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Pang, See-Tong. "A functional genomics approach to study prostate disorders /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-640-5/.
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Shebe, Khadija Ahmed. "Genomics study of anti-tuberculosis drug-induced hypersensitivity reactions." Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15679.
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Introduction: All first-line anti-tuberculosis drugs can be associated with all phenotypes of cutaneous adverse drug reactions (CADR). Second-line drugs are associated with much poorer outcomes. Thus, identifying the offending drug in poly-pharmacy is difficult. Re -challenge with the drug is the gold standard in identifying the offender, however poses unacceptably high risk of CADR recurrence. Population and drug-specific genomics help identify those susceptible to adverse reactions to a drug facilitating avoidance of the drug. Objective: To investigate the genomic susceptibility in patients with confirmed rifampicin and or isoniazid-associated hypersensitivity reactions using both genome- wide association studies and candidate gene approaches. Methods: A case control study using 14 patients with previous tuberculosis-associated CADR who were re-challenged with first-line anti-tuberculosis drugs and subsequently developed re-challenge reactions to either isoniazid or rifampicin as cases. These were compared with 30 controls who had tolerated rifampicin and isoniazid during the re- challenge process (12 patients, Group 1a) and consecutive patients who had been on TB treatment for at least 12 weeks without developing any adverse drug reaction (1 8 patients, Group 1b) and 200 black South Africans from the general population. HLA genotypes of the samples were determined by SeCore® HLA Sequence based typing (Invitrogen, Life technologies, USA), and potential ambiguities were resolved by sequencing-based typing. Results: We found HLA-B*58:02 (OR=3.6; 95% CI: 1.4-8.99) and HLA-DRB1*09:01 (OR=15.3; 95% CI: 2.1-113.1) to be significantly more prevalent in patients who developed rifampicin and isoniazid-associated CADR as compared to black South African general population. However, we found no significant associations between HLA genotype and rifampicin/isoniazid-associated CADR when we compared the cases to our study controls that had tolerated rifampicin and isoniazid. HLA-B *58.02 was not found to be statistically associated with HIV positive status (p=0.42) and DRESS phenotype ( p= 0.6279). The majority of our cases were black Africans. Approximately 80% of our cases and controls were HIV-infected. DRESS/DIHS was the prevalent phenotype of CADR, accounting for approximately 80% of cases and controls. Discussion: To our knowledge, this is the first study to show an association between HLA-B*58:02 and HLA-DRB1*09:01 alleles and severe cutaneous adverse drugs reactions secondary to rifampicin and isoniazid in an African population. We identify 2 candidate HLA alleles that need confirmation of their association in African patients who develop rifampicin or isoniazid-associated CADR in larger studies. The value of identifying candidate alleles could lead to CADR preventative screening prior to initiating anti-tuberculosis therapy in black South Africans. The HLA-B*58:02 noted in our cases and controls tolerant of the drugs might not be associated with CADR but could be a reflection of the HIV status and control in HIV-TB co-infected persons. Conclusion: HLA-B*58:02 and HLA-DRB1*09:01 may be associated with rifampicin and isoniazid-associated CADR. Alternately HLA-B*58:02 may be associated with HIV status rather than CADR. A sufficiently powered study is needed to confirm this association.
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Norman-Marzella, Nancy L. "Evidence-Based Practice Self-Study Education Program for Staff Nurses on Genomics." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/7416.
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Nurses routinely obtain genomic data when collecting family health histories. However, they report low confidence in their knowledge and understanding of genomics and the genetically engineered medications prescribed for their patients. The purpose of this project was the development and implementation of an evidence-based online education program about genetics and genomics to increase the nurses' understanding and ability to provide competent care for their patients receiving treatments based on the science of genomics. Knowles's principles of adult learning theory guided the development and delivery of the online education project to 12 medical-surgical registered nurses employed in a hospital in the northeastern United States. The Johns Hopkins nursing evidence-based practice model provided a guideline for organizing and evaluating the level and quality of evidence. A 2-tailed paired t test showed that the nurses' knowledge and understanding about genetics and genomics increased after participating in the evidence-based education program. The increase in nurses' knowledge on genomics has the potential to provide nurses with the competence and confidence to collaborate with physicians and pharmacists regarding treatment plans incorporating genomics, resulting in effective team collaboration and a positive social change that could improve patient outcomes.
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Weirather, Jason Lee. "Computational approaches to the study of human trypanosomatid infections." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/4976.
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Trypanosomatids cause human diseases such as leishmaniasis and African trypanosomiasis. Trypanosomatids are protists from the order Trypanosomatida and include species of the genera Trypanosoma and Leishmania, which occupy a similar ecological niche. Both have digenic life-stages, alternating between an insect vector and a range of mammalian hosts. However, the strategies used to subvert the host immune system differ greatly as do the clinical outcome of infections between species. The genomes of both the host and the parasite instruct us about strategies the pathogens use to subvert the human immune system, and adaptations by the human host allowing us to better survive infections.
We have applied unsupervised learning algorithms to aid visualization of amino acid sequence similarity and the potential for recombination events within Trypanosoma brucei's large repertoire of variant surface glycoproteins (VSGs). Methods developed here reveal five groups of VSGs within a single sequenced genome of T. brucei, indicating many likely recombination events occurring between VSGs of the same type, but not between those of different types. These tools and methods can be broadly applied to identify groups of non-coding regulatory sequences within other Trypanosomatid genomes.
To aid in the detection, quantification, and species identification of leishmania DNA isolated from environmental or clinical specimens, we developed a set of quantitative-PCR primers and probes targeting a taxonomically and geographically broad spectrum of Leishmania species. This assay has been applied to DNA extracted from both human and canine hosts as well as the sand fly vector, demonstrating its flexibility and utility in a variety of research applications.
Within the host genomes, fine mapping SNP analysis was performed to detect polymorphisms in a family study of subjects in a region of Northeast Brazil that is endemic for Leishmania infantum chagasi, the parasite causing visceral leishmaniasis. These studies identified associations between genetic loci and the development of visceral leishmaniasis, with a single polymorphism associated with an asymptomatic outcome after infection.
The methods and results presented here have capitalized on the large amount of genomics data becoming available that will improve our understanding of both parasite and host genetics and their role in human disease.
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Curreem, Oi-ting Shirly. "The study of environmental adaptability of laribacter hongkongensis by genomic and proteomic approach." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43931686.
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Herniou, Elisabeth Anne. "Use of comparative genomics and phylogenetics to study the evolution of the Baculoviridae." Thesis, Imperial College London, 2003. http://hdl.handle.net/10044/1/7698.
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Martinez-Hernandez, Francisco. "The power of one: Study of the marine virosphere using single-virus genomics." Doctoral thesis, Universidad de Alicante, 2019. http://hdl.handle.net/10045/118218.
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Aunque tradicionalmente las dificultades asociadas a su estudio han subestimado la importancia de los virus en los ecosistemas, hoy en día el desarrollo de nuevas metodologías nos ha hecho comprender que estos juegan un papel relevante a nivel global, sobre todo en los océanos. La secuenciación del genoma vírico de una muestra ambiental (la virómica) y su posterior reconstrucción (ensamblaje de genomas), ha permitido ampliar el número de virus marinos conocidos, sin embargo, también han puesto de manifiesto la enorme diversidad de genomas víricos que continúan sin ser reconstruidos. En esta tesis, la novedosa metodología de Single-virus genomics (SVGs), una técnica en la que se separan virus mediante sorting y se amplifica y secuencia su genoma de forma individual, fue aplicada con éxito sobre muestras marinas, desvelándose el genoma de virus marinos, previamente desconocidos, a pesar de ser altamente abundantes a lo largo de todos los océanos del planeta. El motivo por el que la virómica no ha podido reconstruir estos genomas fue analizado también en la tesis y se le atribuyó a la (micro-)diversidad de estas abundantes poblaciones víricas. Uno de estos virus obtenidos por SVG, el vSAG 37-F6, resultó ser el más abundante en los océanos. Diferentes métodos in silico, basados en análisis de k-mer, espaciadores CRISPR y búsqueda de ARNt, fueron empleados para tratar de identificar su huésped, sin embargo, no dieron resultado, por lo que se diseñó una aproximación experimental. Se diseñaron unos primers de PCR, específicos para el vSAG 37-F6 y se probaron en una colección de células sorteadas individualmente cuyo genoma había sido amplificado (SAGs). Tras comprobar la correcta amplificación (no inespecificidades) en uno de estos SAGs, se secuenció su genoma, mostrando que estaba relacionado con los Pelagibacteriales, por lo que el vSAG 37-F6 se identificó como un pelagifago. Corroborando este resultado 3 contigs diferentes, similares al vSAG 37-F6 fueron encontrados en otros 3 SAGs identificados también como Pelagibacter sp, obtenidos cada uno de ellos en diferentes localizaciones (Océanos Atlántico y Pacífico), y en tres experimentos y trabajos diferentes. Estos Pelagifagos similares al 37-F6 estaban poco relacionados con los obtenidos por técnicas dependientes de cultivo. La abundancia de los virus en muestras ambientales es tradicionalmente estimada de forma relativa mediante el reclutamiento de fragmentos virómicos. Sin embargo, la ausencia de marcadores específicos dificulta el empleo de métodos para calcular su abundancia de forma absoluta, como se hace con los procariotas. En el tercer capítulo de esta tesis, se muestra la aplicación de la técnica de droplet digital PCR (ddPCR) para calcular la abundancia absoluta de 2 pelagifagos, el vSAG 37-F6, y el HTVC010P. Además, son evaluados los pasos críticos de esta metodología, como es el diseño de primers específicos, o la correlación matemática para su cálculo. Las abundancias absolutas de ambos virus fueron calculadas en tres muestras ambientales diferentes, dos del Mar Mediterráneo, y una del Atlántico Norte, procedente del Golfo de Maine (Estados Unidos). La pareja de primers empleada con el vSAG 37-F6 fue diseñada siguiendo el procedimiento propuesto en este trabajo, mientras que para el HTVC010P se empleó una pareja de primers obtenida de la bibliografía. Los valores de abundancia obtenidos estuvieron comprendidos entre los valores de 1,270-14,400 virus mL-1 y de 360 a 8,510 virus mL-1 para el HTVC010P y el vSAG 37-F6 respectivamente. Sin embargo, la secuenciación de los amplicones obtenidos por PCR, mostró una sobreestimación del 6% para los primers del HTVC010P, pero no para los del vSAG 37-F6. Los dos últimos apartados de esta tesis se corresponden con dos trabajos que están actualmente siendo desarrollados por el doctorando. En el primero de ellos se analiza la (micro-)diversidad de las poblaciones del vSAG 37-F6 desde varios puntos de vista. Y para finalizar la técnica de SVGs es aplicada en muestras marinas de profundidad, de las que poco se conoce actualmente.La presente tesis ha sido financiada por el Ministerio de Economía y competitividad español (refs. CGL2013-40564-R and SAF2013-49267-EXP), por la Generalitat Valenciana (ref. ACOM/2015/133 and ACIF/2015/332), y por la Gordon and Betty Moore Foundation (ref. 5334).
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Lee, Yiu-fai. "Analysis for segmental sharing and linkage disequilibrium a genomewide association study on myopia /." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43912217.
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Heeger, Felix [Verfasser]. "Genomics Approaches to the Study of Diversity and Function of Aquatic Fungi / Felix Heeger." Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1176634666/34.
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Rhode, Clint. "Signatures of selection in natural and cultured Abalone (Haliotis midae) : a population genomics study." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/79895.
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Thesis (PhD)--Stellenbosch University, 2013.ENGLISH ABSTRACT: The South African abalone, Haliotis midae, commonly known as perlemoen, is an economically important gastropod mollusc. Historically, this species maintained a lucrative fisheries sector; however with increasingly lower landings there has now been a shift to aquaculture. Efforts to conserve natural populations and to improve abalone aquaculture production are thus running in parallel. Previous studies reported significant disparities in parental contributions in aquaculture populations that could explain the rapid divergence of commercial stocks from wild populations. Furthermore, subtle, but significant, population differentiation has also been reported for wild populations on the west-, south-, and east coast of the South African coastline. This study therefore aimed to investigate the evolutionary forces, in particularly selection, facilitating population divergence in wild and cultured H. midae populations using a population genomics approach. By using both microsatellite- and single nucleotide polymorphism (SNP) markers it was found that approximately 10% to 27% of the H. midae genome may be influenced by selection. When incorporating these loci into analyses of population differentiation (e.g. AMOVA, factorial correspondence analysis and estimates of genetic distance) there was a marked increase in genetic divergence between wild and cultured populations (especially when using microsatellite loci) and amongst populations from different geographic regions (particularly supported by the SNP loci). The differences in population clustering as highlighted by microsatellite- and SNP markers can most likely be attributed to the genomic distribution of the respective loci: The SNP markers were developed from EST sequences and therefore mostly represents protein structural variation; whereas the microsatellite markers, found to be putatively under selection, were mainly located in regulatory motifs. The results of this study therefore confirmed previous observations of divergence amongst wild- and cultured populations, but more importantly demonstrated that selection is an important factor driving this divergence. In wild populations selection probably facilitates adaptation to local environmental conditions, whilst amongst aquaculture population adaptation to captivity, husbandry practices and artificial selection may be important determinants. There is evidence for population bottlenecks in wild- and cultured populations; nonetheless long-term effective population sizes seem to be large. Amongst the wild populations, however, short-term population sizes appear to be small most likely due to differential spawning rates amongst reproductively active animals leading to temporal fluctuation in genetic diversity. The results indicate that contact between wild and cultured abalone should be minimised to prevent any adverse effects due to outbreeding depression. With regards to conservation, an emphasis on maintaining adaptive diversity of the wild stocks might be warranted. Continued genetic monitoring is advisable for both wild and cultured abalone populations as to optimally manage the abalone resource for both conservation and commercial viability and sustainability.
AFRIKAANSE OPSOMMING: Die Suid-Afrikaanse perlemoen, Haliotis midae, is 'n ekonomies belangrike buikpotige weekdier. Histories het hierdie spesie 'n winsgewende vissery gehandhaaf, maar met steeds dalende vangste is daar nou 'n verskuiwing na akwakultuur. Pogings om natuurlike populasies te bewaar en perlemoen te verbeter vir verhoogde akwakultuur produksie loop dus in parallel. Vorige studies het bevind dat beduidende verskille in ouerlike bydraes tot die nageslag, in akwakultuur populasies, kan verduidelik hoekom die populasies so vinnig divergeer van die wilde voorouers. Verder, is subtiele, maar betekenisvolle genetiese differensiasie tussen wilde populasies aan die wes-, suid-en ooskus van die land gevind. Hierdie studie is dus daarop gemik om ondersoek in te stel na die mate waartoe verskeie evolusionêre prosesse, in besonder seleksie, die populasie divergensie in beide wilde en gekweekte H. midae teweegbring deur gebruik te maak van ‘n populasie genomika benadering. Deur gebruik te maak van beide mikrosatelliet- en enkel nukleotied polimorfisme (ENP) merkers is dit bevind dat ongeveer 10% tot 27% van die H. midae genoom moontlik beïnvloed word deur seleksie. Met die gebruik van loki onder seleksie tydens die ontleding van populasie differensiasie (bv. AMOVA, faktoriaal korrespondensie analise en genetiese afstand ramings) was daar 'n merkbare toename in genetiese divergensie tussen wilde- en gekweekte populasies (veral wanneer mikrosatelliet loki gebruik is) en onder die populasies vanuit verskillende geografiese gebiede (veral ondersteun deur die ENP loki). Die verskille in die populasie groeperings soos uitgelig deur die mikrosatelliet- en ENP-merkers kan waarskynlik toegeskryf word aan die genomiese verspreiding van die onderskeie loki: Die ENP-merkers is ontwikkel vanaf uitgedrukte volgorde merker (UVM) volgordes en daarom verteenwoordig dit meestal proteïen strukturele veranderinge, terwyl mikrosatelliet merkers eerder in regulatoriese motiewe geleë is. Die resultate van hierdie studie steun dus vorige waarnemings, maar meer belangrik, het dit getoon dat seleksie ‘n betekenisvolle faktor in populasie divergensie in beide wilde en gekweekte populasies is. In wilde populasies fasiliteer seleksie waarskynlik die aanpassing tot plaaslike omgewingstoestande terwyl seleksie onder die gekweekte populasies teweeggebring kan word as gevolg van aanpassing tot aanhouding, boerdery praktyke en kunsmatige seleksie. Daar is bewyse vir populasie bottelnekke in wilde- en gekweekte populasies; tog blyk langtermyn effektiewe populasiegroottes om redelik groot te wees. Onder die wilde populasies is egter gevind dat kort-termyn populasiegroottes klein kan wees, waarskynlik as gevolg van differensiële broeikoerse onder reproduktiewe diere. Dit het tot gevolg dat daar beduidende fluktuasies is in temporale genetiese diversiteit. Die resultate dui daarop dat kontak tussen wilde en gekweekte perlemoen tot 'n minimum beperk moet word om enige nadelige effekte weens uitteling depressie te voorkom. Verder, met betrekking tot bewaring, is ‘n klem op die handhawing van aangepaste genetiese diversitiet dalk geregverdig. Voortgesette genetiese monitering word aanbeveel vir beide wilde- en gekweekte perlemoen populasies ter wille van die optimale bestuur van die perlemoen hulpbron vir beide bewaring en kommersiële lewensvatbaarheid en volhoubaarheid.
International Foundation for Science
National Research Foundation of South Africa
Stellenbosch University
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Thomas, Samantha Marie. "Induced pluripotent stem cells as a model to study individual variation and comparative genomics." Thesis, The University of Chicago, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10195620.
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The past decade of genetics research has been defined by the discovery of the profound effects non-coding genetic variation can have on the phenotypes that distinguish humans from each other and from our close evolutionary relatives. The full implications of this new understanding are largely unexplored, however, as modern ethics restricts experimentation in humans and most primates, rendering data from dynamic processes almost non-existent. The study of regulatory molecular dynamics has been changed entirely by the availability of protocols to generate iPSCs and differentiate them into adult cell types. The molecular basis of disease mechanisms, drug response, and developmental processes can now be studied in the relevant tissue, presenting an overwhelming spectrum of possible applications. Of particular interest to comparative biologists, long-standing questions about the relative conservation of early developmental states can now, for the first time, be ethically explored in closely related primates. In this dissertation, we first discuss evidence that iPSCs can faithfully model genetic variation, even when sourced from highly dysregulated cells. We then use an iPSC-based model to study the temporal profile of conservation between humans and chimpanzees during early endoderm development and identify patterns of divergence over developmental stages.
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Zhuang, Jiali. "Structural Variation Discovery and Genotyping from Whole Genome Sequencing: Methodology and Applications: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/875.
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A comprehensive understanding about how genetic variants and mutations contribute to phenotypic variations and alterations entails experimental technologies and analytical methodologies that are able to detect genetic variants/mutations from various biological samples in a timely and accurate manner. High-throughput sequencing technology represents the latest achievement in a series of efforts to facilitate genetic variants discovery and genotyping and promises to transform the way we tackle healthcare and biomedical problems. The tremendous amount of data generated by this new technology, however, needs to be processed and analyzed in an accurate and efficient way in order to fully harness its potential. Structural variation (SV) encompasses a wide range of genetic variations with different sizes and generated by diverse mechanisms. Due to the technical difficulties of reliably detecting SVs, their characterization lags behind that of SNPs and indels. In this dissertation I presented two novel computational methods: one for detecting transposable element (TE) transpositions and the other for detecting SVs in general using a local assembly approach. Both methods are able to pinpoint breakpoint junctions at single-nucleotide resolution and estimate variant allele frequencies in the sample. I also applied those methods to study the impact of TE transpositions on the genomic stability, the inheritance patterns of TE insertions in the population and the molecular mechanisms and potential functional consequences of somatic SVs in cancer genomes.
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Zhuang, Jiali. "Structural Variation Discovery and Genotyping from Whole Genome Sequencing: Methodology and Applications: A Dissertation." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/875.
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A comprehensive understanding about how genetic variants and mutations contribute to phenotypic variations and alterations entails experimental technologies and analytical methodologies that are able to detect genetic variants/mutations from various biological samples in a timely and accurate manner. High-throughput sequencing technology represents the latest achievement in a series of efforts to facilitate genetic variants discovery and genotyping and promises to transform the way we tackle healthcare and biomedical problems. The tremendous amount of data generated by this new technology, however, needs to be processed and analyzed in an accurate and efficient way in order to fully harness its potential. Structural variation (SV) encompasses a wide range of genetic variations with different sizes and generated by diverse mechanisms. Due to the technical difficulties of reliably detecting SVs, their characterization lags behind that of SNPs and indels. In this dissertation I presented two novel computational methods: one for detecting transposable element (TE) transpositions and the other for detecting SVs in general using a local assembly approach. Both methods are able to pinpoint breakpoint junctions at single-nucleotide resolution and estimate variant allele frequencies in the sample. I also applied those methods to study the impact of TE transpositions on the genomic stability, the inheritance patterns of TE insertions in the population and the molecular mechanisms and potential functional consequences of somatic SVs in cancer genomes.
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Saunders, Gary Ian. "Comparative genomics of nematodes : Caenorhabditis elegans as a tool to study the Haemonchus contortus genome." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1607/.
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The genome of the Trichostrongylid nematode parasite of small ruminants Haemonchus contortus is being sequenced at the Pathogen Sequencing Unit of the Wellcome Trust Sanger Institute, Cambridge, UK. Currently, in excess of 800 Mb of genomic sequence is available for this on-going project (http://www.sanger.ac.uk/Projects/H_contortus/). Once available, the fully sequenced and assembled genome of H. contortus will be an extremely valuable resource for both novel drug discovery and biological research into this important pathogen. H. contortus resides in the same Clade (Clade V) of the phylum Nematoda as the free-living model organism Caenorhabditis elegans. Therefore, it is ideally placed to extrapolate the wealth of genomic and biological data available for C. elegans. The extent to which such data can be applied to parasitic nematode research was a major focus of this project. I have concentrated on two well documented and important gene classes: those comprising the β-tubulin gene family and those of the RNA-interference (RNAi) pathway. Control methods for H. contortus are becoming increasingly restricted due to the rise in resistance to current anthelmintic drugs. Benzimidazoles (BZ) are a class of anthelmintic to which there is widespread resistance. Mutations and deletions in both of the β-tubulin genes previously identified from H. contortus, isotypes-1 and 2, have been shown to correlate with BZ resistance. I have identified an additional two β-tubulin loci within the H. contortus genome, which now gives a total of four genes for this family. Using C. elegans as a surrogate expression system together with antibody immunolocalisation in H. contortus I have investigated the expression pattern of three of these H. contortus β-tubulin genes and encoded proteins, and compared these with those of the C. elegans β-tubulin gene family. In addition, I have characterised the phylogenetic relationships of all available Trichostrongylid β-tubulin polypeptide sequences. This has allowed the determination of the evolution of this gene family, and possible association of isotypes-1 and 2 with BZ resistance, across these nematodes. RNAi is a well established technique used in C. elegans to silence gene expression using double stranded RNA (dsRNA). However, RNAi is far less effective and repeatable in parasitic nematode species. Using gene searching techniques I have examined whether genes required for RNAi in C. elegans are present and conserved in the H. contortus genome. Although I identified putative homologues of Dicer (dcr-1) and several other RNAi genes, no sequence homologous to the C. elegans rde-4 gene could be found. This gene is essential for the generation of small inhibitory RNAs (siRNAs) in the C. elegans RNAi pathway. Furthermore, no H. contortus genomic sequence encoding a homologue of Ce-SID-2 was identified. SID-2 is essential for dsRNA uptake from the environment, and sequence differences between C. elegans and C. briggsae SID-2 are responsible for the lack of environmental RNAi in the latter. I have also searched the available genomic sequence databases of Pristionchus pacificus and Brugia malayi for RNAi pathway genes and concluded that components of the RNAi pathway may not be conserved across the phylum Nematoda, although full genome sequences will be required to confirm these findings.
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Curreem, Oi-ting Shirly, and 嘉藹庭. "The study of environmental adaptability of laribacter hongkongensis bygenomic and proteomic approach." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43931686.
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Endo, Yoshinori. "Comparative study of mammalian evolution by genomic analyses and pluripotent stem cell technology." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263514.
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Dhladhla, Busisiwe I. R. "Enumeration of insect viruses using microscopic and molecular analyses: South African isolate of cryotophlebia leucotreta granulovirus as a case study." Thesis, Nelson Mandela Metropolitan University, 2012. http://hdl.handle.net/10948/d1008395.
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Baculoviruses have been used as biocontrol agents to control insect pests in agriculture since the 1970s. Out of the fifteen virus families known to infect insects, baculoviruses offer the greatest potential as insect biopesticides, due to their high host specificity which makes them extremely safe to humans, other vertebrates, plants and non-target microorganisms. They comprise of two genera: nucleopolyhedroviruses (NPVs) and granuloviruses (GVs). The South African isolate of Cryptophlebia leucotreta granulovirus (CrleGV-SA) which is infectious for the false codling moth (FCM), Thaumatotibia leucotreta, (Meyrick) (Lepidoptera: Tortricidae), has been successfully developed into two commercial biopesticides; Cryptogran® and Cryptex®, for the control of FCM in citrus crops. The current method of enumeration used for CrleGV-SA virus particles in routine experiments during the production of the GV as biopesticides, is dark field microscopy. However, due to the small size of GVs (300-500 nm in length), the technique is not easy to perform on these viruses, and no systemic comparison has been made of potential alternative methods. Therefore, the main objective of this study was to develop a quantitative enumeration method for CrleGV-SA occlusion bodies (OBs) which is accurate, reliable, and feasible, and compare the developed methods of enumeration to the current method. Purified and semi-purified CrleGV-SA viral stocks were prepared for enumeration studies using spectrophotometry, dark field microscopy, scanning electron microscopy (SEM) and real time qPCR. Spectrophotometry was found to be an unreliable method for enumeration of GVs in the production, standardisation, and quality control of biopesticides. Dark field microscopy and SEM were found to be accurate, and statistically comparable (p = 0.064) enumeration techniques. qPCR is currently being optimised for the enumeration of GVs. This technique was demonstrated to generate accurate standard curves for absolute quantification of virus particles for pure and semi-pure virus preparations. qPCR offers the greatest potential as an accurate enumeration method because it is not affected by contamination with non-biological contaminating debris, nor by other biological material due to the specificity of PCR primers. Further work is required to fully develop qPCR as an enumeration method for GVs. However, dark field microscopy has been successfully validated as an enumeration method. SEM, which has a high resolution compared to light microscopy, has an added advantage over dark field microscopy, which is to distinguish virus particles in semi-pure viral stock preparations during counting. Therefore, SEM currently provides the most unambiguous and feasible enumeration method for GVs in both purified and semi-purified virus samples.
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Logotheti, Marianthi. "Integration of functional genomics and data mining methodologies in the study of bipolar disorder and schizophrenia." Doctoral thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-52644.
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Bipolar disorder and schizophrenia are two severe psychiatric disorders characterized by a complex genetic basis, coupled to the influence of environmental factors. In this thesis, functional genomic analysis tools were used for the study of the underlying pathophysiology of these disorders, focusing on gene expression and function on a global scale with the application of high-throughput methods. Datasets from public databases regarding transcriptomic data of postmortem brain and skin fibroblast cells of patients with either schizophrenia or bipolar disorder were analyzed in order to identify differentially expressed genes. In addition, fibroblast cells of bipolar disorder patients obtained from the Biobank of the Neuropsychiatric Research Laboratory of Örebro University were cultured, RNA was extracted and used for microarray analysis. In order to gain deeper insight into the biological mechanisms related to the studied psychiatric disorders, the differentially expressed gene lists were subjected to pathway and target prioritization analysis, using proprietary tools developed by the group of Metabolic Engineering and Bioinformatics, of the National Hellenic Research Foundation, thus indicating various cellular processes as significantly altered. Many of the molecular processes derived from the analysis of the postmortem brain data of schizophrenia and bipolar disorder were also identified in the skin fibroblast cells. Additionally, through the use of machine learning methods, gene expression data from patients with schizophrenia were exploited for the identification of a subset of genes with discriminative ability between schizophrenia and healthy control subjects. Interestingly, a set of genes with high separating efficiency was derived from fibroblast gene expression profiling. This thesis suggests the suitability of skin fibroblasts as a reliable model for the diagnostic evaluation of psychiatric disorders and schizophrenia in particular, through the construction of promising machine-learning based classification models, exploiting gene expression data from peripheral tissues.
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Munung, Nchangwi Syntia. "African researchers' perceptions and expectations of the benefits of genomics research in Africa : a qualitative study." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/20960.
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Introduction: Genomics research raises a number of ethical, legal and social issues (ELSI), one of which is the concept of benefit sharing. While benefits and benefit sharing are difficult to discuss because of questions on what needs to be shared, with whom and by whom, it cannot be pushed to the side-lines especially as it is a way of promoting justice in health research and of ensuring that research is of social value to study communities. In this study, we explored the perceptions and expectations of African genomics scientists on the benefits of genomics research to Africa. Method: This was a qualitative study and we adopted a grounded theory approach. I conducted 17 in-depth interviews with genomics researchers in Africa to explore their perceptions of benefits and benefit sharing in genomics research in Africa. Transcripts of interviews were imported into QSR-NVivo 10 for thematic analysis. A thematic analysis of informed consent documents used in 13 genomics studies in Africa was also done to explore how research benefits are documented. Results: Research collaboration, research capacity building and access to genomics medicine were perceived to be the main benefits of African genomics science (AGS). In terms of research collaboration, there were perceived fears of exploitation of African researchers and research participants, and the non-sustainability of AGS. To address the problem of exploitation, African researchers expressed the need for fairness in AGS through transparency and equity in research collaborations, enhancing research oversight, African ownership and leadership of AGS, community engagement and research capacity building. In terms of genomics medicine, African genomics researchers perceived that AGS would have an impact on healthcare in Africa in the area of diagnosis, pharmacogenomics and public health. However, there were concerns around access to genomics medicine by African populations, lack of capacity for genomics medicine in Africa and the need for AGS to focus on Africa's healthcare priorities. There was however limited awareness of the concept of benefit sharing among African genomics researchers though they perceived it is as an important concept for AGS. Interviewees suggested that benefit sharing could be in the form of research capacity building, feedback of study findings, science education, community projects and the sharing of profits.
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Keays, Maria C. "The desaturase gene family : an evolutionary study of putative speciation genes in 12 species of Drosophila." Thesis, University of St Andrews, 2011. http://hdl.handle.net/10023/2478.
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The formation and persistence of species are the subject of much debate among biologists. Many species of Drosophila are behaviourally isolated, meaning that heterospecific individuals are not attracted to one another and do not interbreed. Often, this behavioural isolation is at least in part due to differences in pheromonal preference. Drosophila pheromones are long-chain cuticular hydrocarbons (CHCs). Desaturases are enzymes that are important for the production of CHCs. This thesis investigates the evolution of the gene family across 12 species of Drosophila. Desaturase genes were located in all species. Some genes, those that have previously been shown to have important roles in pheromonal communication, have experienced duplication and loss in several species. Two previously undiscovered duplicates were identified. Generally the desaturase gene family is governed by purifying selection, although following duplication these constraints are relaxed and in some cases duplicated genes show compelling evidence of positive selection. One of the loci under positive selection, the novel duplicate desat1b of the obscura group, was found to have a sex-biased expression pattern and alternative splicing in its 5′ UTR. In RNAi knock-down experiments of desaturase gene function in D. melanogaster, several desaturases were shown to affect CHC profiles of males and females, including some that were previously unlinked to CHC production.
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Alegria, Marcos Castanheira. "Identificação de interações proteína-proteína envolvendo os produtos dos Loci hrp, vir e rpf do fitopatógeno Xanthomonas axonopodis pv. citri." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-22082016-162740/.
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O Cancro Cítrico, um dos mais graves problemas fitossanitários da citricultura atual, é uma doença causada pelo fitopatógeno Xanthomonas axonopodis pv. citri (Xac). Um estudo funcional do genoma de Xac foi iniciado com o intuito de identificar interações proteína-proteína envolvidas em processos de patogenicidade de Xac. Através da utilização do sistema duplo-híbrido de levedura, baseado nos domínios de ligação ao DNA e ativação da transcrição do GAL4, nós analisamos os principais componentes dos mecanismos de patogenicidade de Xac, incluindo o Sistema de Secreção do Tipo III (TTSS), Sistema de Secreção do Tipo IV (TFSS) e Sistema de \"Quorum Sensing\" composto pelas proteínas Rpf. Componentes desses sistemas foram utilizados como iscas na triagem de uma biblioteca genômica de Xac. O TTSS é codificado pelos genes denominados hrp (\"hypersensitive response and pathogenicity\"), hrc (\"hrp conserved\") e hpa (\"hrp associated\") localizados no locus hrp do cromossomo de Xac. Esse sistema de secreção é capaz de translocar proteínas efetoras do citoplasma bacteriano para o interior da célula hospedeira. Nossos resultados mostraram novas interações proteínaproteína entre componentes do próprio TTSS além de associações específicas com uma proteína hipotética: 1) HrpG, um regulador de resposta de um sistema de dois componentes responsável pela expressão dos genes hrp, e XAC0095, uma proteína hipotética encontrada apenas em Xanthomonas spp; 2) HpaA, uma proteína secretada pelo TTSS, HpaB e o domínio C-terminal da HrcV; 3) HrpB1, HrpD6 e HrpW, 4) HrpB2 e HrcU e 5) interações homotrópicas envolvendo a ATPase HrcN. Em Xac, foram encontrados dois loci vir que codificam proteínas que possuem similaridade com componentes do TFSS envolvido em processos de conjugação/secreção bacteriana: TFSS-plasmídeo localizado no plasmídeo pXAC64 e TFSS-cromossomo localizado no cromossomo de Xac. O TFSS-plasmídeo, o qual possui maior similaridade com sistemas de conjugação, mostrou interações envolvendo proteínas cujos genes estão localizados na mesma região do plasmídeo pXAC64: 1) interação homotrópica da TrwA; 2) XACb0032 e XACb0033; 3) interações homotrópicas da proteína XACb0035; 4) VirB1 e VirB9; 5) XACb0042 e VirB6; 6) XACb0043 e XACb0021b. O TFSS-cromossomo apresentou interações envolvendo as proteínas: 1) VirD4 e um grupo de 12 proteínas que contém similaridade entre si, incluindo XAC2609 cujo gene encontra-se no locus vir, 2) XAC2609 e XAC2610; 3) Interações homotrópicas da VirB11; 4) XAC2622 e VirB9. A análise do sistema de \"Quorum-Sensing\" composto pelas proteínas Rpf mostrou interações envolvendo componentes do próprio sistema: 1) RpfC e RpfF; 2) RpfC e RpfG; 3) interações homotrópicas da RpfF; 4) RpfC e CmfA, uma proteína similar a Cmf de Dictyostelium discoideum que, neste organismo, é fundamental para processos de \"quorum-sensing\". As interações proteína-proteína encontradas permitiram-nos entender melhor a composição, organização e regulação dos fatores envolvidos na patogenicidade de Xac.Citrus Canker, caused by the bacterial plant pathogen Xanthomonas axonopodis pv. citri (Xac) presents one of the most serious problems to Brazilian citriculture. We have initiated a project to identify protein-protein interactions involved in pathogenicity of Xac. Using a yeast two-hybrid system based on GAL4 DNA-binding and activation domains, we have focused on identifying interactions involving subunits, regulators and substrates of: Type Three Secretion System (TTSS), Type Four Secretion System (TFSS) and Quorum Sensing/Rpf System. Components of these systems were used as baits to screening a random Xac genomic library. The TTSS is coded by the hrp (hypersensitive response and pathogenicity), hrc (hrp conserved) and hpa (hrp associated) genes in the chromosomal hrp locus. This secretion system can translocate efector proteins from the bacterial cytoplasm into the host cells. We have identified several previously uncharacterized interactions involving: 1) HrpG, a two-component system response regulator responsible for the expression of Xac hrp operons, and XAC0095, a previously uncharacterized protein encountered only in Xanthomonas spp; 2) HpaA, a protein secreted by the TTSS, HpaB and the C-terminal domain HrcV; 3) HrpB1, HrpD6 and HrpW; 4) HrpB2 and HrcU; 5) Homotropic interactions were also identified for the ATPase HrcN. Xac contains two virB gene clusters, one on the chromosome and one on the pXAC64 plasmid, each of which codes for a unique and previously uncharacterized TFSS. Components of the TFSS of pXAC64, which is most similar to conjugation systems, showed interactions involving proteins coded by the same locus: 1) Homotropic interactions of TrwA; 2) XACb0032 and XACb0033; 3) XAC0035 homotropic interactions; 4) VirB1 and VirB9; 5) XACb0042 and VirB6; 6) XACb0043 and XACb0021 b. Components of the chromosomal TFSS exhibited interactions involving: 1) VirD4 and a group of 12 uncharacterized proteins with a common C-terminal domain motif, include XAC2609 whose gene resides within the vir locus; 2) XAC2609 and XAC261 O; 3) Homotropic interactions of VirB11; 4) XAC2622 and VirB9. Analysis of Quorum Sensing/Rpf System components revealed interactions between the principal Rpf proteins which control Xanthomonas quorum sensing: 1) RpfC and RpfF; 2) RpfC and RpfG; 3) RpfF homotropic interactions; 4) RpfC and CmfA, a protein that presents similarity with Cmf (conditioned medium factor) of Dictyostelium discoideum, which contrais quorum sensing in this organism. The protein-protein interactions that we have detected reveal insights into the composition, organization and regulation of these important mechanisms involved in Xanthomonas pathogenicity.
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Marwaha, Shruti. "A Genomics and Mathematical Modeling Approach for the Study of Helicobacter Pylori associated Gastritis and Gastric Cancer." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308645.
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Kumwenda, Benjamin. "Comparative genomics study of completely sequenced Thermus sp. strains to enhance and facilitate their application in biotechnology." Thesis, University of Pretoria, 2013. http://hdl.handle.net/2263/40247.
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Thermus bacteria are of special interest because of their ability to live in high temperature environments. Their enzymes exhibit higher and stable activity in industry as compared to mesophilic or synthetic counterparts. Thermus bacteria are capable of reducing heavy metals which is essential in eradication of heavy metal pollution and controlling global warming. Genome rearrangements were investigated in Thermus species and the extent to which they affected the distribution of functionally related genes on the chromosome and its implication on the coherence of the metabolic network. The contribution of horizontal gene transfer to genome rearrangements and the shuffling of genes on the chromosome were analysed. Horizontally transferred genes were identified alongside their donors and recipients, their age and relative time of insertion. Metabolic networks were clustered and compared to determine the extent to which they were affected by rearrangements as a measure of evolutionary pressures experienced by organisms. Factors that enhance protein thermostability were analysed by determining dominant substitutions for amino acid residues and their properties. Protein thermostability was measured using the UNAFold algorithm. Amino acid substitutions were compared between less and highly thermophilic orthologous sequences in T. scotoductus SA-01 and T. thermophilus HB27 respectively. Protein structures were modelled for orthologs that met a defined selection criterion. Dominant amino acid substitutions were analysed in the structures to determine their locations. The contribution of dominant substitutions to energy changes in structures was analysed using FoldX program. Results revealed a uniform distribution of functionally related genes among thermophilic and mesophilic organisms. The contribution of horizontal gene transfer to genome rearrangements was found to be insignificant. Metabolic networks for Thermus species were poorly clustered in correlation with their optimum environmental growth temperatures. Non-polar, small and charged amino acids were found to significantly enhance thermostability. Higher occurrence of alanine substituted by serine and threonine; and arginine substituted by glutamine and lysine were observed to influence thermostability. Structural comparison showed that mutations were mostly located on the surfaces and helices of structures. The positions of mutations appeared to influence their energy contribution to the overall structure as measured by FoldX algorithm.Thesis (PhD)--University of Pretoria, 2013.
gm2014
Biochemistry
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Dunbar, Ellyn. "Genetic and Environmental Influences of Bullying Involvement: A Longitudinal Twin Study." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5311.
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Introduction—Bullying involvement is associated with many long-term adverse outcomes. Bullied children are at risk for internalizing disorders including anxiety, depression and suicidal behavior in childhood and adulthood. Bullies are also at risk for psychiatric disorders, specifically externalizing disorders. Bully victims—children who are both bullied and bullies—have a particularly poor prognosis, with a higher risk for internalizing and externalizing disorders. The purpose of this study is to study the epidemiology, risk of psychiatric disorders, and genetic and environmental influences of being bullied, a bully, and a bully victim—in the sample and individually in males and females.
Methods—Twins (N=2,844, aged 8-17) from the Virginia Twin Study of Adolescent Behavioral Development and the Young Adult Follow-Up were used to study bullying involvement. Child and mother responses from three waves of data collection were used to determine bullying involvement status and to diagnose internalizing and externalizing disorders. The epidemiology of bullying involvement was examined. The odds ratios (OR) of being involved in bullying and having a psychiatric disorder were calculated. The twin methodology was used to estimate the genetic and environmental influences of bullying involvement.
Results—In the sample, 14.56% were bullied, 17.33% were bullies, and 10.69% were bully victims. Males are more often involved in bullying, but females are more severely affected by their involvement. Bullied children are at a higher risk for internalizing disorders, especially young adult depression (OR 1.29). Bullies are at a higher risk for externalizing disorders, and depression (OR 1.72). Bully victims are at a higher risk for nearly every disorder tested. Bullying involvement is heritable, and being bullied has a dominance genetic component. The heritability of being bullied, a bully, and a bully victim is 48.12%, 54.81%, and 62.62% respectively.
Conclusion—Individuals involved in bullying are at risk for serious and long-lasting psychiatric disorders. Interventions need to be developed that target each category of bullying involvement, and the specific disorders that these children are at risk for, while keeping in mind that their involvement is heritable.
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Jain, Sourabh. "Comparative genomic study for identifying gene acquisitions in Megavirales." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0184/document.
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La découverte de virus géants avec une taille de génome géante et des caractéristiques génomiques surprenantes soulève différentes questions sur leur origine et leur évolution. De nombreuses études phylogénétiques ont souligné le rôle décisif des HGT et des échanges génétiques sur l'évolution des MV, mais la plupart d'entre eux sont basés sur des familles MV étroitement liées. Pour enquêter sur les événements HGT, nous avons déterminé la distribution des gènes et les phylogénies de gènes pour les 86 ORFomes MV complets classés dans 6 familles définies et 4 putatives, dans le cadre de leurs homologues d'autres domaines de la vie. À l'aide d'un flux de travail phylogénétique automatisé MimiLook, 4577 OG ont été détectés, dont 91% des OG ont été jugés spécifiques à la famille, alors que 9% sont représentés par des protéines de 2 familles MV ou plus. 414 OG ont été détectés comme événement HGT. Nous avons appliqué une procédure similaire aux 7 898 protéines non orthologues pour détecter les événements de transfert et identifié 259 HGT à partir de protéines non orthologues. Les cas de HGT révèlent la spécificité des donneurs. En conclusion, une distinction claire peut être observée dans le mosaïque du génome des familles de Megavirale éloignées, où elles ont évolué par spécificité génomique et acquisitions de gènes spécifiques à la famille de leur créneau écologique respectif. Notre recherche systématique d'événements HGT d'origine non-mégavirale fournit la première estimation de la contribution totale de HGT dans le mosaïque du génome spécifique à la famille des Megavirales éloignésDiscovery of giant viruses with giant genome size and surprising genomic features raises different question about their origin and evolution. Many phylogenetic studies have pointed out decisive role of HGTs and genetic exchanges on evolution of MVs, but, majority of them are based on closely related MV families. To investigate HGT events, we have determined gene distributions and gene phylogenies for the 86 complete MV ORFomes classified in 6 defined and 4 putative families, in context of their homologs from other domains of life. Using an automated phylogenetic workflow MimiLook, 4577 OGs were detected, out of which, 91% of OGs were found to be family specific, whereas, 9% are represented by proteins from 2 or more MV families. 414 OGs were detected as HGT event. We applied a similar procedure to the 7,898 non-orthologous proteins to detect transfer events and identified 259 HGTs from non-orthologous proteins. Instances of HGT were found to be depicting donor specificity, as viruses of vertebrates/invertebrates acquired genes from donors like Euteleostomii, Eutheria, Baculoviridae and proteobacteria; algal viruses and protozoan viruses were found to be acquiring genes from donors like Dictyostellium, Mammeillales, Firmicutes, Clostridiales. In conclusion, clear distinction can be seen in the genome mosaicism of distantly related Megavirale families, where they evolved via genome specificity and family specific gene acquisitions from their respective ecological niche. Our systematic search for HGT events of non-megavirale origin provides the first estimate of the total contribution of HGT in family specific genome mosaicism of distantly related Megavirales
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Mentzer, Alexander. "Identification and characterisation of the genetic determinants of variable response to antigens from infectious agents." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:702692ee-6971-4bc1-be8e-f6082a10cc92.
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Despite the success of vaccines in routine use worldwide, there are substantial challenges hampering our ability to develop vaccines against extant diseases including malaria and tuberculosis. Novel approaches are urgently required to help us understand immunological correlates of protection against disease and facilitate our understanding of the impact of human genetic variation on the success of diverse vaccines. To identify host genetic factors responsible for variation in antibody responses against vaccine antigens delivered routinely to infants worldwide I performed a genome-wide association study (GWAS) involving 2,499 infants recruited from three diverse sites across Africa. I identified strong genetic associations between variants in the class II major histocompatibility complex (MHC) locus and responses against five antigens: pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin; diphtheria toxin (DT); and hepatitis B surface antigen. To characterise these associations at the gene and allelic level I developed a large, high-resolution (6-digit 'G') population-specific human leukocyte antigen (HLA) imputation reference panel including 697 individuals from the vaccine GWAS typed at 11 genes, highlighting the diversity of HLA across the African continent. Using this panel I imputed HLA into the remaining GWAS dataset to fine-map the associations to specific HLA alleles, amino acid and single nucleotide polymorphism sites; some of which were found to be African specific. I then used these HLA association findings observed with PT response to correlate, through genetics, this trait with susceptibility to whooping cough in an independently recruited and analysed set of cohorts from the UK. I further used these genetic correlations to demonstrate the relevance of levels of PT-specific circulating follicular helper T-cells and TRBV29-1 T-cell receptor gene expression levels in the development of this protective immune response against PT. By using HLA-peptide binding studies I also demonstrate the diversity of mechanisms that are involved in HLA-disease association, showing that the breadth and affinity of DT-peptide binding are increased with HLA-DRB1 alleles associated with increased DT antibody responses. Taken together, these data represent the first comprehensive genetic association study of multiple vaccine responses undertaken in African infants. These results highlight the importance of human genetics in modulating protective responses against vaccine antigens and demonstrate how such associations can be harnessed to understand biological mechanisms of protective efficacy in greater detail that may in turn facilitate future vaccine development.
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Mignogna, Kristin. "Genome-Wide Systems Genetics of Alcohol Consumption and Dependence." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5946.
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Widely effective treatment for alcohol use disorder is not yet available, because the exact biological mechanisms that underlie this disorder are not completely understood. One way to gain a better understanding of these mechanisms is to examine the genetic frameworks that contribute to the risk for developing this disorder. This dissertation examines genetic association data in combination with gene expression networks in the brain to identify functional groups of genes associated with alcohol consumption and dependence.
The first study took advantage of the behavioral complexity of human samples, and experimental capabilities provided by mouse models, by co-analyzing gene expression networks in the mesolimbocortical system of acute alcohol-treated mice and human genetic alcohol dependence association data. This study successfully identified ethanol-responsive gene expression networks with overrepresentation of genes suggestively associated with alcohol dependence in an independent human sample, indicating that gene expression networks in mouse models are informative for identifying mechanistic networks relevant to the risk for developing dependence.
The second study aimed to identify quantitative trait loci for voluntary alcohol drinking behaviors under an intermittent ethanol access paradigm, in the genetically complex Diversity Outbred mice. After determining high heritability for alcohol consumption and dependence amongst the progenitor strains, we identified several specific genetic loci associated with these traits. One locus replicated results from a human association study of alcohol consumption, and provided insight to the potentially contributing genes. Finally, we identified alcohol consumption-correlated gene expression networks in the prefrontal cortex of these mice. We also mapped quantitative trait loci for network expression levels, some of which overlapped with the behavioral loci, indicating that the functions represented by these modules mediate the relationship between the genotypes in that region and drinking behaviors. Overall, our studies revealed neuroplastic and ubiquitin-related genes pathways involved in alcohol consumption in mice and humans, and that likely contribute to the risk for developing dependence.
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Rutschmann, Sereina [Verfasser]. "Evolutionary processes in mayflies (Ephemeroptera) : genomics approaches to the study of ancient origins and recent diversification / Sereina Rutschmann." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1068504730/34.
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Huang, Yun [Verfasser]. "Combining genomics and transcriptomics to study adaptation to lake and river habitats in three-spined sticklebacks / Yun Huang." Kiel : Universitätsbibliothek Kiel, 2018. http://d-nb.info/1152264176/34.
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Cavani, Ligia. "Genetic study of Babesia bovis infection level and the association with tick resistance in Hereford and Braford cattle /." Jaboticabal, 2019. http://hdl.handle.net/11449/181344.
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Orientador: Henrique Nunes de [UNESP] OliveiraCoorientador: Rodrigo Giglioti
Coorientador: Fernando Flores Cardoso
Banca: Danísio Prado Munari
Banca: Ricardo da Fonseca
Banca: Guilherme Jordão de Magalhães Rosa
Banca: Maria Eugênia Zerlotti Mercadante
Resumo: Babesiose bovina é uma doença transmitida pelo carrapato, sendo que a Babesia bovis é considerada a espécie mais patogênica. Ambos são considerados como um entrave na melhoria da produtividade da bovinocultura de corte nos trópicos, especialmente para animais de raças taurinas e suas cruzas. Esse estudo analisou uma população de bovinos Hereford e Braford e foi composto por quatro capítulos com os seguintes objetivos: Capítulo 1) Revisão de literatura; Capítulo 2) Estimação de parâmetros genéticos para contagem de carrapatos (TC) e B. bovis usando modelos lineares e modelos lineares generalizados; Capítulo 3) Avaliar a habilidade de predição e a possibilidade de aplicação da seleção genômica e conduzir estudos de associação genômica ampla (GWAS) para nível de infecção de B. bovis (IB); Capítulo 4) Procurar por estruturas causais entre TC, IB, ganho de peso do nascimento a desmama (WG) e ganho de peso da desmama ao sobreano (YG) usando a abordagem do modelo de equação estrutural (SEM). Os carrapatos foram contados manualmente em um lado do animal. A quantificação de B. bovis foi feita por meio de ensaios de qPCR. No Capítulo 2, os dados de contagem de carrapato e B. bovis estavam em escala logaritímica para as análises usando modelos lineares. O modelo de Poisson foi aplicado para contagem de carrapato sem tranformação logarítimica e para os modelos probit o fenótipo foi considerado como ausência (0) ou presença (1) de B. bovis baseado em três diferentes limiares (BBt1: IB usa... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Bovine babesiosis is a tick-borne disease, and the Babesia bovis is considered the most pathogenic species. Both parasites constitute major drawbacks for improvement of beef cattle productivity in the tropics, especially when purebred and crossbred taurine animals are used. This study analyzed a population of Hereford and Braford cattle and it was composed of four chapters with the following objectives: Chapter 1) Literature review; Chapter 2) Estimate genetic parameters for tick count (TC) and B. bovis using linear and generalized linear models; Chapter 3) Evaluate predictive ability and application of genomic selection and performed genome wide association studies (GWAS) for B. bovis infection level (IB) using single step GBLUP model; Chapter 4) Search for causal structures to investigate potential functional relationships among TC, IB, weight gain from birth to weaning (WG), and weight gain from weaning to yearling (YG) using structural equation modeling (SEM). Tick counts were performed by manually counting adult female ticks on one side of each animal. The B. bovis quantification was performed using a qPCR assay. In the Chapter 2, the tick count and B. bovis records were in log scale for analysis using linear model. A Poisson model was applied for tick count without log transformation and for probit model the phenotype was assessed by absence or presence of B. bovis based on three different thresholds (BBt1: IB using the threshold observed; BBt2: BB using threshold as a ... (Complete abstract click electronic access below)
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Tzika, Athanasia. "Small steps and grand leaps: a study of micro- and macroevolutionary processes." Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210546.
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Evolutionary biology is not a specialty, like genetics or development - it is an explanation of what is investigated by all biological specialties. Thus, the goal of this dissertation was to study both micro- and macroevolutionary processes in a multi-disciplinary framework.Population genetics, conservation, and phylogeny inference. The Jamaican boa (Epicrates subflavus) is an endemic species, whose natural populations greatly and constantly declined since the late 19th century, mainly due to predation by introduced species, human persecution, and habitat destruction. Using species-specific nuclear microsatellite loci and mitochondrial sequences, we investigated the population structure of this endangered reptile. All analyses pinpointed to an Eastern versus (Western+Central) pattern of differentiation in agreement with geological data and patterns of differentiation uncovered in other vertebrate and invertebrate Jamaican species. The same molecular markers were employed on 80 Jamaican boas of the European captive breeding program. This approach allowed us to (i) clarify all ambiguities in the studbook, (ii) correct parental allocation errors and (iii) assess the genetic diversity and the level of inbreeding of the current captive population. These results provide important insights for guiding the development of proper ex-situ and in-situ species survival and habitat management plans for this vulnerable snake. In the same framework of classical evolutionary genetics, we performed preliminary analyses of cytochrome b-like sequences in representatives of all cetacean families (but one), and revealed the presence of at least four nuclear mitochondrial pseudogenes that were independently inserted into the nuclear genome.
Evo-Devo. The emergence of Evolutionary Developmental biology has caused a partial shift in the criteria for the selection of model species. Thus far, the main criterion was the relevance of a species for understanding human biology, whereas in the frame of the new discipline, it is the understanding of the generative mechanisms underlying biological diversity that is put forward. We discussed a few criteria and limitations of major relevance to the choice of model species for Evo-Devo studies, and applied a pragmatic approach to identify possible model species within Amniotes.
Moreover, we developed MANTiS, an application pipeline that aims at integrating genomic, functional and expression data with evolutionary concepts, thus constituting the missing link between multi-species genome comparisons and functional analyses. Using MANTiS, we proceeded in the analysis of 35 metazoan full genomes for identifying all lineage-specific gene gains and losses. These results were combined with functional and expression analyses, and we demonstrated the much higher performance of MANTiS against popular databases of ortholog clusters (InParanoid, OrthoMCL, RoundUp).
Finally, preliminary results of our attempt to adapt the new revolutionary technology of DNA sequencing in microfabricated high-density picoliter reactors (developed by 454/Roche) to the ultra-fast sequencing of brain full transcriptomes in multiple reptilian species are highly promising. As an example, the Crocodylus sample generated more than 72 Mbases (per run), which were successfully assembled in approximately 31,000 contigs. One third of the latter could be matched to known sequences in the transcriptome of related species. After fine-tuning of the in silico analyses, and incorporation of genomic sequence data, we expect our approach to provide important insights not only in the evolution of central nervous system novelties in vertebrates, but in transcriptomes in general as the brain transcriptome is one of the most complex among all organs.
Doctorat en Sciences
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Häkkinen, Suvi T. "A functional genomics approach to the study of alkaloid biosynthesis and metabolism in Nicotiana tabacum and Hyoscyamus muticus cell cultures /." [Espoo, Finland] : VTT, 2008. http://www.vtt.fi/inf/pdf/publications/2008/P696.pdf.
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Melo, Thaise Pinto de [UNESP]. "Genome-wide association study of reproduction traits in Nelore cattle, including additional phenotypic information from non-genotyped animals." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/123734.
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000834416.pdf: 589713 bytes, checksum: e67aef51366f6081936855769601b405 (MD5)Esta dissertação foi dividida em três capítulos, o primeiro é uma revisão de literatura sobre o assunto que será discutido nos capítulos seguintes. No segundo capítulo, foi realizado um estudo de associação genômica ampla para a característica idade ao primeiro parto (IPP) em gado Nelore, que objetivou: 1) avaliar se a informação fenotípica adicional dos animais não genotipados afeta o mapeamento de QTLs da IPP; avaliar, por simulação, se esta informação fenotípica adicional contribui para detectar QTLs mais precisamente para uma característica complexa, com poucos genótipos disponíveis. O terceiro capítulo apresenta um estudo de associação para a característica reconcepção de primíparas (RP) em gado Nelore, cujo objetivo foi detectar importantes regiões genômicas (QTLs) associadas com esta característica. No capítulo dois, estudos de associação foram realizados utilizando as metodologias Bayes C e Weighted single step GBLUP (WssGBLUP) e as 10 janelas de marcadores (de 1Mb) que explicaram a maior proporção da variância para IPP foram identificadas e exploradas. Dois cenários foram investigados, um incluindo todas as fêmeas com informação fenotípica disponível (cenário SI - 43.482 fêmeas), e outro incluindo apenas as fêmeas com genótipo disponível (cenário SII - 1.813 fêmeas). Três iterações foram realizadas no método WssGBLUP, sendo recomputados os efeitos dos animais e dos SNPs a cada iteração. Foi simulada uma população com parâmetros e estrutura similares aos dos dados reais, com dois diferentes níveis de desequilíbrio de ligação (alto e baixo) entre os marcadores adjacentes. No capítulo três, os dados consistiram de 142.878 registros fenotípicos de RP e 2.923 genótipos. Os estudos de associação foram realizados com o método WssGBLUP usando três diferentes pesos (iterações) para os efeitos dos SNPs. Para cada iteração subsequente a variância genética ...
This dissertation was divided in three chapters, the first one is a literature review about the subject that will be discussed in subsequent chapters. In the second chapter, a genome wide association study (GWAS) for age at first calving (AFC) in Nelore cattle was performed, using real and simulated data, aiming to 1) assess if additional phenotypic information from non-genotyped animals affect QTL mapping of AFC; 2) evaluate, by simulation, if this additional phenotypic information contributes to detect QTLs more precisely for a low heritable complex trait, and with few available genotypes. The third chapter presents a GWAS for heifer rebreeding (HR) in Nelore cattle. In chapter two, GWA studies were performed using Bayes C and weighted single step GBLUP (WssGBLUP) methods and the top 10 marker windows (1Mb) that explained the larger proportion of variance for AFC were identified and further explored. Two scenarios were investigated, one including all females with available phenotypic information (SI scenario, with 43,482 females), and the other including just the females with available genotype (SII scenario, with 1,813 females). Three iterations were performed in WssGBLUP, recomputing the animals and SNPs effect in each subsequent iteration. It was simulated a population mimicking the parameters and the structure of the real dataset. Two different disequilibrium linkage levels (low and high) between adjacent markers were simulated. In chapter three, the data consisted of 142,878 HR phenotypic records and 2,923 genotypes. The GWAS was performed with WssGBLUP method using three different weightings (iterations) for the SNP effects. Total genetic variances were calculated for the top 10 1Mb SNP-windows, detected by each iteration. On each subsequent iteration, the genetic variance was distributed for a smaller number of SNPs, and the SNP effects were recomputed. Genes possibly associated with HR were searched to reinforce the suggestive ...
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Melo, Thaise Pinto de. "Genome-wide association study of reproduction traits in Nelore cattle, including additional phenotypic information from non-genotyped animals /." Jaboticabal, 2015. http://hdl.handle.net/11449/123734.
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Orientador: Roberto CarvalheiroCoorientador: Lucia Galvão de Albuquerque
Banca: Henrique Nunes de Oliveira
Banca: Idalmo Garcia Pereira
Resumo: Esta dissertação foi dividida em três capítulos, o primeiro é uma revisão de literatura sobre o assunto que será discutido nos capítulos seguintes. No segundo capítulo, foi realizado um estudo de associação genômica ampla para a característica idade ao primeiro parto (IPP) em gado Nelore, que objetivou: 1) avaliar se a informação fenotípica adicional dos animais não genotipados afeta o mapeamento de QTLs da IPP; avaliar, por simulação, se esta informação fenotípica adicional contribui para detectar QTLs mais precisamente para uma característica complexa, com poucos genótipos disponíveis. O terceiro capítulo apresenta um estudo de associação para a característica reconcepção de primíparas (RP) em gado Nelore, cujo objetivo foi detectar importantes regiões genômicas (QTLs) associadas com esta característica. No capítulo dois, estudos de associação foram realizados utilizando as metodologias Bayes C e "Weighted single step GBLUP" (WssGBLUP) e as 10 janelas de marcadores (de 1Mb) que explicaram a maior proporção da variância para IPP foram identificadas e exploradas. Dois cenários foram investigados, um incluindo todas as fêmeas com informação fenotípica disponível (cenário SI - 43.482 fêmeas), e outro incluindo apenas as fêmeas com genótipo disponível (cenário SII - 1.813 fêmeas). Três iterações foram realizadas no método WssGBLUP, sendo recomputados os efeitos dos animais e dos SNPs a cada iteração. Foi simulada uma população com parâmetros e estrutura similares aos dos dados reais, com dois diferentes níveis de desequilíbrio de ligação (alto e baixo) entre os marcadores adjacentes. No capítulo três, os dados consistiram de 142.878 registros fenotípicos de RP e 2.923 genótipos. Os estudos de associação foram realizados com o método WssGBLUP usando três diferentes pesos (iterações) para os efeitos dos SNPs. Para cada iteração subsequente a variância genética...
Abstract: This dissertation was divided in three chapters, the first one is a literature review about the subject that will be discussed in subsequent chapters. In the second chapter, a genome wide association study (GWAS) for age at first calving (AFC) in Nelore cattle was performed, using real and simulated data, aiming to 1) assess if additional phenotypic information from non-genotyped animals affect QTL mapping of AFC; 2) evaluate, by simulation, if this additional phenotypic information contributes to detect QTLs more precisely for a low heritable complex trait, and with few available genotypes. The third chapter presents a GWAS for heifer rebreeding (HR) in Nelore cattle. In chapter two, GWA studies were performed using Bayes C and weighted single step GBLUP (WssGBLUP) methods and the top 10 marker windows (1Mb) that explained the larger proportion of variance for AFC were identified and further explored. Two scenarios were investigated, one including all females with available phenotypic information (SI scenario, with 43,482 females), and the other including just the females with available genotype (SII scenario, with 1,813 females). Three iterations were performed in WssGBLUP, recomputing the animals and SNPs effect in each subsequent iteration. It was simulated a population mimicking the parameters and the structure of the real dataset. Two different disequilibrium linkage levels (low and high) between adjacent markers were simulated. In chapter three, the data consisted of 142,878 HR phenotypic records and 2,923 genotypes. The GWAS was performed with WssGBLUP method using three different weightings (iterations) for the SNP effects. Total genetic variances were calculated for the top 10 1Mb SNP-windows, detected by each iteration. On each subsequent iteration, the genetic variance was distributed for a smaller number of SNPs, and the SNP effects were recomputed. Genes possibly associated with HR were searched to reinforce the suggestive ...
Mestre
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Li, Xingang. "Heritability enrichment of immunoglobulin G N-glycosylation relevant genes in specific tissues." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2020. https://ro.ecu.edu.au/theses/2386.
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Genome-wide association studies (GWAS) have identified over 60 genetic loci associated with IgG N-glycosylation; however, the causal genes and their abundance in relevant tissues are uncertain. In this study, firstly, I leveraged data from GWAS summary statistics for 8,090 Europeans, and large-scale expression quantitative trait loci (eQTL) data from the genotype-tissue expression of 53 types of tissues (GTEx v7), to derive a linkage disequilibrium score for the specific expression of genes (LDSC-SEG) and conduct a transcriptome-wide association study (TWAS). I identified 55 genes whose predicted levels of expression were significantly associated with IgG Nglycosylation in 14 tissues with regard to three working scenarios, i.e., tissue-specific, pleiotropic and co-associated, for candidate genetic predisposition affecting IgG N-glycosylation traits. Secondly, through pathway enrichment, I defined 23 of 55 candidate genes being enriched in several IgG N-glycosylation-related pathways, such as asparagine N-linked glycosylation, Nglycan biosynthesis and transport to the Golgi and subsequent modification. Thirdly, through phenome-wide association studies (PheWAS), I found most genetic variants underlying TWAS hits being correlated with health measures (height, waist-hip ratio, systolic blood pressure) and diseases, such as systemic lupus erythematosus, inflammatory bowel disease and Parkinson’s disease, which are related to IgG N-glycosylation. This study provides an atlas of genetic regulatory loci and their target genes within functionally relevant tissues, for further studies on the mechanisms of IgG N-glycosylation and its related diseases.
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Lee, Yiu-fai, and 李耀暉. "Analysis for segmental sharing and linkage disequilibrium: a genomewide association study on myopia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43912217.
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Lee, Bo-Hyung. "High thoughput study of biofilm and virulence in Listeria monocytogenes using innovative approaches." Thesis, Université Clermont Auvergne (2017-2020), 2019. http://www.theses.fr/2019CLFAC017.
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Listeria monocytogenes est un pathogène d'origine alimentaire à multiples facettes caractérisé par sa capacité d'adaptation dans des conditions défavorables et par sa prolifération dans une vaste gamme d'environnements, du sol aux cellules hôtes des mammifères. L'hétérogénéité génétique de L. monocytogenes se reflète dans sa structure clonale diversifiée, ce qui corrèle, dans une certaine mesure, avec des traits phénotypiques tels que la virulence ou la résistance au stress. La thèse portait sur deux phénotypes les plus éminents, la formation d'un biofilm et le potentiel de virulence, sous différents angles et à l'aide des technologies les plus récentes. Tout au long des études, des grands panels d'isolats ont été utilisés pour représenter la diversité intraspécifique. Stimulants défavorables tels que le choc froid et la privation d'éléments nutritifs induits par l'étape d'adhésion bactérienne. L'ajout de NaCl aux cultures de croissance a stimulé la production de biofilm et, de manière surprenante, il a considérablement intensifié la maturation du biofilm de cellules privées de nutriments. Un degré élevé de variation de la productivité relative du biofilm a été observé parmi les sérotypes, les génotypes, de même que les isolats selon les conditions de culture. Cependant, un certain génotype (complexe clonal 26) a révélé de manière caractéristique une production de biofilm plus élevée à froid (10°C), suggérant une association du génotype avec le phénotype du biofilm. Pan-GWAS a identifié un certain nombre de gènes parmi lesquels ceux impliqués dans des fonctions telles que la ‘transformation/compétence’, les ‘gènes liés aux phages’ et le ‘métabolisme du phosphate’ devront faire l'objet d'études plus approfondies sur leur rôle dans la formation du biofilm. L'analyse du séquençage de l'ARN a révélé une grande hétérogénéité intraspécifique dans les profils de transcriptome basal qui mettaient en évidence le rôle du réseau de régulation, y compris certains facteurs transcriptionnels avec des rôles clés dans la virulence tels que σB, PrfA, et CodY. La plasticité transcriptomique entre les lignées I et II ainsi que les génotypes hyper et hypovirulents ont confirmé les caractéristiques évolutives et épidémiologiques de L. monocytogenes. De plus, la voie métabolique centrale a été impliquée dans l'infection dans le système modèle de Galleria mellonella. En conclusion, la thèse a exploré la diversité intraspécifique de L. monocytogenes et a donné lieu à de nombreux résultats phénotypiques, génomiques et transcriptomiques. Grâce à l'approche intégrative des omiques en listeriologie, le présent travail contribuera à dévoiler la physiologie et la pathogenèse de la bactérieConditions and proliferation in a wide range of environments from soil to mammalian host cells. The genetic heterogeneity in L. monocytogenes is reflected on its diversified clonal structure which correlates, to some extent, with phenotypic traits such as virulence or stress resistance. The thesis investigated two most prominent phenotypes, biofilm formation and virulence potential, from various perspectives using state-of-the art technologies. Throughout the studies, large panels of isolates were used to represent the intraspecific diversity. Unfavourable stimuli such as cold shock and nutrient deprivation induced bacterial adhesion step. Addition of NaCl to growth cultures stimulated biofilm production and, surprisingly, it significantly intensified biofilm maturation of nutrient-deprived cells. High degree of variation in relative biofilm productivity was observed among serotypes, genotypes, as well as isolates across culture conditions, however, certain genotype (clonal complex 26) revealed distinctively higher biofilm production under cold temperature (10°C) suggesting an association of genotype with biofilm phenotype. Pan-GWAS identified a number of genes among which those implicated in functions such as ‘transformation/competence’, ‘phage-related genes’, and ‘metabolism of phosphate’ will need further investigations for their roles in biofilm formation. RNA sequencing analysis revealed high intraspecific heterogeneity in basal transcriptome profiles that featured the role of regulatory network including certain transcriptional factors with key roles in virulence such as σB, PrfA, and CodY. The transcriptomic plasticity between lineage I and II as well as hyper- and hypovirulent genotypes supported the evolutionary and epidemiological characteristics of L. monocytogenes. Moreover, the central metabolic pathway was implicated in the infection in Galleria mellonella model system. Conclusively, the thesis explored intraspecific diversity in L. monocytogenes and resulted in ample phenotypic, genomic, and transcriptomic findings. With the integrative omics approach in listeriology, the present work will contribute to unveiling the physiology and pathogenesis of the bacterium
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Jian, Xueqiu. "A Family-Based Association Study of Conduct Disorder." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etd/1697.
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Conduct disorder (CD) is a psychiatric syndrome in childhood and adolescence that is one of the most common childhood disorders with continuously increasing prevalence but uncertain pathogenesis. We performed a genome-wide, family-based association study of CD using P2BAT/FBAT software. The data is gathered from Collaborative Study on the Genetics of Alcoholism (COGA) and International Multi-Center ADHD Genetics Project (IMAGE).
Using COGA data, we identified 20 markers which showed suggestive associations (p<10-3) with CD. Nine of them are located in known genes. Two genes, ADAM10 and CAMK2A, which had been reported associated with Alzheimer's disease (AD), bipolar disorder, and depression, were of more concern. Using IMAGE sample, our results were well replicated.
This study identified several CD associated genetic variants, especially two novel candidate genes. These findings may serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in CD.
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Mancia, Annalaura <1976>. "Functional Genomics and Cell Biology of the Dolphin (Tursiops runcatus): Establishment of Novel Molecular Tools to Study Marine Mammals in Changing Environments." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2462/.
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The dolphin (Tursiops truncatus) is a mammal that is adapted to life in a totally aquatic environment. Despite the popularity and even iconic status of the dolphin, our knowledge of its physiology, its unique adaptations and the effects on it of environmental stressors are limited. One approach to improve this limited understanding is the implementation of established cellular and molecular methods to provide sensitive and insightful information for dolphin biology.
We initiated our studies with the analysis of wild dolphin peripheral blood leukocytes, which have the potential to be informative of the animal’s global immune status. Transcriptomic profiles from almost 200 individual samples were analyzed using a newly developed species-specific microarray to assess its value as a prognostic and diagnostic tool. Functional genomics analyses were informative of stress-induced gene expression profiles and also of geographical location specific transcriptomic signatures, determined by the interaction of genetic, disease and environmental factors.
We have developed quantitative metrics to unambiguously characterize the phenotypic properties of dolphin cells in culture. These quantitative metrics can provide identifiable characteristics and baseline data which will enable identification of changes in the cells due to time in culture. We have also developed a novel protocol to isolate primary cultures from cryopreserved tissue of stranded marine mammals, establishing a tissue (and cell) biorepository, a new approach that can provide a solution to the limited availability of samples.
The work presented represents the development and application of tools for the study of the biology, health and physiology of the dolphin, and establishes their relevance for future studies of the impact on the dolphin of environmental infection and stress.
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Somavilla, Adriana Luiza [UNESP]. "Prediction of genomic-enabled breeding values and genome-wide association study for feedlot average daily weight gain in Nelore cattle." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/128158.
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000848601.pdf: 1152843 bytes, checksum: 5736b950765e0d17f2ceda1c91a45237 (MD5)A seleção para taxa de crescimento utilizando o número de dias para atingir determinado peso ou ganho de peso médio resultaria em menores ciclos de produção. Manter o aumento da produtividade exige, entre outros fatores, a utilização de animais melhorados, tanto nos sistemas de pastagem quanto de confinamento. Além disso, as informações genômicas podem ser usadas para predizer os valores genéticos genômicos (GEBVs) mais cedo na vida dos animais, o que reduziria os intervalos de geração e aumentaria os ganhos de produtividade. Inúmeros trabalhos tem sido conduzidos para identificar metodologias apropriadas à determinadas raças e características, o que irá resultar em GEBVs mais acurados. Os objetivos deste estudo foram comparar a acurácia de predição dos GEBVs e a habilidade de identificar regiões genômicas e genes relacionados ao ganho de peso médio diário em bovinos da raça Nelore, pela aplicação de diferentes modelos de regressão e densidades genotípicas. Informações genômica e fenotípica de 804 novilhos nascidos em três safras, filhos de 34 touros, foram utilizadas para predizer GEBVs por meio de três modelos (Bayesian GBLUP, BayesA e BayesC ), quatro densidades genotípicas (Illumina BovineHD BeadChip, TagSNPs, GeneSeek indicus de alta (HDi) e baixa (LDi) densidades) e dois fenótipos ajustados. A estrutura de família foi considerada por meio da análise de componentes principais. Os animais foram distribuídos em subconjunto de treinamento (safras 1 e 2) ou validação (safra 3) para realização da análise de validação cruzada. Estimativas de correlação de Pearson, coeficientes de regressão e erro quadrado médio foram usados para avaliar acurácia, inflação e viés dos GEBVs estimados, respectivamente. O estudo de associação ampla do genoma (GWAS) também foi realizado nos mesmos conjuntos de dados, entretanto, os resultados foram comparados com...
Selection for fast growth rates using number of days to achieve specific weights or average weight gain would result in shorter production periods. Maintaining the rate of productivity increasing will demand, among other factors, genetically improved animals in both pasture and feedlot systems. Besides, genomic information could be used to predict genomic-enabled breeding values (GEBVs) earlier in animals' life, which would reduce generation intervals and increase productivity gains. Numerous studies have been conducted in order to identify appropriate methodologies to specific breeds and traits, which will result in more accurate GEBVs. The aim of this study was to compare the prediction accuracy of GEBVs and the ability to identify genomic regions and genes related to average weight daily gain in Nelore cattle, by applying different regression models and genotypes densities datasets. Genomic and phenotypic information of 804 steers born in three season, offspring of 34 bulls, were used to predict GEBVs through three models (Bayesian GBLUP, BayesA and BayesC ), four genotypic densities (Illumina BovineHD BeadChip, TagSNPs, GeneSeek Genomic Profiler High (HDi) and Low (LDi) density indicus) and two adjusted phenotypes. Family structure was accounted by using principal component analysis. Animals were assigned either to training (seasons 1 and 2) or testing (season 3) subsets to perform the cross-validation analysis. Estimates of Pearson correlation, regression coefficients and mean squared errors were used to access accuracy, inflation and bias of the estimated GEBVs, respectively. Genome-wide association study (GWAS) was also performed on above datasets, however, results were compared based on ...
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Somavilla, Adriana Luiza. "Prediction of genomic-enabled breeding values and genome-wide association study for feedlot average daily weight gain in Nelore cattle /." Jaboticabal, 2015. http://hdl.handle.net/11449/128158.
Full textAbstract:
Orientador: Danísio Prado MunariCoorientador: Luciana Correia de Almeida Regitano
Coorientador: Fabiana Barichello Mokry
Banca: Luiz Lehmann Coutinho
Banca: Rogério Abdallah Curi
Banca: Marcos Vinicius Gualberto Barbosa da Silva
Banca: Nedenia Bonvino Stafuzza
Resumo: A seleção para taxa de crescimento utilizando o número de dias para atingir determinado peso ou ganho de peso médio resultaria em menores ciclos de produção. Manter o aumento da produtividade exige, entre outros fatores, a utilização de animais melhorados, tanto nos sistemas de pastagem quanto de confinamento. Além disso, as informações genômicas podem ser usadas para predizer os valores genéticos genômicos (GEBVs) mais cedo na vida dos animais, o que reduziria os intervalos de geração e aumentaria os ganhos de produtividade. Inúmeros trabalhos tem sido conduzidos para identificar metodologias apropriadas à determinadas raças e características, o que irá resultar em GEBVs mais acurados. Os objetivos deste estudo foram comparar a acurácia de predição dos GEBVs e a habilidade de identificar regiões genômicas e genes relacionados ao ganho de peso médio diário em bovinos da raça Nelore, pela aplicação de diferentes modelos de regressão e densidades genotípicas. Informações genômica e fenotípica de 804 novilhos nascidos em três safras, filhos de 34 touros, foram utilizadas para predizer GEBVs por meio de três modelos (Bayesian GBLUP, BayesA e BayesC ), quatro densidades genotípicas (Illumina BovineHD BeadChip, TagSNPs, GeneSeek indicus de alta (HDi) e baixa (LDi) densidades) e dois fenótipos ajustados. A estrutura de família foi considerada por meio da análise de componentes principais. Os animais foram distribuídos em subconjunto de treinamento (safras 1 e 2) ou validação (safra 3) para realização da análise de validação cruzada. Estimativas de correlação de Pearson, coeficientes de regressão e erro quadrado médio foram usados para avaliar acurácia, inflação e viés dos GEBVs estimados, respectivamente. O estudo de associação ampla do genoma (GWAS) também foi realizado nos mesmos conjuntos de dados, entretanto, os resultados foram comparados com...
Abstract: Selection for fast growth rates using number of days to achieve specific weights or average weight gain would result in shorter production periods. Maintaining the rate of productivity increasing will demand, among other factors, genetically improved animals in both pasture and feedlot systems. Besides, genomic information could be used to predict genomic-enabled breeding values (GEBVs) earlier in animals' life, which would reduce generation intervals and increase productivity gains. Numerous studies have been conducted in order to identify appropriate methodologies to specific breeds and traits, which will result in more accurate GEBVs. The aim of this study was to compare the prediction accuracy of GEBVs and the ability to identify genomic regions and genes related to average weight daily gain in Nelore cattle, by applying different regression models and genotypes densities datasets. Genomic and phenotypic information of 804 steers born in three season, offspring of 34 bulls, were used to predict GEBVs through three models (Bayesian GBLUP, BayesA and BayesC ), four genotypic densities (Illumina BovineHD BeadChip, TagSNPs, GeneSeek Genomic Profiler High (HDi) and Low (LDi) density indicus) and two adjusted phenotypes. Family structure was accounted by using principal component analysis. Animals were assigned either to training (seasons 1 and 2) or testing (season 3) subsets to perform the cross-validation analysis. Estimates of Pearson correlation, regression coefficients and mean squared errors were used to access accuracy, inflation and bias of the estimated GEBVs, respectively. Genome-wide association study (GWAS) was also performed on above datasets, however, results were compared based on ...
Doutor
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Harshfield, Eric Leigh. "Genomics of lipid metabolism : identification of genetic determinants of lipid metabolites and the effect of perturbations of lipid levels on coronary heart disease risk factors." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277818.
Full textAbstract:
Background: Coronary heart disease (CHD) is one of the leading causes of death worldwide, and global mortality rates are expected to continue to rise over the coming decades. In Pakistan in particular, chronic diseases are responsible for 50% of the total disease burden. Circulating lipids are strongly and linearly associated with risk of CHD; however, despite considerable efforts to demonstrate causality, available evidence is conflicting and insufficient. Study of the underlying metabolic pathways implicated in the association between lipids and CHD would help to disentangle and elucidate these complex relationships. Objectives: The primary objectives of this dissertation were to (1) identify the genetic determinants of lipid metabolites and (2) advance understanding of the effect of perturbations in lipid metabolite levels on CHD and its risk factors. Methods: Direct infusion high-resolution mass spectrometry was performed on 5662 participants from the Pakistan Risk of Myocardial Infarction Study to obtain signals for 444 known lipid metabolites. Correlations and associations of the lipids with smoking, physical activity, circulating biomarkers, and other CHD risk factors were assessed. Genome-wide analyses were conducted to analyse the association of each lipid with over 6.7 million imputed single nucleotide polymorphisms. Functional annotation and Gaussian Graphical Modelling were used to link the variants associated with each lipid to the most likely mediating gene, discern the underlying metabolic pathways, and provide a visual representation of the genetic determinants of human metabolism. Mendelian randomisation was also implemented to examine the causal effect of lipids on risk of CHD. Results: The lipids were highly correlated with each other and with levels of major circulating lipids, and they exhibited significant associations with several CHD risk factors. There were 254 lipids that had significant associations with one or more genetic variants and 355 associations between lipids and variants, with a total of 89 sentinel variants from 23 independent loci. The analyses described in this dissertation resulted in the discovery of four novel loci, identified novel relationships between genetic variants and lipids, and revealed new biological insights into lipid metabolism. Conclusion: Analyses of lipid metabolites in large epidemiological studies can contribute to enhanced understanding of mechanisms for CHD development and identification of novel causal pathways and new therapeutic targets.
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Chen, Hui-Min. "A More Accessible Drosophila Genome to Study Fly CNS Development: A Dissertation." eScholarship@UMMS, 2015. http://escholarship.umassmed.edu/gsbs_diss/758.
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Understanding the complex mechanisms to assemble a functional brain demands sophisticated experimental designs. Drosophila melanogaster, a model organism equipped with powerful genetic tools and evolutionarily conserved developmental programs, is ideal for such mechanistic studies. Valuable insights were learned from research in Drosophila ventral nerve cord, such as spatial patterning, temporal coding, and lineage diversification. However, the blueprint of Drosophila cerebrum development remains largely unknown.
Neural progenitor cells, called neuroblasts (NBs), serially and stereotypically produce neurons and glia in the Drosophila cerebrum. Neuroblasts inherit specific sets of early patterning genes, which likely determine their individual identities when neuroblasts delaminate from neuroectoderm. Unique neuroblasts may hence acquire the abilities to differentially interpret the temporal codes and deposit characteristic progeny lineages. We believe resolving this age-old speculation requires a tracing system that links patterning genes to neuroblasts and corresponding lineages, and further allows specific manipulations.
Using modern transgenic systems, one can immortalize transient NB gene expressions into continual labeling of their offspring. Having a collection of knockin drivers that capture endogenous gene expression patterns would open the door for tracing specific NBs and their progenies based on the combinatorial expression of various early patterning genes. Anticipating the need for a high throughput gene targeting system, we created Golic+ (gene targeting during oogenesis with lethality inhibitor and CRISPR/Cas “plus”), which features efficient homologous recombination in cystoblasts and a lethality selection for easy targeting candidate recovery. Using Golic+, we successfully generated T2AGal4 knock-ins for 6 representative early patterning genes, including lab, unpg, hkb, vnd, ind, and msh. They faithfully recapitulated the expression patterns of the targeted genes. After preserving initial NB expressions by triggering irreversible genetic labeling, we revealed the lineages founded by the NBs expressing a particular early patterning gene.
Identifying the neuroblasts and lineages that express a particular early patterning gene should elucidate the genetic origin of neuroblast diversity. We believe such an effort will lead to a deeper understanding of brain development and evolution.
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Plummer, Dylan. "Facilitating the Study of Chromatin Organization with Deep Learning." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1589203000193806.
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Luo, Chengwei. "Development of algorithms for metagenomics and applications to the study of evolutionary processes that maintain microbial biodiversity." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/47730.
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Understanding microbial evolution lies at the heart of microbiology and environmental sciences. Numerous studies have been dedicated to elucidating the underlying mechanisms that create microbial genetic diversity and adaptation. However, due to technical limitations such as the high level of uncultured cells in almost every natural habitat, most of current knowledge is primarily based on axenic cultures grown under laboratory conditions, which typically do not simulate well the natural environment. How well the knowledge from isolates translates to in-situ processes and natural microbial communities remains essentially speculative.
The recent development of culture-independent genomic techniques (aka metagenomics) provides possibilities to bypass some of these limitations and provide new insights into microbial evolution in-situ. To date, most of metagenomic studies have been focused on a few reduced-diversity model communities, e.g., acid mine drainage. Highly complex communities such as those of soil and sediment habitats remain comparatively less understood. Furthermore, a great power of metagenomics, which has not been fully capitalized yet, is the ability to follow the evolution of natural microbial communities over time and environmental perturbations, i.e., times-series metagenomics. Although the recent developments in DNA sequencing technologies have enabled (inexpensive) time-series studies, the bioinformatics approaches to analyze the resulting data have clearly fallen behind. Taken together, to scale up metagenomics for complex community studies, three major challenges remain: 1) the difficulty to process and analyze massive short read sequencing data, often at the terabyte level; 2) the difficulty to effectively assemble genomes from complex metagenomes; and 3) the lack of methods for tracking genotypes and mutational events such as horizontal gene transfer (HGT) through time. Therefore, developing efficient bioinformatics approaches to address these challenges represents an important and timely issue.
This thesis aimed to develop novel bioinformatics pipelines and algorithms for high performance computing, and, subsequently, apply these tools to natural microbial communities to generate quantitative insights into the relative importance of the molecular mechanisms creating or maintaining microbial diversity. The tools are not specific to a particular habitat or group of organisms and thus, can be broadly used to advance our understanding of microbial evolution in different settings.
In particular, the comparative whole-genome analysis of 24 Escherichia isolates form various habitats, including human and non-human associated habitats such as freshwater ecosystems and beaches, showed that organisms with more similar ecologies tend to exchange more genes, which has important implications for the prokaryotic species concept. To more directly test these findings from isolates and quantify the patterns of genetic exchange among co-occurring populations, three years of time-series metagenomics data from planktonic samples from Lake Lanier (Atlanta, GA) were analyzed. For this, it was first important to develop bioinformatics algorithms to robustly assemble population genomes from complex community metagenomes, identify the phylogenetic affiliation of assembled genome and contig sequences, and detect horizontal gene transfer among these sequences. Using these novel algorithms, in situ bacterial lineage evolution was quantitatively assessed, especially with respect to whether or not ecologically distinct lineages evolve according to the recently proposed fragmented speciation model (Retchless and Lawrence, Science 2008). Evidence in support of this model was rarely observed. Instead, it appeared that rampant HGT disseminated ecologically important genes within the population, maintaining intra-population diversity.
By expanding the previous approaches to include methods to assess differential gene abundance and selection pressure between samples, it was possible to quantify how soil microbial communities respond to a decade of warming by 2 0C, which simulated the predicted effects of climate change. It was found that the heated communities showed significant shifts in composition and predicted metabolism, reflecting the release of additional soil carbon compared to the unheated (control) communities, and these shifts were community-wide as opposed to being attributable to a few taxa. These findings indicated that the microbial communities of temperate grassland soils play important roles in mediating the feedback responses to climate change.
Collectively, the findings presented here advance our understanding of the modes and tempo of microbial community adaptation to environmental perturbations and have important implications for better modeling the microbial diversity on the planet. The bioinformatics algorithms and approaches developed as part of this thesis are expected to facilitate future genomic and metagenomic studies across the fields of microbiology, ecology, evolution and engineering.
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Turón, Rodrigo Gemma. "A genome editing based approach to study tumor cell heterogeneity." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667524.
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Colorectal tumors are not homogeneous entities but rather composed of a mixture of cells with different phenotypes, reminiscent of healthy intestinal epithelium cell types. Intestinal epithelium is one of the organs with highest self-renewal rate, maintained by a pool of highly proliferating stem cells located at the base of the crypts. Daughters of the stem cells abandon the crypts and differentiate as they move up the villi, in a process that takes no longer than six days. Recent findings suggest that colorectal cancers (CRCs), like normal intestine, rely on a stem cell hierarchy for its growth. Cancer stem cells, identified by LGR5 gene expression, are at the apex of this hierarchy, and are thought to be the drivers of CRC expansion and metastasis. This thesis is focused on characterizing the growth dynamics of the different tumor compartments and identifying the cells that fuel tumor growth. Moreover, we have also tried to elucidate which is the cell of origin of metastasis.
To complete this project we have first developed new models to study human disease, as most of the previous work relied on genetically modified mouse models to reproduce the disease. Here, we have combined patient-derived organoid 3D cultures and CRISPR/Cas9 genome editing techniques to insert fluorescent reporter proteins under the control of our genes of interest. This has allowed us to visualize different tumor cell types in vivo using LGR5, KRT20 and EMP1 as markers for stemness, differentiation and invasion respectively. In addition, we have also set up a system to follow the progeny of the abovementioned populations in vivo in intact tumors.
We have identified the different tumor compartments by subcutaneously injecting modified human organoids into immunosuppressed mice. Flow cytometry purification and reinjection into secondary hosts of stem-like and differentiated-like cells has enabled us to discover that cancer cells retaining stem cell characteristics are more proficient in tumor initiation than the rest of the tumor. Nevertheless, lineage tracing of the abovementioned genes in an intact tumor cell environment shows how both stem and differentiated progenies are able to give rise to long lasting clones and thus equally fuel tumor growth. Furthermore, we have observed plasticity arising from both cell types, indicative that the cellular hierarchy is disrupted during tumor progression.
In addition, we have defined EMP1 as a putative gene marker for invasive cells. EMP1-High cells are a differentiated subset of tumor cells that harbor migratory properties and secrete myeloid recruiting chemokines to the tumor site. Myeloid cells have been shown to contribute to all steps of metastasis in several cancer types. We hypothesize that this EMP1+ subpopulation is the one that disseminates from the primary tumor and initiates metastasis. For metastatic studies, we have resorted to mouse derived tumor organoids that allow the growth of primary and metastatic disease in fully immunocompetent ice, and we have set up new models to study disease relapse in metastatic sites upon primary tumor removal
Taken together, our data provides new insights on the mode of tumor growth in advanced human colorectal carcinomas and suggests that stem cell traits are not required for tumor growth neither metastatic spread, contrary to what was initially though based on mouse adenoma studies.Els tumors colorectals no són una entitat homogènia sinó que estan formats per una barreja de cèl·lules de fenotips variats, reminiscents dels tipus cel·lulars de l’epiteli intestinal sa. Estudis recents suggereixen que el creixement del càncer colorectal (CCR), igual que el de l’intestí normal, està mediat per una jerarquia amb origen en cèl·lules mare. Les cèl·lules mare del càncer, identificades per l’expressió del gen LGR5, es troben a l’àpex de la jerarquia i impulsen l’expansió del CCR i la metàstasis. Aquesta tesi se centra en caracteritzar la dinàmica d’expansió dels diferents compartiments tumorals i en identificar les cèl·lules que en mantenen el creixement. També hem intentat elucidar quina és la cèl·lula d’origen de la metàstasi. Per a realitzar aquest projecte primer hem desenvolupat nous models per estudiar la malaltia humana, combinant el cultiu d’organoids derivats de pacients i l’edició genòmica mitjançant CRISPR/Cas9. Això ens ha permès visualitzar diferents tipus cel·lulars tumorals in vivo usant LGR5, KRT20 i EMP1 com a marcadors de cèl·lula mare, cèl·lula diferenciada i cèl·lula invasiva, respectivament. Addicionalment, també hem establert un sistema per seguir la progènie de les poblacions mencionades. Hem descobert que tant el compartiment de cèl·lules mare com el diferenciat són capaços de donar lloc a una progènie que persisteix en el temps, suggerint que ambdós tipus cel·lulars contribueixen al creixement tumoral. A més a més, hem observat plasticitat entre els dos compartiments, cosa que indica que la jerarquia cel·lular es perd durant el desenvolupament del tumor. Finalment, mitjançant l’ús d’EMP1 com a marcador de cèl·lules invasives hem identificat un subgrup de cèl·lules diferenciades amb propietats migratòries i amb potencial per reclutar cèl·lules mieloides. La nostra hipòtesi és que la població EMP1+ és la que dissemina del tumor primari i inicia la metàstasi. En resum , les nostres dades suposen una nova visió en l’estudi del mode de creixement del càncer de colon d’estadis avançats en humà, i suggereixen que els trets de cèl·lula mare no són necessaris per creixement tumoral ni la disseminació metastàtica, contràriament al que es pensava inicialment, degut als estudis realitzats en adenoma de ratolí.
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Lin, Ling. "Genetic Approaches to Study Transcriptional Activation and Tumor Suppression: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/610.
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The development of methods and techniques is the driving force of scientific research. In this work, we described two large-scale screens in studying transcriptional activation and tumor suppression.
In Part I, we studied transcriptional activation mechanisms by deriving and characterizing activation defective mutants. Promoter-specific transcriptional activators stimulate transcription through direct interactions with one or more components of the transcription machinery, termed the “target.” The identification of direct in vivo targets of activators has been a major challenge. We perform a large-scale genetic screen to derive and characterize tra1 alleles that are selectively defective for interaction with Gal4 in vivo. Utilizing these mutants, we demonstrated that Tra is an essential target for Gal4 activation, Gal4 and Tra1 bind cooperatively at the promoter and the Gal4–Tra1 interaction occurs predominantly on the promoter. In addition, we demonstrated that the Gal4-interaction site on Tra1 is highly selective.
In Part II, we described a functional genomics approach to discover new tumor suppressor genes. A goal of contemporary cancer research is to identify the genes responsible for neoplastic transformation. Cells that are immortalized but non-tumorigenic were stably transduced with pools of short hairpin RNAs (shRNAs) and tested for their ability to form tumors in mice. ShRNAs in any resulting tumors were identified by sequencing to reveal candidate TSGs, which were then validated both experimentally and clinically by analysis of human tumor samples. Using this approach, we identified and validated 33 candidate TSGs. We found that most candidate TSGs were down-regulated in >70% of human lung squamous cell carcinoma (hLSCC) samples, and 17 candidate TSGs negatively regulate FGFR signalling pathway, and their ectopic expression inhibited growth of hLSCC xenografts. Furthermore, we suggest that by examining at the expression level of TSGs in lung cancer patients, we can predict their drug responsiveness to FGFR inhibitors. In conclusion, we have identified many new lung squamous cell cancer TSGs, using an experimental strategy that can be broadly applied to find TSGs in other tumor types.
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Jones, Donald Thomas. "A study of Hardy-Weinberg equilibrium, linkage equilibrium, and population structure in Hispanics using seven genetic markers." CSUSB ScholarWorks, 1997. https://scholarworks.lib.csusb.edu/etd-project/1478.
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Yan, Shuangchun. "Using the Bacterial Plant Pathogen Pseudomonas syringae pv. tomato as a Model to Study the Evolution and Mechanisms of Host Range and Virulence." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/77293.
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Most plant pathogens are specialists where only few plant species are susceptible, while all other plants are resistant. Unraveling the mechanisms behind this can thus provide valuable information for breeding or engineering crops with durable disease resistance. A group of Pseudomonas syringae strains with different host ranges while still closely related were thus chosen for comparative study. We confirmed their close phylogenetic relationship. We found evidence supporting that these strains recombined during evolution. The Arabidopsis thaliana and tomato pathogen P. syringae pv. tomato (Pto) DC3000 was found to be an atypical tomato strain, distinct from the typical Pto strains commonly isolated in the field that do not cause disease in A. thaliana, such as Pto T1. Comparing A. thaliana defense responses to DC3000 and T1, we found that T1 is eliciting stronger responses than DC3000. T1 is likely lacking Type III effector genes necessary to suppress plant defense. To test this, we sequenced the genomes of strains that cause and do not cause disease in A. thaliana. Comparative genomics revealed candidate effector genes responsible for this host range difference. Effector genes conserved in strains pathogenic in A. thaliana were expressed in T1 to test whether they would allow T1 to growth better in A. thaliana. Surprisingly, most of them reduced T1 growth. One of the effectors, HopM1, was of particular interest because it is disrupted in typical Pto strains. Although HopM1 has known virulence function in A. thaliana, HopM1 reduced T1 growth in both A. thaliana and tomato. HopM1 also increased the number of bacterial specks but reduced their average size in tomato. Our data suggest that HopM1 can trigger defenses in these plants. Additionally, transgenic detritivore Pseudomonas fluorescens that can secrete HopM1 shows dramatically increased growth in planta. The importance of genetic background of the pathogen for the functions of individual effectors is discussed. T1 cannot be manipulated to become an A. thaliana pathogen by deleting or adding individual genes. We now have a list of genes that can be studied in the future for the molecular basis of host range determination.Ph. D.
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Singh, Babita 1986. "Large-scale study of RNA processing alterations in multiple cancers." Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/572859.
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RNA processing and their alterations are determinant to understand normal and disease cell phenotypes. In particular, specific alterations in the RNA processing of genes has been linked to widely accepted cancer hallmarks. With the availability of large-scale genomic and transcriptomic data for multiple cancer types, it is now possible to address ambitious questions such as obtaining a global view of alterations in RNA processing specific to each cancer type as well as in common across all types. The first objective of this thesis is to obtain a global view of RNA processing alterations across different tumor types along with alterations with respect to RNA binding proteins (trans-component), their tumor-type specificity, differential expression, mutations, copy number variation and whether these alterations result in differential splicing. Using data for more than 4000 patients from 11 tumor types, we provide the link between alterations of RNA binding proteins and splicing changes across multiple tumor types. Second objective moves one step further and explores in detail the RNA-processing alterations with respect to mutations on RNA regulatory sequences (cis-components). Using whole genome sequencing data for more than 1000 cancer patients, we thoroughly study the sequence of entire genes and report significantly mutated short regions in coding and non-coding parts of genes that are moreover enriched in RNA putative RNA regulatory sites, including regions deep into the introns. The recurrence of some of the mutations in non-coding regions is comparable to some of already known driver genes in coding regions. We further analyze the impact of these mutations at the RNA level by using RNA sequencing from the same samples. This work proposes a novel and powerful strategy to study mutations in cancer to identify novel oncogenic mechanisms. In addition, we share the immense amount of data generated in these analyses so that other researchers can study them in detail and validate them experimentally.El procesamiento del ARN y sus alteraciones son determinantes para entender el fenotipo de las células en condiciones normales y de enfermedad. En particular, alteraciones en el procesamiento de ARN de determinados genes se han vinculado a características distintivas del cáncer ampliamente aceptadas. Con la disponibilidad de datos genómicos y transcriptómicos a gran escala paramúltiples tipos de cáncer, es posible abordar cuestiones ambiciosas como la obtención de una visión global de las alteraciones en el procesamiento de ARN que son específicas para cada tipo de cáncer, así como de aquellas las comunes a varios tipos. El primer objetivo de esta tesis es obtener una visión global de las alteraciones del procesamiento de ARN en diferentes tipos de tumores, así como de las alteraciones en las proteínas de unión a ARN (componente trans), y si dichas alteraciones resultan en un procesamiento diferencial del RNA. Utilizando datos de más de 4000 pacientes para 11 tipos de tumores, establecemos la relación entre las alteraciones de las proteínas de unión a ARN y cambios de splicing en múltiples tipos de tumores. El segundo objetivo va un paso más allá y explora en detalle las alteraciones del procesamiento de ARN con respecto a mutaciones en las secuencias reguladoras del ARN (componente cis). Utilizando datos de genomas completos para más de 1000 pacientes, estudiamos a fondo la secuencia de genes para identificar regiones cortas significativamente mutadas en partes codificantes y no codificantes por proteína, y que además están enriquecidas en posibles sitios reguladores del ARN, incluyendo regiones intrónicas profundas. La recurrencia de las mutaciones en algunas regiones no codificantes es comparable a la de algunos genes drivers de cáncer conocidos. Además, analizamos el impacto de estas mutaciones a nivel del ARN mediante el uso de datos de secuenciación de ARN de las mismas muestras. Este trabajo propone una estrategia novedosa y potente para estudiar las mutaciones en cáncer con el fin de identificar nuevos mecanismos oncogénicos. Además, compartimos la inmensa cantidad de datos generados en estos análisis para que otros investigadores los puedan estudiar en detalle y validarlos experimentalmente.