• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 721
  • 176
  • 119
  • 115
  • 62
  • 9
  • 8
  • 6
  • 5
  • 4
  • 3
  • 2
  • 2
  • 1
  • 1
  • Tagged with
  • 1806
  • 527
  • 440
  • 332
  • 250
  • 231
  • 219
  • 196
  • 193
  • 179
  • 171
  • 166
  • 156
  • 135
  • 125
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
121

Patterns of short-term genome evolution in E.coli and Shigellae

Balbi, Kevin Jon January 2009 (has links)
The time-dependence of molecular evolution, specifically over short timescales, has been shown to be a major confounding factor in the analysis of nucleotide changes between closely related strains or species. The assumption that selection works extremely quickly to purge all of the deleterious changes is at odds with the Nearly Neutral model of evolution, whereby the majority of changes are only mildly deleterious and therefore impose only a minor fitness cost so they are relatively rapidly purged only in populations with large effective population sizes. The aim of this project was to explore the patterns of nucleotide changes evident between the core genomes of nine E. coli and Shigella strains, with the latter having adopted a specific ecological niche in the recent evolutionary past. The Shigellae and E. coli show little difference in their extant genome compositions, in terms of nucleotide composition and genome size, however there are a markedly higher number of pseudogenes and insertion sequences present in the Shigella genomes. The polymorphism profiles of the core genomes reveal a time-dependency of dN/dS, Ti/Tv, +AT/+GC and the Metabolic cost of Amino acid changes, the nucleotide data showing a clear separation of the E. coli from the Shigellae, with the latter showing trends indicative of weaker purifying selection. Additionally these differences are evident when examining the nucleotide ratios (+AT/+GC & Ti/Tv) along the core genome, also revealing patterns of evolution associated with genome position. A simulation based approach reveals different projected nucleotide contents for the E. coli and Shigellae genomes further highlighting their different evolutionary paths as evident from the polymorphism profiles. The methods employed and developed in this study provide a useful and effective toolset for examining the evolution of bacterial genomes over short timescales, especially in light of the availability of multiple whole genome sequences for a given 'species'.
122

Pathogenicity and selective constraint in the non-coding genome

Short, Patrick January 2019 (has links)
Gene regulation plays a central role in evolution, organismal development, and disease. Despite the critical importance of gene regulation throughout development, there have been few genetic variants in regulatory elements with large effects that have been robustly associated to disease. In this work, my overarching aim was to gain a better understanding of the contribution of genetic variation in regulatory elements to Mendelian disorders and attempted to approach this problem from three different perspectives. I first sought to assess the contribution of regulatory variation to severe developmental disorders using sequence data from 8,000 affected individuals and their parents and to identify individual elements with a high probability of harbouring pathogenic regulatory elements. Next, I used population genetic models and data from more than 28,000 whole genome sequenced individuals to examine the forces of selection operating on non-coding elements genome-wide. Finally, I conducted a pilot experiment to assay >50,000 different non-coding variants across more than 700 different non-coding elements, including variants observed in patients with developmental disorders in a massively parallel reporter assay (MPRA) and collaborated on an assessment of the impact of patient mutations in eleven different enhancers using mouse transgenesis assays. A few key results from the work are summarised below: - I provide evidence that de novo SNVs in non-coding elements contribute to severe developmental disorders, and estimate that they contribute in 1-3% of cases not harbouring a likely diagnostic coding variant. - These de novo SNVs reside primarily in highly evolutionarily conserved regulatory elements and I estimate that a large fraction of conserved non-coding elements (50-70%) are acting as enhancers and a smaller subset (10-15%) have a function related to alternative splicing. - Statistical modelling of the distribution of variants in developmental disorder patients suggests that a small fraction of bases (maximum likelihood estimate of 3%) within a disease-associated non-coding element are likely pathogenic with high penetrance when mutated. - I develop a new genome-wide mutation rate model that accounts for a variety of germline features including recombination rate, replication timing, sequence context, and histone marks which greatly outperforms models based on sequence-context alone. - I find evidence for widespread purifying selection in the non-coding genome that is correlated with nucleotide-level evolutionary conservation, even when the conserved nucleotides lie within otherwise poorly conserved sequence. - I show that the selective constraint on small insertions and deletions is likely greater than the selective constraint on SNVs. - I present data from a pilot experiment assessing more than 50,000 different non-coding variants in a massively parallel reporter assay conducted in both HeLa and Neuroblastoma cells.
123

Identification of disease gene variants that can lead to familial myelodysplasia and acute myeloid leukaemia

Cardoso, Shirleny Romualdo January 2018 (has links)
Myelodysplasia (MDS) is characterised by inefficient haematopoiesis with dysplastic features of blood and bone marrow, reduction of mature blood cells and continuous bone marrow failure (BMF). Acute myeloid leukaemia (AML) is characterised by the accumulation of immature myeloid blasts in the bone marrow. MDS and AML are mostly sporadic clonal disorders affecting older patients. Familial occurrence of MDS/AML is rare, and most of these cases occur in the setting of genetic syndromes. However, it has also been reported to be caused by germline heterozygous mutations in genes including RUNX1, CEBPA, TERC, TERT, GATA2, SRP72, and ANKRD26. Our group has collected 115 families that have two or more individuals with BMF with at least one of whom has MDS or AML. The aim of this project was to identify disease causing gene variants that can lead to familial MDS/AML. Identification of predisposing variants to familial MDS/AML is critical for effective management in these families. This will also provide new insights into the biology of MDS/AML in general. Herein, we have characterised a subset of families with MDS/AML as well as identified candidate disease genes using a range of genetic studies. Specifically, we have: i. Identified new genetic variants in some of the known disease genes such as RUNX1 and GATA2. ii. Our studies have substantiated the discovery of DDX41 as a disease gene as we have identified several families harbouring novel heterozygous loss of function (LoF) DDX41 variants. iii. Identified germline heterozygous LoF RTEL1 variants in a subset of families with myelodysplasia and liver disease. This defines a new disease group in this field, RTEL1 can now be added to the list of familial MDS/AML disease genes. iv. We have identified nine new candidate disease genes which are involved in RNA splicing, transcription factor, DNA modification, cell signalling and intracellular transport.
124

Investigation into the structure and function of a novel cellular structure

Abrehart, Robert W. January 2016 (has links)
Down's syndrome (DS) is a congenital disorder caused by trisomy of chromosome 21, giving rise to symptoms including intellectual disability, poor muscle tone and characteristic facial features. Located on chromosome 21 is a gene encoding ubiquitin specific protease 25 (USP25), a member of the deubiquitinating family of enzymes. Studies of partial trisomies have revealed that although the USP25 gene is situated outside the critical region of chromosome 21 required to be triplicated to induce full DS symptoms, it is in a region linked to mild mental retardation and muscle hypotonia. Previous data has shown that, when overexpressed, USP25 forms novel rod shaped structures approximately 3-5 μm in length and 0.3-0.6 μm wide, and with a copy number, on average, of no more than 1-2 per cell. These structures do not associate with any known cellular organelle or with any component of the cytoskeleton. In this work, endogenous USP25 rods were detected in cultures of primary human foetal astrocytes, and a comparison of healthy and DS human primary foetal astrocytes revealed that in the DS culture a higher percentage of astrocytes contain rods. The domains of USP25 required for rod formation were identified using a series of GFP-tagged deletion constructs. USP25 rods could be purified from HEK293 cells using subcellular fractionation techniques and were assayed for deubiquitinating activity; however, none was detected suggesting that rods may be catalytically inactive. Interacting partners of USP25 were identified using mass spectrometry, but none were found to localise in rods. Additionally, a USP25 null human embryonic stem cell line was generated in order to interrogate the function of USP25 in astrocytes, and was found to be deficient in maintaining the integrity of an epithelial cell layer in an in vitro model of the blood brain barrier.
125

Genomic Evolution of Glioblastoma

Ladewig, Erik January 2018 (has links)
Understanding how tumors evolve and drive uncontrolled cellular growth may lead to better prognosis and therapy for individuals suffering from cancer. A key to understanding the paths of progression are to develop computational and experimental methods to dissect clonal heterogeneity and statistically model evolutionary routes. This thesis contains results from analysis of genomic data using computational methods that integrate diverse next generation sequencing data and evolutionary concepts to model tumor evolution and delineate likely routes of genomic alterations. First, I introduce some background and present studies into how tumor genomic sequencing tells us about tumor evolution. This will encompass some of the principles and practices related to tumor heterogeneity within the field of computional biology. Second, I will present a study of longitudinal sampling in Glioblastoma (GBM) in cohort of 114 individuals pre- and post-treatment. We will see how genomic alterations were dissected to uncover a diverse and largely unexpected landscape of recurrence. This details major observations that the recurrent tumor is not likely seeded by the primary lesion. Second, to dissect heterogeneity from clonal evolution, multiple biopsies will be added to extend our longitudinal GBM cohort. This new data will introduce analyses to explicate inter and intra-tumor heterogeneity of GBM. Specifically, we identify a metric of intratumor heterogeneity able to identify multisector biopsies and propose a model of tumor growth in multiple GBM. These results will relate to clinical outcome and are in agreement with previously established hypotheses in truncal mutation targeting. Fourth, I will introduce new models of clonal growth applicable to 2 patient biopsies and then fit these to our GBM cohort. Simulations are used to verify models and a brief proof is presented.
126

Ecological insights into unexplored Archaea through environmental ecophysiology, single-cell genomics and cultivation

Weber, Eva January 2017 (has links)
No description available.
127

Evolution Of Duplicated Han-Like Genes In Petunia X Hybrida.

Powers, Beck 01 January 2017 (has links)
Gene duplications generate critical components of genetic variation that can be selected upon to affect phenotypic evolution. The angiosperm GATA transcription factor family has undergone both ancient and recent gene duplications, with the HAN-like clade displaying divergent functions in organ boundary establishment and lateral organ growth. To better determine the ancestral function within core eudicots, and to investigate their potential role in floral diversification, I conducted HAN-like gene expression and partial silencing analyses in the asterid species petunia (Petunia x hybrida). My results indicate duplication of HAN-like genes at the base of Solanaceae followed by expression diversification within the flower. Although no aberrant phenotypes were apparent following single gene knockdowns, silencing of both paralogs lead to leaf senescence. Together with other functional studies, these data suggest a possible ancestral role for HAN-like genes in core eudicot shoot apical meristem development, followed by functional diversification following both speciation and duplication.
128

Investigating Genetic Diversity of Phytophthora spp. and Related Oomycetes

Hulvey, Jonathan Patrick 01 August 2010 (has links)
Oomycetes, like fungi, are filamentous heterotrophs, but unlike true fungi are diploid and share a photosynthetic ancestor. Many of these organisms are plant and animal pathogens, and members of the genus Phytophthora cause devastating disease on a diverse array of agricultural plant hosts. Several diverse topics in oomycete biology are investigated in this dissertation. Chapter 2 is a report on loss of heterozygosity in Phytophthora capsici in response to chemical mutagenesis.The research presented in Chapters 3 and 4 are centered on documenting biodiversity and genetic diversity of populations of Phytophthora species obtained from infected plant hosts. The final chapter (Chapter 5) involves determining genetic diversity, ecology, and enzymatic activities of Pythiaceous oomycetes from marsh wetlands of the southeastern US.
129

Development and assessment of machine learning attributes for ortholog detection

Lin, Ying. January 2006 (has links)
Thesis (Ph.D.)--University of Delaware, 2006. / Principal faculty advisor: John Case, Dept. of Computer and Information Sciences. Includes bibliographical references.
130

A Two-colour Reporter Screen and Application to Cell Cycle Transcription

Kainth, Parminder 18 February 2010 (has links)
Development of genome-wide reagents has allowed systematic analysis of gene function. The experimental accessibility of budding yeast makes it a test-bed for technology development and application of new functional genomic tools and resources that pave the way for comparable efforts in higher eukaryotes. In this Thesis, I describe a two-color GFP-RFP reporter system I developed to assess the consequences of genetic perturbations on a promoter of interest. The dual-reporter system is compatible with the synthetic genetic array methodology, an approach that enables marked genetic elements to be introduced into arrays of yeast mutants via an automated procedure. I use this approach to probe cell cycle-regulation of histone gene transcription by introducing an HTA1 promoter-GFP reporter gene construct into an ordered array of ~4500 yeast deletion mutants. I scored defects in reporter gene expression for each mutant, generating a quantitative analysis of histone promoter activity. The results of my screen motivated a number of follow-up experiments, including chromatin immunoprecipitation, transcript profiling and genome-wide analysis of nucleosome positions, which revealed a previously unappreciated pathway that specifies regions of repressed chromatin in a cell cycle-sensitive manner. A novel aspect of this pathway is that it involves histone chaperones and a chromatin boundary element. Specifically, we discovered that the histone chaperone Rtt106 works with two other chaperones, Asf1 and the HIR complex, to create a repressive chromatin structure at histone promoters which is bound by the protein Yta7. It was clear from previous work that Asf1 and HIR repress transcription at HTA1 and that HIR localizes to and functions through a specific element in histone promoters. However, there was no previous data demonstrating a role for Rtt106 in cell cycle-dependent gene transcription. In sum, I describe a new genomic screen that I used to discover a novel pathway regulating cell cycle-dependent transcription. While I examined histone gene expression as proof-of-principle, my screening system could be applied to virtually any pathway for which a suitable reporter can be devised. I anticipate this methodology will enable yeast researchers to collect quantitative data on hundreds of gene expression pathways.

Page generated in 0.0506 seconds