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1
Sauer, Sascha. "Technology development for genotyping single nucleotide polymorphisms." [S.l.] : [s.n.], 2001. http://www.diss.fu-berlin.de/2002/102/index.html.
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Lau, Chi Chiu. "Hepatitis B virus and single nucleotide polymorphisms." HKBU Institutional Repository, 2007. http://repository.hkbu.edu.hk/etd_ra/810.
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Schwonbeck, Susanne. "Analyse von Single-Nucleotide-Polymorphisms an Glas-Oberflächen." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974115568.
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Schwonbeck, Susanne. "Analyse von Single Nucleotide Polymorphisms an Glas-Oberflächen." Phd thesis, Universität Potsdam, 2004. http://opus.kobv.de/ubp/volltexte/2005/221/.
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Ziel der vorliegenden Arbeit war die Entwicklung einer SNP-Genotypisierungsmethode
mit auf Mikroarrays immobilisierten PCR-Produkten. Für die Analyse wurde
ein faseroptischer Affinitätssensor bzw. ein Durchfluss-Biochip-Scanner
mit integrierter Fluoreszenzdetektion verwendet. An den immobilisierten
Analyten (PCR-Produkten) wurde eine Fluoreszenzoligonukleotidsonde hybridisiert
und anschließend die Dissoziation der Sonde im Fluss verfolgt. Die Diskriminierung
von Wildtyp- und Mutanten-DNA erfolgte durch die kinetische Auswertung
der Dissoziationskurven sowie durch die Analyse der Fluoreszenzintensität.
Die Versuche am faseroptischen Affinitätssensor zeigten, dass DNA-DNA-Hybride sowohl von Oligonukleotiden als auch von PCR-Produkten ein typisches Dissoziationsverhalten aufweisen, wobei fehlgepaarte Hybride eine signifikant schnellere Dissoziation zeigen als perfekt passende Hybride. Dieser Geschwindigkeitsunterschied lässt sich durch den Vergleich der jeweiligen kinetischen Geschwindigkeitskonstanten kD quantitativ erfassen.
Da die Kopplung des Analyten an der Chipoberfläche sowie die Hybridisierungs- und Dissoziationsparameter essentiell für die Methodenentwicklung war, wurden die Parameter für ein optimales Spotting und die Immobilisierung von PCR-Produkten ermittelt. Getestet wurden die affine Kopplung von biotinylierten PCR-Produkten an Streptavidin-, Avidin- und NeutrAvidin-Oberflächen sowie die kovalente Bindung von phosphorylierten Amplifikaten mit der EDC/Methylimidazol-Methode. Die besten Ergebnisse sowohl in Spotform und -homogenität als auch im Signal/Rausch-Verhältnis wurden an NeutrAvidin-Oberflächen erreicht.
Für die Etablierung der Mikroarray-Genotypisierungsmethode durch kinetische Analyse nach einem Hybridisierungsexperiment wurden Sondenlänge, Puffersystem, Spotting-Konzentration des Analyten sowie Temperatur optimiert. Das Analysensystem erlaubte es, PCR-Produkte mit einer Konzentration von 250 ng/µl in einem HEPES-EDTA-NaCl-Puffer auf mit NeutrAvidin beschichtete Glasträger zu spotten. In den anschließenden Hybridisierungs- und Dissoziationsexperimenten bei 30 °C konnte die Diskriminierung von homocygoter Wildtyp- und homocygoter Mutanten- sowie heterocygoter DNA am Beispiel von Oligonukleotid-Hybriden erreicht werden.
In einer Gruppe von 24 homocygoten Patienten wurde ein Polymorphismus im SULT1A1-Gen analysiert. Sowohl durch kinetische Auswertung als auch mit der Analyse der Fluoreszenzintensität wurde der Genotyp der Proben identifiziert. Die Ergebnisse wurden mit dem Referenzverfahren, der Restriktionschnittstellenanalyse (PCR-RFLP) validiert. Lediglich ein Genotyp wurde falsch bestimmt, die Genauigkeit lag bei 96%.
In einer Gruppe von 44 Patienten wurde der Genotyp eines SNP in der Adiponectin-Promotor-Region untersucht. Nach Vergleich der Analysenergebnisse mit denen eines Referenzverfahrens konnten lediglich 14 der untersuchten Genotypen bestätigt werden. Ursache für die unzureichende Genauigkeit der Methode war vor allem das schlechte Signal/Rausch-Verhältnis.
Zusammenfassend kann gesagt werden, dass das in dieser Arbeit entwickelte Analysesystem für die Genotypisierung von Einzelpunktmutationen geeignet ist, homocygote Patientenproben zuverlässig zu analysieren. Prinzipiell ist das auch bei heterocygoter DNA möglich. Da nach aktuellem Kenntnisstand eine SNP-Analysemethode an immobilisierten PCR-Produkten noch nicht veröffentlicht wurde, stellt das hier entwickelte Verfahren eine Alternative zu bisher bekannten Mikroarray-Verfahren dar. Als besonders vorteilhaft erweist sich der reverse Ansatz der Methode.
Der hier vorgestellte Ansatz ist eine kostengünstigere und weniger hoch
dimensionierte Lösung für Fragestellungen beispielsweise in der Ernährungswissenschaft,
bei denen meist eine mittlere Anzahl Patienten auf nur einige wenige SNPs
zu untersuchen ist. Wenn es gelingt, durch die Weiterentwicklung der Hardware
bzw. weiterer Optimierung, eine Verbesserung des Signal/Rausch-Verhältnisses
und damit die Diskriminierung von heterocygoter DNA zu erreichen, kann
diese Methode zukünftig bei der Analyse von mittelgroßen Patientengruppen
alternativ zu anderen Genotypisierungsmethoden verwendet werden.
The aim of this thesis was the development of a SNP genotyping method
involving PCR products immobilised on microarrays. For the analysis a fibre
optic affinity biosensor and a flow-through biochip scanner were used.
Fluorescent probes were hybridized with the immobilised PCR products. In
order to start the dissociation process the surface was rinsed with buffer
and the fluorescence intensity was measured.
Two different cases were studied: First, the full-matched DNA hybrid
(wildtyp single strand with complementary wildtype single strand), second
the mis-matched hybrid (wildtype single strand and mutant single strand).
After determinating the reaction rates (kD) as kinetic parameter the kD
values of both cases were compared. The experiments showed a significant
difference in the kD value of the full- and the mis-match hybrids.
Therefore, mutant and wildtype DNA were discriminated by kinetic analysis
of the dissociation process and analysis of the fluorescence intensity.
To set up the complete analysis process the reaction parameters like
coupling of the PCR products had to be optimised. Both affininty coupled
(streptavidin, neutravidin, avidin - biotin) and covalent methods
(EDC/methylimidazol) were carried out. Best results in spot homogeinity and
spot appearance were obtained with coupling of biotinylated PCR products on
neutravidin coated chip surfaces. Additionally, the length of the probe,
the spotting concentration, the spotting buffer and the reaction
temperature were optimised. In the optimised analysis PCR products (250
µg/µl) were spotted onto neutravidin coated surfaces. The hybridisation
and dissociation processes were carried out at 30°C. A HEPES-EDTA-NaCl
buffer was used for spotting, diluting of the fluorescent probe and rinsing
the microarray surface. A fluorescent probe was used with 13 nucleotides in
length. The mis- or full-matching base indicating the polymorphism was
located in the center position of the probe.
The analysis system was tested with the genomic DNA of a group of 24
homocygote individuals with a SNP in the SULT1A1 gene region. The
hybridisation and dissociation processes were carried out and the reaction
rates were determinated. Subsequently after the analysis in the
flow-through biochip scanner the fluorescence intensity of the
spots were measured. The results showed very good comparability with
results of a PCR-RFLP analysis (one false genotype). Additionally, a group
of 44 heterocygote DNA samples with one SNP in the adiponectin promotor
region were also genotyped. Compared to a reference method only 14
genotypes were correctly determined. This was mostly due to a low
signal-noise-ratio and needs to be further investigated.
Besides the problem in analysing heterocygote DNA samples the developed
analysis system is very useful for genotyping SNP in homocygote DNA
samples. The successful analysis of heterocygote sample is principally
possible and with further investigations/optimisation, a better analysis
should be possible.
The most important advantage of the developed method is the reverse
approach of binding PCR products at the surface instead of
oligonucleotides. This allows the parallel genotyping of several
individuals. Other advantages include low costs and medium sized dimensions
in terms of throughput.
5
Reeves, Emma. "Functional consequences of single nucleotide polymorphisms in ERAAP." Thesis, University of Southampton, 2011. https://eprints.soton.ac.uk/375582/.
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Dallin, Joshua Jeffrey. "Analytical Comparison of Bovine Parentage Single Nucleotide Polymorphisms." DigitalCommons@USU, 2015. https://digitalcommons.usu.edu/etd/4450.
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Often on cattle operations and dairy farms, where multiple bulls are exposed to cows either by live cover or artificial insemination, error can be present in parentage record keeping for breed registries or production use. Research has evolved to the integration of using single nucleotide polymorphisms (SNPs) to answer questions where cases of unknown parentage may exist. With the evolution of the research, differentiated panels have been created specifically for parentage analysis. Our objective was to complete an analytical comparison between two specific panels, a proven 88 parentage SNP panel and a recently developed 25 SNP panel. A smaller panel would be beneficial in a parentage test as the smaller panel would reduce time and costs associated with the parentage analysis. In this study, nearly 4,000 cattle samples were collected and prepared from offspring, sires, and dams. Parentage calling software was used to identify the parentage assignments of the samples. Through these procedures and comparisons, it was determined that the smaller 25 SNP panel did not have the magnitude or strength necessary to be able to correctly identify cattle in the same manner as the 88 SNP panel.
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Barbati, E. "SINGLE NUCLEOTIDE POLYMORPHISMS AND MICRORNAS AFFECTING PTX3 PRODUCTION." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/168370.
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Pentraxins are fluid phase pattern recognition receptors phylogenetically
conserved from arachnids to mammals. Based on the primary structure, pentraxins are
divided in short pentraxins, like the C-reactive protein and the serum amyloid P, and
long pentraxins, like PTX3. PTX3 is expressed by several cell types, including
mononuclear phagocytes, myeloid dendritic cells, fibroblasts, smooth muscle cells
and endothelial cells in response to pro-inflammatory cytokines and microbial
components. This molecule is involved in innate immunity, tissue remodelling,
female fertility and in tuning the inflammatory response. In particular, PTX3 plays a
protective role in cardiovascular diseases (CVD), such as acute myocardial infarction
(AMI) and atherosclerosis, in preclinical studies. Moreover, PTX3 has emerged as
novel diagnostic and prognostic biomarker in CVD, reflecting the inflammatory
involvement of the vascular bed. In AMI patients, PTX3 levels peak 6-8 hours after
the onset of symptoms and in this context it balances pro-inflammatory and antiinflammatory
stimuli.
Since single nucleotide polymorphisms (SNPs) and microRNAs represent two
ways in which gene expression can be modified/regulated, we addressed their role in
the modulation of PTX3 expression.
Given that PTX3 gene SNPs have been reported to be associated to different
clinical conditions, in particular in innate resistance to infections, we assessed the role
of PTX3 SNPs in affecting PTX3 plasma levels and CVD susceptibility. Despite the
characterized role of PTX3 in inflammation, a regulation of PTX3 by microRNAs,
which are fundamental fine-tuners of this process, has not yet been described.
Therefore, we investigated the role of microRNAs in regulating PTX3 expression.
To our first aim, we performed a candidate-gene association study on Caucasian
subjects, in about 1500 healthy individuals and 1700 AMI patients. PTX3 plasma
levels were measured by ELISA in healthy subjects as well as in AMI patients from
GISSI-Prevenzione trial. Blood was collected from AMI patients at least 5 days after
the last event. A significant difference in PTX3 levels was detected between AMI
patients and controls, suggesting the persistence of high PTX3 plasma levels in AMI
patients up to three months after the last event. Moreover, in AMI patients, PTX3
plasma levels significantly correlated with mortality, but not with cardiovascular
death or reinfarction, confirming the prognostic value of this parameter previously
described as an independent predictor of 3-months mortality in this pathological
condition. Moreover, we report that the 3 PTX3 SNPs analysed (the intronic
rs2305619 and rs1840680 and the exonic rs3816527), alone or combined in
haplotypes, are associated with different PTX3 plasma levels. However, we did not
find a correlation between the 3 SNPs analysed and the clinical condition of the
subject.
About our second aim, data reported in this thesis reveal the existence of a
complex network of microRNAs able to down-regulate the basal as well as the TNFα-
and IL-1β-induced PTX3 production. The effect of microRNA over-expression was
evaluated through the transfection of synthetic pre-miR in the human 8387
fibrosarcoma cell line, able to produce constitutively PTX3. The direct interaction
miRNA:mRNA was evaluated through a luciferase reporter assay. Our results reveal
that specific microRNAs, like miR-9 and miR-29, directly target and regulate PTX3
mRNA. Other microRNAs, including miR-29, impair PTX3 expression acting on
molecules of the signalling pathway that leads to PTX3 transcription. Among these
miRNAs there are also miR-146a and miR-155, two of the major microRNAs
involved in controlling the inflammatory response. Another microRNA, miR-181c,
impairs PTX3 production by targeting key molecules involved in PTX3 induction and
by directly acting on the messenger of ERp18, a molecule involved in PTX3 folding.
In conclusion, our results underline the complexity of PTX3 regulation, revealing
that both PTX3 SNPs and microRNAs are fundamental players of this process.
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Freeman, Julia Carol. "Single Nucleotide Polymorphisms Linked to Essential Hypertension in Kasigau, Kenya." TopSCHOLAR®, 2013. http://digitalcommons.wku.edu/theses/1316.
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Hypertension, or high blood pressure (BP), is an ever-growing epidemic in the developing world. Understanding the genetics behind essential hypertension (EH), or hypertension with no known cause, is especially important. In this study, three single nucleotide polymorphisms (SNPs) known to be linked to an increase in susceptibility to EH were quantified from a cohort of Kenyans living in the Kasigau region. The SNPs are located in three genes that are part of the renin angiotensin system, the primary regulatory pathway in humans controlling BP. They include: AGT (rs699), AGTR1 (rs5186), and HSD11β2 (rs5479). Overall, by using a fluorescent-based RT-PCR technique, the genotype distribution of AGT (rs699) was 0.63 C/C, 0.34 C/T, and 0.03 T/T. When evaluated as normotensive, prehypertensive, Stage I, or Stage II categories the allele frequencies for f(C)= 0.77,0.85,0.81, 0.77, respectively, and demonstrated Hardy Weinberg Equilibrium (HWE) as assessed by Χ2, p < 0.05. The genotype distribution of AGTR1 (rs5186) was 0.96 A/A, 0.03 A/C, and 0.00 C/C and the genotype distribution of HSD11β2 (rs5479) was 0.46 A/A, 0.46 A/C, and 0.08 C/C. The majority of genotype frequencies for each SNP were in HWE, with the exception of the AGT (rs699) SNP found in the sublocation of Bughuta suggesting other evolutionary selective pressures may be at work in this subpopulation. The high prevalence of the susceptible C allele for AGT (rs699) likely implies it is a critical factor in the high prevalence of EH observed in this population.
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Chen-Cheng, Charles. "JAMALAH--a system for the detection of single nucleotide polymorphisms." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/40606.
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Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1996.Includes bibliographical references (leaves 70-75).
by Charles Chen-Cheng.
M.Eng.
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Perla, Sravan K. "Epigenetic Regulation of the Human Angiotensinogen by Single Nucleotide Polymorphisms." University of Toledo Health Science Campus / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=mco1544800350207546.
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Thompson, Nadine. "Single Nucleotide Polymorphisms in the Folypoly-gamma-glutamate synthetase Gene." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/672.
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Folic acid is an essential vitamin utilized in the one-carbon metabolism pathway for the synthesis of purine and thymidine nucleotides, which are necessary for cell growth and proliferation. As a result, the enzymes that participate in the metabolism of folic acid have been good targets for cancer chemotherapy. Folylpoly-γ-glutamate synthetase (FPGS) is an enzyme in the folate metabolism pathway that catalyzes the addition of glutamic acid to the naturally occurring folates, thereby allowing the retention of folate cofactors in cells. Similarly, in the case of cancer chemotherapy, antifolates, such as Lometrexol and Tomudex are retained in cells through the activity of FPGS. Consequently, any single nucleotide polymorphisms (SNPs) that exist in the fpgs gene may decrease or increase the cytotoxicity of antifolates and, ultimately, the clinical response rate to antifolate therapy. The goal of this project is to define the position and frequency of single nucleotide polymorphisms (SNPs) in the mRNA made from the fpgs gene from peripheral blood of one hundred normal individuals. Six Polymerase Chain Reaction (PCR) primers were designed to amplify the gene as three overlapping pieces and four primers were designed for sequencing of the three PCR products. In this study, we found polymorphic sites at nucleotides 64, 123, 253, 423, 1334 and 1781. The majority of the samples (49/88) expressed rnRNA with point mutations on at least one allele at base 64, while 8 samples had a SNP at base 123. At nucleotide 123, 6 samples expressed the heterozygote GIA genotype, and one sample expressed the homozygote A/A allele at this site. At nucleotide 423, two samples expressed a G allele and also the common C allele. While the SNPs at nucleotide 64, 123, and 423 caused a silent or conservative mutation in the gene, in sample 82, a mutation C253T produced an amino acid change from an arginine to tryptophan, which may cause a functional change in the fpgs protein, due to the significant change in size and charge of the wild type amino acid. Similarly, sample 26 expessed a homozygote T/T allele at nucleotide 1334 instead of the common C/C allele expressed in the remaining samples. This point mutation caused a valine to alanine amino acid change. We also detected a SNP that is expressed after the stop codon in sample 40.
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Consolandi, C. "Development of DNA microarrays for human single nucleotide polymorphisms detection." Doctoral thesis, Università degli Studi di Milano, 2004. http://hdl.handle.net/2434/62035.
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One major goal of genetic research is to understand the role of genetic variation. By far the most common type of such variation in humans involves single DNA bases, and is termed single nucleotide polymorphism (SNP). In order that DNA chip technology continue to emerge as an alterative to conventional DNA diagnostic methods, questions about the conformation and activity of DNA on surfaces must be addressed. We developed three robust chemical methods for the covalent attachment of amino-modified oligonucleotides on glass surfaces based on polymeric coatings, providing robust platforms to prepare oligonucleotide arrays. We explored the feasibility of using oligonucleotide-array methods for molecular typing of a highly polymorphic genomic region by using the PCR-LDR strategy. We set up a low resolution microarray-based molecular tool for allele discrimination, which is of interest in clinical applications. Our goal was the identification of Single Nucleotide Polymorphisms in the Human LeukocyteAntigen gene. The methodology we proposed presents interesting features as genotyping tool: the reaction principle is robust, the assay easily automated, thereaction format flexible and capable to analyse different samples in parallel.
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Khalil, Mahmoud Salah. "Transforming growth factor beta 1 : role in the progression of chronic renal failure." Thesis, Sheffield Hallam University, 2002. http://shura.shu.ac.uk/19437/.
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TGF-beta1 plays an important role in the pathogenesis of experimental and clinical glomerulosclerosis and tubufointerstitial fibrosis. Associations have been described between polymorphisms of cytokine and growth factor genes and susceptibility to, or progression of, an increasing number of diseases. In this study, single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene were investigated as possible markers for the progression of chronic renal failure (CRF). One hundred and forty two Caucasian patients with CRF were screened for four TGFB1 SNPs: T-509C in the promoter region; Arg25Pro and Leu10Pro in exon 1 and Thr263Ile in exon 5. There were significant differences between CRF patients and controls in allele frequencies of two of the SNPs (Leu10Pro and C-509T), indicating an association with susceptibility to CRF, We also observed a significant association between rate of progression of CRF (the slope of the reciprocal of serum creatinine v time) and genotype, both at codon 25 (odds ratio 3.77, 95% confidence interval, 2.2 - 6, p < 0.001) and at the -509 promoter site (odds ratio 1.67, 95% confidence interval 1.1-2.5), p < 0.005) in patients with primary nephropathy (excluding PKD). Genotype at codon 25 was also associated with severity of proteinuria (p= 0.038), plasma TGF-B1 protein levels (p = 0,01), and the severity of glomerulosclerosis (p < 0.05). Genotype at C-509T was associated with the level of renal tubular TGF-B1 immunostmning (p = 0.0006) and with renal interstitial inflammatory cellular infiltration (p=0,015). There was a highly significant correlation between the degree of cellular infiltration in renal tissues and tubular TGF-beta1 immunostaining.
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Leung, Wing C. "Effects of single nucleotide polymorphisms in BCMO1 on β-carotene conversion." Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443996.
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Sanqoor, Shaikha Hassan. "Single nucleotide polymorphisms : characterisation and application to profiling of degraded DNA." Thesis, University of Central Lancashire, 2009. http://clok.uclan.ac.uk/5700/.
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Single nucleotide polymorphisms (SNPs) are one of the forensic markers used to resolve the problem of DNA typing from degraded samples. It has been found in previous studies that when profiling heavily degraded forensic samples the small amplicon required for SNP analysis has an advantage over the larger STR loci, which are routinely used in forensic case work. A total of 66 SNPs from the non-coding region of the 22 pairs of autosomal chromosomes were identified and SNP assays developed. Instead of selecting the SNPs from the available GenBank® sites, SNPs were typed from Arab individuals from Kuwait and United Arab Emirates (UAE) to identify polymorphic SNPs. In order to obtain SNP data from Arab populations, a total of 10 unrelated Arab individuals from Kuwait and UAE were typed. The Affymetrix GeneChip® Mapping 250 K Array Sty І was employed to generate profiles for approximately 238,000 SNPs. Only autosomal SNPs were selected from the data. Following selection, allele frequencies were estimated using the SNaPshot™ technique (Applied Biosystems) with 25 UAE individuals. For this technique, PCR forward and reverse primers were designed to generate PCR products less than 150 bp. The single base extension primers were designed to hybridise 1 bp upstream from the target SNP. SNP characterization, including Hardy¬Weinberg equilibrium and pair wise linkage disequilibrium, was carried out using the software package Arlequin v 3.1. Allele frequencies were calculated using Excel spreadsheets. PowerStats v.12 software used for discrimination power and match probability estimation. All the 66 SNPs were polymorphic with average heterozygosity levels of 47%. A high heterozygosity level is very valuable for forensic application improving the individualization of forensic samples (Vallone et al. 2005). The probability that two individuals having identical genotype profile was found to be very low, 3.058 x 10-25. The combined power of discrimination was found to be 0.999999999. This indicated that the selected SNPs met the parameters needed for forensic application. The SNPs genotype sensitivity gave profiles from minute amounts of DNA template as little as 100 pico grams (pg) and optimal and reproducible results at 300 pg of DNA template. The profiling of DNA from forensic samples is not always possible. This can be due to insufficient amount of samples being recovered and in many cases, DNA degradation. Biological materials that are recovered from the scene of the crime have often been exposed to sub-optimal environmental conditions such as high temperature and humidity. SNPs performance on degraded samples was tested on artificially degraded saliva and semen samples. Controlled temperature and humidity experiments were performed to study the effect of these environmental factors on the samples. Also uncontrolled experiments on samples being subjected to different weather conditions (UK summer and UAE winter and summer) was performed in order to study and compare both weather effects on saliva samples. The triplex sets of SNPs that were developed for such study showed full allele profiles when compared to STRs, the current method used in forensic labs. In addition, SNPs produced a higher success rate than STRs when tested with samples obtained from human teeth remains and on samples subjected to DNase 1 digestion. The small size of SNPs, between 90 and 147 base pair (bp), showed more resistance to degradation than the STRs size ranging between 100 and 360 bp. This study demonstrated that the 66 SNPs selected are useful markers when the typing of degraded samples by STRs fails to produce complete or partial profiles.
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Alimat, Sharizah Binti. "Application of single nucleotide polymorphisms (SNPs) to forensic casework in Malaysia." Thesis, University of Central Lancashire, 2014. http://clok.uclan.ac.uk/10981/.
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The analysis of degraded DNA can be problematic. Recent advances in the identification and analysis of single nucleotide polymorphisms (SNPs) have demonstrated the advantage of these markers over short tandem repeats (STRs) in that they only require small amplicons. However, before applying to casework, it is important to develop allele frequency databases from relevant populations. The main aim of the study is to characterize three Malaysian major ethnic groups; Malay, Chinese and Indian, using 52 autosomal SNP markers that have been identified in the SNPforID project. Sanchez et. al., 2006 reported a multiplex of 52 SNP markers in one PCR reaction with two single base reaction (SBE) in the detection of SNPs using capillary electrophoresis (CE). The amplicons for PCR ranged from 59 bp to 115 bp. Whilst for SBE reactions ranged from 16 nt to 92 nt. In their study, full complete profile was obtained from 500 pg DNA input. The study was carried out on three major populations: African, Asian and European. As in this study, a total of 325 Malaysian samples (109 from Malays, 107 from Chinese and 109 from Indians) were genotyped. In order to genotype the population samples reliably and robustly, four sets of 13-plex SNPs were developed. Internal validation was carried out using both genetic analyzers, ABI PRISM® 310 and 3500 Genetic Analyzer. Sensitivity and reproducibility studies demonstrated that the assays were highly sensitive, requiring as little as 30 pg of DNA. Full, complete and clear profiles were generated. Data were collected and evaluated statistically for forensic usefulness. Across the three ethnic groups, few significant departures from HWE, at p values <0.05 were observed at 3 SNP markers in Malays, 4 SNP markers in Chinese and 9 SNP markers in Indian samples. Five markers (rs2107612, rs722098, rs2076848, rs907100 and rs1528460) in the Indians and one marker (rs1528460) in the Chinese, showed the lowest p value, that is p=0.0. However, after Bonferroni correction at p <0.00096 significant deviation(s) from HWE was observed at 1 SNP marker (code marker 26) in the Malays, 2 SNP markers (code marker 46 and 54) in the Chinese and 5 SNP markers (code marker 12, 21, 36, 38 and 54) in the Indians. In addition, a pair of loci (at code markers 3 and 53) was found to be associated in the Malays after the Bonferroni correction (at p <0.0000377). As for forensic parameters, the combined mean match probabilities for the 52 SNPs of Malay, Chinese, and Indian were 1 in 3.9654e-19, 5.3964e-18, and 1.7459e-19, corresponding to a combined power of discrimination of >99.99999999%, respectively. Paired Fst values obtained in the study showed, as expected, that Malay group is closely related to the Chinese population, with the Indian population being more distant.
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Mohamad, Razali Rozaimi Bin. "Studies on the relationship between single nucleotide polymorphisms and protein interactions." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/25959.
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This thesis presents an analysis of the relationship between single nucleotide polymorphism (SNPs) and protein-protein interactions. The aim of the thesis is to investigate the distribution of non-synonymous single nucleotide polymorphism (nsSNPs) in terms of their locations in the protein core, at the protein-protein interface sites and on the other areas on the protein surface. The analysis used experimentally verified human protein-protein interactions and nsSNPs from the UniProt humsavar database. A further investigation was performed on a larger SNP dataset from the 1000 Genomes Project (1KGP). Both investigations identified a significant preference for disease-causing SNPs to occur at the protein interface compared to other areas on the protein surface. The three-dimensional structures of protein-protein interfaces were examined in order to propose stereo-chemical explanations for the disease-causing effect of nsSNPs in the humsavar dataset. In addition, three methodologies (i.e., usage of SNP server, structural analysis and usage of GMAF) that could help identify pathogenic variants were presented. Structural analysis was also performed on non-diseasecausing SNPs in order to investigate their possible effects on protein-protein interactions. The result showed that some of the previously classified non-diseasecausing SNPs could potentially be disease-causing SNPs. The myVARIANT program was developed. The program obtains SNPs from 1KGP, maps them to structures, evaluates their distribution on structures and performs a structural analysis. In conclusion, the thesis demonstrates the important role that protein-protein interactions play in disease pathogenesis.
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Gowrisankar, Sivakumar. "Predicting Functional Impact of Coding and Non-Coding Single Nucleotide Polymorphisms." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225422057.
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Mercer, Heather Milliken. "The Distribution of Single Nucleotide Polymorphisms in Pyoderma Gangrenosum: Biomarker Discovery." Kent State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=kent1383769612.
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Liu, Yang. "Data mining methods for single nucleotide polymorphisms analysis in computational biology." HKBU Institutional Repository, 2011. http://repository.hkbu.edu.hk/etd_ra/1287.
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Nasr, Amre Osman. "Single nucleotide polymorphisms related to immune responses in Plasmodium falciparum malaria /." Stockholm : Wenner-Gren Institute for Experimental Biology, Stockholm university, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8168.
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Wang, Tai-Chun. "Computational experiment for the solution of single nucleotide polymorphisms (SNPS) problems." Thesis, The University of Sydney, 2011. https://hdl.handle.net/2123/29228.
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Single Nucleotide Polymorphisms (SNPs) have recently received significant attention
from researchers in different life science disciplines. The discovery of novel SNPs
from expressed sequence tags could be an economical method for researchers when
handling those species which do not have complete reference sequences. However,
distinguishing sequence errors from putative SNPs is a significant problem for in
silico methods. Previous researchers have indicated that series of SNPs from the
same chromosome, called haplotypes, contain more information than individual
SNPs. Thus, reconstructing individual haplotypes from SNP fragments becomes one
of the core problems in whole genome sequencing research. Unfortunately, current
methods do not have the ability to efficiently handle high error-rate data sets or
longer individual haplotypes. Besides the single individual haplotype reconstruction
problem, the tag SNP selection problem is the other haplotype-related application
that is currently being focused on by researchers. Tag SNP is a kind of biomarker
used to tag haplotypes. However, this has been proven to be a NP-hard problem.
This study addresses three SNP-related topics—novel SNP discovery, tag SNP selection
and single individual haplotype reconstruction—and presents novel computational
methods associated with these areas. When mining SNPs from expressed sequence
tag data sets, a fuzzy logic system, in conjunction with several statistical
measurements, was used to produce highly reliable results. A pipeline framework
which merged the advantages of block-based and LD—based models was introduced
for selecting highly correlated tag SNPs. A radix tree-like structure and genetic algorithm
were implemented in order to reconstruct the single individual haplotype reconstruction
problem based on the minimum error correction strategy.
Different species’ data types were used in this study, and the experimental results
indicate that our methods provide the best solution for each topic at the present time.
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Liu, Shuk Ming. "Single nucleotide polymorphism in human microsomal glutathione s-transferase gene and colorectal cancer /." View Abstract or Full-Text, 2003. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202003%20LIU.
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Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003.Includes bibliographical references (leaves 95-105). Also available in electronic version. Access restricted to campus users.
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Svensson, Emma M. "Detecting Sex and Selection in Ancient Cattle Remains Using Single Nucleotide Polymorphisms." Doctoral thesis, Uppsala universitet, Evolutionsbiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-123261.
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All contemporary taurine cattle originated some 10,000 years ago when their wild ancestor, the aurochs, was domesticated in the Near East. Although the aurochs was widespread also in Europe, there is no evidence for a local domestication. The aurochs has been extinct since 1627 and therefore little is known about its biology. Following domestication, cattle were selected for traits of interest to humans. All modern cattle breeds were developed in the 19th century and the only sources of information about prehistoric breeding practices, and breeds, come from a few ancient Roman Empire and medieval European written accounts. The aim for this thesis was to investigate the effects early selection may have had on the cattle genome and to investigate genetic variation in European aurochs. Using second-generation sequencing and coalescent simulation analyses of aurochs Y chromosomal DNA, I estimated effective population size to between 20,000-80,000 aurochs bulls, indicating that a large population was present when domestic cattle entered Europe. A Y chromosomal SNP revealed that the two male lineages present in modern cattle were also present in European aurochs, and that the frequency of these lineages in domestic cattle fluctuated over time. This indicates that cattle were mobile and that bottlenecks, possibly due to selective breeding, occurred. I used nuclear SNPs to trace genetic variation in North European cattle through time and show that when genetics is combined with archaeology and osteology, even small but notable changes in the use of cattle can be detected. There has been a significant decrease in genetic variation over time, with the most dramatic changes associated with the formation of breeds during the 19th century.
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Lu, Yang 1972. "High throughput study of the translational effect of human single nucleotide polymorphisms." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116089.
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Introduction: As a part of the Gene Regulators in Disease project (GRID), this study aims to create a novel high throughput method to discover the genetic effect on gene translation, taking advantage of the rationale that efficiently translated mRNAs associate with multiple ribosomes, while less active ones with fewer or none.Methods: Lymphoblastoid cell lines (LCLs) from 44 HapMap European individuals were used for polyribosomal fractionation and establishing the sample bank for the future study. The fractionated mRNA samples of 10 out of the 44 individuals were run on an Illumina GoldenGate Beadarray to detect allelic imbalance (developed by the group of T.J. Hudson and T.M. Pastinen).
Results: This study established a high-quality RNA bank, including 1,100 RNA fraction samples. By the Illumina chip, translational imbalance was detected in 75 out of 1483 (5.06%) assays, and 63 out of269 (23.4%) genes. The translational effect was well replicable by the resequencing method.
Conclusion: This study found that genetic effect on gene translation is a common mechanism of expression regulation. Our best hit found in the integrin beta 1 binding protein 1 gene (ITGB1BP1 ) highlights the role of mRNA 3'UTR secondary structure in gene translation.
Keywords: Gene translation, High throughput genotyping, Human genetics, Polyribosome, RNA, Single nucleotide polymorphism
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Dixon, Lindsey Ann. "Investigation into the use of Single Nucleotide Polymorphisms for forensic identification purposes." Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/56095/.
Full textAbstract:
Major limitations of the short tandem repeat (STR) loci that form the basis of criminal DNA databases are the 'partial' profiles that result from degradation of the longer repeat sequences. In contrast, Single Nucleotide Polymorphisms (SNPs) can be encompassed in smaller amplicons increasing the chance of amplification in degraded and limited samples. To aid SNP analysis a range of studies were performed including creation of the ASGOTH (Automated SNP Genotype Handler) software for rapid and accurate sample genotyping on microarrays. A multiplex assay for simultaneous detection of 20 SNPs plus a sex-determining locus by single-tube PCR amplification and electrophoretic detection was also developed. All loci conformed to Hardy- Weinberg equilibrium and showed independent inheritance. Computer simulations characterised the effects of inbreeding and supported the use of current STR Fst correction factors. Both paternity testing and kinship analysis were compared to STR DNA profiling results. Interpretation criteria were formulated for correct genotyping of the 21-SNP multiplex to control for stochastic variation at low DNA inputs. Each locus was individually characterised for allele dropout, homozygous thresholds and heterozygous balance. The performance of the 21-SNP multiplex on degraded samples was compared with the AMPF/STR SGMplus (SGM+) STR method currently used for the UK National DNA Database and other DNA profiling techniques used across Europe. Applying the 21-SNP multiplex to casework samples previously profiled using low copy number (LCN) SGM+ amplification indicated that partial SNP profiles could be generated in samples that had given partial LCN SGM+ profiles, but samples failing to amplify using LCN PCR parameters would also fail with SNPs. This study demonstrated the use of SNPs for human forensic identification purposes as an adjunct to current STR methods and has formed the basis of further work on degraded DNA and the design of the next generation of DNA profiling systems.
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Spaniolas, Stelios. "Food forensics : the application of single nucleotide polymorphisms technology for food authentication." Thesis, University of Nottingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446391.
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Serao, Nick, Dianelys Gonzalez-Pena, Jonathan Beever, Dan Faulkner, Bruce Southey, and Sandra Rodriguez-Zas. "Single nucleotide polymorphisms and haplotypes associated with feed efficiency in beef cattle." BioMed Central, 2013. http://hdl.handle.net/10150/610391.
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BACKGROUND:General, breed- and diet-dependent associations between feed efficiency in beef cattle and single nucleotide polymorphisms (SNPs) or haplotypes were identified on a population of 1321 steers using a 50K SNP panel. Genomic associations with traditional two-step indicators of feed efficiency - residual feed intake (RFI), residual average daily gain (RADG), and residual intake gain (RIG) - were compared to associations with two complementary one-step indicators of feed efficiency: efficiency of intake (EI) and efficiency of gain (EG). Associations uncovered in a training data set were evaluated on independent validation data set. A multi-SNP model was developed to predict feed efficiency. Functional analysis of genes harboring SNPs significantly associated with feed efficiency and network visualization aided in the interpretation of the results.RESULTS:For the five feed efficiency indicators, the numbers of general, breed-dependent, and diet-dependent associations with SNPs (P-value<0.0001) were 31, 40, and 25, and with haplotypes were six, ten, and nine, respectively. Of these, 20 SNP and six haplotype associations overlapped between RFI and EI, and five SNP and one haplotype associations overlapped between RADG and EG. This result confirms the complementary value of the one and two-step indicators. The multi-SNP models included 89 SNPs and offered a precise prediction of the five feed efficiency indicators. The associations of 17 SNPs and 7 haplotypes with feed efficiency were confirmed on the validation data set. Nine clusters of Gene Ontology and KEGG pathway categories (mean P-value<0.001) including, 9nucleotide bindingion transport, phosphorous metabolic process, and the MAPK signaling pathway were overrepresented among the genes harboring the SNPs associated with feed efficiency.CONCLUSIONS:The general SNP associations suggest that a single panel of genomic variants can be used regardless of breed and diet. The breed- and diet-dependent associations between SNPs and feed efficiency suggest that further refinement of variant panels require the consideration of the breed and management practices. The unique genomic variants associated with the one- and two-step indicators suggest that both types of indicators offer complementary description of feed efficiency that can be exploited for genome-enabled selection purposes.
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Grochola, Lukasz Filip. "Identification and functional analysis of single nucleotide polymorphisms that affect human cancer." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:aacc7084-81a8-4e97-b1ac-024d9bed106e.
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Aims: The p53 regulatory network is crucial in directing the suppression of cancer formation and mediating the response to commonly used cancer therapies. Functional genetic variants in the genes comprising this network could help identify individuals at greater risk for cancer and patients with poorer responses to therapies, but few such variants have been identified as yet. Methods: We first develop and apply three different screens that utilize known characteristics of functional single nucleotide polymorphisms (SNPs) in the p53 network to search for variants that associate with allelic differences in (i) recent natural selection, (ii) chemosensitivity profiles, and (iii) the gender- and age- dependent incidence of soft-tissue sarcoma. Secondly, we study and explore the functional mechanisms associated with the identified variants. Results: We identify SNPs in the PPP2R5E, CD44, YWHAQ and ESR1 genes that associate with allelic differences in the age of tumour diagnosis (up to 32.5 years, p=0.031), cancer risk (up to 8.1 odds ratio, p=0.004) and overall survival (up to 2.85 relative risk, p=0.011) in sarcomas, ovarian and pancreatic cancers, and exhibit allelic differences in the cellular responses to cytotoxic chemotherapeutic agents (up to 5.4-fold, p=5.6x10-47). Lastly, we identify candidate causal SNPs in those genes and describe the regulatory mechanisms by which they might affect human cancer. Conclusions: Together, our work suggests that the inherited genetics of the p53 pathway have a great potential to further define populations in their abilities to react to stress, suppress tumor formation and respond to therapies.
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O’Mara, Tracy Ann-Maria. "The association of single nucleotide polymorphisms with endometrial cancer risk and prognosis." Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/63648/1/Tracy_O%E2%80%99Mara_Thesis.pdf.
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Endometrial cancer is one of the most common female diseases in developed nations and is the most commonly diagnosed gynaecological cancer in Australia. The disease is commonly classified by histology: endometrioid or non-endometrioid endometrial cancer. While non-endometrioid endometrial cancers are accepted to be high-grade, aggressive cancers, endometrioid cancers (comprising 80% of all endometrial cancers diagnosed) generally carry a favourable patient prognosis.
However, endometrioid endometrial cancer patients endure significant morbidity due to surgery and radiotherapy used for disease treatment, and patients with recurrent disease have a 5-year survival rate of less than 50%. Genetic analysis of women with endometrial cancer could uncover novel markers associated with disease risk and/or prognosis, which could then be used to identify women at high risk and for the use of specialised treatments. Proteases are widely accepted to play an important role in the development and progression of cancer. This PhD project hypothesised that SNPs from two protease gene families, the matrix metalloproteases (MMPs, including their tissue inhibitors, TIMPs) and the tissue kallikrein-related peptidases (KLKs) would be associated with endometrial cancer susceptibility and/or prognosis.
In the first part of this study, optimisation of the genotyping techniques was performed. Results from previously published endometrial cancer genetic association studies were attempted to be validated in a large, multicentre replication set (maximum cases n = 2,888, controls n = 4,483, 3 studies). The rs11224561 progesterone receptor SNP (PGR, A/G) was observed to be associated with increased endometrial cancer risk (per A allele OR 1.31, 95% CI 1.12-1.53; p-trend = 0.001), a result which was initially reported among a Chinese sample set. Previously reported associations for the remaining 8 SNPs investigated for this section of the PhD study were not confirmed, thereby reinforcing the importance of validation of genetic association studies.
To examine the effect of SNPs from the MMP and KLK families on endometrial cancer risk, we selected the most significantly associated MMP and KLK SNPs from genome-wide association study analysis (GWAS) to be genotyped in the GWAS replication set (cases n = 4,725, controls n = 9,803, 13 studies). The significance of the MMP24 rs932562 SNP was unchanged after incorporation of the stage 2 samples (Stage 1 per allele OR 1.18, p = 0.002; Combined Stage 1 and 2 OR 1.09, p = 0.002). The rs10426 SNP, located 3' to KLK10 was predicted by bioinformatic analysis to effect miRNA binding. This SNP was observed in the GWAS stage 1 result to exhibit a recessive effect on endometrial cancer risk, a result which was not validated in the stage 2 sample set (Stage 1 OR 1.44, p = 0.007; Combined Stage 1 and 2 OR 1.14, p = 0.08). Investigation of the regions imputed surrounding the MMP, TIMP and KLK genes did not reveal any significant targets for further analysis.
Analysis of the case data from the endometrial cancer GWAS to identify genetic variation associated with cancer grade did not reveal SNPs from the MMP, TIMP or KLK genes to be statistically significant. However, the representation of SNPs from the MMP, TIMP and KLK families by the GWAS genotyping platform used in this PhD project was examined and observed to be very low, with the genetic variation of four genes (MMP23A, MMP23B, MMP28 and TIMP1) not captured at all by this technique. This suggests that comprehensive candidate gene association studies will be required to assess the role of SNPs from these genes with endometrial cancer risk and prognosis. Meta-analysis of gene expression microarray datasets curated as part of this PhD study identified a number of MMP, TIMP and KLK genes to display differential expression by endometrial cancer status (MMP2, MMP10, MMP11, MMP13, MMP19, MMP25 and KLK1) and histology (MMP2, MMP11, MMP12, MMP26, MMP28, TIMP2, TIMP3, KLK6, KLK7, KLK11 and KLK12). In light of these findings these genes should be prioritised for future targeted genetic association studies.
Two SNPs located 43.5 Mb apart on chromosome 15 were observed from the GWAS analysis to be associated with increased endometrial cancer grade, results that were validated in silico in two independent datasets. One of these SNPs, rs8035725 is located in the 5' untranslated region of a MYC promoter binding protein DENND4A (Stage 1 OR 1.15, p = 9.85 x 10P -5 P, combined Stage 1 and in silico validation OR 1.13, p = 5.24 x 10P -6 P). This SNP has previously been reported to alter the expression of PTPLAD1, a gene involved in the synthesis of very long fatty acid chains and in the Rac1 signaling pathway. Meta-analysis of gene expression microarray data found PTPLAD1 to display increased expression in the aggressive non-endometrioid histology compared with endometrioid endometrial cancer, suggesting that the causal SNP underlying the observed genetic association may influence expression of this gene. Neither rs8035725 nor significant SNPs identified by imputation were predicted bioinformatically to affect transcription factor binding sites, indicating that further studies are required to assess their potential effect on other regulatory elements.
The other grade- associated SNP, rs6606792, is located upstream of an inferred pseudogene, ELMO2P1 (Stage 1 OR 1.12, p = 5 x 10P -5 P; combined Stage 1 and in silico validation OR 1.09, p = 3.56 x 10P -5 P). Imputation of the ±1 Mb region surrounding this SNP revealed a cluster of significantly associated variants which are predicted to abolish various transcription factor binding sites, and would be expected to decrease gene expression. ELMO2P1 was not included on the microarray platforms collected for this PhD, and so its expression could not be investigated.
However, the high sequence homology of ELMO2P1 with ELMO2, a gene important to cell motility, indicates that ELMO2 could be the parent gene for ELMO2P1 and as such, ELMO2P1 could function to regulate the expression of ELMO2. Increased expression of ELMO2 was seen to be associated with increasing endometrial cancer grade, as well as with aggressive endometrial cancer histological subtypes by microarray meta-analysis. Thus, it is hypothesised that SNPs in linkage disequilibrium with rs6606792 decrease the transcription of ELMO2P1, reducing the regulatory effect of ELMO2P1 on ELMO2 expression. Consequently, ELMO2 expression is increased, cell motility is enhanced leading to an aggressive endometrial cancer phenotype.
In summary, these findings have identified several areas of research for further study. The results presented in this thesis provide evidence that a SNP in PGR is associated with risk of developing endometrial cancer. This PhD study also reports two independent loci on chromosome 15 to be associated with increased endometrial cancer grade, and furthermore, genes associated with these SNPs to be differentially expressed according in aggressive subtypes and/or by grade. The studies reported in this thesis support the need for comprehensive SNP association studies on prioritised MMP, TIMP and KLK genes in large sample sets. Until these studies are performed, the role of MMP, TIMP and KLK genetic variation remains unclear. Overall, this PhD study has contributed to the understanding of genetic variation involvement in endometrial cancer susceptibility and prognosis. Importantly, the genetic regions highlighted in this study could lead to the identification of novel gene targets to better understand the biology of endometrial cancer and also aid in the development of therapeutics directed at treating this disease.
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Ramdayal, Kavisha. "Incidence and Regulatory Implications of Single Nucleotide Polymorphisms among Established Ovarian Cancer Genes." Thesis, Online access, 2009. http://etd.uwc.ac.za/usrfiles/modules/etd/docs/etd_gen8Srv25Nme4_5111_1277754725.pdf.
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Nasr, Amre. "Single nucleotide polymorphisms related to immune responses in Plasmodium falciparum malaria." Doctoral thesis, Stockholms universitet, Wenner-Grens institut för experimentell biologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8168.
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The current research is directed towards dissection of host genetic factors involved in host immune response and the malaria disease outcome. A possible association between FcγRIIa polymorphism and anti-malarial antibody (A.M.A) responses were investigated in Sudanese patients in relation to clinical outcome of falciparum malaria. The frequency of the R/R131 genotype was significantly higher in patients with severe malaria as compared with mild malaria. A.M.A IgG3 was shown to be associated with reduced risk of clinical malaria in individuals carrying the H/H131 genotype. Low levels of IgG2 reactive with the Pf332-C231 antigen were associated with lower risk of severe malaria in individuals carrying the H131 allele. Fulani and Masaleit, two sympatric ethnic groups in Sudan, are characterized by marked differences in susceptibility to falciparum malaria. We investigated whether the two populations differ in the frequency of GM/KM allotypes. The distribution of GM/KM phenotypes differed significantly among the two groups, with Gm 6 being significantly lower among the Fulani, and the combined frequency of Km 1,3 and Gm 1,17 5,6,13,14 phenotypes was found to be higher among Masaleit. In interethnic study we investigated whether the two groups differ in the frequency of FcγRIIa and HbAS genotypes. The frequency of the H/H131, R/R13 and HbAS genotypes differed significantly among the two groups. Moreover, the Fulani showed higher levels of A.M.A IgG2 and lower IgG1 and IgG3 when compared to their sympatric non-Fulani neighbours. A tri-allelic SNP (C/T/A) in the CRP gene was investigated for possible ethnic associations. The A allele, which is associated with higher basal CRP levels, was found to be less frequent in the Fulani compared with non-Fulani ethnic groups both in Sudan and Mali. In conclusion, our results suggest possible associations between FcγRIIa, CRP genotypes, GM/KM allotypes, and anti-malarial antibody responses and the clinical outcome of falciparum malaria.
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Lo, Robert Su Chun. "Single nucleotide polymorphisms of mannan binding lectin and complications of chronic liver disease." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37781.
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Background: Mannan-binding lectin (MBL) is an innate immune system pattern recognition protein that kills a wide range of pathogenic microbes through complement activation. Infection is a major complication in patients with chronic liver disease (CLD). Infection is also thought to lead to variceal bleeds. These complications cause significant mortality and morbidity. MBL single nucleotide polymorphisms (SNPs) may result in an inability to protect against pathogens which may contribute to the development of infection including spontaneous bacterial peritonitis (SBP). Association between MBL SNPs and SBP/variceal bleed is unclear. The aim of this thesis is to comprehensively assess the association of MBL SNPs and SBP/variceal bleed, and its role as a prognostic marker in liver related death. Methods: A case control study was performed. CLD patients with a prior history of complications (SBP/variceal bleed) were compared to those without. All patients were followed up subsequently in a longitudinal study to assess MBL SNPs as a risk factor for liver related death. Lastly, an open labelled proof of concept study was performed to determine the effect of 4 weeks probiotics therapy on bacterial translocation, systemic inflammation and the severity of liver disease. Results: No significant relationships were found between MBL SNPs and baseline inflammation or bacterial translocation. MBL SNPs was not a risk factor for the occurrence of SBP/variceal bleed in both the univariate and multivariate analaysis. In a Kaplan-Meier survival anaylsis, MBL SNPs was not associated with increased liver related death. MBL SNPs was also not an independent predictor in a multivariate Cox-regression analysis. The introduction of 4 weeks of probiotics therapy did not alter the baseline inflammation, bacterial translocation and severity of liver disease significantly. Conclusion: The results of this thesis suggest that MBL SNPs do not associate with the occurence of CLD complications (SBP/variceal bleed), and that MBL SNPs is not a prognostic marker for liver related death.
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Fiaschi, Linda. "Novel guidelines for the analysis of single nucleotide polymorphisms in disease association studies." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/11808/.
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How genetic mutations such as Single Nucleotide Polymorphisms (SNPs) affect the risk of contracting a specific disease is still an open question for numerous different medical conditions. Two problems related to SNPs analysis are (i) the selection of computational techniques to discover possible single and multiple SNP associations; and (ii) the size of the latest datasets, which may contain millions of SNPs. In order to find associations between SNPs and diseases, two popular techniques are investigated and enhanced. Firstly, the ‘Transmission Disequilibrium Test’ for familybased analysis is considered. The fixed length of haplotypes provided by this approach represents a possible limit to the quality of the obtained results. For this reason, an adaptation is proposed to select the minimum number of SNPs that are responsible for disease predisposition. Secondly, decision tree algorithms for case-control analysis in situations of unrelated individuals are considered. The application of a single tool may lead to limited analysis of the genetic association to a specific condition. Thus, a novel consensus approach is proposed exploiting the strengths of three different algorithms, ADTree, C4.5 and Id3. Results obtained suggest the new approach achieves improved performance. The recent explosive growth in size of current SNPs databases has highlighted limitations in current techniques. An example is ‘Linkage Disequilibrium’ which identifies redundancy in multiple SNPs. Despite the high accuracies obtained by this method, it exhibits poor scalability for large datasets, which severely impacts on its performance. Therefore, a new fast scalable tool based on ‘Linkage Disequilibrium’ is developed to reduce the size through the measurement and elimination of redundancy between SNPs included in the initial dataset. Experimental evidence validates the potentially improved performance of the new method.
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Fletcher, Jeremy Charles. "THE USE OF PYROSEQUENCING FOR THE ANALYSIS OF Y CHROMOSOME SINGLE NUCLEOTIDE POLYMORPHISMS." Master's thesis, University of Central Florida, 2004. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4487.
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The potential value of the Y chromosome for forensic applications has been recognized for some time with the current work dedicated to Short Tandem Repeat analysis and Single Nucleotide Polymorphism (SNP) discovery. This study examined the ability of two different SNP analysis methods to determine if they could be utilized in forensic applications and ultimately be developed into an established system for Y chromosome SNP analysis. This study examined two principle SNP analysis systems: single base extension and Pyrosequencing. Pyrosequencing was determined to be superior to single base extension, due to the wealth of information provided with sequencing and the flexibility of designing primers for analysis. Using Pyrosequencing, 50 Y chromosome loci were examined and the minimum loci required for maximum diversity for the development of a Y chromosome SNP analysis system were chosen. Thirteen loci were selected based on their ability to discriminate 60 different individuals from three different racial groups into 15 different haplogroups. The Y chromosome SNP analysis system developed utilized nested PCR for the amplification of all 13 loci. Then they were sequenced as groups, ranging from one to three loci, in a single reaction. The Y chromosome SNP analysis system developed here has the potential for forensic application since it has shown to be successful in the analysis of blood, buccal swabs, semen, and saliva, works with as little as 5 pg of starting DNA material, and will amplify only male DNA in the presence of male/female mixtures in which the female portion of the sample overwhelmed the male portion 30,000 to 1.M.S.
Department of Chemistry
Arts and Sciences
Chemistry
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Pego, Ana Miguel Fonseca. "Investigation on the relationship between violent death, cocaine abuse and single nucleotide polymorphisms." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/9/9143/tde-10092018-171545/.
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Violence is a dreadful phenomenon spread throughout the world, resulting in unfortunate events that can ultimately cause death. It is known that some countries play a much worrying role in this scenario than others. Brazil is one of them. The present study has focused on identifying the use of cocaine within 105 postmortem cases arriving at the Institute of Legal Medicine of São Paulo (IML-SP) through analytic toxicological methods and latter applying genetic testing to see whether the presence of certain single nucleotide polymorphisms (SNPs) is more predominant within users rather than non-users, which would help to better understand one\'s susceptibility to abuse the drug. Both blood and hair samples have been analysed through ultra-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) in order to distinguish between recent or chronic cocaine use among violent individuals whose violence has ultimately leaded to their death. Two dilute-and-shoot methods have been validated and used for this purpose, and the final residue was analysed through the UPLC-ESIMS/ MS system. From the 105 postmortem cases, a rather high proportion of cocaine and its metabolites was found. A chronic use of the drug was denoted in 53% of the cases, which were positive for cocaine and benzoylecgonine, followed by 43% for norcocaine, 40% for cocaethylene and 13% for anhydroecgonine methyl ester, in hair. As for blood, reflecting the use of cocaine prior to death, 51% of the cases have shown to be positive for benzoylecgonine, followed by 41% for cocaine, 23% for cocaethylene and 20% for norcocaine. These findings suggest a probable association between the use of the drug and risky/violent behaviours. Genetic wise, a significant difference has been observed for SNP rs4263329 from the BCHE gene in its dominant model, with higher frequencies of the genotypes A/G and G/G seen in cocaine users rather than non-users (OR=8.91; 95%CI=1.58-50.21; ρ=0.01). Likewise, also SNP rs6280 from the DRD3> gene presented a significant association in both its additive and dominant model, suggesting that the C allele may be playing a role in cocaine use as both genotypes T/C and C/C were significantly more frequent in users than non-users. This association was not lost when adjusted for covariants using logistic regression (OR=4.96; 95%CI=1.07; ρ=0.04). Finally, a statistically significant association (ρ = 0.003) was also encountered among individuals with both A/G and G/G genotypes within SNP rs4263329 and the use of cocaine HCl (f(A/G+G/G)=44.7%) versus crack-cocaine (f(A/G+G/G)=7.7%) and nonusers (f(A/G+G/G)=16.2%). In conclusion, this study has found significant associations within two SNPs related to cocaine use, however, due to several inherent limitations, these must be confirmed by further studies with a higher number of subjects and within a more controlled setting. Definite assumptions may not be made at this point and future researches are to be conducted.A violência é um fenômeno aterrador espalhado por todo o mundo, resultando em eventos que podem, em última instância, causar a morte. Sabe-se que, em alguns países esse cenário é mais preocupante que em outros. O Brasil é um deles. O presente estudo teve como objetivo identificar o uso de cocaína em 105 casos postmortem provenientes do Instituto de Medicina Legal de São Paulo (IML-SP) por meio de métodos toxicológicos analíticos e posterior aplicação de testes genéticos para verificar se a presença de determinados polimorfismos de nucleotídeo único (SNPs) é mais predominante dentro dos usuários do que dos não usuários, o que explicaria uma possível suscetibilidade de um indivíduo ao abuso da droga. Amostras de sangue e cabelo foram analisadas através de cromatografia líquida de ultra-eficiência acoplada a espectrometria de massas e ionização por electrospray (UPLC-ESI-MS/MS) para distinguir entre uso recente ou crônico de cocaína entre indivíduos violentos cuja violência levou à sua morte. Para tal, dois métodos de extração baseados na técnica de \"dilute-and-shoot\" foram validados e utilizados para esse fim, e o resíduo final foi analisado através de um sistema UPLC-ESI-MS/MS. Dos 105 casos postmortem, foi encontrada uma proporção significativa de cocaína e seus produtos de biotransformação. O uso crônico da droga foi denotado em 53% dos casos, sendo estes positivos para cocaína e benzoilecgonina, seguidos de 43% para norcocaína, 40% para cocaetileno e 13% para anidroecgonina metil éster, no cabelo. Quanto ao sangue, refletindo o uso de cocaína antes da morte, 51% dos casos mostraram-se positivos para benzoilecgonina, seguido de 41% para cocaína, 23% para cocaetileno e 20% para norcocaína. Esses dados corroboram a hipótese provável da relação entre o uso da droga e comportamentos de risco/violentos. Quanto à genética, uma diferença significativa foi observada para o SNP rs4263329 do gene BCHE em seu modelo dominante, com maiores frequências dos genótipos A/G e G/G vistos em usuários de cocaína ao contrário de não usuários (OR=8,91; 95%IC=1,58-50,21; ρ=0,01). Da mesma forma, também o SNP rs6280 do gene DRD3 apresentou uma associação significativa tanto no seu modelo aditivo quanto dominante, sugerindo que o alelo C pode estar desempenhando um papel no uso de cocaína, pois ambos os genótipos T/C e C/C foram significativamente mais frequentes nos usuários do que não usuários. Essa associação não foi perdida quando ajustada para co-variáveis usando regressão logística (OR=4,96; 95%IC=1,07; ρ=0,04). Finalmente, uma associação estatisticamente significativa (ρ=0,003) também foi encontrada entre indivíduos com ambos os genótipos A/G e G/G dentro do SNP rs4263329 e o uso de cocaína HCl (f(A/G + G/G)=44,7%) versus crack (f(A/G + G/G)=7,7%) e não usuários (f(A/G + G/G)=16,2%). Em conclusão, este estudo encontrou associações significativas em dois SNPs relacionados ao uso de cocaína, no entanto, devido a várias limitações inerentes, estas devem ser confirmadas por mais estudos com um maior número de indivíduos e dentro de um cenário mais controlado. Hipóteses definitivas não poderão ser feitas neste momento e futuras pesquisas devem ser conduzidas.
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Leach, Oliver. "Functional characterisation of multiple sclerosis-associated single nucleotide polymorphisms in the eomesodermin region." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:9b6bc711-181a-41ab-ae41-8dfb31878f77.
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Multiple sclerosis (MS) is a common inflammatory neurological disease affecting young adults, causing significant disability and increased mortality. Genome wide association studies (GWAS) have uncovered over 100 single nucleotide polymorphisms (SNPs) associated with MS susceptibility, most of which lie outside transcribed DNA and therefore do not have obvious consequences. SNPs in two such non-coding DNA segments upstream of the EOMES gene, encoding Eomesodermin (Eomes) have been consistently associated with MS, as well as with the two other autoimmune diseases rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Eomes has been shown to be important for embryonic and neural development, as well as in the immune system, the latter of which was the focus of this investigation. The association of genetic polymorphisms in the EOMES region with MS was interrogated using computational methods. Imputation analysis enabled detection of new variants, which aligned with regions of epigenetic significance and possible regions of DNA-interaction, implying an effect on regulation of gene expression. Subsequently, Eomes expression was characterised in peripheral blood cell populations, with the highest expression detected in natural killer cells and effector/memory T cell subsets, including MAIT cells, an innate-like lymphocyte population. To investigate potential genotype dependent changes in Eomes expression and the effect on downstream pathways, studies were performed using samples from healthy donors prospectively genotyped for the two MS associated loci. Despite observing significant differences in expression between genotype groups in a pilot study, findings in a larger cohort did not reach the threshold for significance. Finally, the presence of MAIT cells was investigated in the context of MS and these cells were detected in MS lesions. Collectively, in this D.Phil project I have illustrated potential ways in which the functional relevance of disease-associated SNPs in non-coding regions can be studied. This has been thoroughly investigated through computational studies, analysis of gene expression in peripheral blood cells, and in genotype-dependent studies of both expression and downstream function.
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Waterfall, Christy Marie. "Strategies for the detection of single nucleotide polymorphisms using the polymerase chain reaction." Thesis, University of Bath, 2002. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269677.
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Mullersman, Jerald Eric. "Effect of Gender on the Association of Single-Nucleotide Polymorphisms with Bipolar Disorder." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1230.
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Bipolar disorder is a relatively common form of mental illness that depends strongly on genetic inheritance for expression. The author of this study has sought to evaluate whether the gender of subjects influences which genetic variants are associated with the disease. A portion of the cases from a previously published study were analyzed using PLINK software and the association of single-nucleotide polymorphisms was evaluated separately for all cases, for female subjects alone, and for male subjects alone. The results obtained for male subjects alone reached higher levels of statistical significance than when both genders were evaluated together or when female subjects were evaluated alone. The most significantly scoring polymorphisms were distinctly different for the 2 genders. In particular, a site downstream of the ion exchanger SLC24A3 and upstream of the Rab5-interacting protein RIN2 gene on chromosome 20 (rs6046396) yielded very high significance in men (p=3.91 X 10-9).
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Lemos, Marcos Vinícius Antunes de. "Copy number variations and single-nucleotide polymorphisms associated with beef fatty acid profile in nellore cattle /." Jaboticabal, 2017. http://hdl.handle.net/11449/150817.
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Orientador: Fernando Sebastián Baldi ReyCoorientador: Angélica Simone Cravo Pereira
Coorientador: Gregório Miguel Ferreira de Camargo
Banca: Ana Fabrícia Braga Magahães
Banca: Rodrigo Pelicioni Savegnago
Banca: Raysildo Barbosa Lobo
Banca: Aline Silva Mello Cesar
Resumo: Objetivou-se identificar regiões no genôma de bovinos da raça Nelore que apresentam variações no número de cópias (CNV) e, associar estes CNV com o perfil de ácidos graxos da carne. Além disso, objetivou-se realizar associação genica ampla utilizando os método de single step (GWASss) a fim de detectar regiões genômicas associadas aos ácidos graxos dos grupos saturados, mono e poliinsaturados, assim como os omegas 3, 6 e sua relação. O estudo de caracterização e distribuição dos CNVs ao longo do genoma de bovinos Nelore, foi realizado através do software PennCNV utizando dados genotípicos de 3.794 aniamais, resultando em 399.361 CNVs identificados. Após controle de qualidade, 2.902 foram mantidos nas analises, resultando em 195.873 CNVs, com tamanho medio de 54,744 pb, maximo de 8.7 Mb e minimo 3 kb. As regiões de CNV foram geradas pela sobreposição dos CNVs através do software CNVRuler. Os cromossomos que mostraram maior incidencia de CNVR foram BTA19 (24,26%), BTA23 (18,68%) e BTA25 (18,05%). Ja os que mostraram menor incidencia foram BTA29 (1,63%), BTA13 (9,72%) and BTA8 (9,72%). As 9.805 regiões da CNV estimadas no presente estudo cobrem aproximadamente 13.05% do genoma bovino e sobrepõem-se a 5.495 genes conhecidos que envolvem processos biológicos que poderiam estar envolvidos na adaptação ambiental da subespécie a áreas tropicais. O estudo de GWASss identificou 115 janelas que explicaram mais de 1% da variação genética aditiva para os 22 ácidos graxos estudados. A ident... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The objective of this study was to identify genomic regions of Nellore cattle that present variations in the number of copies (CNV) and to associate these CNV with the fatty acid profile of the meat. In addition, the objective of this study was to carry out a genome-wid association using the single step method (GWASss) to detect genomic regions associated with saturated, mono and polyunsaturated fatty acids, as well as omega 3, 6 and their relationship. The study of the characterization and distribution of CNVs along the Nellore genome was performed by PennCNV software using genotypic data of 3,794 animals, resulting in 399,361 CNVs identified. After quality control, 2,902 were maintained in the analyzes, resulting in 195,873 CNVs, with an average size of 54,744 pb, maximum of 8.7 Mb and minimum 3 kb. The CNV regions were generated by the overlap of the CNVs by CNVRuler software. The chromosomes that showed the highest incidence of CNVR were BTA19 (24.26%), BTA23 (18.68%) and BTA25 (18.05%). Those with the lowest incidence were BTA29 (1.63%), BTA13 (9.72%) and BTA8 (9.72%). The 9,805 CNV regions estimated in the present study covered approximately 13.05% of the bovine genome and overlaped 5,495 genes known to envolve in biological processes that could be involved in the environmental adaptation of the subspecies to tropical areas. The GWASss study showed 115 windows that explained more than 1% of the additive genetic variation for the 22 fatty acids studied. The identification of these regions and their genes, such as ELOVL5, ESRRG, PCYT1A and the ABC group genes (ABCA5, ABCA6 and ABCA10) are genes directly and indirectly related to lipid metabolism. The GWAS between AG phenotypes and CNVs resulted in a total of 186 CNVRs that were significant for the saturated (43), monosaturated (42), poly... (Complete abstract click electronic access below)
Doutor
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Tate, Helena. "The effect of single nucleotide polymorphisms and mutations on congenital thrombotic thrombocytopenic purpura phenotype." Thesis, University of Westminster, 2017. https://westminsterresearch.westminster.ac.uk/item/q430y/the-effect-of-single-nucleotide-polymorphisms-and-mutations-on-congenital-thrombotic-thrombocytopenic-purpura-phenotype.
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Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease with a reported incidence of 6 cases per million per year in the UK. It is characterised by episodes of microangiopathic haemolytic anaemia and thrombocytopenia, with the widespread presence of platelet-rich thrombi in the microcirculation, leading to end-organ damage. TTP is a clinically heterogeneous disorder caused by autoantibody inhibition or clearance or by a deficiency in activity or secretion of the von Willebrand factor cleaving protease (ADAMTS13). Over 100 mutations have been identified in ADAMTS13 yet, in some cases, these mutations in congenital TTP alone do not explain the disease phenotype, particularly in late-onset congenital TTP. One aim of this study was to analyse the effect of single nucleotide polymorphisms (SNPs), in conjunction with ADAMTS13 mutations, which have been identified in a cohort of TTP patients with varied clinical phenotype. Twenty mutant expression plasmids containing an ADAMTS13 mutation and/or SNP have been constructed by site-directed mutagenesis (SDM). Fourteen plasmids contained a new non-synonymous mutation (C3484T) which has been rectified by further SDM. After full sequencing of the plasmid ADAMTS13 insert, 24 clones were identified as viable and the resultant protein was expressed in HEK293T cells and analysed by Western blot and ADAMTS13 antigen ELISA. Blots were scanned by densitometry and the intensity of the protein species corresponding to ADAMTS13 determined using ImageJ. The predicted effects of mutations and/or SNPs were annotated by the in silico computational tools SIFT, PolyPhen2, I-Mutant 2.0 and SNPEffect 4.0.Results from this genotype study were compared to clinical phenotype by correlating data held within the TTP Registry at University College London. The resultant analysis showed the mutations located in the N-terminal end of ADAMTS13 protein induced more secretory defects and SNPs had less of an effect on phenotype. The p.R7W and p.A1033T SNPs showed more of an effect on secretion of ADAMTS13 when the mutation was located in the Cterminal end (p.R1060W) which is associated with late-onset phenotype. However, other environmental factors such as changes in the ADAMTS13-VWF axis during pregnancy and infection make a correlation between genotype and phenotype in TTP more challenging.
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Hayward, Laura E. "Identification of Functional Single Nucleotide Polymorphisms Associated with Breast Cancer Based on Chromatin Modifications." Scholarship @ Claremont, 2016. http://scholarship.claremont.edu/cmc_theses/1312.
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Breast cancer affects 1 in 8 women and can be deadly; yet when detected early enough it is often treatable. Thus, early detection of breast cancer is imperative to save lives. The success of early detection depends, in part, on being able to stratify risk. A new approach to determining risk involves identifying genetic variants that alter an individual’s risk for developing breast cancer. This thesis identified key functional candidates involved in breast cancer development, some of which have been verified by other studies. For a few of the functional candidates, further research needs to be done in order to determine the biological significance they play in the development of breast cancer. The functional candidates were identified by comparing SNPs in Linkage Disequilibrium with high risk SNPS—determined by GWAS—using histone modification markers to identify functional genomic elements in breast cell lines. The results yielded three top tier candidates and multiple second tier candidates. Further research should be done in order to assess the risk involved with these variants and the underlying biological mechanism. As genetic testing becomes more accessible to the public, the identification and understanding of these high risk variants will be an essential tool in preventing and treating breast cancer.
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Balasubramanian, Karthika. "Search for an association between single nucleotide polymorphisms of NPY2R and metabolic syndrome traits." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/fullcit?p1477883.
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Thesis (M.S.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed July 13, 2010). Available via ProQuest Digital Dissertations. Includes bibliographical references (leaves 43-46).
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Barnett, Catherine Margaret Eleanor. "Association of Single Nucleotide Polymorphisms in Surfactant Protein A and D with Otitis Media." The University of Waikato, 2007. http://hdl.handle.net/10289/2338.
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Otitis Media is one of the most common childhood diseases. Recurrent acute otitis media RAOM is characterized by repeated episodes of inflammation of the middle ear in conjunction with middle ear fluid, and often with an inflamed or bulging eardrum. Defective clearance by the Eustachian tube results in mucus build-up and is characteristic of otitis media with effusion (OME). Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, respiratory syncytial virus, and rhinovirus are the most common contributors to otitis media pathogenesis. In New Zealand, OME has been implicated with conductive hearing loss in childhood and has been shown to significantly impact on speech and language development. New Zealand Māori and Polynesian children have displayed significantly higher hearing test failure rates than European-Caucasian children. The collectins, Surfactant Protein (SP)-A and -D are encoded by three genes (SP-A1, SP-A2, and SP-D) and are host defense proteins present in the middle ear and Eustachian tube. Single nucleotide polymorphisms (SNPs) in SP-A1 and SP-A2 have been associated with increased or decreased susceptibility to otitis media, meningococcal disease, and range of respiratory diseases. Using allele-specific primers and real-time PCR with SYBR Green I melting curve analysis, four groups of individuals were genotyped for eleven SP-A1, SP-A2, and SP-D SNPs: European-Caucasian individuals with RAOM/OME; New Zealand Māori/Polynesian individuals with RAOM/OME; individuals with meningococcal disease; and a control group. The computer program, Haploview, was employed to perform χ2 analyses and identify statistically significant associations of alleles/haplotypes with RAOM/OME or meningococcal disease. In the European-Caucasian population, two SP-A1 alleles, one SP-A2 allele, and four haplotypes (CGAGC, 1A3, 1A9, and 1A10) were found to be associated with increased risk of RAOM/OME (P lt; 0.05). Conversely, haplotypes 6A2 and 1A2 were found to be protective against susceptibility to RAOM/OME (P lt; 0.05). In New Zealand Māori and Polynesian individuals, two SP-A1 alleles, three SP-A2 alleles, one SP-D allele, and four haplotypes (6A8, 6A10, 1A3, and 1A10) were found to be associated with increased risk of RAOM/OME (P lt; 0.05). An additional four haplotypes (6A2, 1A0, 1A2, and TA) were determined to be protective against susceptibility to RAOM/OME (P lt; 0.05). However, protective SPA1/SPA2/SPD haplotype 6A2-1A0-TA was significantly under-represented in the New Zealand Māori and Polynesian population (P lt; 0.05). A single allele and haplotype were associated with increased risk of meningococcal disease (P lt; 0.05). The findings of this study confirm that specific genetic variants of SP-A and SP-D are associated with either increased or decreased risk of developing RAOM and/or OME. Furthermore, it was demonstrated that New Zealand Māori and Polynesian individuals appear to exhibit more haplotypes susceptible to RAOM/OME. This may provide a partial explanation for the higher RAOM/OME-related failure rates of hearing tests in New Zealand Māori and Polynesian children. However, there are numerous socio-economic and environmental factors that also contribute to otitis media pathogenesis which were not considered in this study. The effects of the SP-A1, SP-A2, and SP-D alleles and haplotypes on the bacterial/viral binding efficiencies of SP-A and SP-D need to be investigated by further research, using a large population, to confirm the association with susceptibility or resistance with RAOM/OME.
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Thain, Katherine Roberta. "Identifying functional single nucleotide polymorphisms in two candidate genes (PROC and PCSK9) in sepsis." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44755.
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Genetic variation contributes to outcome from sepsis. A large number of associations have been observed between genetic variants and sepsis outcome, however, identification of causal single nucleotide polymorphisms (SNPs), or their mechanisms of action, have not been successfully elucidated. The aims of this project are to identify causal variants in two candidate genes and determine whether these variants are involved in the mechanisms leading to altered outcomes in sepsis.
The known pathophysiology of sepsis is complex and involves dysregulation of several systemic processes, including the coagulation and inflammatory systems. Based on this knowledge, and known literature on genetic variation in coagulation genes, PROC was chosen as a candidate gene in which to search for causal SNPs. In addition, based on the known role of lipids in sepsis, as well as the already identified causal SNPs in the PCSK9 gene, PCSK9 was selected as a second candidate gene to test the hypothesis that genetic variation in lipid mediators alters outcome in sepsis.
Two intronic SNPs were found in the PROC gene (rs2069915 and rs2069916) that are in high linkage disequilibrium and appear to modify untranslated mRNA, leading to lower concentrations of circulating protein C in individuals homozygous for the major alleles of these SNPs. Furthermore, in the PCSK9 gene, an intronic SNP (rs644000) was found that appears to mark known Loss-of-Function and Gain-of-Function coding SNPs, and was associated with outcome in two cohorts of patients with septic shock, and with a reduction of cytokine levels in a subset of these patients. Additionally, using murine genetic Pcsk9 knock-out and pharmacologic inhibition strategies in a murine model of systemic bacteremia, a markedly attenuated global, cardiovascular and inflammatory cytokine response to lipopolysaccharide administration was observed. Furthermore, increased endotoxin clearance was measured after PCSK9 knock-out. Together these results indicate that reduction of PCSK9 activity in both mice and humans reduces the inflammatory response and improves outcome in septic shock.
The work presented here furthers the understanding of the role played by non-coding SNPs in protein expression and has implications for a new, potentially personal, drug strategy for sepsis patients in intensive care units.
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Maugeri, Narelle. "Effects of single nucleotide polymorphisms on the expression of HSP70 genes, HSPA1A and HSPA1B." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531979.
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Jardim, Priscila Magalhães da Veiga. "Mapeamento genético de marcadores SNPs (Single Nucleotide Polymorphisms) em cana-de-açúcar (Saccharum spp.)." Universidade Federal de Goiás, 2018. http://repositorio.bc.ufg.br/tede/handle/tede/9009.
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Sugarcane is an important culture quite relevant to the Brazilian economy. The production is growing as well as a cultivated area is increasing every year. The genome of this culture is still deficient due to complications such as high ploidy and the big genome that presents. Among the different genetic characterization studies, the development of genetic maps is important for providing information about the genome structure of a species. In addition, it can help develop the techniques of interpretation and use of genetic information. They provide more understanding of how genetic information is organized in the genome of sugarcane supplying a lack in the basic element in this culture. The maps constructed for sugarcane, so far, not shown saturated. This work was obtained a map for sugarcane using SNP markers based on genotyping-by-sequencing technology in next-generation sequencing using the target sequencing strategy (RAPiD-Seq). For obtaining the map, 103 clones RB97327 and RB72454 were used. Probes were designed based on sequence similarity using the sorghum genome as a reference. The construction of the binding groups, considering as a binding criterion of a recombination fraction equal 0.20; allowed the identification of 249 binding groups for the biparental population with 1: 1 segregation. A total of 20555 polymorphic were scored in the analysis. The sum of the average sizes of homeologia groups identified, using the sorghum genome as a reference, was 3964.68 cM for the female parent and 3797.05 cM for the male parent.
A cana-de-açúcar é uma cultura de importância bastante relevante para a economia brasileira. A produção de cana-de-açúcar no Brasil é crescente assim como a área cultivada vem aumentando a cada ano. A compreensão do genoma da cana-de-açúcar ainda é deficiente devido a complicações como alta ploidia e o grande genoma que a cultura apresenta. Dentre os diferentes estudos de caracterização genética, o desenvolvimento de mapas genéticos é importante por fornecer informações acerca da estrutura do genoma de uma espécie. Além disso, pode auxiliar no desenvolvimento das técnicas de interpretação e uso da informação genética. Eles possibilitam a compreensão mais abrangente da organização da informação genética no genoma da cana-de-açúcar suprindo uma carência do estudo básico sobre essa cultura. Os mapas construídos para cana-de-açúcar, até agora, não se mostraram completos. Neste trabalho foi obtido um mapa de ligação para cana-de-açúcar utilizando marcadores SNPs baseados na tecnologia de genotipagem por sequenciamento de nova geração utilizando a estratégia de target sequencing (RAPiD-Seq). Para a obtenção do mapa foram utilizados 103 genótipos obtidos do cruzamento entre os clones RB97327 e RB72454. Foram desenhadas sondas baseadas em sequenciamento de semelhança utilizando o genoma de sorgo como referência. A construção dos grupos de ligação, considerando-se como critério de ligação uma fração de recombinação de 0,20; permitiu a identificação de 249 grupos de ligação para a população biparental com segregação 1:1. Foram consideradas 20555 marcas polimórficas nas análises de construção do mapa de ligação. A soma dos tamanhos médios dos grupos de homeologia identificados, utilizando-se o genoma de sorgo como referência, foi de 3964,68 cM para o genitor feminino e de 3797,05 cM para o genitor masculino.
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Trevisoli, Priscila Anchieta. "Association of predicted deleterious single nucleotide polymorphisms with carcass traits in meat-type chickens." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/11/11139/tde-21082018-152925/.
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Breeding has been the mainly responsible for the increase of poultry efficiency in the last decades. The breeding programs are geared towards higher meat yield and feed efficiency. Among the used genomic approaches, genome wide association studies (GWAS) identified quantitative trait loci (QTLs) associated with carcass traits in a meat-type population (TT Reference Population). GWAS analysis identifies variants in linkage disequilibrium with the possible causal mutation and with the aim of refining these results, association study with missense single nucleotide polymorphisms can be useful. A missense SNP can be predicted as deleterious via Sorting Intolerant From Tolerant (SIFT) score when the amino acid change has the potential to impact the protein function and consequently may affects the phenotype. Therefore, in this study, predicted deleterious SNPs within QTLs regions were identified and associated with thigh, drumstick, abdominal fat and breast weight and their yields. Mixed model was used with sex, incubation and SNPs genotypes as fixed effects and family as random effect. From the 20 SNPs analyzed, six were significantly associated (p <0.05) with weight and yield of thigh, breast and drumstick. Three of them s736010549, rs739508259 and rs313532967 are located in the genes WDR77, VWA8 and BARL, respectively. These genes are involved in biological process as steroid hormone signaling pathway, estrogen binding, and regulation of cell proliferation. We determined these genes as candidates for muscle growth. Our strategy allowed the identification of potential causal mutations associated with muscle growth and development.O melhoramento genético é o principal responsável pelo aumento da eficiência da produção avícola nas últimas décadas e os programas de melhoramento de aves estão direcionados para um maior rendimento de carne e eficiência alimentar. Dentre as abordagens genômicas, estudos de associação genômica ampla (GWAS) identificaram loci associados com características quantitativas (QTLs) de carcaça em uma população de frangos de corte. Análise de GWAS identifica regiões em desequilíbrio de ligação com possíveis mutações causais e com o objetivo de refinar esses resultados, estudos de associações usando polimorfismos de base única (SNPs) não sinônimos podem ser úteis. O SNP não sinônimo pode ser predito como deletério por meio do Sorting Intolerant From Tolerant (SIFT) score quando a alteração de aminoácidos tem o potencial de impactar a função da proteína e consequentemente pode afetar o fenótipo. Portanto, neste estudo, SNPs preditos como deletérios localizados em regiões de QTLs foram identificados e associados com peso e rendimento de coxa, sobrecoxa, gordura abdominal e peito de frangos de corte. Modelo misto foi utilizado, com sexo, incubação e genótipos dos SNPs como efeitos fixos e família como efeito aleatório. De 20 SNPs analisados, seis foram associados significativamente (p<0,05) com peso e rendimento de coxa, sobrecoxa e peito, e três deles rs736010549, rs739508259 e rs313532967 estão presentes nos genes WDR77, VWA8 e BARL, respectivamente. Estes genes estão relacionados com processos biológicos como via de sinalização de esteroide, receptores de estrogênio e de ácidos biliares. Nossa estratégia permitiu a identificação de potenciais mutações causais associadas com crescimento e desenvolvimento muscular.
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Carvalho, Thaysa Buss. "Avaliação de SNPs (Single Nucleotide Polymorphisms) nas diferentes formas clínicas da doença de Chagas." Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/152931.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A doença de Chagas (DC), causada pelo protozoário Trypanosoma cruzi (T. cruzi), ainda é considerada como um problema de saúde pública em muitos países da América Latina. De acordo com a Organização Mundial da Saúde, estima-se que entre seis a sete milhões de pessoas no mundo estejam infectadas. Indivíduos na fase crônica da doença podem ser classificados como assintomáticos ou sintomáticos (estes, desenvolvendo as formas clínicas cardíaca, digestiva ou mista). Os assintomáticos correspondem a 70% dos indivíduos nessa fase e, embora apresentem sorologia positiva para anticorpos anti T-cruzi, não desenvolvem manifestações clínicas da doença. O motivo pelo qual alguns pacientes permanecem assintomáticos, e outros desenvolvem sintomas severos, ainda é desconhecido. Fatores genéticos do hospedeiro são bastante relevantes e podem explicar a heterogeneidade encontrada em pacientes que vivem com a doença em áreas endêmicas. Diante disso, o presente trabalho teve como objetivo avaliar SNPs (Single Nucleotide Polymorphisms) no gene TNF-α (rs1800629) e ACAT-1 (rs1044925) em indivíduos com DC crônica e verificar se os mesmos estão relacionados com a susceptibilidade para manifestação de formas clínicas sintomáticas com uso da técnica PCR-RFLP. Foram genotipadas 124 amostras para o gene TNF-α e 135 para o gene ACAT-1. Foi observada associação significativa da presença do alelo A do gene TNF- α em indivíduos sintomáticos em relação aos assintomáticos (p = 0,045). Também houve associação significativa entre o alelo G (p = 0,008) e o genótipo GG (p = 0,001) do gene TNF-α e os genótipos AA (p = 0,047) e AC (p = 0,016) do gene ACAT-1 nos indivíduos assintomáticos em relação aos sintomáticos. Nossos resultados sugerem que a presença do alelo A do gene TNF-α possa estar relacionada com a presença de manifestações clínicas sintomáticas na fase crônica da doença e o alelo G, bem como, genótipo GG possam estar associados com ausência de sintomas clínicos em indivíduos nessa fase. A respeito do SNP do gene ACAT-1, nossos dados sugerem efeito protetor dos genótipos AA e AC segundo apresentação de sintomas da doença na fase crônica, o que representa dado inédito em chagásicos.
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi (T. cruzi), is still considered a public health problem in many Latin America countries. According to the World Health Organization, it is estimated that between six and seven million people worldwide are infected. Disease’s chronic phase individuals may be classified as asymptomatic or symptomatic (these, developing as clinical cardiac, digestive or mixed forms). Asymptomatic individuals account for 70% of the patients at this stage and, although they have positive serology for anti-T-cruzi antibodies, they do not develop it’s clinical manifestations. The reason why some patients remain asymptomatic, and others develop severe symptoms, is still unknown. Host’s genetic factors are quite relevant and may explain the heterogeneity found in patients living with the disease in endemic areas. The objective of this study was to evaluate SNPs in the TNF-α (rs1800629) and ACAT-1 (rs1044925) genes in individuals with chronic CD and to verify if the polymorphisms are related to the susceptibility to manifestation of symptomatic clinical forms using the PCR-RFLP technique. Were genotyped 124 samples for the TNF-α gene and 135 for the ACAT-1 gene. Significant association for the presence of the A allele of the TNF-α gene was observed for symptomatic individuals in relation to the asymptomatic ones (p = 0.045). There was also a significant association between the G allele (p = 0.008) and the GG genotype (p = 0.001) of the TNF-α gene and the AA (p = 0.047) and AC (p = 0.016) genotypes of the ACAT-1 gene for asymptomatic patients. Our results suggests that the presence of the TNF-α gene A allele may be related to the presence of symptomatic clinical manifestations in the chronic phase of the disease and the G allele as well as the GG genotype may be associated with absence of clinical symptoms in individuals at this stage. Regarding the ACAT-1 gene SNP, our data suggests a protective effect of AA and AC genotypes according to the to the presentation of chronic disease symptoms, which is an unprecedented finding in chagasic patients.
CAPES: 1578310
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Pfister, Edith L. "Therapeutic Silencing of Mutant Huntingtin by Targeting Single Nucleotide Polymorphisms: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/618.
Full textAbstract:
Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder. Invariably fatal, HD is caused by expansion of the CAG repeat region in exon 1 of the Huntingtin gene which creates a toxic protein with an extended polyglutamine tract 1. Silencing mutant Huntingtin messenger RNA (mRNA) is a promising therapeutic approach 2-6. The ideal silencing strategy would reduce mutant Huntingtin while leaving the wild-type mRNA intact. Unfortunately, targeting the disease causing CAG repeat expansion is difficult and risks targeting other CAG repeat containing genes.
We examined an alternative strategy, targeting single nucleotide polymorphisms (SNPs) in the Huntingtin mRNA. The feasibility of this approach hinges on the presence of a few common highly heterozygous SNPs which are amenable to SNP-specific targeting. In a population of HD patients from Europe and the United states, forty-eight percent were heterozygous at a single SNP site; one isoform of this SNP is associated with HD. Seventy-five percent of patients are heterozygous at least one of three frequently heterozygous SNPs. Consequently, only five allele-specific siRNAs are required to treat three-quarters of the patients in the European and U.S. patient populations. We have designed and validated siRNAs targeting these SNPs.
We also developed artificial microRNAs (miRNAs) targeting Huntingtin SNPs for delivery using recombinant adeno-associated viruses (rAAVs). Both U6 promoter driven and CMV promoter driven miRNAs can discriminate between matched and mismatched targets in cell culture but the U6 promoter driven miRNAs produce the mature miRNA at levels exceeding those of the vast majority of endogenous miRNAs. The U6 promoter driven miRNAs can produce a number of unwanted processing products, most likely due to a combination of overexpression and unintended export of the pri-miRNA from the nucleus. In contrast, CMV-promoter driven miRNAs produce predominantly a single species at levels comparable to endogenous miRNAs. Injection of recombinant self complementary AAV9 viruses carrying polymerase II driven Huntingtin SNP targeting miRNAs into the striatum results in expression of the mature miRNA sequence in the brain and has no significant effect on endogenous miRNAs. Matched, but not mismatched SNP-targeting miRNAs reduce inclusions in a knock-in mouse model of HD. These studies bring us closer to an allele-specific therapy for Huntington’s disease.