Rozprawy doktorskie: „Human genetic variants”

1

Okyere-Boakye, Ivan W. "Studies on genetic variants of human plasma transferrin". Thesis, Queen Mary, University of London, 1997. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1639.

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The work presented in this thesis is concerned with the characterisation of human plasma transferrins showing abnormal electrophoretic mobilities on polyacrylamide gels. The work is divided into three studies: (i) a study of transferrin variants detected by nondenaturing polyacrylamide gel electrophoresis; (ii) a study of the plasma concentrations of individuals showing transferrin phenotypes associated with the three most common Tf C alleles, Tf Cl, Tf C2 and Tf C3; and (iii) a study of a reported nondegenerate nucleotide difference in the sequence of the cloned human transferrin gene. In the first study, six transferrin variants (3 Tf Br,,.,,, s and 3 Tf D. 5) showing abnormal electrophoretic mobilities on nondenaturing polyacrylamide gels, and the two Tf C variants, Tf Cl and Tf C2 which occur at polymorphic levels (> 1%) in human populations, were isolated and purified from human plasma. Transferrins were purified by a combination of DEAE Sephacel anion-exchange chromatography, SP. Sephadex cation-exchange chromatography and G-200 gel-filtration chromatography. A series of comparative studies were then carried out on the isolated transferrins to determine whether the six transferrin variants detected in this thesis and the Tf C2 variant, showed similar characteristics to the wild-type Tf Cl. Transferrins were studied for sialic acid content of the two glycan chains, and for molecular weights and isoelectric points of the iron-free (apo) and iron-saturated (holo) transferrin forms. Metal-binding properties were examined by studying the binding of Fe", Cu", Al" and Ga"'. Iron-binding was studied at physiological and endosomal pH (7.5 and 5.5 respectively) using FENTA as the iron donor. Binding of Cue*, Al"' and Ga'* were examined at physiological pH using CUNTA, ALNTA and GANTA respectively. The ability of transferrins to retain bound iron was examined by studying pH-induced iron release over a pH range of 6.0-4.0. Conformational stabilities were determined by studying the iron-binding abilities of apotransferrins following exposure to urea or thermal denaturation, and by studying iron loss from holo transferrins following exposure to urea or thermal denaturation. Other than expected differences in isoelectric points, and slightly faster rates of iron loss from variant holo transferrins titrated at physiological pH, all variant transferrins were found to show similar characteristics to Tf Cl, with identical molecular weights and sialic acid content, similar metal-binding properties, and similar stabilities to urea or thermal denaturation. The results indicate that the structure and function of the variant transferrins are not adversely affected by their differences in primary structure. The second study examined the relationship between plasma transferrin concentration and transferrin phenotypes representing five of the six most common Tf C phenotypes (i. e. Tf Cl, Tf C2, Tf C2-1, Tf C3-1 and Tf C3-2), to determine whether plasma concentrations were dependent on transferrin phenotype as suggested in literature. Transferrin phenotypes of 931 unrelated individuals were determined by electrophoresis of plasma on polyacrylamide isoelectric focusing gels. Plasma transferrin concentrations were determined by single radial immunodiffusion using rabbit anti-human transferrin IgG. A significant difference was found between the plasma concentrations of the five transferrin phenotypes (p < 0.01) indicating that transferrin concentration was dependent on phenotype. The results suggest that the two Tf C alleles, Tf C2 and Tf C3 are associated with low plasma concentrations. The third study was initiated to investigate a report in literature that a nondegenerate nucleotide difference of adenine for guanine at base 1086 in exon 8 of the human transferrin gene, may indicate the presence of a hitherto unrecognised transferrin variant with Asn rather than a wild-type Asp at position 310 of the amino acid sequence. The nucleotide sequenceo f exon 8 from 220 unrelatedi ndividuals showing transferrin phenotypes associated with the three most common Tf C alleles, Tf Cl, Tf C2 and Tf C3, and from 5 individuals showing abnormal transferrin phenotypes in the first study, were amplified by polymerase chain reaction. Amplified products were digested with the restriction endonuclease, Fok I which has a single recognition site in exon 8 containing the proposed wild-type guanine at base 1086, or with Bsm I which also shows a single recognition site containing the proposed adenine nucleotide. The study failed to detect the presence of the proposed transferrin variant, confirming that the wild-type guanine was present in all 225 individuals.

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Rohde, Kerstin, Martin Federbusch, Annette Horstmann, Maria Keller, Arno Villringer, Michael Stumvoll, Anke Tönjes, Peter Kovacs i Yvonne Böttcher. "Genetic variants in AKR1B10 associate with human eating behavior". Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-169923.

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Background: The human Aldoketoreductase 1B10 gene (AKR1B10) encodes one of the enzymes belonging to the family of aldoketoreductases and may be involved in detoxification of nutrients during digestion. Further, AKR1B10 mRNA (messenger ribonucleic acid) expression was diminished in brain regions potentially involved in the regulation of eating behavior in rats which are more sensitive to cocaine and alcohol. We hypothesized that the human AKR1B10 gene may also play a role in the regulation of human eating behavior.

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3

Zhao, Jing. "Rare and common genetic variant associations with quantitative human phenotypes". Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/53923.

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This dissertation aims at investigating the association between genotypes and phenotypes in human. Both common and rare regulatory variants have been studied. The phenotypes include disease risk, clinical traits and gene expression levels. This dissertation describes three different types of association study. The first study investigated the relationship between common variants and three sub-clinical traits as well as three complex diseases in the Center for Health Discovery and Well Being study (CHDWB). The second study is GWAS analysis of TNF-α and BMI/CRP conducted as a contribution to meta-GWAS analyses of these traits with investigators at the University of Groningen in the Netherlands, and the 1000 Genomes Consortium. The third study was the most original contribution of my thesis as it assessed the association between rare regulatory variants in promoter regions and gene expression levels. The results clearly show an enrichment of rare variants at both extremes of gene expression. This dissertation provides insight into how common and rare variants associate with broadly-defined quantitative phenotypes. The demonstration that rare regulatory variants make a substantial contribution to gene expression variation has important implications for personalized medicine as it implies that de novo and other rare alleles need to be considered as candidate effectors of rare disease risk.

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4

Ndungu, Anne. "Rare genetic variants and susceptibility to severe bacterial diseases". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:9c5745f9-50f9-469a-8771-2e49e75db7ac.

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Infectious diseases are a major cause of morbidity and mortality worldwide. Streptococcus pneumoniae and Neisseria meningitidis are major causes of severe bacterial disease which can manifest as invasive disease such as bacteraemia and meningitis. Exposure to these pathogens is relatively widespread, yet only a minority of individuals develop invasive disease. A host genetic component to infectious disease susceptibility has been implied from twin and adoptee studies. A role for rare large effect genetic variants in predisposition to infection has been demonstrated through the study of individuals with primary immunodeficiencies. However, a majority of these studies have been undertaken in individuals with a history of recurrent disease or in multi-case families. The relative role of rare genetic variants of moderate to large effect at the population level has not been widely explored. This thesis presents effort made using next generation sequencing methods to identify rare genetic variants that lead to increased susceptibility to bacterial disease focussing on meningococcal disease, pleural infection(empyema), pneumococcal disease and sepsis phenotypes. Using an exome sequencing approach in 13 cases with invasive meningococcal disease, a novel mutation leading to a complement deficiency and increased risk of meningococcal infection was identified and functionally validated in one individual. This mutation in the CFP gene was demonstrated as leading to impaired properdin secretion. Further analysis implicated loss of function mutations in CD4 and ZAP70 as novel loci for meningococcal disease susceptibility. A case control association analysis for sepsis susceptibility highlighted the possible role for small Rho GTPases in sepsis pathology. By aggregating all rare predicted deleterious mutations in a gene, four genes in this pathway, (ROCK2, ARHGAP18, FYN and CDC42BPG) were implicated as having an excess of rare deleterious variants in sepsis samples compared to population controls. A similar approach identified low frequency genetic variants in the CD109 gene as predisposing to empyema susceptibility in children. Finally, preliminary evidence from adult individuals with invasive pneumococcal disease points to a potential role of the RNASE7 gene in invasive pneumococcal disease susceptibility. This association was primarily due to a predicted deleterious missense mutation present in cases and absent in controls. Taken together, these results have identified a number of potential loci with rare variants associated with susceptibility to severe phenotypes of bacterial diseases.

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Alston, Jessica Shea. "Genetic and Functional Studies of Non-Coding Variants in Human Disease". Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10515.

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Genome-wide association studies (GWAS) of common diseases have identified hundreds of genomic regions harboring disease-associated variants. Translating these findings into an improved understanding of human disease requires identifying the causal variants(s) and gene(s) in the implicated regions which, to date, has only been accomplished for a small number of associations. Several factors complicate the identification of mutations playing a causal role in disease. First, GWAS arrays survey only a subset of known variation. The true causal mutation may not have been directly assayed in the GWAS and may be an unknown, novel variant. Moreover, the regions identified by GWAS may contain several genes and many tightly linked variants with equivalent association signals, making it difficult to decipher causal variants from association data alone. Finally, in many cases the variants with strongest association signals map to non-coding regions that we do not yet know how to interpret and where it remains challenging to predict a variants likely phenotypic impact. Here, we present a framework for the genetic and functional study of intergenic regions identified through GWAS and describe application of this framework to chromosome 9p21: a non-coding region with associations to type 2 diabetes (T2D), myocardial infarction (MI), aneurysm, glaucoma, and multiple cancers. First, we compare methods for genetic fine-mapping of GWAS associations, including methods for creating a more comprehensive catalog of variants in implicated regions and methods for capturing these variants in case- control cohorts. Next, we describe an approach for using massively parallel reporter assays (MPRA) to systematically identify regulatory elements and variants across disease-associated regions. On chromosome 9p21, we fine-map the T2D and MI associations and identify, for each disease, a collection of common variants with equivalent association signals. Using MPRA, we identify hundreds of regulatory elements on chromosome 9p21 and multiple variants (including MI- and T2D-associated variants) with evidence for allelic effects on regulatory activity that can serve as a foundation for further study. More generally, the methods presented here have broad potential application to the many intergenic regions identified through GWAS and can help to uncover the mechanisms by which variants in these regions influence human disease.

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Zeron-Medina, Cuairan Jorge. "The identification and characterisation of germline genetic variants that affect human cancer". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:8942602e-c0f8-4793-8020-d2eadd41b252.

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Single nucleotide polymorphisms (SNPs) have great potential to serve as important biomarkers in the clinic to identify those at increased risk for developing cancer, progressing more rapidly, and not responding to therapies. However, the clinical application of cancer-associated SNPs has proven to be more complicated than expected. One of the necessary steps will certainly be the description of the molecular and cellular mechanisms behind the observed associations. The p53 tumour suppressor pathway harbours well-described SNPs that affect p53 signalling and cancer. The aim of the work presented in this thesis was to utilise this knowledge to more efficiently characterise cancer-associated SNPs. Firstly, cancer-associated SNPs in a p53 network gene, CD44, were studied. Specifically, based on CD44’s known roles in both p53-dependent and independent signalling, it was predicted that the cancer-associated SNPs could function as biomarkers for chronic lymphocytic leukaemia progression, and for the response to anti-EGFR therapy for colorectal cancer. Indeed, supportive data is presented. Next, a methodology is presented that aims to identify cancer-associated SNPs in functional p53 binding sites using genome-wide datasets. Interestingly, a SNP is identified that dramatically influences the ability of p53 to regulate transcription of the KITLG oncogene and that associates with one of the largest risks of cancer identified to date. Intriguingly, the SNP is also shown to have undergone positive selection throughout human evolution, signifying a selective advantage, but similar SNPs are demonstrated to be rare in the genome due to negative selection, indicating that polymorphisms in p53 binding sites have been primarily detrimental to humans. Lastly, and in order to begin to explore if other polymorphic transcription factor binding motifs could be found in cancer-associated SNPs, a methodology was designed to identify SNPs in E-box transcription factor binding motifs, as they are sensitive to single base pair changes and affect cancer. Taken together, the work presented in this thesis shows how the study of how SNPs associate with, and impact upon, cancer has great potential to improve both biological knowledge and clinical outcomes.

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Ludwig, Leif Si-Hun [Verfasser]. "Functional studies of genetic variants in human erythropoiesis / Leif Si-Hun Ludwig". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1133074413/34.

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Hasan, Mohammad Shabbir. "Identifying and Analyzing Indel Variants in the Human Genome Using Computational Approaches". Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/90797.

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Insertion and deletion (indel), a common form of genetic variation, has been shown to cause or contribute to human genetic diseases and cancer. Despite this importance and being the second most abundant variant type in the human genome, indels have not been studied as much as the single nucleotide polymorphism (SNP). With the advance of next-generation sequencing technology, many indel calling tools have been developed. However, performance comparison of commonly used tools has shown that (1) the tools have limited power in identifying indels and there are significant number of indels undetected, and (2) there is significant disagreement among the indel sets produced by the tools. These findings indicate the necessity of improving the existing tools or developing new algorithms to achieve reliable and consistent indel calling results. Two indels are biologically equivalent if the resulting sequences are the same. Storing biologically equivalent indels as distinct entries in databases causes data redundancy and misleads downstream analysis. It is thus desirable to have a unified system for identifying and representing equivalent indels. This dissertation describes UPS-indel, a utility tool that creates a universal positioning system for indels so that equivalent indels can be uniquely determined by their coordinates in the new system. Results show that UPS-indel identifies more redundant indels than existing algorithms. While mapping short reads to the reference genome, a significant number of short reads are unmapped and excluded from downstream analyses, thereby causing information loss in the subsequent variant calling. This dissertation describes Genesis-indel, a computational pipeline that explores the unmapped reads to identify missing novel indels. Results analyzing sequence alignment of 30 breast cancer patients show that Genesis-indel identifies many novel indels that also show significant enrichment in oncogenes and tumor suppressor genes, demonstrating the importance of rescuing indels hidden in the unmapped reads in cancer and disease studies. Somatic mutations play a vital role in transforming healthy cells into cancer cells. Therefore, accurate identification of somatic mutations is essential. Many somatic mutations callers are available with different strengths and weaknesses. An ensemble approach integrating the power of the callers is warranted. This dissertation describes SomaticHunter, an ensemble of two callers, namely Platypus and VarDict. Results on synthetic tumor data show that for both SNPs and indels, SomaticHunter achieves recall comparable to the state-of-the-art somatic mutation callers and the highest precision, resulting in the highest F1 score.
Doctor of Philosophy
Insertion and deletion (indel), a common form of genetic variation in the human genome, is associated with genetic diseases and cancer. However, indels are heavily understudied due to experimental and computational challenges. This dissertation addresses the computational challenges in three aspects. First, the current approach of representing indels is ambiguous and causes significant database redundancy. A universal positioning system, UPS-indel, is proposed to represent equivalent indels unambiguously and the UPS-indel algorithm is theoretically proven to find all equivalent indels and is thus exhaustive. Second, a significant number of indels are hidden in DNA reads not mapped to the reference genome. Genesis-indel, a computational pipeline that explores the unmapped reads to identify novel indels that are initially missed, is developed. Genesis-indel has been shown to uncover indels that can be important genetic markers for breast cancer. Finally, mutations occurring in somatic cells play a vital role in transforming healthy cells into cancer cells. Therefore, accurate identification of somatic mutation is essential for a better understanding of cancer genomes. SomaticHunter, an ensemble of two sensitive variant callers, is developed. Simulated studies using whole genome and whole exome sequences have shown that SomaticHunter achieves recall comparable to state-of-the-art somatic mutation callers while delivering the highest precision and therefore resulting in the highest F1 score among all the callers compared.

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Arefayene, Million. "Identification and functional characterization of genetic variants in the human indoleamine 2, 3-dioxygenase (INDO) gene". Thesis, Connect to resource online, 2008. http://hdl.handle.net/1805/1704.

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Thesis (Ph.D.)--Indiana University, 2008.
Title from screen (viewed on June 4, 2009). Department of Pharmacology and Toxicology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): David A. Flockhart. Includes vita. Includes bibliographical references (leaves 124-139).

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Nisar, Samia. "Role of ATP2B4 and human malaria : looking for functional genetic variants associated with malaria". Thesis, Aix-Marseille, 2020. http://theses.univ-amu.fr.lama.univ-amu.fr/200911_NISAR_992dobfs271wcdsgy656twqjfn399ockic_TH.pdf.

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GWAS pour le paludisme grave identifié 30 variantes génétiques situées dans régions non codantes, avec seulement quelques associations répliquées dans des populations indépendantes. Dans cette étude, nous avons cherché à identifier les variantes génétiques potentielles situées dans ces loci et à démontrer leur activité fonctionnelle. Nous avons systématiquement étudié l'effet régulateur des SNP en déséquilibre liaison avec les tagSNPs associés au paludisme sévère dans plusieurs populations. L'annotation et priorisation ont conduit à l'identification d'une région régulatrice contenant 5 SNP ATP2B4 en déséquilibre liaison avec le tagSNP. Nous confirmé l'association de rs10900585 et trouvé des associations significatives de paludisme sévère avec nos candidats dans population sénégalaise. Nous montré que cette région avait à la fois une activité promoteur et un activateur et que l'individu et combinaison de SNP avaient un effet en utilisant des dosages de luciférase. En outre, la délétion médiée par CRISPR / Cas9 de cette région a diminué le transcrit ATP2B4 et les niveaux de protéines et a augmenté la concentration intracellulaire de Ca2+ dans les cellules K562. Ensemble, nos données montrent les variantes génétiques associées au paludisme grave modifient l'activité d'un promoteur avec une fonction d'activateur. Nous montré que cet amplificateur contrôle l'expression de l'ATP2B4 qui code l'ATPase 4 (PMCA4) transportant le calcium dans la membrane plasmique, qui est la principale pompe à calcium des globules rouges. La modification de l'activité de cet Epromoter affecte le risque de paludisme sévère probablement par l'effet de la concentration de calcium sur la parasitémie
Genome-wide association studies (GWAS) for severe malaria have identified 30 genetic variants mostly located in non-coding regions, with only few associations replicated in independent populations. In this study, we aimed at identifying potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium with the tagSNPs associated with severe malaria in several populations. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing 5 ATP2B4 SNPs in linkage disequilibrium with the tagSNP rs10900585. We confirmed the association of rs10900585 and also found significant associations of severe malaria with our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we showed that this region had both a promoter and an enhancer activity and that both individual SNPs and the combination of SNPs had an effect using luciferase reporter assays. In addition, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in K562 cell line. Taken together, our data show that severe malaria associated genetic variants alters the activity of a promoter with enhancer function. We showed that this enhancer controls the expression of ATP2B4 that encodes plasma membrane calcium-transporting ATPase 4 (PMCA4), which is the major calcium pump on red blood cells. Altering the activity of this Epromoter affects the risk of severe malaria probably through calcium concentration effect on parasitaemia

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Rees, Matthew Geoffrey. "Genetic, functional, and phenotypic analysis of human variants in the glucokinase regulatory protein gene". Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589604.

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Genome-wide association (GWA) studies have provided significant insight into the underlying genetic components of common human diseases such as type 2 diabetes (T2D). However, the translation of such genetic findings into biological and clinical insight remains a major challenge. One of the genes implicated in T2D pathogenesis and effects on related glycaemic and lipidaemic traits by the GWA approach is GCKR, encoding glucokinase regulatory protein (GKRP). GKRP inhibits the glycolytic enzyme glucokinase (GCK) in the liver, sequestering it in an inactive form in the nucleus. Together, GCK and GKRP exert a significant proportion of control of hepatic glycolytic flux, facilitating glucose uptake and disposal in the fed state and inhibiting glycolysis in the fasting state. A common nonsynonymous variant in GCKR, p.P446L, was identified by a combination of genetic and functional approaches as the likely causative variant underlying the GWA findings. The P446L variant protein has been shown to have diminished capacity to inhibit GCK relative to wild-type (WT) GKRP, resulting in enhanced hepatic glycolytic flux and activation of liver synthetic pathways, including those generating triglycerides. Genes such as GCKR harbouring common variants of discernible functional effect may also contain rare variants of large effect. Accordingly, I aimed to comprehensively identify and functionally characterise nonsynonymous variants across the allelic frequency spectrum in GCKR, both by applying and adapting existing kinetic techniques and by developing methodologies to assess the effects of variants on the subcellular localisation of GKRP and GCK. Additionally, I aimed to relate these findings back to clinically important phenotypes, and to further characterise the binding of GCK and GKRP by searching for novel small- molecule modulators of this interaction. Using fluorescent fusion proteins transiently transfected into HeLa cells, I showed that human GKRP localises to the nucleus and sequesters human GCK. I also demonstrated that the common P446L variant significantly reduces the ability of G KRP to localise to the nucleus and sequester GCK. I then investigated the cellular and kinetic characteristics of 18 additional nonsynonymous GCKR variants identified in the National Institutes of Health's ClinSeqTM cohort, determining that the majority of variants affected protein function, and that these effects could be divided into distinct sub-classes. Variants causing a significant loss of function were associated with increased lipid levels in the cohort. Finally, I developed robust assays capable of measuring the interaction of re comb in ant GKRP and GCK in a format suitable for quantitative high-throughput screening of up to 400,000 small-molecule compounds. While no compounds that specifically affected this interaction have been identified to date, the assays developed could be useful in future studies of GCK and GKRP. These data provide further insight into the critical regulatory role of GCKR in metabolism, the structure and function of the GKRP protein, and the potential pathogenic consequences of human variants within GCKR.

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Bradshaw, Gabrielle. "Investigation of genetic variants in human immunodeficiency and an Australian non-Hodgkin lymphoma population". Thesis, Queensland University of Technology, 2020. https://eprints.qut.edu.au/180906/2/Gabrielle_Bradshaw_Thesis.pdf.

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This investigative study identified a missense moesin protein variant R171WMSN as the disease-causing mutation in an unknown primary immunodeficiency disorder (PID) through an exome sequencing (WES) approach. As PIDs can confer incidence of lymphoproliferative disorders, candidate genes and variants identified by WES were also investigated in another lymphoid abnormality, i.e. non-Hodgkin lymphoma (NHL), to determine association with NHL subtypes. In addition, variants located within microRNAs and their targets were investigated in association with NHL susceptibility in an Australian cohort of matched NHL cases and healthy controls where SNPs in MIR143 were shown to be significantly associated with NHL risk.

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

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Cai, Xuyu. "Single-Neuron Sequencing to Explore Somatic Genetic Variants in Normal and Pathological Human Brain Development". Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10858.

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The human brain is one of the most exquisite structures in nature, featuring extreme functional complexity and capacities that allow for advanced cognitive abilities. During the development of the human brain, neural progenitors undergo massive proliferation, which is known to inevitably result in spontaneous mutations; yet the degree of somatic mosaicism within the human brain is unexplored. Several hypotheses have been proposed that various types of somatic mosaicism may serve as an adaptive mechanism to diversify neurons and thereby promote the functional complexity of human brains. Previously proposed mechanisms to increase somatic mosaicism within the brain include elevated somatic LINE-1 element retrotransposition, and the creation of somatic aneuploidy during neurogenesis. On the other hand, genomic diversity needs to be balanced by genomic stability, in order to protect against deleterious mutations that reduce the fitness of the cells, or oncogenic mutations that might promote cancers. In fact, brain-specific somatic mutations have also been proposed to contribute to the unexplained burden of neurological diseases. To directly study genomic variability from cell-to-cell within the human brain, we developed a method to isolate and amplify single neuronal genomes from postmortem and surgically resected human brain tissues. We quantified the frequency of somatic LINE-1 retrotransposition events and aneuploidy in human cortical neurons, and found that the frequencies of both are low, with no sign of brain-specific elevation, arguing against the hypotheses that these two mutational sources are obligate generators of neuronal diversity. Additionally, aneuploidy analysis was performed on bulk and single cortical cells from a hemimegalencephaly brain. Hemimegalencephaly is an asymmetrical brain overgrowth syndrome caused by somatic mutations in brain. Single-cell analysis identified an unexpected mosaic tetrasomy of chromosome 1q, affecting both neuronal and glial populations, as a genetic cause of hemimegalencephaly. These results demonstrate that single-neuron sequencing allows systematic assessment of genomic diversity in the human brain and the identification and characterization of pathogenic somatic mutations underlying neurological disorders.

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Makino, Seiko. "Investigation of expression quantitative trait loci and regulatory genetic variants in primary human immune cells". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:67d0c1e8-c6f1-4ca7-a311-52f20b79128b.

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The post human genome sequence era has begun to explore various aspects of the functional genome in relation to disease including gene expression, genetic variation and epigenetics. The genetic determinants of common and complex phenotypes are difficult to resolve even though their heritability is recognised. Recent genome-wide association studies (GWAS) for common diseases has identified many new disease susceptibility associated loci. These loci often lie in non-coding regions of the genome and disease associated genetic variants are proposed to act by modulating gene expression. This thesis investigated genetic variation as determinants of gene expression in the context of the immune system especially focused on the innate immune and inflammatory responses. Different primary human immune cell types were collected from healthy volunteers of European ancestry to achieve this. In order to identify genetic variants associating with gene expression, expression quantitative trait loci (eQTL) mapping was conducted in a cell type specific manner. The primary dataset (n=288) consists of CD19⁺ B-cells from the adaptive immune system and CD14⁺ monocytes from the innate immune system. 78% of the total cis eQTL were found to be cell type specific and include genes relating to their roles in the immune response. Trans eQTL showed greater cell type specificity and include master regulatory eQTL on the LYZ locus at chromosome 12q15 in monocytes and the KLF4 (9p31) in B-cells. The identified eQTL are implicated in association with autoimmune disease susceptibility including inflammatory bowel disease, diabetes and rheumatoid arthritis. The second analysed dataset (n=64) consists of CD14+ monocytes and macrophages differentiated ex vivo. Macrophages are involved in many inflammatory diseases as well as in the innate immune response. The differential gene expression and eQTL mapping analyses were conducted to investigate macrophages specific gene expression signatures and associations to genetic variants. Macrophage eQTL are involved in signal transduction for the inflammatory response (IL1RN and STAT4) and lipid metabolism (PPARG) with implication for metabolic disease association. The eQTL analyses using primary immune cell types provide insights into genetic variation in association to gene expression which is involved in autoimmunity and disease susceptibility.

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Badarinarayan, Nandini [Verfasser]. "Next-generation sequencing of centenarians to identify genetic variants predisposing to human longevity / Nandini Badarinarayan". Kiel : Universitätsbibliothek Kiel, 2018. http://d-nb.info/115376850X/34.

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Evans, Jonathan. "APOE, PCSK9, and CETP genetic variants as potential biomarkers of dyslipidaemia in black South Africans with Type 2 Diabetes Mellitus". Master's thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29630.

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Dyslipidaemia is a commonly encountered clinical condition and is a major risk factor for cardiovascular diseases. Although there are many factors associated with dyslipidaemia, a strong genetic component is evident. Apolipoprotein E (APOE), proprotein convertase subtilisin/kexin type 9 (PCSK9), and cholesteryl ester transfer protein (CETP) are key regulators of plasma cholesterol levels. Thus, genetic variation in the genes coding for these proteins contributes to dyslipidaemia. In this study, a cohort of black South African Type 2 Diabetes Mellitus (T2DM) patients was characterized for mutations in genes coding for APOE, PCSK9, and CETP, and the possible effects of these variants on their lipid profiles was evaluated. Participants (n=417) were recruited from the Chris Hani Baragwaneth Hospital Diabetes Clinic, Johannesburg from whom blood samples were obtained for DNA extraction. The cohort was further stratified into two groups; individuals on statin treatment (Sim+, n=291), and the second that was not on treatment (Sim-, n=87). Lipid profiles were determined by enzymatic methods. DNA was genotyped for APOE, PCSK9, and CETP variants using PCRRFLP and Sanger sequencing. Analysis of the effects of the genetic variants was carried out in two ways. Firstly, for all the participants combined, and then by separating those on statin treatment from those without (Sim+ vs. Sim-). Genotype and allele frequencies were calculated followed by genotype-phenotype correlations with lipid profiles. Univariate analysis showed a significant association between the APOE4 isoform and lower HDL-c levels in the combined cohort (p=0.034). The effects were more pronounced in the Sim- group (p=0.004) but were absent in the Sim+ group. Contrary to above, APOE2 was significantly associated with lower total cholesterol (TC) (p< 0.001) and lower LDL-c (p< 0.001) when compared to APOE3 in the combined cohort. Upon analysing treatment groups, the correlations were observed in the Sim+ group (p=0.027 and p=0.003, respectively), while there were no observed correlations in the Sim- group. The CETP rs34065661C/G and G/G genotypes were significantly associated with increased HDL-c levels (p=0.017; when applying a dominant genetic model) in the combined cohort, as well as in the Sim+ group (p=0.026). Multivariate analysis, using a generalized linear model, confirmed associations between APOE rs429358C and lower HDL-c (OR=0.881, p=1.64e04), and APOE rs7412T and decreased LDL-c (OR=0.759, p=0.012). No significant associations were observed for PCSK9 polymorphisms. We report significant associations between APOE and CETP genetic variations and altered lipid levels in this black South African T2DM population. These genetic variants could be biomarkers for dyslipidaemia among Africans. However, it is imperative that the APOE, PCSK9, and CETP genes are fully characterized for additional polymorphisms in order to come up with a better genetic profile that explains the variance in lipid levels observed in the black South African population. The impact of these genetic variants could be relevant to other black African populations as well.

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Lamlum, Hanan. "Variation in human tissue inhibitor of metalloproteinase 1 gene and its effect on the control of connective tissue remodelling in cardiovascular disease". Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365809.

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Montalvo, Zulueta Nigreisy. "Development of federated learning models for improved genetic variant assessment in a multi-site clinical setting". Electronic Thesis or Diss., Université Paris Cité, 2024. http://www.theses.fr/2024UNIP5289.

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L'apprentissage fédéré (FL) est une technique d'apprentissage automatique qui permet à plusieurs détenteurs de données d'entraîner un modèle de manière collaborative, sans partager les données brutes. Cette approche est particulièrement pertinente dans le domaine de la génétique, où les données sont souvent réparties entre plusieurs institutions, et où des contraintes réglementaires, telles que le Règlement Général sur la Protection des Données, limitent la centralisation des données. En plus d'améliorer la confidentialité et la sécurité des données, FL permet l'entraînement de modèles plus robustes en accédant à des ensembles de données plus vastes et plus diversifiés. FL a été proposé pour la première fois en 2016 comme approche pour entraîner des modèles d'apprentissage automatique sur une fédération d'appareils mobiles, coordonnée par un serveur central. Dans leur mise en œuvre, le serveur définissait un modèle global, et transmettait ses paramètres à un sous-ensemble de clients. Les clients optimisaient ensuite le modèle reçu, en effectuant une descente de gradient stochastique sur leurs données locales, puis renvoyaient les mises à jour locales au serveur. Le serveur créait un nouveau modèle global en agrégeant les mises à jour locales par moyenne pondérée. Ce processus était répété soit pendant un nombre prédéfini de tours, soit jusqu'à la convergence du modèle. FL a également été adapté aux environnements cross-silo, où les clients (généralement entre 2 et 50) sont des organisations telles que des hôpitaux et des instituts de recherche. L'objectif de cette thèse est d'étudier l'efficacité de FL cross-silo pour l'évaluation clinique des variantes génétiques humains. À cet effet, nous avons utilisé la base de données publique ClinVar pour simuler des collaborations multi-institutionnelles réalistes dans l'évaluation des variantes nucléotidiques simples, codantes et non codantes, ainsi que des variations du nombre de copies. Concrètement, nous avons évalué la performance de plusieurs modèles d'apprentissage automatique supervisé, entraînés de manière fédérée entre plusieurs institutions, pour classifier les variantes génétiques comme pathogènes ou non pathogènes. Nous avons ensuite comparé ces performances à celles de modèles centralisés et celles de modèles locaux propres à chaque institution. Pour ce qui est de la comparaison avec les performances de modèles centralisés, les performances de FL étaient équivalentes ou supérieures. Pour ce qui est de la comparaison avec les performances de modèles locaux, les performances de FL étaient dans la grande majorité des cas supérieures. Ces résultats démontrent les avantages à utiliser l'apprentissage fédéré dans la collaboration entre les institutions. Dans nos expériences, nous avons évalué plusieurs stratégies d'agrégation de FL, notamment FedProx, FedAdagrad, FedAdam et FedYogi, qui font référence aux méthodes utilisées par le serveur pour combiner les mises à jour locales en un nouveau modèle global. Nos résultats ont montré que FedProx offrait généralement les meilleures performances. De plus, nous avons analysé la dégradation des performances du modèle de FL et de son modèle centralisé équivalent lorsqu'une institution décidait de ne pas participer à l'entraînement collaboratif. Nous avons constaté que, dans la plupart des cas, le modèle de FL se montrait plus résilient que les approches centralisées, démontrant sa capacité à se généraliser de manière adéquate à des ensembles de données non vus, même avec des ensembles d'entraînement plus réduits. À notre connaissance, cette thèse présente la première étude simulée de FL pour la classification de la pathogénicité des variantes génétiques. Avec nos conclusions, nous espérons encourager l'adoption de FL pour établir des collaborations multi-institutionnelles sécurisées dans l'interprétation des variantes humains
Federated learning (FL) is a machine learning (ML) technique that enables multiple data holders to collaboratively train a model, without raw data sharing. This approach is particularly relevant in the field of genomics, where data is often distributed across institutions, and regulatory constraints, such as General Data Protection Regulation (GDPR) and Health Insurance Portability and Accountability Act (HIPAA), restrict data centralization. In addition to improving privacy and data security, FL allows the training of more robust ML models, by leveraging access to a larger and more diverse dataset. FL was first proposed by Google researchers in 2017 as an approach for training ML models on a federation of mobile devices coordinated by a central server. In this setup, the mobile devices contained data that was either sensitive or large in size with respect to the ML model. In their implementation, the server defined a global ML model and communicated the parameters to a subset of clients. The clients then optimized the received model by performing Stochastic Gradient Descent on local data, and sent back the local updates to the server. The server derived a new global model by aggregating the local updates through weighted averaging. This process was repeated for a predefined number of rounds or until the model converged. FL has also been adapted to cross-silo settings, where clients (typically 2-50) are organizations, such as hospitals and research institutions. The objective of this thesis is to study the effectiveness of cross-silo FL for the clinical assessment of human genetic variants. To that extent, we leveraged the public-available database ClinVar for simulating realistic multi-institutional collaborations in the assessment of coding Single Nucleotide Variants (SNVs), non-coding SNVs, and copy number variants (CNVs). Concretely, we evaluated the performance of a diverse set of supervised ML models, trained in a FL manner across multiple institutions, in classifying genetic variants into pathogenic or non-pathogenic, and compared it to the centralized and individual- institution (local) model counterparts. Our results showed that FL generally achieved competitive or superior performance than the centralized model, and systematically outperformed the local models, highlighting the advantages of collaboration. In the experiments we benchmarked several FL aggregation strategies, including FedProx, FedAdagrad, FedAdam, and FedYogi, which refer to the methods used by the server to combine local updates into a new global model. Our results showed that FedProx generally provided the best performance. Furthermore, we analyzed the performance degradation of both FL and its centralized model counterpart when one institution decided not to participate in the collaborative training. We found that FL was more resilient than centralized approaches in most cases, demonstrating that FL can generalize adequately to unseen datasets with smaller training sets. To the best of our knowledge, this thesis presents the first simulated FL study for the pathogenicity classification of genetic variants. With our findings, we expect to incentive the adoption of FL for establishing secure multi-institutional collaborations in human variant interpretation

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Manyisa, Noluthando. "Whole exome sequencing to investigate genetic variants of non-syndromic hearing impairment in a population of African ancestry". Master's thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29272.

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Introduction: Hearing impairment occurs when a child has hearing loss greater than 30dB in their better hearing ear and an adult cannot detect sound lower than 40dB in the better hearing ear. It is a common sensory disorder that affecting approximately 360 million worldwide, with an incidence of 6 in 1000 live births in developing countries such as those in Sub-Saharan Africa. 50 % of hearing impairment, in developed countries, is due to genetic factors, with 70% of genetic hearing impairment being classified as non-syndromic hearing impairment, which occurs when the hearing impairment presents with no other clinical manifestations. Hearing impairment is associated with over 150 genes, of which two connexin genes, GJB2 and GJB6, are the most prevalent genes associated with hearing impairment in European, Asian and North American of European ancestries populations. These genes have however been shown to be insignificant causes of Hearing Impairment in African populations. Aim: The aim of this study is to determine the rates for putative pathogenic variants in 172 hearing impairment associated genes, among Cameroonian patients affected by hearing impairment, and non-hearing-impaired controls. Methods: Patients and controls Patients were recruited from various schools of the Deaf and Ear, Nose and Throat (ENT) clinics in Cameroon. The patients were examined by qualified medical geneticists and ophthalmologist and detailed family history and medical history was obtained from the patients and their parents. 19 patients, who were negative for GJB2 and GJB6 mutations and presented with putative non-syndromic hearing impairment, were selected from a cohort of 582 patients for the present study. The control population consisted of 130 ethnically matched groups without any personal or familial history of hearing impairment. The controls were recruited from Yaoundé Central Hospital and Laquintinie Hospital in Cameroon. Whole exome sequencing DNA was extracted from whole blood using the salting out procedure and the Puregene Blood kit®. The DNA was subjected to spectrometry and gel electrophoresis to determine the quantity and quality of the DNA samples. The samples were then subjected to whole exome sequencing on the Illumina platform using the Nextera Rapid Capture Exome Kit at an average read depth of 30X, whereby only 18 patients were successfully sequenced. The exomes were then subjected to FastQC and SolexaQC++ for quality control measures and aligned to the hg19 reference genome using GATK and VariantMetaCaller. Bioinformatics analysis Variant annotation was performed using Annovar and the annotated variants were filtered based in rarity and pathogenicity. Tests for genetic differentiation and principle component analysis was performed on the combined patient exomes and combine control exomes. The first principle component analysis included data from African populations from the 1000 Genomes Phase 3 as well as six control samples from the Democratic Republic of Congo; and the second principle component analysis analysed on the Cameroonian patients and control population. Population structure analysis was followed by protein-protein interaction analysis using custom python and R script and pathway enrichment analysis using Enrichr combined with a second custom R script. The proportion of derived and ancestral alleles was computed by downloading the SNP ancestral alleles from Ensembl and verifying the presence of the SNPs in dbSNP database. The combined patient and control exomes were annotated using the VCFtools “fillOaa” script. The ancestral alleles were computed by dividing the number of times the alternative allele matched the ancestral allele with the number of copies of all the alternative alleles across all samples at the particular position. The ancestral alleles were categorised into six bins, based on their minor allele frequency, in the patient and control populations and this was used to contrast their proportions of derived and ancestral alleles. Furthermore, the proportion of ancestral and derived alleles in hearing impairment associated genes was computed at SNP based level for the Cameroonian population and contrasted with population from the Democratic Republic of Congo. Variants validation by Sanger sequencing Primers were designed to amplify the fragment surrounding the purported SNPs in MYO15A, MYO3A, and COL9A3 as well as for the fragments surrounding the population specific SNPs in VTN, RPL3L and DHRS4L2. Polymerase chain reaction was performed for the MYO15A, and MYO3A fragments. This was followed by purification of the PCR products and direct cycle Sanger sequencing of the PCR products. The sequencing products were then purified through ethanol precipitation and the fragments were suspended in HiDi Formamide and run on the capillary electrophoresis. The variants in MYO3A, MYO15A and COL9A3 were viewed in Integrated Genomics Viewer using the Bam files as well. Results Putative deleterious variants Single nucleotide polymorphism (SNPs) in MYO3A, MYO15A and COL9A3, were filtered out as putative causative mutations for three, four and two patients respectively. Direct Sanger Sequencing and viewing the patients BAM files did not confirm the presence of any of these putative pathogenic in the patients. Variations in USH2A, HSD17B4 and MYO1A were also filtered out but these variants were not considered disease causing, after a careful genotype to phenotypes correlations. Population genetics variants differentiations At a population level, specific variations were identified in FOXD4L2, DHRS2L6, RPL3L and VTN. Significant genetic differentiation was shown to exist between the control population and the patients’ population with regard to specific variants in VTN and RPL3L; furthermore, it was shown that these variants in VTN and RPL3L interact with other hearing impairment associated proteins with evidences that that VTN is hub protein for a hearing impairment associated pathway along with nine other genes. Conversely, this was not the case for variants described in FOXD4L2 and DHRS2L6. In known hearing Impairment genes, the proportion of ancestral alleles was lowest for the patients’ population for variations with minor allele frequencies between 0.0 and 0.1. The proportion of derived and ancestral alleles was also shown to differ between the Cameroonian and the population from the Democratic Republic of Congo, indication possible regional differences in aetiology of Hearing impairment amongst multiple African populations. Discussion Low putative pathogenic variants in known hearing impairment genes among Africans The low pick up rate for putative pathogenic variants in our patients follows a similar trend observed in the African American populations, with hearing impairment, as well as data from targeted exome sequencing from South African and Nigerian populations. This result is also in agreeance with other studies that interrogated hearing impairment in African populations utilising other means besides next generation sequencing. This result also highlights the importance of validating any results obtained from next generation sequencing through traditional approaches such as Sanger Sequencing or viewing the BAM files on IGV, specifically in African population, poorly represented in Exome databases. Bioinformatics Analysis Exhibited some Specific Variants among Cameroonian Protein-protein interactions and enrichment analysis indicated that VTN and RPL3L, and their interacting proteins, are significantly associated with osteoclast differentiation, which is associated with hearing impairment in osteogenesis imperfecta. VTN was further shown as a hub protein of a protein subnetwork, along ATPB2. The presence of a second protein acting as a hub protein may account for why aberrations in VTN have not been associated with a disease; whereby ATPB2 may ameliorate the pathogenic phenotype that ought to be observed in the presence of null mutations in VTN. Evolutionary adaptation of human hearing Data indicates the patient population carried a higher proportion of derived alleles in known hearing impairment genes, at low minor allele frequencies; possibly indicating, the interactive modifiers capacities of multiple hearing impairment genes, or alternatively, the polygenetic nature of hearing impairment in some patients. The proportion of ancestral and derived alleles was contrasted in the Cameroonian and the population from the Democratic Republic of Congo and it indicated that the variations that may result in hearing impairment in the one population may not be the same variations that result in hearing impairment in the other population Due to this, it is necessary to determine the causative variants resulting in disease in each of these populations independently. Conclusion and perspectives The results support a low pick up rate of putative variants in 172 known genes in groups of Cameroonian patients with HI, underscoring the current Targeted panel sequencing for HI may not be relevant for some African populations. The result also support the need of confirmation of variants found in WES, as well careful genotype to phenotypes correlations, particularly among African, whose sequences exome is relatively low in Exomes databases, and as a result could lead to more false positive results. Population genetic analysis has provided novel insight in the genetic architecture of HI among this group of Africans; particularly, the differential frequencies of ancestral alleles vs derived alleles in HI genes among patients vs controls underline the possibility of multigenic influence on the phenotype of Hearing Impairment that have not been well investigated, and may also signal evolutionary enrichment of some variants of HI genes in the populations as the result of natural selections, that deserve further investigation. The result supports the need of intensive familial studies in multiple African populations in order to unravel the novel genes and those variants that are relevant in clinical practice for people of African ancestry.

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Yang, Wei-Shiung. "Functional analysis of the human lipoprotein lipase gene promoter and its naturally-occurring variants /". Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/10268.

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Bains, Onkar Singh. "Altered metabolism of daunorubicin and doxorubicin by genetic variants of human aldo-keto and carbonyl reductases". Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/29557.

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The anthracyclines, doxorubicin (DOX) and daunorubicin (DAUN) are commonly used to treat a variety of cancers. Their use is associated with life-threatening adverse events, especially chronic cardiotoxicity, in some patients. There may be a genetic basis for this variation, arising from altered metabolism by non-synonymous single nucleotide polymorphisms (ns-SNPs) in genes encoding for the aldo-keto reductase (AKR) and carbonyl reductase (CBR) enzymes, which are responsible for the biotransformation of these two drugs. The first two studies (Chapters 2 and 3) of this thesis examined the effect of ns-SNPs in 8 AKR and 3 CBR genes on the in vitro metabolism of both anthracyclines to their major metabolites, doxorubicinol (DOXol) and daunorubicinol (DAUNol) using purified, human wild-type and genetic variant enzymes. Michaelis-Menten kinetic curves were plotted and the metabolic capacities of the wild-type and variant enzymes were compared using catalytic efficiency (kcat/Km). In the presence of DAUN, 7 AKR and 5 CBR variants exhibited significantly reduced metabolic activity while 3 AKR and 5 CBR variants demonstrated significantly reduced activity with DOX as substrate. These findings suggest that genetic variants of human AKRs and CBRs are capable of decreasing the in vitro metabolism of DOX and DAUN. There is considerable controversy in the literature on how DAUN and DOX contribute to the variable adverse events seen in patients treated with these drugs. Some studies suggest that the toxic species are the major metabolites, DAUNol and DOXol, while others suggest the parent drug is more toxic. To study this, I examined whether a strong and consistent association exists between metabolic activity and drug toxicity among nine cell lines from different tissues (Chapter 4). My findings indicated that there is a strong, and inversely proportional, association between cytotoxicity and DAUN or DOX metabolism. Furthermore, the cell lines that were resistant to the toxic effects of these drugs had significantly greater expression of the AKRs and CBRs. Overall, these data provide a foundation of biochemical evidence to design in vivo studies that will elucidate the role of altered metabolism by genetic variants of human AKRs and CBRs in the development of anthracycline-induced cardiotoxicity.

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Vafa, Homann Manijeh. "Human genetic factors involved in immunity to Plasmodium falciparum infection". Doctoral thesis, Stockholm University, Wenner-Gren Institute for Experimental Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-7555.

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This study investigated the associations between IL-4 -590 C/T and IL-10 -1087 A/G polymorphisms and malariometric indexes in the Fulani and the Dogon ethnic groups living in sympatry in Mali and differing in susceptibility to malaria. The correlations between antibodies level and parasitological data as well as splenomegaly were assessed. The impact of IL-4 -590 variants on the levels of the studied antibodies was also studied.

The allele and genotype frequencies of both studied SNPs differed significantly between the two groups. The Fulani IL-4 T allele carriers had a significantly higher infection prevalence compared with those carrying the CC genotype. No correlation between anti-malarial antibody levels and parasite prevalence was seen in any of the communities. In the Fulani, the increase in total IgE levels was related to the presence of infection. Malaria-specific IgG4 levels were negatively correlated to the number of clones within the Fulani. The Fulani IL-4 T allele carriers had higher total and malaria-specific IgE levels, compared to the CC genotype carriers. These results suggest that the amount of antibodies may not be the key element in the protection against malaria. IgG4 might be involved in protection against malaria. The impact of IL-4 -590 variants on the antibody levels may be affected by other genetic/epigenetic/epistatic or environmental factors.

In the study in Senegal, multiplicity of infection (MOI) increased after the transmission season in all subjects, except in α-thalassaemic and in G6PD-mutated children, suggesting that α-thalassaemia may protect against infection by certain parasite strains. G6PD-mutated individuals may resist against increase in MOI after the transmission season due to rapid clearance of infection at an early stage. HbAs and the ABO system do not affect MOI in asymptomatic individuals. MOI was positively correlated to parasitemia, and did not vary over age (in the range of 2 to 10 years). No relation between MOI and clinical attack was noted.

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Cui, Hongzhu. "In Silico Edgetic Profiling and Network Analysis of Human Genetic Variants, with an Application to Disease Module Detection". Digital WPI, 2020. https://digitalcommons.wpi.edu/etd-dissertations/596.

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In the past several decades, Next Generation Sequencing (NGS) methods have produced large amounts of genomic data at the exponentially increasing rate. It has also enabled tremendous advancements in the quest to understand the molecular mechanisms underlying human complex traits. Along with the development of the NGS technology, many genetic variation and genotype–phenotype databases and functional annotation tools have been developed to assist scientists to better understand the intricacy of the data. Together, the above findings bring us one step closer towards mechanistic understanding of the complex phenotypes. However, it has rarely been possible to translate such a massive amount of information on mutations and their associations with phenotypes into biological or therapeutic insights, and the mechanisms underlying genotype-phenotype relationships remain partially explained. Meanwhile, increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. Among them, protein- protein interaction (PPI) network studies have attracted perhaps most attention. Our overarching goal of this dissertation is to (i) perform a systematic study to investigate the role of pathogenic human genetic variant in the interactome; (ii) examine how common population-specific SNVs affect PPI network and how they contribute to population phenotypic variance and disease susceptibility; and (iii) develop a novel framework to incorporate the functional effect of mutations for disease module detection. In this dissertation, we first present a systematic multi-level characterization of human mutations associated with genetic disorders by determining their individual and combined interaction-rewiring effects on the human interactome. Our in-silico analysis highlights the intrinsic differences and important similarities between the pathogenic single nucleotide variants (SNVs) and frameshift mutations. Functional profiling of SNVs indicates widespread disruption of the protein-protein interactions and synergistic effects of SNVs. The coverage of our approach is several times greater than the recently published experimental study and has the minimal overlap with it, while the distributions of determined edgotypes between the two sets of profiled mutations are remarkably similar. Case studies reveal the central role of interaction- disrupting mutations in type 2 diabetes mellitus and suggest the importance of studying mutations that abnormally strengthen the protein interactions in cancer. Second, aided with our SNP-IN tool, we performed a systematic edgetic profiling of population specific non-synonymous SNVs and interrogate their role in the human interactome. Our results demonstrated that a considerable amount of normal nsSNVs can cause disruptive impact to the interactome. We also showed that genes enriched with disruptive mutations associated with diverse functions and have implications in various diseases. Further analysis indicates that distinct gene edgetic profiles among major populations can help explain the population phenotypic variance. Finally, network analysis reveals phenotype-associated modules are enriched with disruptive mutations and the difference of the accumulated damage in such modules may suggest population-specific disease susceptibility. Lastly, we propose and develop a computational framework, Discovering most IMpacted SUbnetworks in interactoMe (DIMSUM), which enables the integration of genome-wide association studies (GWAS) and functional effects of mutations into the protein–protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non- synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest functional impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. With the advancement of next-generation sequencing technology that drives precision medicine, there is an increasing demand in understanding the changes in molecular mechanisms caused by the specific genetic variation. The current and future in-silico edgotyping tools present a cheap and fast solution to deal with the rapidly growing datasets of discovered mutations. Our work shows the feasibility of a large- scale in-silico edgetic study and revealing insights into the orchestrated play of mutations inside a complex PPI network. We also expect for our module detection method to become a part of the common toolbox for the disease module analysis, facilitating the discovery of new disease markers.

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Film, Sydney T. "Three Dimensional Structure and Human Genetic Variants of PMS1 Protein; Potential Medical Consequences Due to Inefficient DNA Mistmatch Repair". Walsh University Honors Theses / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=walshhonors1555695424580962.

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Ginevičienė, Valentina. "Analysis of the variety of human genome loci associated with fast and long–lasting adaptation to the load of physical activity". Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20101022_095402-52939.

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The genetic diversity of physical capacity in the Lithuanian population has a pattern similar to that of other populations. The knowledge of the individual genomes of the athletes is especially important for sports theory, practice and medicine. This research is devoted to the issue of the effect of genetic factors on the components of sporting physical capacity. We have accumulated a sample of the Lithuanian elite athletes which was studied genetically according to a phenotype. We have created a DNA biobase of the Lithuanian elite athletes of various sporting disciplines and collected information about the genotypes and phenotypes of physical development and functional capacity of the athletes. This is the first time in Lithuania that the elite athletes were investigated according to allelic distribution of 6 candidate gene variants most associated with physical capacity. The genetic diversity of the physical capacity in the Lithuanian population has a pattern manifested by variation in the allele/genotype frequencies of the selected candidate gene markers in the Lithuanian athlete groups and general population. The indexes of physical development and functional capacity of the Lithuanian athletes correspond to the elite levels. Inherited qualities and adaptation to physical loads of the athletes can be assessed by statistical analysis of phenotypic indexes. Each group of athletes investigated had a typical genotype/allele combination. The genotypes of the gene variants... [to full text]
Žmonių populiacijų tyrimai atskleidžia jų fizinio pajėgumo genetinę įvairovę. Tokių ypatumų turi ir Lietuvos populiacija. Sportininkų individualaus genomo žinojimas ypač svarbus sporto teorijai, praktikai ir medicinai. Darbas skirtas svarbiausiems klausimams, susijusiems su genetinių veiksnių įtaka sportinio fizinio pajėgumo komponentams. Darbo metu buvo sukaupta Lietuvos didelio meistriškumo sportininkų imtis, kuri ištirta genetiškai ir pagal fenotipą. Sukurtoje Lietuvos didelio meistriškumo įvairių sporto šakų sportininkų DNR mėginių biobazėje sukaupta informacija apie sportininkų genotipus ir sportininkų fizinio išsivystymo bei funkcinio pajėgumo fenotipiniai duomenys. Parinkti stipriausi genai kandidatai, siejami su žmogaus fiziniu pajėgumu. Didelio meistriškumo sportininkai pirmą kartą Lietuvoje buvo tirti pagal 6 genų kandidatų DNR žymenų alelių, dažniausiai asocijuojamų su fiziniu pajėgumu, paplitimą. Tirtų genų kandidatų žymenų genotipų/alelių dažnių įvairovė išskirtose sportininkų grupėse ir bendroje Lietuvos populiacijoje turi savitumų. Visų tirtų Lietuvos sportininkų fizinio išsivystymo ir funkcinio pajėgumo rodikliai atitinka didelio meistriškumo sportininkų lygį. Fenotipinių rodiklių statistinė analizė parodė sportininkų organizmo įgimtus gebėjimus ir prisitaikymą prie fizinių krūvių. Kiekvienos išskirtos sporto šakų grupės sportininkams būdinga genotipų/alelių kombinacija. Tirtų genetinių variantų genotipai turi skirtingos įtakos vyrų bei moterų fiziniam... [toliau žr. visą tekstą]

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Dröge, Carola [Verfasser], Ralf [Akademischer Betreuer] Kubitz, Lutz [Gutachter] Schmitt i Bruno [Gutachter] Stieger. "The identification and characterization of genetic variants in human hepatobiliary transporters / Carola Dröge ; Gutachter: Lutz Schmitt, Bruno Stieger ; Betreuer: Ralf Kubitz". Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2017. http://d-nb.info/1149330430/34.

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Marwaha, Ashish Kumar. "Genetic variants in the IL-2 pathway disrupt the immune balance between regulatory T cells and Th17 cells in human type 1 diabetes". Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50431.

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Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-producing β cells by autoreactive lymphocytes. CD4+FOXP3+ T regulatory cells (Tregs) are essential for immune tolerance, and murine studies suggest that their dysfunction can lead to T1D. Tregs require the cytokine interleukin-2 (IL-2) for maintenance of their suppressive function, and polymorphic variants in IL-2/IL-2R pathway genes are associated with T1D. Tregs can display plasticity by converting into Th17 cells, and intermediate FOXP3+IL-17+ cells have been identified. We hypothesized that pancreatic β cell destruction in T1D is driven by conversion of autoreactive Treg cells into a Th17 phenotype due to defective Treg IL-2 signaling in T1D subjects, who have polymorphic variants in the IL2RA gene. We assessed by flow cytometry the proportion of Treg and Th17 subsets in peripheral blood mononuclear cells from T1D subjects. The subjects were genotyped to determine whether they had the T1D-associated IL2RArs3118470 CC risk haplotype. Samples from T1D subjects were also obtained before the onset of disease. We found that Tregs are potentially transitioning towards a Th17 phenotype in recent-onset T1D subjects as they have an elevated proportion of FOXP3+IL-17+ cells and Th17 cells in their peripheral blood. We went on to show that T1D subjects with the T1D-associated IL2RArs3118470 CC risk haplotype have Treg cells with IL-2 signaling deficits and an increase in the proportion of IL-17+FOXP3+ cells in their peripheral blood at diagnosis. We did not find changes in the overall proportions of Tregs and Th17 cells in T1D subjects sampled before the onset of diagnosis. However, we observed a subset of CD39-expressing Treg cells were reduced in proportion before disease onset and could act as a biomarker of T1D. In conclusion, we show that defective IL-17-secreting Tregs are involved with T1D pathogenesis in a genetically identifiable subset of subjects, and provide a rationale for the treatment of T1D with therapeutics that target the IL-17 pathway.
Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate

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Martínez, Marigorta Urko 1983. "Genetic architecture of complex disease in humans :a cross-population exploration". Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/96909.

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The aetiology of common diseases is shaped by the effects of genetic and environmental factors. Big efforts have been devoted to unravel the genetic basis of disease with the hope that it will help to develop new therapeutic treatments and to achieve personalized medicine. With the development of high-throughput genotyping technologies, hundreds of association studies have described many loci associated to disease. However, the depiction of disease architecture remains incomplete. The aim of this work is to perform exhaustive comparisons across human populations to evaluate pressing questions. Our results provide new insights in the allele frequency of risk variants, their sharing across populations and the likely architecture of disease
La etiología de las enfermedades comunes está formada por factores genéticos y ambientales. Se ha puesto mucho empeño en describir sus bases genéticas. Este conocimiento será útil para desarrollar nuevas terapias y la medicina personalizada. Gracias a las técnicas de genotipado masivo, centenares de estudios de asociación han descrito una infinidad de genes asociados a enfermedad. Pese a ello, la arquitectura genética de las enfermedades no ha sido totalmente descrita. Esta tesis pretende llevar a cabo exhaustivas comparaciones entre poblaciones para responder diversas preguntas candentes. Nuestros resultados dan pistas sobre la frecuencia de los alelos de riesgo, su presencia entre poblaciones y la probable arquitectura de las enfermedades.

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Lundtoft, Christian [Verfasser], Marc [Gutachter] Jacobsen i Jürgen [Gutachter] Scheller. "IL-7-signalling and IL7RA genetic variants: Impact on T-cell functions in human infectious and autoimmune diseases / Christian Lundtoft ; Gutachter: Marc Jacobsen, Jürgen Scheller". Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/1163449857/34.

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Lintner, Katherine E. "The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus". The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460986052.

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Arnold, Matthias [Verfasser], Hans-Werner [Akademischer Betreuer] [Gutachter] Mewes, Florian [Gutachter] Kronenberg i Fabian J. [Gutachter] Theis. "Supporting the evidence for human trait-associated genetic variants by computational biology methods and multi-level data integration. / Matthias Arnold ; Gutachter: Florian Kronenberg, Fabian J. Theis, Hans-Werner Mewes ; Betreuer: Hans-Werner Mewes". München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1113749164/34.

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

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Jorge, Susan Elisabeth Domingues Costa 1983. "Estudo funcional de variantes estruturais da hemoglobina humana". [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310886.

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Orientadores: Maria de Fatima Sonati, Munir Salomão Skaf
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-14T12:16:23Z (GMT). No. of bitstreams: 1 Jorge_SusanElisabethDominguesCosta_M.pdf: 12500595 bytes, checksum: 271d153e901aa04d248746dbcf6d90c6 (MD5) Previous issue date: 2009
Resumo: A hemoglobina (Hb), pigmento respiratório de todos os organismos vertebrados, encontra-se em elevadas concentrações nas hemácias e é responsável pelo transporte de O2 dos pulmões para os tecidos. A Hemoglobina humana constitui-se de dois pares de cadeias polipeptídicas (globinas), cada qual envolvendo um grupo prostético heme, que se liga reversivelmente ao O2. Mais de 1000 variantes estruturais da Hb humana já foram descritas, parte delas relacionada a manifestações clinicas importantes. Algumas variantes apresentam alteração funcional, que se traduz em afinidade modificada pelo O2. Quando elevada, há uma produção compensatoriamente maior de hemácias, levando a policitemia; quando diminuída, resulta em cianose. O Laboratório de Hemoglobinopatias do Departamento de Patologia Clinica da FCM/UNICAMP e um dos laboratórios de referencia no pais, tendo identificado, ate o momento, 12 hemoglobinas novas e 51 variantes raras. Destas, as variantes novas Hb Hb Boa Esperanca (?16 Lys?Thr), Hb Itapira (?30 Glu?Val), Hb Bom Jesus da Lapa (?30 Glu?Ala), Hb Olinda [ß22 (b4) -25 (b7)], Hb Caruaru (ß 122 Phe?Ser) e Hb S-Sao Paulo (ß6 Glu?Val ; ß65 Lys?Glu) foram aqui caracterizadas funcionalmente, assim como as variantes raras Hb Iwata (a87 His??Arg), Hb Sunshine Seth (?94 Asp?His), Hb Deer Lodge (ß2 His?Arg), Hb Deer Lodge (ß2 His??Arg) + Hb S (ß6 Glu??Val), Hb G-Siriraj (ß7 Glu??Lys), Hb G-Siriraj (ß7 Glu??Lys) e Hb C (ß6 Glu??Lys) em associacao, Hb M-Saskatoon (ß63 His??Tyr), Hb Redondo (ß92 His? Asn), Hb Koln (ß98 Val??Met), Hb Coimbra (ß99 Asp??Glu) e Hb Dhonburi (ß126 Val?Gli)+ Btal. O metodo analitico empregado foi descrito por Rossi-Fanelli & Antonini (1958), e analisa espectrofotometricamente o comportamento da Hb frente a conhecidas pressões parciais de oxigênio (pO2), possibilitando a medida de afinidade (p50), da constante de Hill (n), que verifica o fenômeno de cooperatividade entre as cadeias globinicas para ligação do O2, o efeito Bohr (que indica facilidade na ligação Hb-O2 conforme e elevado o pH do meio), bem como a interação com o Inositol Hexafosfato (IHP), um fosfato polianion que dificulta a ligação entre a Hb e o O2. A exceção das Hbs Itapira e Bom Jesus da Lapa, em concentrações reduzidas nos hemolisados, todas as demais apresentam afinidade alterada pelo oxigênio. Como complementação ao estudo funcional, as Hbs Caruaru e São Paulo também foram submetidas a analise por dinâmica molecular, através dos programas VMD (Visual Molecular Dynamics), com dados inseridos nos softwares CHARMM (Chemistry at Harvard Molecular Mechanics) e NAMD (Nanoscale Molecular Dynamics). As demais variantes tiveram sua analise estrutural individualizada feita através da visualização de estruturas nativas depositadas no Protein Data Bank, para melhor compreensão da relação entre o aminoácido substituído e a função protéica alterada. Deste modo, foi possível estabelecer correlações entre a estrutura e a função e inferir sobre as manifestações clinicas resultantes da presença destas heme proteínas anômalas, ilustrando-se assim a importância desses estudos para a completa caracterização das variantes.
Abstract: The human hemoglobin (Hb) is the respiratory pigment of human organisms, found in high concentrations in the erythrocytes and is responsible for transporting O2 from the lungs to the peripheral tissues. This molecule is composed by two pairs of polypeptide chains (globin), each one involving a prosthetic group heme, which bind reversibly to the O2. More than 1000 structural variants had been described already; part of them related to important clinical manifestations. Some variants present functional alteration, with modified affinity for the O2. When it is increased, it has a higher compensatory production of the erythrocytes, causing policitemia; when decreased, it results on cyanosis. The Laboratory of Hemoglobinopaties of the Department of Clinical Pathology of the FCM/UNICAMP is one of the references laboratories in the country, and identified, until this moment, 12 new hemoglobins and 51 rare variants. The new variants Hb Hb Boa Esperanca (?16 Lys?Thr), Hb Itapira (?30 Glu?Val), Hb Bom Jesus da Lapa (?30 Glu?Ala), Hb Olinda [ß22 (b4) -25 (b7)], Hb Caruaru (ß 122 Phe?Ser) e Hb S-Sao Paulo (ß6 Glu?Val ; ß65 Lys?Glu) were, in the present study, functionally characterized, as well as the rare variants Hb Iwata (a87 His??Arg), Hb Sunshine Seth (?94 Asp?His), Hb Deer Lodge (ß2 His?Arg), Hb Deer Lodge (ß2 His??Arg) + Hb S (ß6 Glu??Val), Hb G-Siriraj (ß7 Glu??Lys), Hb G-Siriraj (ß7 Glu??Lys) e Hb C (ß6 Glu??Lys) em associacao, Hb M-Saskatoon (ß63 His??Tyr), Hb Redondo (ß92 His? Asn), Hb Koln (ß98 Val??Met), Hb Coimbra (ß99 Asp??Glu) e Hb Dhonburi (ß126 Val?Gli)+ Btal. The analytical method used was described for Rossi-Fanelli & Antonini (1958), which analyses, by spectrophotometer, the behavior of the Hb against known partial pressures of oxygen (pO2), making possible the measure of affinity (p50), the constant of Hill (n), that verifies the cooperativity, the Bohr effect (that it indicates the relation between Hb-O2 binding according to the pH), as well as the interaction with Inositol Hexaphosphoric acid (IHP), that difficult linkage between the Hb and the O2. Except from Hb Itapira and Hb Bom Jesus of the Lapa, in reduced concentrations at the total hemolysate, all the others presented modified affinity to the oxygen. As a complement of the functional study, the Hb Caruaru and Hb S-Sao Paulo were also submitted to previous molecular dynamics simulation. All the other variants were structurally analyzed by the study of the native structure deposited at the Protein Data Bank, to understand better the relation between the substituted residue and the modified one at the protein function. Therefore, it was possible to establish correlations between the structure and the function and to infer on the clinical manifestations because of the presence of these anomalous proteins, illustrating the importance of these studies for the complete characterization of the variants.
Mestrado
Ciencias Biomedicas
Mestre em Ciências Médicas

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Indap, Amit R. "Discovering rare variants from populations to families". Thesis, Boston College, 2013. http://hdl.handle.net/2345/3927.

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Thesis advisor: Gabor T. Marth
Partitioning an individual's phenotype into genetic and environmental components has been a major goal of genetics since the early 20th century. Formally, the proportion of phenotypic variance attributable to genetic variation in the population is known as heritability. Genome wide association studies have explained a modest percentage of variability of complex traits by genotyping common variants. Currently, there is great interest in what role rare variants play in explaining the missing heritability of complex traits. Advances of next generation sequencing and genomic enrichment technologies over the past several years have made it feasible to re-sequence large numbers of individuals, enabling the discovery of the full spectrum of genetic variation segregating in the human population, including rare variants. The four projects that comprise my dissertation all revolve around the discovery of rare variants from next generation sequencing datasets. In my first project, I analyzed data from the exon sequencing pilot of the 1000 Genomes Project, where I discovered variants from exome capture sequencing experiments in a worldwide sample of nearly 700 individuals. My results show that the allele frequency spectrum of the dataset has an excess of rare variants. My next project demonstrated the applicability of using whole-genome amplified DNA (WGA) in capture sequencing. WGA is a method that amplifies DNA from nanogram starting amounts of template. In two separate capture experiments I compared the concordance of call sets, both at the site and genotype level, of variant calls derived from WGA and genomic DNA. WGA derived calls have excellent concordance metrics, both at the site and genotypic level, suggesting that WGA DNA can be used in lieu of genomic DNA. The results of this study have ramifications for medical sequencing experiments, where DNA stocks are a finite quantity and re-collecting samples maybe too expensive or not possible. My third project kept its focus on capture sequencing, but in a different context. Here, I analyzed sequencing data from Mendelian exome study of non-sensorineural hearing loss (NSHL). A subset of 6 individuals (5 affected, 1 unaffected) from a family of European descent were whole exome sequenced in an attempt to uncover the causative mutation responsible for the loss of hearing phenotype in the family. Previous linkage analysis uncovered a linkage region on chr12, but no mutations in previous candidate genes were found, suggesting a novel mutation segregates in the family. Using a discrete filtering approach with a minor allele frequency cutoff, I uncovered a putative causative non-synonymous mutation in a gene that encodes a transmembrane protein. The variant perfectly segregates with the phenotype in the family and is enriched in frequency in an unrelated cohort of individuals. Finally, for my last project I implemented a variant calling method for family sequencing datasets, named Pgmsnp, which incorporates Mendelian relationships of family members using a Bayesian network inference algorithm. My method has similar detection sensitivities compared to other pedigree aware callers, and increases power of detection for non-founder individuals
Thesis (PhD) — Boston College, 2013
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology

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Masekoameng, Tshepiso. "Sickle cell trait and targeted genomic variants in chronic kidney disease an African cohort". Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31357.

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Background Chronic Kidney Disease (CKD), has a high and increasing burden in sub-Saharan Africa. Environmental factors that have been associated to CKD are associated with multiple co-morbidities such as hypertension, diabetes, and HIV. Some genetics factors such APOL1 have been associated with the highest burden of CKD among population of African ancestries. Other emerging genetic factors such as Sickle Cell trait (SCT) have been investigated mostly among African Americans. Sickle Cell trait (SCT) has the highest burden in sub-Saharan Africans, because of a natural selection, attributed to its protective advantages against the severest form of Malaria, caused by Plasmodium falciparum. Many studies showed that SCT has an impact on the normal functioning of the kidneys among African Americans with some studies indicating significant association between SCT and CKD. However, no study has been reported from Sub-Saharan Africa, where most SCT carrier reside. Moreover, there are multiple other loci and variants in the genome that have been associated with CKD in many populations, and that are used for Polygenic Risk Score (PRS) models but have not been explored in populations living in Africa. Aims This project aimed to study in a sub-Saharan African cohort, the association between 1) Sickle cell trait (SCT) with Chronic Kidney disease (CKD), and 2) the association of CKD with 29 targeted single nucleotide polymorphisms (SNPs) identified in multiple Genome-Wide Association studies (GWAS). Methods Patients and controls: 300 Cameroonian adult participants were included: 150 CKD cases and 150 non-CKD age, sex, and comorbidities matched controls. Molecular methods: SCT heterozygosity was determined by RFLP-PCR using the restriction enzyme DdeI. A total of 29 targeted SNPs was genotyped using MassArray and TaqMan techniques, followed by Sanger sequencing in a subset of samples. 11 Statistical Analysis: Descriptive statistics and logistic regression, and Fisher exact test were used. Functional pathway analysis: following the identification SNPs with significant association with CKD, we performed functional pathway test using the Linux programme Cytoscape. Results The mean age of cases was 53 years (range 46-55 years), with 43% that were female; there were no age and sex significant differences with controls. We identified, an expected, association between CKD and various co-morbidities, demographic and anthropometric variables: hypertension (p value = 5.16X10-9 ), HIV (p value = 2.68x10- 9 ), diabetes (p value = 7.12X10-7 ), BMI (p value = 4.58X10-8 ) and age (p value = 4.5X10-8 ). HbAS carrier status was significantly associated CKD (p value= 4.3X10-9 ; Odds Ratio:7.05). Only three targeted SNPs (3/29) previously associated with CKD in GWAS among African Americans, European and Asian population, were significantly associated with CKD among this group of Cameroonians (KBTBD2 rs3750082, PTPRO rs7956634 and LPR2 rs4667594 with p values of 0.02335, 0.0408 and 0.0398). Genes protein-protein interactions analysis identified the two key functional pathways and one network cluster that could play a crucial role in kidney dysfunctions. Lastly, we distinguished that HbS carrier state doesn’t influence the relationship between APOL1 G1/G2 risk alleles and CKD (p value = 0.5725) in this group from subSaharan Africans. Conclusion and perspectives Our study illustrates a strong association between SCT and CKD, an important discovery that will have a major implication in preventative medicine policies and practices in both sub-Saharan African where there is a very high prevalence of SCT. The data also has global resonance, with the projected increase in the prevalence of 12 individual with SCT, due to migration and the improve life expectancy and genetic fitness of people living with both SCT and SCD. We identified a relatively low proportion of (3/29) of target SNPs positively associated with CKD among this group of Cameroonians. The study illustrates that the vast majority of targeted SNPs associated with CKD in GWAS studies in multiple populations including African American, Europeans, and Asians, are not relevant for sub-Saharan Africans, indicating the urgent need to include diverse populations, specifically those living in Africa. Therefore, the data support the possible bias in currently available Polygenic Risk Score generated from GWAS data, where population from sub-Saharan Africa are largely underrepresented. The data further indicate that there is potential to discover new loci associated with CKD when investigating populations of African ancestry living in Africa.

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Jabot-Hanin, Fabienne. "Recherche des facteurs génétiques contrôlant la réponse à l’infection par Mycobacterium tuberculosis et le développement d’une tuberculose maladie". Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB253/document.

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La tuberculose, causée par Mycobacterium tuberculosis, connaît actuellement une résurgence inquiétante, et l’OMS estime à plus de 10 millions le nombre de nouveaux cas cliniques en 2015 avec environ 1,8 millions de décès dus à la maladie. Environ un tiers de la population mondiale est exposée à M.tuberculosis, et après exposition, la plupart des individus sont infectés par la mycobactérie. La grande majorité (~90%) des individus infectés ne présentera jamais de symptomatologie clinique. Parmi les 10% qui développent la maladie, environ la moitié le fera dans les deux années suivant l’infection, ce qui est en général considéré comme une forme primaire de tuberculose. Les autres patients présenteront leur maladie à distance de l’infection primaire (parfois plusieurs dizaines d’années plus tard) ; il s’agit des formes pulmonaires classiques de l’adulte. Chez l’homme, le rôle de certains facteurs génétiques a été maintenant démontré dans le développement d’une tuberculose active, à la fois la tuberculose pulmonaire de l’adulte et les formes plus disséminées de l’enfant, et aussi dans le contrôle de l’infection tuberculeuse. Cependant, la plus grande part de ces facteurs génétiques reste à identifier. Le premier objectif de ma thèse était d'identifier les facteurs génétiques de l'hôte modulant les phénotypes immunologiques de production d'Interféron gamma in vitro (IGRA) après exposition à M. tuberculosis dans un échantillon de 590 individus ayant été en contact avec un cas avéré de tuberculose dans le Val de Marne, en région parisienne. Puis, dans un second temps, de voir si les facteurs trouvés pouvaient être répliquées dans un échantillon familial d'Afrique du Sud, zone de très forte endémie tuberculeuse. Pour cela, j'ai tout d'abord réalisé des analyses de liaison génétique à l'échelle du génome entier sur plusieurs phénotypes quantitatifs d'IGRA. Celles-ci ont permis de mettre en évidence 2 loci majeurs (p < 10-4) répliqués en Afrique du Sud et liés à la production d'interféron gamma induite pour l’un par le bacille du BCG, et pour l’autre, par la part spécifique de l'antigène ESAT6 de M. tuberculosis (absent de la plupart des mycobactéries environnementales et du BCG), indépendamment de la capacité intrinsèque de réponse aux mycobactéries. La seconde étape a consisté en la réalisation d'une étude d'association sur les régions de liaison ainsi identifiées. Un variant associé au phénotype spécifique de l’ESAT6 (p < 10-5) a ainsi été trouvé, variant contribuant de manière significative au pic de liaison précédemment découvert (p<0.001) et ayant été rapporté comme modulant l’expression du gène ZXDC. Le second objectif de la thèse concernait l’identification de variants génétiques rares sous-jacents à la déclaration d’une tuberculose pulmonaire chez les individus infectés par le bacille. A cette fin, j’ai comparé les exomes de 120 patients tuberculeux à ceux de 136 individus infectés par le bacille mais non malades, tous originaires du Maroc. Cette étude m’a permis d’identifier le gène BTNL2, en bordure de la région HLA, dans lequel près de 10% des patients comportaient un variant rare perte de fonction contrairement aux contrôles qui n’en présentaient aucun
Tuberculosis remains a major public health concern, with approximately 10.4 million new cases and 1.8 million deaths due to the disease in 2015 according to WHO. While an estimated one third of the world population is estimated to be infected with Mycobacterium tuberculosis, only about 10% of infected individuals go on to develop a clinical disease. Among them, half will declare the disease in the 2 years following infection, which is generally considered as primary tuberculosis. The other patients will develop the disease more distant in time of primary infection, sometimes several tens of years latter; these are classical pulmonary forms in adults. In humans, the role of genetic factors have been demonstrated in the development of active tuberculosis, in pulmonary forms as in disseminated forms in childhood, et also in the control of M.tuberculosis infection. Nevertheless, most of these genetic factors remain to identify. The first aim of my PhD was to identify genetic factors controlling in vitro interferon-gamma production phenotypes (IGRA) after exposure to M.tuberculosis in a sample of 590 subjects who were in contact with a proven tuberculous patient in Val-de-Marne, Paris suburbs, and in a second time, to try to replicate the findings in a south African familial sample where the tuberculosis is highly endemic. For this purpose, I first performed genome-wide genetic linkage analysis for several quantitative IGRA phenotypes. They led to identify 2 major loci (p<10-4) replicated in South-Africa and linked to the interferon-gamma production induced by live BCG for the first one, and for the second one, by the specific part of the ESAT6 antigen of M.tuberculosis (absent from most of environmental mycobacteria and from BCG), independently of intrinsic ability to respond to mycobacteria. The second step was an association study in the identified linkage regions. A variant associated to the specific ESAT6 phenotype was found (p<10-5), which was significantly contributing to the linkage peak (p<0.001) and previously reported as eQTL of ZXDC gene. The second objective of my PhD was the identification of rare genetic variants underlying the development of pulmonary tuberculosis in infected individuals. To this end, I compared exome data from 120 tuberculous patients and 136 infected individuals without any clinical symptoms. All of them were from Morocco. This study resulted in the lighting of BTNL2 gene, very closed to the HLA region, in which around 10% of patients had a rare loss of function variant whereas the controls didn’t have any

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Roudabush, Robert M. "Variants and Polymorphisms of Three Repetitive DNA Families in the Human Genome". Digital Commons @ East Tennessee State University, 1989. https://dc.etsu.edu/etd/2779.

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A novel 0.6 kb LINE family in human DNA, designated L2Hs, has been described (Musich and Dykes 1986). Studies employing clone N6.4, containing three 0.6 kb segments of this family, indicate that these sequences are interspersed and moderately repetitive. Two additional variant sequences of the L2Hs family, N6.1 and N6.3, have been identified. Restriction mapping of each cloned segment indicates similarities among N6.4, N6.3 and N6.1. When the cloned DNAs were cleaved with restriction enzymes and subjected to cross-hybridization, each cloned insert produced a pattern indicating that the sequences contained in N6.1 and N6.3 are represented in at least one of the three 0.6 kb segments within the clone N6.4. Hybridization of human genomic DNA digested with KpnI or KpnI+AccI reveals differences in nuclear organization for these segments. For any particular human DNA, the hybridization patterns for each of the three probes overlap. However, these differences indicate that the inserts in N6.1 and N6.3 and one of the N6.4 inserts each represents a subset of the L2Hs LINE family. Sequence analysis of N6.1 indicates that the probability of a functional translation product from N6.1 transcript is not high. The sequence contains stop and nonsense codons in all reading frames. However, the DNA has properties suggesting a structural, non-coding role. The N6.1 sequence contains 11 regions of alternating purine and pyrimidines which can affect the three dimensional structure and, therefore, the structural behavior of the molecule. In addition, putative binding regions for microtubule-associated proteins have been identified. A cloned variant of the XbaI family of repetitive DNAs, PuHu7, was identified. Studies of its genomic organization showed a tandem arrangement similar to other, previously described members of this family. The genomic organization of a previously undescribed repetitive DNA family is also reported. This family descriptor is the clone PuHu26. Hybridization of genomic DNA digested with HindIII showed that sequences homologous to PuHu26 are tandemly organized. Genomic DNA cleaved with EcoRI revealed that a subpopulation of the PuHu26 family contains EcoRI restriction sites spaced at multiples of approximately 172 bp.

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Geard, Amy. "Association of variants in APOL1, MYH9 and HMOX1 WITH micro-Albuminuria among Sickle Cell disease patients from Cameroon". Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/23042.

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Introduction: Sickle Cell Disease (SCD) is a monogenic, multi-organ hemoglobinopathy disorder that is highly prevalent in Africa, with nearly 300 000 newborn cases per year. The underlying pathophysiological mechanism of the disease involves alteration of the normal soft and biconcave disc shape of erythrocytes, to that of a rigid crescent. These abnormal red blood cells cause vaso-occlusion and intravascular hemolysis, resulting in a variety of clinical manifestations, including acute pain crises, anemia, and damage to various organs. Kidney disease is a clinical proxy of severity, developing only in a subset of patients, and is subject to modification by genetic variations. Indeed, reports have shown significant association between proteinuria and specific genetic variants in MYH9 and APOL1, and between estimated Glomerular Filtration Rate (eGFR) and End Stage Kidney Disease (ESKD) with HMOX1 variants among adult African Americans affected by SCD. However, the association between these variants and micro-albuminuria, a primary indicator of renal dysfunction, has not been investigated, nor has any study of these variants been performed among SCD patients in Africa. Aim: The aim of this study was to investigate the association of targeted single nucleotide polymorphisms (SNPs) in APOL1, MYH9 and HMOX1, as well as a 5' promoter dinucleotide repeat in HMOX1, with micro-albuminuria among SCD patients from Cameroon; and to compare the results to that from a cohort of non-SCD Cameroonian individuals affected by ESKD.

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Mhandire, Kudakwashe. "Virus restriction gene variants and their possible role in neurocognitive function in children born to HIV-infected mothers". Master's thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/3100.

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Includes abstract.
Includes bibliographical references.
Host genetic variation is an important determinant of HIV infection, disease progression and HIV-associated neurocognitive deficits. However, there is no sufficient knowledge on the role of genetic variants especially among African populations. This study is focused on investigating variation in HIV/AIDS restriction genes; CCR2, CX3CR1, SDF1, RANTES, APOBEC3G and MBL2 and their possible role in HIV infection and neurocognitive function among children born to HIV infected mothers, recruited in Harare, Zimbabwe. A total of 116 children comprising of 73 perinatally exposed to HIV (34 who were born infected and 39 who were uninfected) and 43 unexposed controls were recruited in 2011(at ages 7-9 years) from a cohort of mother-baby pairs that has been followed up since 2002. The demographic characteristics of the recruited children were captured from their medical records. A McCarthy Scale of Children‟s Abilities (MSCA) was administered to determine each child‟s neurocognitive status. Genotyping for allelic variants was done using PCR-RFLP, SNaPshot® and Sanger DNA sequencing. Statistical analysis was carried out to determine association between genotypes, HIV status and neurocognitive function. The observation of different genetic variants or combinations of genotypes between the HIV-exposed and infected group and that of the HIV-exposed but uninfected group may be a pointer to critical pathways in differential HIV susceptibility. Exposure and infection with HIV is controlled by a multitude of genes/processes, thus, SNPs are unlikely to show statistically significant effects individually and may be more useful in a multifactorial model, as observed from comparisons of genotype combinations and haplotypes. The role of host genetic variation on neurocognitive function remains disputed but our observations suggest innate immune factors such as MBL2 may have a pronounced effect. Therefore, it may be possible to genotype for a suite of genes and use them as markers of either HIV susceptibility or neuro-developmental patterns.

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Akinyi, Maureen Veronica. "Functional analysis of A 5' untranslated variant in rhodopsin : implications for the retinitis pigmentosa phenotype". Master's thesis, University of Cape Town, 2011. http://hdl.handle.net/11427/10007.

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Retinitis Pigmentosa (RP) is a group of heterogeneous retinal degenerative diseases that predominantly affect rod photoreceptor cells. Symptoms include night blindness and gradual peripheral vision loss, which progresses to a complete loss of vision. Clinical, phenotypic and genetic heterogeneity are frequently observed in RP. Mutations in Rhodopsin (RHO) have been identified as a major cause of RP. A sequence variant identified in the 5' untranslated region of RHO, g.269A>G, also known as c.-26A>G, was proposed to increase the risk of developing RP. In this study, the functional effect of this variant, individually and in cis with known pathogenic variants, was investigated using mammalian cell lines in order to determine whether the variant is a modifier of disease phenotype.

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Morris, Jennifer Claire. "The cloning and eukaryotic expression of two naturally occurring variants of human pro-opiomelanocortin cDNA". Thesis, University of Reading, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262265.

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Ruppelt, Theresa. "Single nucleotide polymorphism array analysis in copy number variant detection: assessment of its feasibility in the diagnostic setting". Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/23720.

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Intellectual disability/developmental delay (ID/DD) is a significant problem in child health affecting 2 to 3% of the population worldwide. While the underlying aetiology of ID/DD in a large proportion (about 50%) of these patients is unknown, 15 to 20% of the internationally reported cases detected using microarray technologies are due to copy number variants (CNVs), whereas only 3 to 5% of ID/DD can be identified with conventional cytogenetics. The Affymetrix® Cytoscan™ High Density (HD) Array (Affymetrix, Santa Clara, CA) containing over 2.4 million markers for copy number (CN) was used to detect genome-wide high resolution CN and single nucleotide polymorphisms (SNPs) in a cohort of 27 carefully selected patient samples. The patient selection was done based on relevant phenotypes, which included dysmorphism, ID/DD, suspected syndromes, and family history. Data analysis was performed using the Affymetrix Chromosome Analysis Suite (ChAS) (Affymetrix, Santa Clara, CA, USA software). Seven of the patients demonstrated pathogenic CNVs. Diagnoses included Kleefstra syndrome, Mowat-Wilson syndrome, Wolf-Hirschhorn syndrome, tetrasomy 9p, and a susceptibility locus for neurodevelopmental disorders due to a deletion of chromosome 1q21.1. This indicated a 26% detection rate in this cohort. In addition, three variants of unknown significance (VOUS) were detected. The aim of this study was to determine the potential relevance and applicability of microarray technologies for the detection of CNVs in the Western Cape ID/DD population of South Africa (SA) and in so doing, to introduce and develop molecular cytogenetics skills in the routine diagnostic cytogenetic environment. The results obtained in this study confirmed the significant improvement in the detection rate of CNVs in patients with ID/DD and thus the diagnostic utility of this technology for the detection of CNVs in ID/DD patients was confirmed.

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Chakrabortty, Sharmistha. "SNPs and Indels Analysis in Human Genome using Computer Simulation and Sequencing Data". University of Toledo Health Science Campus / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1501726874739045.

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Planas, Fèlix Mercè. "Detection and classification of somatic structural variants, and its application in the study of neuronal development". Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/672163.

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The identification and analysis of genomic variation across individuals has been central in biology, first through comparative genomics to answer evolutionary questions, and then in the context of biomedicine, where it is actually becoming central to the study of most diseases. Next generation sequence technologies are allowing the systematic analysis of thousands of different types of genetic variation, enhancing the identification of disease markers and the understanding of the molecular basis of disease. For the past years, there has been a burst of new methodology for genome analysis around diseases coming from hundreds of groups around the world. Specific computational methods and strategies are being designed and improved around the identification and interpretation of genomic variation. The identification and classification of different types of genomic variants in the context of biomedicine is a key and foundational step for the development of a personalized medicine. This has been particularly central in the field of cancer genomics, which has based the research of the past ten to fifteen years in the sequencing of genomic DNA, and the identification and interpretation of (mostly) somatic and germline variation. Throughout these years, a large number of methods for variant detection have been developed with different action ranges. Despite all these developments, the identification of genomic variants has still room for improvement, not only at the level of sensitivity and specificity, but also at the computational level. Given the emergence of many initiatives for personalized medicine around the world, and the expected number of genomes that will have to be analyzed within health care systems, we require robust algorithms, designed together with a matching implementation that will minimize the computational costs of the analysis. With this aim, during this thesis, I have pushed and designed and implemented an algorithm for the efficient processing of genomic data, in close collaboration with computer scientists of our center that defined the implementation, focusing on lowering the energy and the time of the analysis. This methodology, which relies on a reference free approach of read classification, has been protected with a patent, and is being used as the foundation for the development of SMuFin2, a more accurate and computationally efficient version of the initial SMuFin from 2014. We here show that our method is able to process whole genome sequences very fast and with a minimal energy consumption, compared with existing methods, and that has great potential for the identification of all ranges of variants, including insertions of non-human DNA. Further developments on SMuFin2 are needed to finally assess its full variant calling capabilities. Despite their great importance and their clear role in the biology of the cell, somatic variation that occurs in healthy tissues has remained diffuse in their roles. In the case of development, some hypotheses have been proposed to explain the observed somatic DNA damage that occurs during brain development (e.g., replication stress). But the real impact and the underlying mechanisms of this somatic variation are not yet understood. In order to seed light on the type and potential functional impact of somatic variation in brain development, we established a new collaboration to identify, and describe somatic DNA rearrangements induced by Pgbd5 during brain development and adult state in 36 mice neural tissue samples. The detection of somatic variants in healthy tissues presents more challenges than in the cancer scenario, where a variant is present in a significant number of cells and is easier to detect. We have identified, classified and interpreted the landscape of somatic variation in neural development and identified interesting differences between adult and embryonic variation load, and specific types of variants, as the potential result of the activity of these transposase-like genes.

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Franch, Expósito Sebastià. "Variants del número de còpia al càncer colorectal: predisposició germinal i perfils genòmics tumorals". Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668923.

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El càncer de còlon i recte, o càncer colorectal (CCR), és el tercer tipus de càncer amb més incidència mundial quan ambdós sexes es tenen en compte. El CCR sorgeix per l’acumulació de mutacions genètiques en gens claus que provoquen la progressió del teixit normal i fins al desenvolupament final del càncer. El CCR és d’entre les neoplàsies comuns la que presenta més proporció de casos amb agregació familiar. Estudis de parents i de bessons han estimat que un 30-35% dels casos de CCR presenten alguna forma d’herència familiar de la malaltia, o CCR germinal. Aproximadament un quart dels casos que presenten agregació familiar per CCR s’identifiquen entre les anomenades formes hereditàries, associades a mutacions d’alta penetrància en gens coneguts i que aporten alt risc a desenvolupar la malaltia. Les variants de número de còpia (CNVs, copy number variants) formen part del conjunt de les variants estructurals i representen variacions genòmiques “no balancejades” (duplicacions o delecions), alterant el caràcter diploide del genoma i aportant diversitat a la població genètica humana. Gràcies al desenvolupament de mètodes estadístics aplicats a l’anàlisi de dades de seqüenciació massiva, aquestes formes de variants genòmiques estructurals també poden ésser detectades mitjançant la seva inferència en dades de seqüenciació de l’exoma o del genoma. La predisposició genètica de molts casos amb forta agregació familiar per CCR i que no presenten mutacions als gens de les formes hereditàries encara és desconeguda. El primer estudi d’aquesta tesi presenta la identificació de CNVs potencialment implicades en la predisposició al CCR en famílies amb forta agregació per aquesta patologia, mitjançant la seva inferència en les dades de seqüenciació de l’exoma del DNA germinal de membres d’aquestes famílies. S’ha identificat, validat i caracteritzat una duplicació de 392 Kb del cromosoma 1 (chr1:117591257-117982865) en una de les famílies estudiades. En la regió genòmica de la duplicació s’hi localitzen quatre gens (TTF2, TRIM45, VTCN1 i MAN1A2) i un miRNA (MIR942), localitzat en l’intró 18 del gen TTF2. Per tal de caracteritzar els possibles efectes moleculars de la variant a sobre d’aquests gens, s’han estudiat els nivells d’expressió gènica i proteica d’aquests. D’altra banda, el concepte d’alteracions del número de còpia (CNAs, copy number alterations) va molt lligat al context tumoral somàtic. L’aneuploïdia, o adquisició d’alteracions numèriques i estructurals dels cromosomes, es considera un dels processos més importants a l’hora de facilitar la progressió tumoral, diferenciant-se entre les alteracions àmplies (broad): guanys i pèrdues de cromosomes o braços cromosòmics; i les alteracions focals, que afecten regions puntuals del genoma. Diversos estudis han demostrat la presència de patrons recurrents de CNAs específiques entre els distints tipus de càncer. La caracterització i integració d’aquest tipus d’esdeveniments genòmics amb anotacions moleculars o clíniques pot ajudar a la identificació de CNAs com a potencials bio-marcadors. Al segon estudi d’aquesta tesi s’ha desenvolupat l’eina bioinformàtica CNApp, amb l’objectiu d’analitzar i integrar la detecció de CNAs amb les anotacions molecular i/o clíniques disponibles en les mostres estudiades. CNApp genera perfils complets del genoma utilitzant segments genòmics, calcula la càrrega de CNAs diferenciant entre alteracions broad i focals, i utilitza sistemes d’aprenentatge automàtic per a la re-classificació de mostres. Aplicant aquesta eina a les 10.635 mostres del consorci TCGA, s’ha aconseguit diferenciar els distints tipus tumorals d’acord al seu perfil genòmic i segons el seu teixit d’origen. A més, CNApp ha estat capaç de re-classificar els distints subtipus moleculars de CCR depenent dels nivells de càrrega d’alteracions broad o focals, a més d’identificar certes regions genòmiques específiques entre els mateixos subtipus. CNApp facilita l’anàlisi de dades genòmiques amb un maneig senzill i òptim, i és accessible a https://tools.idibaps.org/CNApp/.
Colorectal cancer (CRC) is the third most common cancer worldwide. A considerable number of cases with strong familial CRC aggregation and early disease onset remain unresolved at the genetic level. The first work analyzes germline whole- exome sequencing data from 38 families with strong CRC aggregation without alterations in known hereditary genes to infer rare candidate copy number variants involved in the predisposition to this disease. A duplication in chromosome 1 in one family stood out as interesting. TTF2, TRIM45, VTCN1 and MIR942 genes were found to be included in the duplication. Expression studies pointed to TTF2 and MIR942 overexpression in duplication carriers, and tumor immunohistochemistry showed TTF2 protein overexpression and under-expression of the TMEM158 protein, a predicted target of MIR942. The identified duplication may correspond to the mutational event involved in colorectal cancer predisposition in this family. On the other hand, somatic copy number alterations (CNAs) are a hallmark of cancer, but their role in tumorigenesis and clinical relevance remain largely unclear. In the second study, we developed CNApp, a web- based tool that allows a comprehensive exploration of CNAs by using genomic segmented data. CNApp generates genome-wide profiles, computes CNA scores for broad, focal and global CNA burdens, and uses machine learning-based predictions to classify samples. We applied CNApp to the TCGA pan-cancer dataset of 10,635 genomes showing that CNAs classify cancer types according to their tissue-of-origin, and that each cancer type shows specific ranges of broad and focal CNA scores. Moreover, CNApp reproduces recurrent CNAs in hepatocellular carcinoma and predicts colon cancer molecular subtypes and microsatellite instability based on broad CNA scores and discrete genomic imbalances. In summary, CNApp facilitates CNA-driven research by providing a unique framework to identify relevant clinical implications. CNApp is hosted at https://tools.idibaps.org/CNApp/.

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Rodrigues, Marilene Elizabete Pavan. "Variantes do gene RALDH2 e doenças cardíacas congênitas". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-09012008-153110/.

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Nós investigamos o papel da variação genética do gene RALDH2 e as doenças cardíacas congênitas (DCCs). Seis SNPs foram utilizados em um estudo de TDT. Testes de associação foram desenvolvidos e tanto os marcadores testados quanto os haplótipos analisados não mostraram associação com a doença. Análise do polimorfismo A151G indica que a variante produz mudanças substanciais na estrutura do RNAm. Esta variante está localizada em um exonic splicing enhancer (ESE). Estudos funcionais de splicing não mostraram impacto significante desta variante sobre a alteração do splicing do gene. Este estudo foi aplicado à outra mutação (G151T) encontrada no exon 4 durante o sequenciamento do gene RALDH2 e mostrou aumento no sinal de splicing. Nós encontramos mais quatro mutações: rs34645259 (5\'UTR), T157G (exon 4), rs4646626 (exon 9) e rs35251510 (exon 11). Em resumo, não foi encontrada associação entre DCCs e variações genéticas no gene RALDH2. As mutações encontradas deverão ser analisadas funcionalmente de forma a definir seu papel na perturbação da via do AR em humanos.
The aim of the study was to investigate the role of genetic variation in the RALDH2 locus and congenital heart disease. Six different SNPs were analyzed in 101 patient-parents trios in a TDT study. None of the markers displayed any association with CHD. No single haplotype was associated with an increased risk of CHD. Analysis of the A151G polymorphism indicated that the variant produced substantial changes in mRNA structure. This variant is also localized in a putative exonic splicing enhancer (ESE). Functional splicing studies failed to reveal a significant impact of this variant and gene splicing. This methodology was applied to another mutation (G151T) found in exon 4 during the sequencing of RALDH2 gene and an increase in splicing signal was observed. We found four mutations more: rs34645259, T157G (exon 4), rs4646626 and rs35251510. In summary, no association between CHD and genetic variation at the RALDH2 locus in humans was found. Potential functional genetic variants should be further studied in order to define their real role in RA pathway disturbances.

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

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

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Beskow, Anna. "Genetic Risk Factors for Cervical Carcinoma in situ". Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3318.

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Oncogenic human papillomaviruses (HPVs) are implicated in 99.7 % of cervical cancer cases but require the co-operation of other factors. To investigate potential genetic risk factors we have typed the HLA class II DRB1 and DQB1 loci in 478 women diagnosed with cervical carcinoma in situ and in 608 age-matched controls. Quantitative measurements of HPV 16, HPV 18/45 and HPV 31 were obtained. The DRB1*1501 and DQB1*0602 alleles were found to increase the risk of HPV 16 infection. Carriers of DRB1*1501 and DQB1*0602 were also shown to have an increased risk of a higher viral load compared to non-carriers. The DRB1*1301 and DQB1*0603 alleles were found to protect from HPV 18/45 and 31 infections as well as resulting in a lower viral load in carriers compared to non-carriers. Women with a high HPV 16, 18/45 or 31 viral load were more prone to long-term infections and women with a low HPV 16 viral load were more prone to short-term infections. Carriers of DRB1*1501 and DQB1*0602 alleles were also shown to have an increased risk of long-term infections compared to short-term infections. We also tested if an HPV susceptibility locus found for epidermodysplasia verruciformis (EV) was also linked to HPV susceptibility in cervical cancer. We did not find any linkage to this locus in a set of 77 families, each with at least three cases diagnosed with cervical carcinoma in situ. Other potential risk factors tested were HPV 16 E6 variants together with a p53 codon 72 polymorphism and HLA class II alleles. We found an association between the E6 L83V variant and the HLA DR4-DQ3 haplotype, as well as an increased frequency of Arg homozygosity of p53 in women infected with the L83V variant. These results show that alleles at HLA class II loci represents risk factors for persistent HPV infection and thereby also contribute to the risk of development of cervical carcinoma in situ.

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Noh, Hyun Ji. "Comparative approaches to the genetics of human neuropsychiatric disorders". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:8cb9ee02-1b12-4b78-bb62-3bbf4d5eba26.

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In this thesis, I investigate the genetics of neuropsychiatric disorders by analysing large data sets derived from high-throughput experiments, using novel comparative genomics approaches. In the first project, I explore characteristics of rare, de novo copy number variants identified among autism patients by employing various bioinformatics resources including Mouse Genome Informatics phenotypes, Gene Ontology terms, and protein-protein interactions. I describe how I objectively identified a number of mouse model phenotypes that are significantly associated with autism, and that provide insight into the aetiologies for both copy number deletions and duplications. In the second project, I investigate the genetics of obsessive-compulsive disorder by resequencing genomic regions of human case-control cohorts and the best spontaneous disease model organisms, namely dogs with canine compulsive disorder, and breed-matched controls. Targeted sequencing experiments yielded a large number of high-quality genetic variants in both humans and dogs. I prioritised variants and genes using case- control comparisons and functional annotations such as types of mutation, evolutionary conservation status and regulatory marks. In turn, I generated several hypotheses that are experimentally tractable. Replication of these findings in a larger cohort is necessary, although it lies beyond the scope of this thesis. Results from both projects indicate that the analytical frameworks employed in this thesis could be profitably applied to other neuropsychiatric disorders.

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