selectivo. En el caso de la enfermedad compleja estudiada, la enfermedad coronaria, nuestros resultados indican que la distribución espacial de los polimorfismos de riesgo en poblaciones europeas depende, al igual que sucede con otros marcadores genéticos, principalmente de la historia de poblaciones, especialmente del poblamiento del continente europeo, la posterior reexpansión después del último periodo glacial y de las gran expansión poblacional de los agricultores durante el neolítico.
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Lao, Grueso Oscar. "Història natural de les malalties genètiques mendelianes i complexes." Doctoral thesis, Universitat Pompeu Fabra, 2004. http://hdl.handle.net/10803/7210.
Full textAbstract:
Las enfermedades genéticas se clasifican típicamente en dos grandes grupos: las enfermedades mendelianas y las enfermedades complejas. Mientras que las enfermedades mendelianas se caracterizan por ser de baja frecuencia en la población y estar causadas por mutaciones en un gen particular, las enfermedades complejas son el principal problema sanitario en los países desarrollados y se encuentran producidas por la interacción de factores ambientales y factores genéticos. En este caso no se puede hablar de mutación en un determinado gen, sino de polimorfismo que incrementa en una pequeña fracción el riesgo a padecer la enfermedad. En la presente tesis se ha estudiado la distribución espacial de la variabilidad genética tanto en enfermedades mendelianas (en concreto la fibrosis quística, la fenilcetonuria y la b-talasemia) como en una enfermedad compleja (la enfermedad coronaria) en poblaciones europeas y de todo el mundo. Los resultados obtenidos sugieren que la distribución geográfica de la variabilidad genética de las enfermedades mendelianas depende principalmente de factores demográficos y de la historia de las poblaciones. Ahora bien, este efecto no es independiente de factores selectivos. En particular, fenómenos de selección equilibradora pueden incrementar o disminuir la variabilidad genética en una población dependiendo de el momento en el que se dio el evento selectivo. En el caso de la enfermedad compleja estudiada, la enfermedad coronaria, nuestros resultados indican que la distribución espacial de los polimorfismos de riesgo en poblaciones europeas depende, al igual que sucede con otros marcadores genéticos, principalmente de la historia de poblaciones, especialmente del poblamiento del continente europeo, la posterior reexpansión después del último periodo glacial y de las gran expansión poblacional de los agricultores durante el neolítico.
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Wright, Daniel John. "Investigating the relationship between markers of ageing and cardiometabolic disease." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275588.
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Human ageing is accompanied by characteristic metabolic and endocrine changes, including altered hormone profiles, insulin resistance and deterioration of skeletal muscle. Obesity and diabetes may themselves drive an accelerated ageing phenotype. Untangling the causal web between ageing, obesity and diabetes is a priority in order to understand their aetiology and improve prevention and management. The role of biological ageing in determining the risk of obesity and associated conditions has often been examined using mean leukocyte telomere length (LTL), a marker of replicative fatigue and senescence. However, considering phenotypes which represent different domains of biological and functional ageing as exposures for obesity and related traits could allow the elucidation of new understudied phenotypes relevant to cardio-metabolic risk in the wider population. This PhD considers the causal role of (1) hand grip strength (HGS), a marker of overall strength and physical functioning, and (2) resting energy expenditure, an indicator of overall energy metabolism and the major component of daily energy expenditure, in cardio-metabolic risk. I also characterise a new and readily-quantifiable marker of age-related genomic instability, mosaic loss of the Y chromosome (mLOY). Observational evidence implicates each of these phenotypes in cardio-metabolic conditions and intermediate phenotypes. However, it is not possible to infer causality from these observational associations due to confounding and reverse-causality. Mendelian randomisation offers a solution to these limitations and can allow the causal nature of these relationships to be investigated. Using population-based data including UK Biobank, this thesis presents the first large-scale genetic discovery effort for each trait and provides new biological insight into their shared and separate aetiology. I used identified variants to investigate the bidirectional causal associations of each trait with cardio-metabolic outcomes, intermediate phenotypes and other related traits such as frailty and mortality. In total I identified 16 loci for hand grip strength, 19 for mLOY, and one signal for REE. I have shown that HGS is likely to be causally linked to fracture risk, and I have identified the important shared genetic architecture between mLOY, glycaemic traits and cancer. I have also demonstrated that at least one known genetic variant contributing to obesity risk acts partially via reduced REE. Overall the findings of my PhD contribute to our wider understanding of the aetiological role of ageing processes in metabolic dysfunction, and have implications for both basic science and translational applications.
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Basheer, Atia. "Genetic studies of incubation behaviour and Mendelian traits in chickens." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8077.
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Finding the genes that underlie variation in production and developmental traits has important economic applications. Incubation behaviour represents a loss of production in conventional breeds of chicken adapted to local conditions and was what motivated this thesis. The Mendelian traits of comb type, crest, Silkie and normal feathers, feathered leg, fibromelanosis, comb colour, skin and shank colour, feather colour and patterns are of interest because of the insight they give to genes and development and were also investigated in the thesis. We used White Leghorn and Silkie lines of chicken to detect the genetic loci controlling incubation behaviour and Mendelian traits using linkage based analysis in an F2 cross. The evidence for QTL affecting incubation status over the whole period on chromosome 5 was strong (P<0.05). After the addition of 218 new informative SNP markers across the genome including chromosome 5 the 95% confidence interval spanned a region around 45 cM having previously been 95 cM. Three other suggestive QTL for incubation status were found after the addition of SNP markers on chromosome 1, 18, 19, E22C19W28 at 70, 0, 1 and 13cM respectively. The mode of action of the incubation status QTL indicates that the White Leghorn allele was either promoting incubation behaviour or that heterozygotes have performance that exceeds the homozygotes except the QTL on chromosome 1 where the Silkie allele is promoting incubation behaviour as might be expected. A highly significant QTL (P<0.01) for early incubation behaviour (25-30 weeks) was found on chromosome 8 at 18 cM. This QTL has an additive effect with the possession of a Silkie allele increasing the likelihood of incubation behaviour. Other suggestive QTL for early incubation behaviour were found on chromosome 26 and 1 at 0 and 66cM respectively. For Mendelian traits, genome wide significant (P<0.01) genetic loci for comb type, crest type and feather type was found on chromosome 7 at 77cM, linkage group E22C19W28 at 7cM and on chromosome 3 at 169cM respectively. Significant genetic loci (P<0.01) for leg colour and skin colour were found on chromosome 20 at 56cM and 60cM respectively. In the present study, loci for all feather patterns were found on E22C19W28 even after removing animals carrying the dominant white alleles, suggesting dominant white or another allele at the locus was still influential. Comb type and incubation behaviour were investigated at the gene level. Thyroid stimulating hormone receptor (TSHR) is believed to be involved in the process of domestication and was found at the peak position of the most significant QTL on chromosome 5 for incubation behaviour. Functional exploration of Wnt genes as a candidate gene for comb type was investigated by in-situ hybridization in Silkie and White Leghorn embryos. The Wnt6 gene showed expression in the region of the presumptive comb development of embryos. In conclusion, for the first time genetic loci that explain maternal behaviour have been described. The coincidence of the incubation behaviour locus on chromosome 5 with the site of the strongest selective sweep in poultry, the TSHR, and the coincidence of QTL on chromosome 1 and 8 with thyroid hormone activity it would appear that the thyrotrophic axis may be critical to the loss of incubation behaviour and improved reproductive performance with domestication. Further analysis of these loci should be able to produce markers that can reduce the propensity for birds to incubate. Comb type marker might allow introgression of this trait to prevent comb damage in commercial hens.
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Zhang, Lu, and 张璐. "Identification and prioritization of single nucleotide variation for Mendelian disorders from whole exome sequencing data." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48521905.
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With the completion of human genome sequencing project and the rapid development of sequencing technologies, our capacity in tackling with genetic and genomic changes that underlie human diseases has never been greater. The recent successes in identifying disease causal single nucleotide variations (SNVs) for Mendelian disorders using whole exome sequencing may bring us one step further to understand the pathogenesis of Mendelian diseases. However, many hurdles need to be overcome before the promises can become widespread reality.
In this study, we investigated various strategies and designed a toolkit named PriSNV for SNV identification and prioritization, respectively. The SNV identification pipeline including read alignment, PCR duplication removal, indel realignment, base quality score recalibration, SNV and genotype calling was examined by simulation and real sequencing data. By incorporating sequencing errors and small indels, most of the read alignment software can achieve satisfied results. Nonetheless, the reads with medium size and large indels are prone to be wrongly mapped to the reference genome due to the limitation of gap opening strategies of available read alignment software. In addition, although mapping quality can only reflect certain information of the mapping error rate, it is still important to be adopted to filter out obvious read alignment errors. The PCR duplication removal, indel realignment and base quality score recalibration have proven to be necessary and can substantially reduce the false positive SNV calls. Based on the same quality criterion, Varscan performs as the most sensitive software for SNV calling, unfortunately at mean time the false positive calls are enriched in its result.
In order to prioritize the small subset of functionally important variants from tens of thousands of variants in whole human exome, we developed a toolkit called PriSNV, a systematic prioritization pipeline that makes use of information on variant quality, gene candidacy based on the number of novel nonsynonymous mutations in a gene, gene functional annotation, known involvement in the disease or relevant pathways, and location in linkage regions. Prediction of functional impact of the coding variants is also used to aid the search for causal mutations in Mendelian disorders. For the patient affected by Chron's disease, the candidate genes can be substantially reduced from 9615 to 3 by the gene selection strategies implemented in PriSNV.
In general, our results for SNV identification can help the biologists to realize the limitation of available software and shed light on the development of new strategies for accurately identifying SNV calls in the future. PriSNV, the software we developed for SNV prioritization, can provide significant help to biologists in prioritizing SNV calls in a systematic way and reducing search space for further analysis and experimental verification.<br>published_or_final_version<br>Paediatrics and Adolescent Medicine<br>Master<br>Master of Philosophy
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Sun, Benjamin Boyang. "Genetic determinants of the human plasma proteome and their application in biology and disease." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269287.
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Proteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels (protein quantitative trait loci (pQTLs)). Limitations in high-throughput proteomic measurement technology have meant well-powered genome-wide association studies for large number of proteins so far have lagged behind many of the other "omic" studies such as transcriptomics and metabolomics. This is made more challenging by the complexity of human plasma, characterised by high dynamic range spanning several magnitudes of concentrations and a large number of low abundance proteins. By using an expanded high-throughput multiplex aptamer-based proteomic assay with more than twice the proteome coverage of previous studies, I am able to greatly expand on existing knowledge on genetic determinants of human plasma proteins through testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. I identify 1,927 genetic associations with 1,478 proteins, replicating many previous associations as well as gaining novel insights into the genetic architecture of the human plasma proteome. I use several approaches to highlight the application of pQTLs to biology and disease. I show several examples linking distant pQTLs to biologically plausible genes and demonstrate the mediation of distant pQTL by local protein levels, highlighting the role of protein-protein interactions. In addition, I find epistatic effects of genetically determined phenotypes (blood group and secretor status) on protein levels. Through linking previous disease associations, I show that disease associated variants are enriched for pQTLs and I provide insights into possible mechanisms underpinning some of the disease loci. Finally, I identify causal roles for protein biomarkers in disease through multivariable Mendelian randomisation (MR) analysis, leveraging on the simultaneous measurement of multiple functionally related proteins in a locus to account for potential pleiotropic effects. Whereas MR studies of plasma proteins have been constrained by availability of few suitable genetic instruments, the data generated here remedy this bottleneck by furnishing an extensive toolkit. Overall, the work within this thesis foreshadows major advances in post-genomic science through increasing application of novel bioassay technologies to major population biobanks.
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Silvério, Lucio Ely Ribeiro. "A resolução de problemas em genética mendeliana." Florianópolis, SC, 2005. http://repositorio.ufsc.br/handle/123456789/102825.
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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Programa de Pós-Graduação em Educação Científica e Tecnológica.<br>Made available in DSpace on 2013-07-16T02:01:31Z (GMT). No. of bitstreams: 1
222418.pdf: 6861444 bytes, checksum: e20e34db867803d88f307a75a6a82896 (MD5)<br>A resolução de problemas é uma das estratégias de ensino mais utilizadas nas aulas de genética no Ensino Médio. Este tipo de atividade pode favorecer a compreensão da estrutura conceitual da genética e ajudar a desenvolver habilidades importantes como a interpretação de dados e a análise de procedimentos e resultados em um problema, além de competências específicas como a aplicação de algoritmos adequados na solução de um problema de genética. Embora pareça haver concordância na literatura quanto à importância desta estratégia, o que se percebe no cotidiano das aulas é que os alunos cometem muitos erros e têm dificuldades em executar esta tarefa que, em geral, ainda é usada como forma de avaliar seu conhecimento sobre este conteúdo. Com este trabalho investiguei aspectos da relação entre resolução de problemas de lápis e papel e aplicação de conceitos em genética mendeliana por alunos do Ensino Médio. O estudo foi realizado através de questionário e entrevista semi-estruturada com alunos de uma escola pública de Florianópolis-SC. As estratégias de resolução, a aplicação de conceitos envolvendo meiose, formação de gametas, localização e segregação de alelos e as dificuldades na resolução de diferentes problemas de genética foram identificados e analisados. Os resultados obtidos a partir da interação entre as respostas ao questionário e as entrevistas feitas com os alunos indicam o uso de recursos algorítmicos como a principal estratégia de resolução dos problemas, muitas vezes sem a devida compreensão sobre o contexto e o motivo para usá-los. Os resultados indicaram também que os alunos aplicam determinados conceitos básicos mais por força da memorização de suas definições do que pela compreensão de seu significado. Isto mostra que existe uma razoável distância entre os conhecimentos procedimentais e conceituais na resolução de problemas nesta área, limitando a capacidade do aluno aprender genética de forma significativa a partir desta estratégia. As dificuldades identificadas são bem diversas e poderiam ser resumidas da seguinte forma: aquelas ligadas à cognição do aluno, suas concepções alternativas e seu domínio conceitual; as que dizem respeito à maneira como o professor organiza e executa esta atividade, privilegiando determinados tipos de problemas e suas estratégias de resolução; e finalmente as dificuldades relativas à estrutura curricular e objetivos da genética no Ensino Médio. Em função disto, proponho algumas alternativas pedagógicas como forma de colaborar para maior interação entre a metodologia empregada na atividade e a proposta de problemas que associem domínio conceitual e procedimental, levando em conta os conhecimentos prévios que o aluno já possui.
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Burgess, Stephen. "Statistical issues in Mendelian randomization : use of genetic instrumental variables for assessing causal associations." Thesis, University of Cambridge, 2012. https://www.repository.cam.ac.uk/handle/1810/242184.
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Mendelian randomization is an epidemiological method for using genetic variationto estimate the causal effect of the change in a modifiable phenotype onan outcome from observational data. A genetic variant satisfying the assumptionsof an instrumental variable for the phenotype of interest can be usedto divide a population into subgroups which differ systematically only in thephenotype. This gives a causal estimate which is asymptotically free of biasfrom confounding and reverse causation. However, the variance of the causalestimate is large compared to traditional regression methods, requiring largeamounts of data and necessitating methods for efficient data synthesis. Additionally,if the association between the genetic variant and the phenotype is notstrong, then the causal estimates will be biased due to the “weak instrument”in finite samples in the direction of the observational association. This biasmay convince a researcher that an observed association is causal. If the causalparameter estimated is an odds ratio, then the parameter of association willdiffer depending on whether viewed as a population-averaged causal effect ora personal causal effect conditional on covariates. We introduce a Bayesian framework for instrumental variable analysis, whichis less susceptible to weak instrument bias than traditional two-stage methods,has correct coverage with weak instruments, and is able to efficiently combinegene–phenotype–outcome data from multiple heterogeneous sources. Methodsfor imputing missing genetic data are developed, allowing multiple genetic variantsto be used without reduction in sample size. We focus on the question ofa binary outcome, illustrating how the collapsing of the odds ratio over heterogeneousstrata in the population means that the two-stage and the Bayesianmethods estimate a population-averaged marginal causal effect similar to thatestimated by a randomized trial, but which typically differs from the conditionaleffect estimated by standard regression methods. We show how thesemethods can be adjusted to give an estimate closer to the conditional effect. We apply the methods and techniques discussed to data on the causal effect ofC-reactive protein on fibrinogen and coronary heart disease, concluding withan overall estimate of causal association based on the totality of available datafrom 42 studies.
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Stamm, Demetra Serena North Kari E. "Genetic investigation of both complex and Mendelian disorders neural tube defects and Native American myopathy /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1401.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.<br>Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics." Discipline: Genetics and Molecular Biology; Department/School: Medicine.
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Brown, Cecilia, and Cecilia Brown. "Genetic Requirements for Building a Brain of Sufficent Size: Insights from Mendelian Congenital Microcephaly Disorders." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625705.
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Congenital microcephaly (conMiC) is a manifestation of severely disrupted prenatal brain development, caused by genetic defects, toxins, severe maternal malnutrition, or infection. The Zika virus outbreak and the devastating impact of Zika infection on the fetal brain have focused much attention on the cellular and molecular pathophysiology of conMiC. Mendelian conMiC disorders offer a unique opportunity for understanding gene and protein networks that direct cellular processes essential for prenatal brain development. Using OMIM and literature searches, I analyzed 68 conMiC disorders and their 65 corresponding genes. ConMiC-disorder phenotypes were characterized by analyzing the co-occurrence of ID, retinal abnormalities, seizures, and short stature. Short stature co-occurred with 70% of conMiC disorders, while seizures and retinopathy co-occurred with 68% and 37%, respectively. In 53% of conMiC disorders, seizures and short stature overlapped, while all features overlapped in 22% of conMiC disorders; only 7% of conMiC disorders lacked one of these co-occurring features. This shows conMiC genes are rarely specialized for brain growth, with generalized functions in overall body growth, retinal development, and/or regulation of neural activity. ConMiC-gene transcript accumulation in the brain is typically greatest during the prenatal period, and then declines postnatally, suggesting active transcriptional repression. Nonetheless, in neurons and glia of the adult brain, 44 conMiC genes had confirmed persistent protein accumulation. Experimental evidence indicates transcription in neural progenitor cells (NPCs) for at least 82% of conMiC genes. The spatiotemporal expression patterns of conMiC genes tend to align well with their biological functions and corresponding mutant phenotypes. Nearly 60% of conMiC gene products have functions in the cell cycle and/or DNA repair. Most conMiC disorders are caused by recessive, loss-of-function mutations. There are direct binding and regulatory interactions amongst many conMiC genes, which interact in larger networks and shared pathways. Depletion of single conMiC gene products can affect the transcript and/or protein levels of other conMiC gene products, which could have a “domino effect”, and disrupt entire networks important for brain development. Further evidence for this model is that 22 conMiC genes are consistently dysregulated in Zika-infected developing human brain tissue. Due to the complexity of conMiC genes and their interactions, there are many unique challenges to developing treatments for conMiC, particularly conMiC caused by maternal Zika-virus infection. However, insights to treatment strategies could be gained by using human genetics to find potential modifiers, screening for drugs that can normalize disrupted cell cycle and DNA-repair processes, or can stabilize protein complexes that are disrupted due to a conMiC gene mutation.
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Ying, Dingge, and 应鼎阁. "Identification of shared extended haplotypes in both population-based studies of complex disease and family-based studies of Mendelian disorders." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205837.
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Recent founder mutations may play important roles in complex diseases and Mendelian disorders. Detecting shared haplotypes of identity by descent (IBD) could facilitate discovery of these mutations. Several programs address this such as threshold-based methods on genetic distance and probabilistic model-based methods, but they are usually limited to only detecting pair-wise shared haplotypes and not providing a comparison between cases and controls.
In this study, a novel algorithm and a applied software package (HaploShare)is developed to detect extended haplotypes that are shared by multiple individuals, which also allows comparisons between cases and controls. A catalog of haplotypes is firstly generated from healthy controls from the same population and used for phasing genotypes in cases. By accounting for all possible haplotype pairs that could explain the genotypes for each individual in a given haplotype block and possible transitions between blocks, the effect of phase uncertainty on detection power is minimized. In cases, haplotypes shared by pairs are identified and used to detect sharing of these haplotypes by different pairs. A likelihood ratio of a shared haplotype due to IBD or chance is estimated for each extended haplotype. Controls are used similarly through many rounds of simulations to obtain an empirical null distribution of the largest likelihood ratios of shared haplotypes, to give statistical estimates of shared haplotypes detected in cases that may be associated with an underlying disease.
Series of tests were performed to investigate the performance of HaploShare. Simulations of shared haplotypes demonstrated that HaploShare has better power not only on the detection of pair-wise shared haplotypes but multiple shared haplotypes in most of the simulation scenarios, comparing with other four commonly used programs. False positive rate (FPR) and the false discovery rate (FDR) were also evaluated by statistical calculation. According to the result, both of the two values were extremely low (FPR = 6.28x10-6 , FDR = 0.006), indicating that very few randomly shared haplotypes can be wrongly reported as IBD by HaploShare.
HaploShare was also tested on real cases on population data and family linkage analysis. 14 out of 173 Hirschsprung's disease cases were reported by HaploShare of carrying a common haplotype of 250 kb in length, which was consistent with previous findings by direct genotyping and candidate approach. Another testing case is an affected family with 8 cases and 9 unaffected individuals. Disease linked region can be correctly identified by traditional methods if all the data and the entire pedigree were provided. HaploShare showed the ability to locate the shared region even when very limited cases are available, which is clearly beyond the detection power of traditional methods.
The results from empirical simulations and real case applications indicate that HaploShare could effectively make use of population genotype information to improve the power of detection of shared haplotypes. The method may extend the findings in human genetics of both complex and single gene diseases.<br>published_or_final_version<br>Psychiatry<br>Doctoral<br>Doctor of Philosophy
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Boustred, Christopher Robert. "Approaches to the analysis of genetic variation in Mendelian disease genes in a population context : cardiovascular and respiratory applications." Thesis, University of Bristol, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627938.
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Genetic variation underlies the molecular basis of disease and its identification is the focus of the research underpinning both risk prediction and disease treatment strategies. The investigation of Mendelian diseases has led to the discovery of aetiological mutations, improved understanding of disease mechanisms and novel treatments for affected individuals. Furthermore, these discoveries have provided insights into biological mechanisms underlying more common multi-factorial disorders. Common genetic variation does not appear to explain the heritability of common diseases investigated to date. However, associations between common variants in Mendelian disease gene regions and complex diseases support the hypothesis that rarer variants within these genes could contribute to complex disease risk. The aim of this thesis was to develop high-throughput, cost effective methods for genetic variant screening, and apply them to the detection of rare genetic variants. High-resolution melt curve analysis (HRMCA), next generation sequencing (NGS) and statistical imputation were investigated as methods to identify rare variants. Cost efficient methods were developed by combining NGS with multi-dimensional DNA pooling and the targeting of candidate genes. The sensitivity of HRMCA was shown to be poor for regions of high GC% content. Two-dimensional pooling in conjunction with targeted NGS of known Mendelian genes was shown to be a sensitive detection technique. Associations were identified between rare variants and ECG traits in the general population. Variants identified as having a causal role in long QT syndrome (e.g. ANK2, p .Glu1425Gly) were identified in the general population, highlighting the difficulties in determining causality of genetic variants. The utility of whole exome sequencing (WES) was investigated for identifying aetiological mutations in cases of recessive respiratory disease. A known causal mutation (RSPH9 p.Lys268del) was identified in a single individual and negative molecular diagnosis was established in another. An incidentalloss-of-function mutation (p.Arg427X) in EGFL6, a gene reported to have an essential role in early human development was identified in an 11 yr old and functionally characterized. Cost efficient variant screening with NGS can be achieved in large sample sizes through target emichment and multi-dimensional pooling techniques. Optimum methods for variant screening depend on budget, genetic heterogeneity, GC% and sample size. Interpreting the effects of genetic variants on phenotypes remains a significant challenge that requires development of statistical, computational, in vivo, in vitro and systems analysis methods.
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Kho, Pik Fang. "Genetic epidemiology of endometrial cancer." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/211383/1/Pik%20Fang_Kho_Thesis.pdf.
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Endometrial cancer is the fifth most common cancer diagnosed in women in developed countries. This research used genetics to assess relationships between endometrial cancer and, previously identified and novel, risk factors. This work brings new insights by providing evidence that HDL and LDL cholesterol levels are linked to endometrial cancer risk. Further, I have shown that two gynaecological diseases, which are comorbid with endometrial cancer, also share genetic risk architecture with endometrial cancer. This work also advances the understanding of biological mechanisms of endometrial cancer by identifying candidate susceptibility genes.
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Welter, Leocir José. "Distorção de segregação mendeliana e mapeamento de loco de resistencia a TSWV utilizando marcadores microssatélites em um cruzamento interespecífico de pimenta (Capsicum annuum L.x C.chinese L.)." Florianópolis, SC, 2003. http://repositorio.ufsc.br/xmlui/handle/123456789/85940.
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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Agrárias. Programa de Pós-Graduação em Recursos Genéticos Vegetais.<br>Made available in DSpace on 2012-10-21T01:31:38Z (GMT). No. of bitstreams: 0<br>O presente trabalho objetiva a construção de um mapa genético baseado numa população de mapeamento composta de 93 indivíduos F2, resultantes do cruzamento interespecífico entre a linhagem CNPH-679 (C. chinense), resistente à doença virótica "tomato spotted wild virus" (TSWV), e a linhagem suscetível AG-672 (C. annuum). Dos 229 pares de iniciadores microssatélites que foram utilizados para genotipar os genitores, 160 (69,9%) revelaram polimorfismo, 51 (22,3%) revelaram monomorfismo e 18 (7,8%) amplificaram apenas em C. annuum. Dentre os marcadores polimórficos, 127 foram empregados para genotipar a população de mapeamento, sendo que destes, 97 puderam ser interpretados. Estes marcadores foram submetidos ao teste do X2, demonstrando que 88,7% dos marcadores apresentaram distorção de segregação em relação à proporção Mendeliana esperada 1:2:1 (p<0,01). Apesar da elevada distorção de segregação, os 97 marcadores foram utilizados na construção do mapa genético, dos quais 89 foram ordenados em seis grupos de ligação. O comprimento total do mapa obtido foi de 220,6 cM, correspondendo a apenas 9,73% a 14,73% do comprimento total estimado para o genoma de Capsicum. O baixo comprimento total do presente mapa é resultado, em parte, do elevado número de marcadores microssatélites (46) que agruparam em pontos específicos, geralmente intermediários, dos grupos de ligação. Quando considerados apenas os alelos amplificados, na população de mapeamento, pelos marcadores que foram localizados em pontos diferentes dos grupos de ligação, o teste do X2 desvendou um desvio de segregação em favor do genitor C. chinense, sendo que, 56% dos alelos amplificados foram doados por este (p<0,01). A análise individual destes marcadores revelou que pelo menos oito regiões genômicas estão associadas com a distorção de segregação e a direção dos desvios de segregação é variável de acordo com a região analisada. Três destas regiões são afetadas pela seleção gamética, sendo duas em favor do alelo C. chinense e uma em favor do alelo C. annuum. As cinco regiões restantes foram influenciadas pela seleção zigótica, três delas favoráveis aos indivíduos heterozigotos, uma favorável aos indivíduos com genótipo C. annuum e uma favorável aos indivíduos com os genótipos C. chinense e heterozigoto, simultaneamente. Com o estudo observou-se ainda uma evidência significativa de ligação entre o marcador microssatélite CA50 e o loco Tsw, que confere resistência ao vírus TSWV, com distância genética estimada em 18 cM.
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Vincent, Quentin. "Epidémiologie et génétique humaine de l’ulcère de Buruli." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05S019/document.
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L'ulcère de Buruli (UB), infection à Mycobacterium ulcerans, troisième mycobactériose mondiale, connait une émergence rapide depuis 1980, essentiellement dans les pays d'Afrique subsaharienne. Jusqu’ici, les connaissances épidémiologiques sur l’UB étaient fondées sur des séries de cas cliniques non confirmés par laboratoire. Nous avons constitué la plus grande cohorte de cas confirmés à ce jour rassemblant plus de 1200 patients traités au CDTUB de Pobè au Bénin entre 2005 et 2011, afin de décrire l'épidémiologie clinique de la maladie et d'explorer l’architecture génétique de la susceptibilité à cette maladie. Les patients atteints d’UB sont des enfants (âge médian au diagnostic de 12 ans), présentant une lésion unique (96%), large (plus de 15 cm, 36%), ulcérative (66%) du membre inférieur (60%). Nous rapportons une présentation clinique atypique de l’UB, dans laquelle les patients présentent exclusivement une ostéomyélite à M. ulcerans. Le sex-ratio varie avec l’âge : les garçons sont majoritaires parmi les enfants (57% de patients masculins chez les moins de 15 ans), et les femmes parmi les adultes (33% de patients masculins). La présentation clinique dépend de l’âge et du sexe. 9% des patients masculins ont présenté une ostéomyélite contre 4% des patients féminins. Un an après la fin du traitement, 22% des patients présentent des séquelles fonctionnelles fixées. Une présentation clinique comportant une lésion oedémateuse, osseuse, de grande taille ou plusieurs lésions est significativement associée avec le développement de séquelles fonctionnelles (OR 7.64, IC95% [5.29-11.31]). Les patients coinfectés par le VIH ont un risque significativement plus élevé de développer un UB sévère (OR 2.77, IC95% [1.32-6.33]). Nous avons exploré l’architecture génétique de la susceptibilité à l’UB dans une perspective mendélienne et une perspective complexe. Le cas le plus sévère de la maladie observé dans ce centre appartient à une famille consanguine dans laquelle la ségrégation du phénotype suggère un défaut génétique mendélien récessif. Une analyse de liaison génétique par cartographie d'homozygotie suggère l’implication du locus des béta-défensines sur le chromosome 8 dans la pathogénèse de l'UB, et mène à l’identification d’une délétion homozygote ségrégeant parfaitement avec la maladie. Dans une perspective complexe, une étude d’association pangénomique a été réalisée après génotypage d’une cohorte de 400 cas et 400 témoins exposés sur plus de 2 millions de SNPs par la puce Illumina Omni2.5 et a permis l’identification de nombreux signaux d’intérêt. L’étude de réplication est en cours. La compréhension de la physiopathologie de l'infection à M. ulcerans est cruciale pour générer de nouvelles pistes thérapeutiques et vaccinales. La dissection du contrôle génétique de l'infection par l'hôte est en ce sens indispensable<br>Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most frequent mycobacteriosis worldwide. It has been rapidly emerging in sub-Saharan African countries since 1980. Until now, knowledge of BU epidemiology relied on series of non laboratory-confirmed clinical cases. From 2005-2011, we recruited the current largest cohort of laboratory-confirmed cases (more than 1,200 patients) at the Pobe CDTUB, Benin, to describe the clinical epidemiology of the disease and to explore the genetic architecture of human susceptibility to BU. Typically, patients with BU were children (median age at diagnosis 12 years) presenting with a unique (96%) large (≥15 cm, 36%) ulcerative (66%) lesion of the lower limb (60%). Atypical clinical presentation of BU included osteomyelitis with no identifiable present or past BU skin lesions. The sex ratio of BU widely varied with age, with male patients accounting for 57% of patients aged 15 years and younger, but only 33% of those older than 15 years. Clinical presentation of BU was significantly dependent on age and sex. 9% male patients had BU osteomyelitis, whereas only 4% of female patients did. 1 year after treatment, 22% of patients with follow-up information presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7•64, 95% CI 5•29–11•31) and operationally defines severe BU. When coinfected with HIV, patients had a significantly higher risk to develop severe BU (OR 2.77, IC95% [1.32-6.33]). We explored the genetic architecture of susceptibility to BU in both mendelian and complex genetic frameworks. The most severe case of the disease to have been treated at the Pobe CDTUB belonged to a consanguineous family in which the segregation of the phenotype was indicative of a recessive mendelian genetic defect. Genetic linkage analysis by homozygosity mapping suggested the implication of the beta-defensin locus on chromosome 8 in BU pathogenesis and lead to the identification of a homozygous deletion, which co-segregated perfectly with the disease in the family. In a complex genetics approach, we undertook a genome-wide association study, which involved the genotyping of more than 2 million SNPs (Illumina Omni2.5) in a cohort of 400 cases and 400 exposed controls. We identified many signals of interest. The replication study is ongoing. Understanding BU physiopathology is crucial to the development of efficient vaccines and drugs. Dissection of the genetic control of the infection by M. ulcerans by its human host therefore constitutes an indispensable step
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Tsai, Yi-Ting. "Therapy and mechanism of Mendelian eye diseases." Thesis, 2018. https://doi.org/10.7916/D8K37BHV.
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Retinal degenerative diseases cause varying degrees of irreversible vision loss in millions of people worldwide. Common to all retinal degenerative diseases is the malfunction or demise of photoreceptor cells or its supportive cells, retinal pigment epithelium cell in the retina. A considerable part of these diseases were resulted from the inherited mutations of essential genes expressed in these retinal cells. The understanding of pathologic mechanism as well as developing of therapeutic treatment for these diseases were discussed in this study.
A cutting-edge therapeutic genome editing technology is studied in the first part of study. This technology was invented to treat retinitis pigmentosa via engineered nucleases, which has great clinical potential for autosomal dominant genetic disorders that were previously irreparable by conventional gene therapy interventions. Though customizable gene editing tools can be engineered to target specific mutation sites, however it is too daunting for diseases like retinitis pigmentosa, a progressive retinal degenerative condition associated with more than 150 mutations in the rhodopsin gene alone. Here in this study, we present an “ablate-and-replace” combination strategy that 1) destroys expression of the endogenous gene by CRISPR/Cas9 in a mutation-independent manner, and 2) enables expression of wild-type protein through exogenous cDNA. As proof of concept, we show that our CRISPR-based therapeutic machinery efficiently ablates mRho in vivo, and when combined with gene replacement therapy, ameliorates rod photoreceptor degeneration and improves visual function in two genetically distinct autosomal dominant retinitis pigmentosa animal models.
This mutation-independent, ablate-and-replace strategy represents the first electrophysiological recovery by a CRISPR-mediated therapy in an autosomal dominant disorder and it offers a clinically relevant, universal strategy to overcome allelic heterogeneity in debilitating inherited conditions.
For the second part of the study, gene editing technology was used to study the pathogenesis of Doyne honey comb dystrophy, another Mendelian disease with extensive similarities to age-related macular degeneration. This monogenic disorder is caused by a unique point mutation on an extracellular matrix protein EFEMP1, expressed by retinal pigment epithelium cell. To precisely gauge the physiological effect resulted from this mutation, CRISPR-mediated gene correction was used to create isogeneic cell pairs from patient donated tissue-derived stem cells. These stem cells were differentiated into retinal pigment epithelium cell before analysis. We found unfolded protein response and immune response were not involved in the pathogenesis, which contradicts existing theories. Via proteomics analysis, we found expression level of a cholesterol catabolic enzyme was affected by the EFEMP1 mutation while those proteins controlling the cholesterol transport remains constant. This result provides supportive evidence to explain the aberrant intracellular accumulation of cholesterol found in patient retinal pigment epithelium cells. This imbalance in lipid homeostasis also suggests Doyne honey comb dystrophy is a retinal pigment epithelium cell-autonomous disease.
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Çakir, Mustafa. "Exploring prospective secondary science teachers' understandings of scientific inquiry and mendelian genetics concepts using computer simulation." 2004. http://www.etda.libraries.psu.edu/theses/approved/WorldWideIndex/ETD-582/index.html.
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Lišková, Kateřina. "Výuka Mendelovské dědičnosti pomocí didaktické hry." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-434109.
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This diploma thesis focuses on the education of genetics to grammar schools and students' comprehension of genetics. This abstract scientific discipline is considered difficult to learn so I decided to prepare educational materials with the aim to improve students' understanding of the topic. The main aim of the thesis was to prepare and test a didactic game focused on Mendelian inheritance and compare the effectivity of this kind of interactive education compared with the classical explanatory style of education. Other aims included evaluating the influence of other variables; comparing the difficulty of individual terms in genetics and the connection within chosen triplet of terms; and identifying the most common misconceptions. The data was collected in four classes of upper graders at two grammar schools by newly prepared questionnaire focused on demographic and knowledge. The results showed that the didactic game was as efficient as the classical explanatory method at creating short term knowledge Students had a bigger problem with explaining the connection among the terms than defining the individual terms. The most complicated term reported by the students was chromosome. It was the only term in which there wasn't any improvement between pre-test and post-test. Part of this thesis is also...
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Dessy, Tatiana. "Méthode d'inférence par bootstrap pour l'estimateur sisVIVE en randomisation mendélienne." Thèse, 2018. http://hdl.handle.net/1866/22135.
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(8126406), Zhipeng Liu. "INTEGRATIVE OMICS REVEALS INSIGHTS INTO HUMAN LIVER DEVELOPMENT, DISEASE ETIOLOGY, AND PRECISION MEDICINE." Thesis, 2019.
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<div><div><div><p>Transcriptomic regulation of human liver is a tightly controlled and highly dynamic process. Genetic and environmental exposures to this process play pivotal roles in the development of multiple liver disorders. Despite accumulating knowledge have gained through large-scale genomics studies in the developed adult livers, the contributing factors to the interindividual variability in the pediatric livers remain largely uninvestigated. In the first two chapters of the present study, we addressed this question through an integrative analysis of both genetic variations and transcriptome-wide RNA expression profiles in a pediatric human liver cohort with different developmental stages ranging from embryonic to adulthood. Our systematic analysis revealed a transcriptome-wide transition from stem-cell-like to liver-specific profiles during the course of human liver development. Moreover, for the first time, we observed different genetic control of hepatic gene expression in different developmental stages. Motivated by the critical roles of genetics variations and development in regulating hepatic gene expression, we constructed robust predictive models to impute the virtual liver gene expression using easily available genotype and demographic information. Our model is promising in improving both PK/PD modeling and disease diagnosis for pediatric patients. In the last two chapters of the study, we analyzed the genomics data in a more liver disease- related context. Specifically, in the third chapter, we identified Macrophage migration inhibitory factor (MIF) and its related pathways as potential targets underlying human liver fibrosis through an integrative omics analysis. In the last chapter, utilizing the largest-to-date publicly available GWAS summary data, we dissected the causal relationships among three important and clinically related metabolic diseases: non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and obesity. Our analysis suggested new subtypes and provided insights into the precision treatment or prevention for the three complex diseases. Taken together, through integrative analysis of multiple levels of genomics information, we improved the current understanding of human liver development, the pathogenesis of liver disorders, and provided implications to precision medicine.</p></div></div></div>