Tesi sul tema "Sequence selection"
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1
Tang, Fung Michael, e 鄧峰. "Sequence classification and melody tracks selection". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B29742973.
2
Tang, Fung Michael. "Sequence classification and melody tracks selection /". Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25017470.
3
Hoffman, Michael M. "Quantifying evolution and natural selection in vertebrate noncoding sequence". Thesis, University of Cambridge, 2008. https://www.repository.cam.ac.uk/handle/1810/245947.
Abstract (sommario):
When studying genomic evolution, biologists find it important to identify varying patterns of natural selection. Many traditional methods of classifying directional selection have relied on models that categorize mutations as function-altering or neutral, and then comparing the rates of the two categories of mutations. The most well-known methods specifically compare nonsynonymous and synonymous substitutions in protein-coding sequence. The recent availability of whole genome sequences, especially those of various mammals and other vertebrates, enables us to develop alternative methods for analyzing molecular evolution and selection that rely on noncoding sequence. Furthermore, our greater understanding of the importance of noncoding DNA demands such methods. This thesis contains the results of the first in-depth genomic-scale analysis using intron substitutions to estimate the neutral rate of evolution. Performing this analysis across several genomes requires the development of a new model of gene evolution and related methods. I find strong correlation between estimates of the neutral rate made with intron methods and estimates made with synonymous coding nucleotides for both human–dog and mouse–rat comparisons. However, the two estimates cannot be considered directly equivalent. This thesis also describes a novel method that estimates a rate of function affecting evolution in promoter regions by inspecting the effect of simulated mutations on transcription factor binding. This involves the development and use of a probabilistic method that uses a hidden Markov model to predict the binding of transcription factors. I report the results of applying these new methods to the human genome for the identification of transcription factor binding sites, and for the identification of natural selection.
4
Garske, Tini. "Mutation-selection models of sequence evolution in population genetics". Thesis, Open University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412399.
5
Buxton, David. "The impact of striatal neuropeptides and topography on action sequence selection". Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/22081/.
Abstract (sommario):
Many common behaviours are a sequence of several actions. As action sequences are learned their activation often becomes habitual, allowing smooth, rapid, and semi-automatic execution; learning and performing action sequences is central to normal motor function. The striatum is the primary input nucleus for the basal ganglia and receives glutamatergic cortical afferents. These afferents innervate localised populations of medium spiny neurons (MSNs) and may encode 'action requests'. Striatal interactions ensure that only non-conflicting, high salience requests are selected, but the mechanisms enabling clean, rapid switching between sequential actions are poorly understood. Substance P (SP) and enkephalin are neuropeptides co-released with GABA by MSNs preferentially expressing D1 or D2 dopamine receptors respectively. SP facilitates subsequent glutamatergic inputs to target MSNs while enkephalin has an inhibitory effect. We construct models of these glutamatergic effects and integrate them into a basal ganglia model to demonstrate that diffuse neuropeptide connectivity enhances action selection. For action sequences with an ordinal structure, patterning SP connectivity to reflect this ordering enhances the selection of correctly–ordered actions and suppresses disordered selection. We also show that selectively pruning SP connections allows context–sensitive inhibition of specific undesirable requests that otherwise interfere with action group selection. We then construct a striatal microcircuit model with physical topography and show that inputs to this model generate oscillations in MSN spiking. Input salience and active neuronal density have differentiable impacts on oscillation amplitude and frequency, but the presence of oscillations has little effect on the mean MSN firing rate or action selection. Our model suggests that neuropeptide interactions enhance the contrast between selected and rejected action requests, and that patterned SP connectivity enhances the selection of ordered sequences. Our model further suggests that striatal topography does not directly impact action selection, but that evoked oscillations may represent an additional form of population coding that could bind together semantically related MSN groups.
6
Besenmatter, Werner. "Protein engineering with genetic selection : tolerance of enzyme activity to sequence change /". Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=16912.
7
Ibeh, Neke. "Inferring Viral Dynamics from Sequence Data". Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35317.
Abstract (sommario):
One of the primary objectives of infectious disease research is uncovering the direct
link that exists between viral population dynamics and molecular evolution. For
RNA viruses in particular, evolution occurs at such a rapid pace that epidemiological
processes become ingrained into gene sequences. Conceptually, this link is easy to
make: as RNA viruses spread throughout a population, they evolve with each new
host infection. However, developing a quantitative understanding of this connection
is difficult. Thus, the emerging discipline of phylodynamics is centered on reconciling
epidemiology and phylogenetics using genetic analysis. Here, we present two research studies that draw on phylodynamic principles in order to characterize the progression and evolution of the Ebola virus and the human immunodefficiency virus (HIV). In the first study, the interplay between selection and epistasis in the Ebola virus genome is elucidated through the ancestral reconstruction of a critical region in the Ebola virus glycoprotein. Hence, we provide a novel mechanistic account of the structural changes that led up to the 2014 Ebola virus outbreak. The second study applies an approximate Bayesian computation (ABC) approach to the inference of epidemiological parameters. First, we demonstrate the accuracy of this approach with simulated data. Then, we infer the dynamics of the Swiss HIV-1 epidemic, illustrating the applicability of this statistical method to the public health sector. Altogether, this
thesis unravels some of the complex dynamics that shape epidemic progression, and
provides potential avenues for facilitating viral surveillance efforts.
8
Sherborne, Amy Louise. "Balancing selection at the major histocompatibility complex (MHC) : sequence diversity and inbreeding avoidance". Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501605.
Abstract (sommario):
The major histocompatibility complex (MHC) is a much studied region of the mammalian genome because of its uniquely high level of polymorphism. Both natural and sexual selection have been implicated in the maintenance of MHC diversity. The elevated heterozygosity observed at the MHC could reflect overdominant heterozygote advantage against pathogenic infection. Equally, MHC disassortative mating would lead to an excess of heterozygotes.
9
Al-Ouran, Rami. "Motif Selection: Identification of Gene Regulatory Elements using Sequence CoverageBased Models and Evolutionary Algorithms". Ohio University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1449003717.
10
Niu, Jia. "Translation of DNA into Evolvable Sequence-Defined Synthetic Polymers". Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11351.
Abstract (sommario):
Laboratory directed evolution have enabled the discovery of numerous functional natural and synthetic macromolecules with tailor-made functions. However, approaches that use enzymes to effect the crucial translation from an information carrier molecule such as DNA or RNA to synthetic polymers are limited to producing close analogs of nucleic acids, either due to a strict requirement to hybridize with a nucleic acid template or as a consequence of the limited substrate scope of polymerase enzymes.Chemistry and Chemical Biology
11
Berglund, Lisa. "Selection of antigens for antibody-based proteomics". Doctoral thesis, Stockholm : School of Biotechnology, Royal Institute of Technology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-4706.
12
Murrel, Benjamin. "Improved models of biological sequence evolution". Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/71870.
Abstract (sommario):
Thesis (PhD)--Stellenbosch University, 2012.ENGLISH ABSTRACT: Computational molecular evolution is a field that attempts to characterize how genetic sequences evolve over phylogenetic trees – the branching processes that describe the patterns of genetic inheritance in living organisms. It has a long history of developing progressively more sophisticated stochastic models of evolution. Through a probabilist’s lens, this can be seen as a search for more appropriate ways to parameterize discrete state continuous time Markov chains to better encode biological reality, matching the historical processes that created empirical data sets, and creating useful tools that allow biologists to test specific hypotheses about the evolution of the organisms or the genes that interest them. This dissertation is an attempt to fill some of the gaps that persist in the literature, solving what we see as existing open problems. The overarching theme of this work is how to better model variation in the action of natural selection at multiple levels: across genes, between sites, and over time. Through four published journal articles and a fifth in preparation, we present amino acid and codon models that improve upon existing approaches, providing better descriptions of the process of natural selection and better tools to detect adaptive evolution.
AFRIKAANSE OPSOMMING: Komputasionele molekulêre evolusie is ’n navorsingsarea wat poog om die evolusie van genetiese sekwensies oor filogenetiese bome – die vertakkende prosesse wat die patrone van genetiese oorerwing in lewende organismes beskryf – te karakteriseer. Dit het ’n lang geskiedenis waartydens al hoe meer gesofistikeerde waarskynlikheidsmodelle van evolusie ontwikkel is. Deur die lens van waarskynlikheidsleer kan hierdie proses gesien word as ’n soektog na meer gepasde metodes om diskrete-toestand kontinuë-tyd Markov kettings te parametriseer ten einde biologiese realiteit beter te enkodeer – op so ’n manier dat die historiese prosesse wat tot die vorming van biologiese sekwensies gelei het nageboots word, en dat nuttige metodes geskep word wat bioloë toelaat om spesifieke hipotesisse met betrekking tot die evolusie van belanghebbende organismes of gene te toets. Hierdie proefskrif is ’n poging om sommige van die gapings wat in die literatuur bestaan in te vul en bestaande oop probleme op te los. Die oorkoepelende tema is verbeterde modellering van variasie in die werking van natuurlike seleksie op verskeie vlakke: variasie van geen tot geen, variasie tussen posisies in gene en variasie oor tyd. Deur middel van vier gepubliseerde joernaalartikels en ’n vyfde artikel in voorbereiding, bied ons aminosuur- en kodon-modelle aan wat verbeter op bestaande benaderings – hierdie modelle verskaf beter beskrywings van die proses van natuurlike seleksie sowel as beter metodes om gevalle van aanpassing in evolusie te vind.
13
Chakravorty, Hirak. "Equilibrium and non-equilibrium analysis of folding and sequence selection in mean field random heteropolymers". Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399162.
14
Moilanen, J. (Jukka). "Non-neutral sequence variation in human mitochondrial DNA: selection against deleterious mutations and haplogroup-related polymorphisms". Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514271661.
Abstract (sommario):
Abstract
Mitochondrial DNA (mtDNA) is a maternally inherited 16.6 kbp circular genome that codes for 13 subunits of the mitochondrial respiratory chain, 2 rRNAs and 22 tRNAs. The mutation rate in mtDNA is high and therefore, mutations have accumulated sequentially to lineages that have diverged tens of thousands of years ago. The neutral theory predicts that a proportion of these variations may be slightly deleterious, associated with diseases and selected against, but the issue is still controversial.
This study reports an analysis of selection against mutations in mtDNA. First, the population prevalence of one of the most pathogenic mtDNA mutations, the common MELAS mutation (3243A>G), was determined in a population-based screening setting in Northern Ostrobothnia, and the reproductive capacity, or genetic fitness, of women with the mutation was estimated in order to measure for the first time the degree of host-level selection against this highly pathogenic mutation. The frequency of 3243A>G was high, as the minimum estimate for the prevalence was 10.2/100,000, and this together with the geographical distribution of maternal ancestors of the mutation carriers suggested that nuclear genes may be involved in the population history of the mutation. Surprisingly, the genetic fitness of mutation carriers was not reduced, suggesting that the average host-level selection against carriers is not strong. Second, all available complete human mtDNA sequences worldwide (N=847) were collected into a database and analysed for evidence to support the hypothesis concerning slightly deleterious mutations and selective constraints imposed by lineage-specific interactions. 465 distinct missense and 6 nonsense mutations were identified. 48% of the amino acid replacements changed the polarity, 44% hydropathy, 32% aliphaticity, 26% size, 13% aromaticity, and 8% charge. Nonconservative amino acid replacements were found to be more common among the evolutionarily recent mutations than among the older ones, and mutations that have arisen more than once during human evolution showed different properties from the remaining ones. The major continent-specific mtDNA lineages were analysed in terms of nucleotide diversity indices, neutrality tests and nonsynonymous/synonymous rate ratios, and patterns suggesting selective constraints possibly due to lineage-specific interactions were identified. Moreover, a general correlation between nucleotide position and nucleotide polymorphism was identified in the mtDNA.
The results are compatible with the assumption that selection has a marked role in human mtDNA evolution and that selective constraints may vary between populations, so that the pathogenic potential of a given mutation may depend markedly on the presence of other, interacting mutations.
15
Green, Michael C. "An Efficient Primer Selection Process Combining Progressive and Iterative Multiple Sequence Alignment Strategies: ClustalW and HMMER". DigitalCommons@CalPoly, 2011. https://digitalcommons.calpoly.edu/theses/547.
Abstract (sommario):
This thesis describes a method for using a computationally efficient algorithm to identify candidate DNA primer sequences. DNA sequencing primers are a critical element of polymerase chain reaction (PCR) and DNA sequence analysis. A variety of methods for deriving DNA primers exist, but such methods are often computationally intensive, or do not use available sequence data that could potentially serve as a possible resource for primer identification. Though no current algorithm exists which will always yield a correct primer for every need, evaluation of multi-sequence alignments may provide a reliable source for primer candidates. However, an exact mathematical solution for multi-sequence alignments, using currently available computational resources, is only viable for a very small number of sequences. Any solution for a larger number of sequences will therefore use other computational methods and heuristics to estimate an alignment.
The solution presented here, featuring a combination of ClustalW and HMMER alignment tools, is able to identify conserved regions in sequence data in a computationally efficient manner, and from these regions, suggest viable primer candidates. Computational complexity for the HMMER alignment effort has been maintained at O(MN); the suggested process for creating sequence alignments lead to a 15-fold improvement in performance over conventional methods, while also successfully identifying fungal specific primers, with individual examples showing 90% or greater match for the given fungal phylum.
It was found that alignment quality could be further improved by using simple sorting methods against input sequence data.
16
Islas, Anguiano Jose Angel. "Optimal Strategies for Stopping Near the Top of a Sequence". Thesis, University of North Texas, 2015. https://digital.library.unt.edu/ark:/67531/metadc822812/.
Abstract (sommario):
In Chapter 1 the classical secretary problem is introduced. Chapters 2 and 3 are variations of this problem. Chapter 2, discusses the problem of maximizing the probability of stopping with one of the two highest values in a Bernoulli random walk with arbitrary parameter p and finite time horizon n. The optimal strategy (continue or stop) depends on a sequence of threshold values (critical probabilities) which has an oscillating pattern. Several properties of this sequence have been proved by Dr. Allaart. Further properties have been recently proved. In Chapter 3, a gambler will observe a finite sequence of continuous random variables. After he observes a value he must decide to stop or continue taking observations. He can play two different games A) Win at the maximum or B) Win within a proportion of the maximum. In the first section the sequence to be observed is independent. It is shown that for each n>1, theoptimal win probability in game A is bounded below by (1-1/n)^{n-1}. It is accomplished by reducing the problem to that of choosing the maximum of a special sequence of two-valued random variables and applying the sum-the-odds theorem of Bruss (2000). Secondly, it is assumed the sequence is i.i.d. The best lower bounds are provided for the winning probabilities in game B given any continuous distribution. These bounds are the optimal win probabilities of a game A which was examined by Gilbert and Mosteller (1966).
17
Shimagaki, Kai. "Advanced statistical modeling and variable selection for protein sequences". Electronic Thesis or Diss., Sorbonne université, 2021. http://www.theses.fr/2021SORUS548.
Abstract (sommario):
Au cours des dernières décennies, des techniques de séquençage de protéines ont été développées et des expériences continues ont été menées. Grâce à tous ces efforts, de nos jours, nous avons obtenu plus de deux-cents millions données relative à des séquences de protéines. Afin de traiter une telle quantité de données biologiques, nous avons maintenant besoin de théories et de technologies pour extraire des informations de ces données que nous pouvons comprendre et pour apporter des idées. L'idée clé pour résoudre ce problème est la physique statistique et l'état de l'art de le Machine Learning (ML). La physique statistique est un domaine de la physique qui peut décrire avec succès de nombreux systèmes complexes en extrayant ou en réduisant les variables pour en faire des variables interprétables basées sur des principes simples.ML, d'autre part, peut représenter des données (par exemple en les reconstruisant ou en les classifiant) sans comprendre comment les données ont été générées, c'est-à-dire le phénomène physique à l'origine de la création de ces données. Dans cette thèse, nous rapportons des études de modélisation générative de séquences protéiques et de prédictions de contacts protéines-résidus à l'aide de la modélisation statistique inspirée de la physique et de méthodes orientées ML. Dans la première partie, nous passons en revue le contexte général de la biologie et de la génomique. Ensuite, nous discutons des modélisations statistiques pour la séquence des protéines. En particulier, nous passons en revue l'analyse de couplage direct (DCA), qui est la technologie de base de notre rechercheOver the last few decades, protein sequencing techniques have been developed and continuous experiments have been done. Thanks to all of these efforts, nowadays, we have obtained more than two hundred million protein sequence data. In order to deal with such a huge amount of biological data, now, we need theories and technologies to extract information that we can understand and interpret.The key idea to resolve this problem is statistical physics and the state of the art of machine learning (ML). Statistical physics is a field of physics that can successfully describe many complex systems by extracting or reducing variables to be interpretable variables based on simple principles. ML, on the other hand, can represent data (such as reconstruction and classification) without assuming how the data was generated, i.e. physical phenomenon behind of data. In this dissertation, we report studies of protein sequence generative modeling and protein-residue contact predictions using statistical physics-inspired modeling and ML-oriented methods. In the first part, we review the general background of biology and genomics. Then we discuss statistical modelings for protein sequence. In particular, we review Direct Coupling Analysis (DCA), which is the core technology of our research. We also discuss the effects of higher-order statistics contained in protein sequences and introduces deep learning-based generative models as a model that can go beyond pairwise interaction
18
Gamble, Christopher Thomas. "A Bayesian chromosome painting approach to detect signals of incomplete positive selection in sequence data : applications to 1000 genomes". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:e1f3b484-59b9-4703-ae09-67079408c424.
Abstract (sommario):
Methods to detect patterns of variation associated with ongoing positive selection often focus on identifying regions of the genome with extended haplotype homozygosity - indicative of recently shared ancestry. Whilst these have been shown to be powerful they have two major challenges. First, these methods are constructed to detect variation associated with a classical selective sweep; a single haplotype background gets swept up to a higher than expected frequency given its age. Recently studies have shown that other forms of positive selection, e.g. selection on standing variation, may be more prevalent than previous thought. Under such evolution, a mutation that is already segregating in the population becomes beneficial, possibly as a result of an environmental change. The second challenge with these methods is that they base their inference on non-parametric tests of significance which can result in uncontrolled false positive rates. We tackle these problems using two approaches. First, by exploiting a widely used model in population genomics we construct a new approach to detect regions where a subset of the chromosomes are much more related than expected genome-wide. Using this metric we show that it is sensitive to both classical selective sweeps, and to soft selective sweeps, e.g. selection on standing variation. Second, building on existing methods, we construct a Bayesian test which bi-partitions chromosomes at every position based on their allelic type and tests for association between chromosomes carrying one allele and significantly reduced time to common ancestor. Using simulated data we show that this approach results in a powerful, fast, and robust approach to detect signals of positive selection in sequence data. Moreover by comparing our model to existing techniques we show that we have similar power to detect recent classical selective sweeps, and considerably greater power to detect soft selective sweeps. We apply our method, ABACUS, to three human populations using data from the 1000 Genome Project. Using existing and novel candidates of positive selection, we show that the results between ABACUS and existing methods are comparable in regions of classical selection, and are arguably superior in regions that show evidence for recent selection on standing variation.
19
Zhang, Nan. "Feature selection based segmentation of multi-source images : application to brain tumor segmentation in multi-sequence MRI". Phd thesis, INSA de Lyon, 2011. http://tel.archives-ouvertes.fr/tel-00701545.
Abstract (sommario):
Multi-spectral images have the advantage of providing complementary information to resolve some ambiguities. But, the challenge is how to make use of the multi-spectral images effectively. In this thesis, our study focuses on the fusion of multi-spectral images by extracting the most useful features to obtain the best segmentation with the least cost in time. The Support Vector Machine (SVM) classification integrated with a selection of the features in a kernel space is proposed. The selection criterion is defined by the kernel class separability. Based on this SVM classification, a framework to follow up brain tumor evolution is proposed, which consists of the following steps: to learn the brain tumors and select the features from the first magnetic resonance imaging (MRI) examination of the patients; to automatically segment the tumor in new data using a multi-kernel SVM based classification; to refine the tumor contour by a region growing technique; and to possibly carry out an adaptive training. The proposed system was tested on 13 patients with 24 examinations, including 72 MRI sequences and 1728 images. Compared with the manual traces of the doctors as the ground truth, the average classification accuracy reaches 98.9%. The system utilizes several novel feature selection methods to test the integration of feature selection and SVM classifiers. Also compared with the traditional SVM, Fuzzy C-means, the neural network and an improved level set method, the segmentation results and quantitative data analysis demonstrate the effectiveness of our proposed system.
20
Kudella, Patrick [Verfasser], e Dieter [Akademischer Betreuer] Braun. "Sequence self-selection by the network dynamics of random ligating oligomer pools / Patrick Kudella ; Betreuer: Dieter Braun". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/123264546X/34.
21
Schwarb, Hillary. "The importance of stimulus-response rules in sequence learning". Thesis, Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/28221.
22
Kabir, Mitra. "Prediction of mammalian essential genes based on sequence and functional features". Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/prediction-of-mammalian-essential-genes-based-on-sequence-and-functional-features(cf8eeed5-c2b3-47c3-9a8f-2cc290c90d56).html.
Abstract (sommario):
Essential genes are those whose presence is imperative for an organism's survival, whereas the functions of non-essential genes may be useful but not critical. Abnormal functionality of essential genes may lead to defects or death at an early stage of life. Knowledge of essential genes is therefore key to understanding development, maintenance of major cellular processes and tissue-specific functions that are crucial for life. Existing experimental techniques for identifying essential genes are accurate, but most of them are time consuming and expensive. Predicting essential genes using computational methods, therefore, would be of great value as they circumvent experimental constraints. Our research is based on the hypothesis that mammalian essential (lethal) and non-essential (viable) genes are distinguishable by various properties. We examined a wide range of features of Mus musculus genes, including sequence, protein-protein interactions, gene expression and function, and found 75 features that were statistically discriminative between lethal and viable genes. These features were used as inputs to create a novel machine learning classifier, allowing the prediction of a mouse gene as lethal or viable with the cross-validation and blind test accuracies of ∼91% and ∼93%, respectively. The prediction results are promising, indicating that our classifier is an effective mammalian essential gene prediction method. We further developed the mouse gene essentiality study by analysing the association between essentiality and gene duplication. Mouse genes were labelled as singletons or duplicates, and their expression patterns over 13 developmental stages were examined. We found that lethal genes originating from duplicates are considerably lower in proportion than singletons. At all developmental stages a significantly higher proportion of singletons and lethal genes are expressed than duplicates and viable genes. Lethal genes were also found to be more ancient than viable genes. In addition, we observed that duplicate pairs with similar patterns of developmental co-expression are more likely to be viable; lethal gene duplicate pairs do not have such a trend. Overall, these results suggest that duplicate genes in mouse are less likely to be essential than singletons. Finally, we investigated the evolutionary age of mouse genes across development to see if the morphological hourglass pattern exists in the mouse. We found that in mouse embryos, genes expressed in early and late stages are evolutionarily younger than those expressed in mid-embryogenesis, thus yielding an hourglass pattern. However, the oldest genes are not expressed at the phylotypic stage stated in prior studies, but instead at an earlier time point - the egg cylinder stage. These results question the application of the hourglass model to mouse development.
23
Brandström, Mikael. "Bioinformatic Analysis of Mutation and Selection in the Vertebrate Non-coding Genome". Doctoral thesis, Uppsala University, Department of Evolution, Genomics and Systematics, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8240.
Abstract (sommario):
The majority of the vertebrate genome sequence is not coding for proteins. In recent years, the evolution of this noncoding fraction of the genome has gained interest. These studies have been greatly facilitated by the availability of full genome sequences. The aim of this thesis is to study evolution of the noncoding vertebrate genome through bioinformatic analysis of large-scale genomic datasets.
In a first analysis we addressed the use of conservation of sequence between highly diverged genomes to infer function. We provided evidence for a turnover of the patterns of negative selection. Hence, measures of constraint based on comparisons of diverged genomes might underestimate the functional proportion of the genome.
In the following analyses we focused on length variation as found in small-scale insertion and deletion (indel) polymorphisms and microsatellites. For indels in chicken, replication slippage is a likely mutation mechanism, as a large proportion of the indels are parts of tandem-duplicates. Using a set of microsatellite polymorphisms in chicken, where we avoid ascertainment bias, we showed that polymorphism is positively correlated with microsatellite length and AT-content. Furthermore, interruptions in the microsatellite sequence decrease the levels of polymorphism.
We also analysed the association between microsatellite polymorphism and recombination in the human genome. Here we found increased levels of microsatellite polymorphism in human recombination hotspots and also similar increases in the frequencies of single nucleotide polymorphisms (SNPs) and indels. This points towards natural selection shaping the levels of variation. Alternatively, recombination is mutagenic for all three kinds of polymorphisms.
Finally, I present the program ILAPlot. It is a tool for visualisation, exploration and data extraction based on BLAST.
Our combined results highlight the intricate connections between evolutionary phenomena. It also emphasises the importance of length variability in genome evolution, as well as the gradual difference between indels and microsatellites.
24
Wagner, Brandie D. "Permutation based microarray gene selection methods with covarience adjustment applicable to complex diseases /". Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
Abstract (sommario):
Thesis (Ph.D. in Analytic Health Sciences) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 57-60). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
25
Beane, Melinda. "Development of response strategy selection during sequence-based learning and performance to manage attention and to facilitate behavioral flexibility /". view abstract or download file of text, 2006. http://proquest.umi.com/pqdweb?did=1251836221&sid=1&Fmt=2&clientId=11238&RQT=309&VName=PQD.
Abstract (sommario):
Thesis (Ph. D.)--University of Oregon, 2006.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 81-89). Also available for download via the World Wide Web; free to University of Oregon users.
26
Ali, Isse. "Analysing and predicting differences between methylated and unmethylated DNA sequence features". Thesis, De Montfort University, 2015. http://hdl.handle.net/2086/12616.
Abstract (sommario):
DNA methylation is involved in various biological phenomena, and its dysregulation has been demonstrated as being correlated with a number of human disease processes, including cancers, autism, and autoimmune, mental health and neuro-degenerative ones. It has become important and useful in characterising and modelling these biological phenomena in or-der to understand the mechanism of such occurrences, in relation to both health and disease. An attempt has previously been made to map DNA methylation across human tissues, however, the means of distinguishing between methylated, unmethylated and differentially-methylated groups using DNA sequence features remains unclear. The aim of this study is therefore to: firstly, investigate DNA methylation classes and predict these based on DNA sequence features; secondly, to further identify methylation-associated DNA sequence features, and distinguish methylation differences between males and females in relation to both healthy and diseased, sta-tuses. This research is conducted in relation to three samples within nine biological feature sub-sets extracted from DNA sequence patterns (Human genome database). Two samples contain classes (methylated, unmethy-lated and differentially-methylated) within a total of 642 samples with 3,809 attributes driven from four human chromosomes, i.e. chromosomes 6, 20, 21 and 22, and the third sample contains all human chromosomes, which encompasses 1628 individuals, and then 1,505 CpG loci (features) were extracted by using Hierarchical clustering (a process Heatmap), along with pair correlation distance and then applied feature selection methods. From this analysis, author extract 47 features associated with gender and age, with 17 revealing significant methylation differences between males and females. Methylation classes prediction were applied a K-nearest Neighbour classifier, combined with a ten-fold cross- validation, since to some data were severely imbalanced (i.e., existed in sub-classes), and it has been established that direct analysis in machine-learning is biased towards the majority class. Hence, author propose a Modified- Leave-One-Out (MLOO) cross-validation and AdaBoost methods to tackle these issues, with the aim of compositing a balanced outcome and limiting the bias in-terference from inter-differences of the classes involved, which has provided potential predictive accuracies between 75% and 100%, based on the DNA sequence context.
27
Bebber, Michelle Rae. "UNDERSTANDING TEMPER SELECTION IN THE PREHISTORIC CERAMIC SEQUENCE OF THE SCIOTO RIVER VALLEY, ROSS COUNTY, OHIO (500 B.C. – AD 1400)". Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1479821741762486.
28
Pegard, Marie. "New models for implementation of genome-wide evaluation in black poplar breeding program". Thesis, Orléans, 2018. http://www.theses.fr/2018ORLE2058/document.
Abstract (sommario):
Les espèces forestières sont particulières à bien des égards par rapport aux autres espècesdomestiquées. Les arbres forestiers ont de longues phases juvéniles, entrainant de long et couteuxcycles de sélection et nécessitant une sélection en plusieurs étapes indépendantes. Bien que cetteméthode soit efficace du point de vue opérationnel, elle reste couteuse en temps et en ressources,entrainant une dilution de l’intensité et de la précision de sélection. Au vu de ces contraintes,les arbres sont de bons candidats pour la mise en oeuvre de l’évaluation génomique. La sélectiongénomique (SG) repose sur le classement et la sélection d’individus à partir de l’informationcontenu dans leur génome sans utilisé une étape d’évaluation phénotypique et ainsi accélérerle processus de sélection.Ce travail visait à identifier les situations, les critères et les facteursdans lesquelles la SG pourrait être une option réalisable pour le peuplier. Notre étude a montréque les avantages de l’évaluation génomique dépendent du contexte. C’est dans des situationsles moins avantageuse que l’évaluation génomique se montre la plus performante, elle profiteégalement de la densification de l’information génétique de faible à moyenne suite à une étaped’imputation de haute qualité. La sélection génomique pourrait être une option intéressante àstade précoce, où la précision de la sélection est généralement faible et la variabilité génétiqueabondante. Notre travail a également montré qu’il est important d’évaluer les performancesavec des critères alternatifs, comme ceux liés au classement, notamment lorsque ces critèresrépondent au contexte opérationnel du programme d’élevage étudiéForest species are unique in many ways compared to other domesticated species. Forest trees have long juvenile phases, leading to long and costly selection cycles and requiring selection in several independent stages. Even if this method is operationally effective, it remains costly in terms of time and resources, resulting in a diluted intensity and accuracy of selection.In view of these constraints, trees are good candidates for the implementation of genomic evaluation. Genomic selection (SG) is based on the classification and selection of individuals from the information contained in their genome without using a phenotypic evaluation step and thus accelerating the selection process, in order to identify the situations, criteria and factors in which SG could be a feasible option for poplar. Our study showed that the benefits of genomic evaluation are context-dependent. Genomic evaluation is most effective in theless-advantageous situations, it also benefits from low to medium density genetic information following a high-quality imputation step. Genomic selection could be an interesting option at an early stage, when the accuracy of selection is generally low and genetic variability is abundant.Our work has also shown that it is important to evaluate performance with alternative criteria,such as those related to ranking, especially when these criteria fit the operational context of the breeding programme under study
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Walsh, Capdevila Sandra 1991. "Insights into the adaptative history of African human populations from whole-genome sequence data". Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668469.
Abstract (sommario):
Africa is the origin source of modern humans. Despite that African populations harbor the highest levels of genetic diversity worldwide, they remain underrepresented in genetic studies. Therefore, in order to fully understand modern human evolutionary history it is fundamental to include more African populations in genetic studies. The work in this thesis is a small contribution to the study of African evolutionary history. In particular we have focused on two different locations of Africa, eastern and southern Africa. We have tried to unravel candidates of positive (or adaptive) selection through the analysis of whole-genome sequences of five Ethiopian populations and one KhoeSan population. Moreover, we have tried to fill the gap between genotype and phenotype of a candidate of adaptive selection in an Ethiopian population.Àfrica és la font d'origen dels humans moderns. Malgrat que les poblacions Africanes són les que contenen la major diversitat genètica al món, estan molt poc representades en estudis genètics. Així doncs, per poder plenament entendre la història evolutiva humana és fonamental incloure més poblacions Africanes en estudis genètics. Aquesta tesi és una petita contribució en l'estudi de la història evolutiva humana a l'Àfrica. Ens hem centrat en dos localitzacions diferents, a l'est i al sud de l'Àfrica. Hem intentat dilucidar les possibles senyals de selecció positiva (o adaptativa) a través de l'anàlisi de seqüències completes de genomes de cinc poblacions d'Etiòpia i una KhoeSan. A més a més, en l'última part de la tesi s'ha intentat entendre a nivell funcional la relació entre el genotip i el fenotip d'un candidat de selecció adaptativa descobert en una població d'Etiòpia.
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Borukhovich, Ian. "Intrinsic Local Balancing of Hydrophobic and Hydrophilic Residues in Folded Protein Sequences". Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/596407.
Abstract (sommario):
Protein sequences may evolve to avoid highly hydrophobic local regions of sequence, in part because such sequences promote nonnative aggregation. Hydrophobic local sequences are avoided in proteins even in buried regions, where native structure requirements tend to favor them. In this dissertation, I describe three explorations of this hydrophobic suppression. In Chapter 2, I examine the occurrence of hydrophobic and polar residues in completely buried β-strand elements, and find evidence for hydrophobic suppression that decreases as a β-strand becomes more exposed. In Chapter 3, I present a generalized study of the tendency of local sequences to deviate from the hydropathy (hydrophobicity) expected based on their solvent exposure. First, I examined the hydropathy of local and nonlocal sequence groups over a large range of solvent exposures, within folded protein domains in the ASTRAL Compendium database; second, I calculated the tendency of residues within 10 positions of a nonpolar or polar reference residue to deviate from the hydropathy expected based on their structural environment. Both analyses suggested that protein sequences exhibit 'local hydropathic balance' across a range of 6-7 residues, meaning that polar and nonpolar residues are more dispersed in the sequence than expected based on solvent exposure patterns. This balance occurs in all major fold classes, domain sizes and protein functions. An unexpected finding was that it partly arises from a tendency of buried or exposed residues to be flanked by polar or nonpolar residues, respectively. This relationship may result from evolutionary selection for folding efficiency, which might be enhanced by reduced local competition for buried or exposed sites during folding. Finally, in Chapter 4, I present several exploratory analyses, including a decision-tree approach, to visualize the influence of a large number of sequence-structure properties on residue hydrophobicity. Overall, the work in this dissertation confirms that hydrophobic suppression and local hydropathic balance in general are intrinsic properties of folded proteins. I speculate that local hydropathic balance results from selection for reduced aggregation propensity, increased folding efficiency and increased native state specificity. The concept of local hydropathic balance might be used to improve the properties of designed and engineered proteins.
31
Yin, Pei. "Segmental discriminative analysis for American Sign Language recognition and verification". Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/33939.
Abstract (sommario):
This dissertation presents segmental discriminative analysis techniques for American Sign Language (ASL) recognition and verification. ASL recognition is a sequence classification problem. One of the most successful techniques for recognizing ASL is the hidden Markov model (HMM) and its variants. This dissertation addresses two problems in sign recognition by HMMs. The first is discriminative feature selection for temporally-correlated data. Temporal correlation in sequences often causes difficulties in feature selection. To mitigate this problem, this dissertation proposes segmentally-boosted HMMs (SBHMMs), which construct the state-optimized features in a segmental and discriminative manner. The second problem is the decomposition of ASL signs for efficient and accurate recognition. For this problem, this dissertation proposes discriminative state-space clustering (DISC), a data-driven method of automatically extracting sub-sign units by state-tying from the results of feature selection. DISC and SBHMMs can jointly search for discriminative feature sets and representation units of ASL recognition.
ASL verification, which determines whether an input signing sequence matches a pre-defined phrase, shares similarities with ASL recognition, but it has more prior knowledge and a higher expectation of accuracy. Therefore, ASL verification requires additional discriminative analysis not only in utilizing prior knowledge but also in actively selecting a set of phrases that have a high expectation of verification accuracy in the service of improving the experience of users. This dissertation describes ASL verification using CopyCat, an ASL game that helps deaf children acquire language abilities at an early age. It then presents the "probe" technique which automatically searches for an optimal threshold for verification using prior knowledge and BIG, a bi-gram error-ranking predictor which efficiently selects/creates phrases that, based on the previous performance of existing verification systems, should have high verification accuracy.
This work demonstrates the utility of the described technologies in a series of experiments. SBHMMs are validated in ASL phrase recognition as well as various other applications such as lip reading and speech recognition. DISC-SBHMMs consistently produce fewer errors than traditional HMMs and SBHMMs in recognizing ASL phrases using an instrumented glove. Probe achieves verification efficacy comparable to the optimum obtained from manually exhaustive search. Finally, when verifying phrases in CopyCat, BIG predicts which CopyCat phrases, even unseen in training, will have the best verification accuracy with results comparable to much more computationally intensive methods.
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Yenihayat, Guven. "Opportunistic Multiple Relaying In Wireless Ad Hoc Networks". Master's thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613334/index.pdf.
Abstract (sommario):
Cooperative relaying systems aim to improve weak communication links by exploiting the spatial diversity obtained by the statistically independent channels between relays and the destination. In this thesis a cooperative relaying scheme called the Opportunistic Multiple Relaying (OMR) is proposed with its special receiver structure. Unlike most relaying schemes in the literature, multiple relay nodes are allowed to transmit in nonorthogonal channels in OMR without requiring any control overhead for relay coordination. OMR is compared to a benchmark scheme called the Selection Relaying (SR) in which the relay node is preselected by the source before transmission according to the average channel quality information. It is observed that OMR performs significantly better than SR in terms of error performance.
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Tucker, Dominic M. "Mapping and Characterization of Phytophthora sojae and Soybean Mosaic Virus Resistance in Soybean". Diss., Virginia Tech, 2009. http://hdl.handle.net/10919/79598.
Abstract (sommario):
Phytophthora sojae, the causal organism of stem and root rot, and Soybean mosaic virus (SMV) cause two of the most highly destructive diseases of soybean (Glycine max L. Merr). P. sojae can be managed either through deployment of race-specific resistance or through quantitative resistance termed partial resistance. In the current study, partial resistance to P. sojae was mapped in an interspecific recombinant inbred line (RIL) population of Glycine max by Glycine soja. One major quantitative trait loci (QTL) on molecular linkage group (MLG)-J (chromosome 16) and two minor QTL on MLG-I (chromosome 20) and -G (chromosome 18) were mapped using conventional molecular markers. Additionally, partial resistance to P. sojae was mapped in the same RIL population using single feature polymorphism (SFP) markers that further fine mapped the P. sojae QTL and identified potential candidate genes contributing to resistance. In a separate study, race-specific resistance was characterized in PI96983 discovering a potentially new allele of Rps4 on MLG-G. Finally, using the newly available whole-genome shotgun sequence of soybean, Rsv4 conferring resistance to strains of SMV known in the US, was localized to an approximately 100 kb region of sequence on chromosome 2 (MLG-D1B). Newly designed PCR-based markers permit for efficient selection of Rsv4 by breeding programs. Identified candidate genes for Rsv4 are discussed. Genomic resources developed in all of these studies provide breeders the tools necessary for developing durable resistance to both SMV and P. sojae.Ph. D.
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Künstner, Axel. "Birds as a Model for Comparative Genomic Studies". Doctoral thesis, Uppsala universitet, Evolutionsbiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-159766.
Abstract (sommario):
Comparative genomics provides a tool to investigate large biological datasets, i.e. genomic datasets. In my thesis I focused on inferring patterns of selection in coding and non-coding regions of avian genomes. Until recently, large comparative studies on selection were mainly restricted to model species with sequenced genomes. This limitation has been overcome with advances in sequencing technologies and it is now possible to gather large genomic data sets for non-model species. Next-generation sequencing data was used to study patterns of nucleotide substitutions and from this we inferred how selection has acted in the genomes of 10 non-model bird species. In general, we found evidence for a negative correlation between neutral substitution rate and chromosome size in birds. In a follow up study, we investigated two closely related bird species, to study expression levels in different tissues and pattern of selection. We found that between 2% and 18% of all genes were differentially expressed between the two species. We showed that non-coding regions adjacent to genes are under evolutionary constraint in birds, which suggests that noncoding DNA plays an important functional role in the genome. Regions downstream to genes (3’) showed particularly high level of constraint. The level of constraint in these regions was not correlated to the length of untranslated regions, which suggests that other causes play also a role in sequence conservation. We compared the rate of nonsynonymous substitutions to the rate of synonymous substitutions in order to infer levels of selection in protein-coding sequences. Synonymous substitutions are often assumed to evolve neutrally. We studied synonymous substitutions by estimating constraint on 4-fold degenerate sites of avian genes and found significant evolutionary constraint on this category of sites (between 24% and 43%). These results call for a reappraisal of synonymous substitution rates being used as neutral standards in molecular evolutionary analysis (e.g. the dN/dS ratio to infer positive selection). Finally, the problem of sequencing errors in next-generation sequencing data was investigated. We developed a program that removes erroneous bases from the reads. We showed that low coverage sequencing projects and large genome sequencing projects will especially gain from trimming erroneous reads.
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Cook, Kevin Michael Brooks. "Probability of Belonging to a Language". BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4023.
Abstract (sommario):
Conventional language models estimate the probability that a word sequence within a chosen language will occur. By contrast, the purpose of our work is to estimate the probability that the word sequence belongs to the chosen language. The language of interest in our research is comprehensible well-formed English. We explain how conventional language models assume what we refer to as a degree of generalization, the extent to which a model generalizes from a given sequence. We explain why such an assumption may hinder estimation of the probability that a sequence belongs. We show that the probability that a word sequence belongs to a chosen language (represented by a given sequence) can be estimated by avoiding an assumed degree of generalization, and we introduce two methods for doing so: Minimal Number of Segments (MINS) and Segment Selection. We demonstrate that in some cases both MINS and Segment Selection perform better at distinguishing sequences that belong from those that do not than any other method we tested, including Good-Turing, interpolated modified Kneser-Ney, and the Sequence Memoizer.
36
Borge, Thomas. "Genetics and the Origin of Two Flycatcher Species". Doctoral thesis, Uppsala University, Evolutionary Biology, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3919.
Abstract (sommario):
In this thesis, different genetic tools are used to investigate pre- and postzygotic barriers to gene exchange and their role in speciation in the pied flycatcher (Ficedula hypoleuca) and the collared flycatcher (F. albicollis). This species complex consists of four genetically distinct clades that apparently diverged in allopatry (I). Sequencing of introns from autosomal and Z-linked genes from the two species reveals signs of selection on the Z-chromosome. Sexual selection acting on Z-linked genes might explain this pattern (II). By using large-scale genotyping of single nucleotide polymorphisms (SNPs), introgression is observed at autosomal- but not Z-linked loci, mostly from the pied- to the collared flycatcher. Male plumage characters and genes involved in hybrid fitness are largely mapped to the Z-chromosome (III). By studying mate choice of female hybrids I show that there is a link between female preferences and the Z chromosome (IV). The rate of introgression in island versus clinal hybrid zones is consistent with regional differences in hybrid fertility. Asymmetric gene flow from allopatry on the islands may oppose reinforcement, leading to introgression and a partial breakdown of postzygotic isolation. Adaptive introgression may explain the high rate of introgression observed at one of the genetic markers (V). For late breeding female collared flycatchers it appears to be adaptive to use pied flycatchers as social fathers but conspecific males as genetic fathers. Additionally, females in mixed species pairs may reduce hybridization costs by producing an excess of male hybrid offspring that are more fertile than females (VI).
In conclusion, the Z-chromosome appears to play a major role in flycatcher speciation. Sexual selection and reinforcement are important mechanisms in the divergence of these birds. However, gene flow from allopatry, introgression of adaptive genes and adaptive hetrospecific pairing by late breeding collared flycatcher females may work in the opposite direction.
37
Mondal, Mayukh 1989. "New insights into human migration, demography and adaptation of Indian and South Asian populations from genome analyses". Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/511362.
Abstract (sommario):
Human genome project published their first human whole genome sequence on 2001 at the cost of billions of dollars. Since, the cost of sequencing is decreasing faster than Moore’s law. Now, we not only have sequenced thousands of modern humans’ whole genome, we also obtained whole genome sequences of extinct hominin and other ancient modern humans with relatively good quality. These sequences granted us some unexpected results: like how recently modern humans left Africa and populated around all over the world (which is called recent African origin model) while doing so how they have admixed with multiple hominin populations. Until now modern biology (unlike physics) always dominated by empirical results compared to theoretical concepts, which forces people to perceive biology as a descriptive science. As we are obtaining more and more data every day, it is now time to push our theoretical concepts before empirical results in biology. Here in this thesis, we provided deeper knowledge about ancestry of Indian, Asian and Pacific populations. We were also able to reveal an unknown hominin population existed even before it is sequenced. In addition to these, we demonstrated strong natural selection could change human morphology drastically in a short period.El projecte del genoma humà va publicar la primera seqüència completa del genoma humà el 2001 amb un cost de milers de millions de dòlars. Després d'això, el cost de la seqüenciació està disminuint més ràpid que la llei de Moore. Actualment no només tenim la seqüència de del genoma humà, sinó que tenim la de molts humans i d’homínids extingits amb una qualitat relativement bona. L’estudi de les seqüències de molts genomes humans varen proporcionar la base per postular que els humans moderns es varen originar a Àfrica, i en la sortida d’Àfrica (Out Of Africa) varen poblar la resta del món, amb una certa barreja amb diferents poblacions d'homínids. La base del treball en biologia i en genòmica evolutiva ha estat fonamentalment empírica (a diferència de la física), però actualment la disponibilitat de moltes dades permet empenyer la recerca cap a aspectes molt més analítics: aquest és l’enfocament del nostre treball en seqüències de DNA. Aquí, en aquesta tesi, hem proporcionat un coneixement més profund sobre l’origen i l'ascendència de poblacions indígenes, d’Àsia i del Pacífic, centrant-nos en la India continental i especialment en les Illes Andaman. També hem estat capaços de revelar l’existència d’una població d'homínids desconeguts que es va barrejar amb els ancestres d’aquestes poblacions. A més, hem demostrat que una forta selecció natural pot canviar dràsticament la morfologia humana en un curt període de temps i que explicaria la morfologia pigmea del pobladors de les illes Andaman.
38
Soldevila, Trepat Marta. "Genetic variation in humans and chimpanzees in the prion protein gene". Doctoral thesis, Universitat Pompeu Fabra, 2005. http://hdl.handle.net/10803/7189.
Abstract (sommario):
En el gen de la proteïna priònica, o PRNP, hem observat que el particular patró de variació que hem trobat basant-nos en dades de seqüenciació en humans es deu a selecció positiva, i que el mètode utilitzat per detectar selecció és crític. Utilitzant dades basades en SNPs es pot introduir un biaix al aplicar tests de neutralitat basats en diversitat de seqüències, i això pot portar a conclusions errònies. A més, hem vist que els polimorfismes en els codons 129 i 219 presenten gran diferències de freqüència en diferents poblacions humanes i també hem vist que aquestes posicions estan fixades en ximpanzés. La variació trobada en controls ha estat comparada amb el patró de variació existent en pacients per la mateixa regió. La reseqüenciació del gen PRNP en un gran nombre de mostres humanes i de ximpanzés ens ha permès obtenir un gran nombre d´informació d´aquest gen.In the prion gene or PRNP, we have observed that the particular pattern of variation that we have found in this gene based on sequencing data in humans is due to positive selection, and that the method and the approach used to detect this selection critical. Ascertainment bias can be introduced by using SNP data and applying neutrality tests based on sequence diversity, therefore leading to anomalous conclusions being drawn. Moreover, we have seen that polymorphisms in codon 129 and 219 have big differences in frequency in different human populations and we have also seen that these positions are fixed in chimpanzees. The normal variation that we found in controls have been then compared with patients for the same region. The resequencing of PRNP in a very large sample of humans and chimpanzees has provided a great deal of information on this gene.
39
Pfeifer, Susanne. "Statistical challenges in the detection of mutation and variation using high throughput sequencing". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:e49ce2fa-aa2c-42d7-bb54-c63e50d14afb.
Abstract (sommario):
The aim of this thesis is to obtain a better understanding of mutation rates within as well as between the genomes of humans and chimpanzees using data generated by high throughput sequencers. I will start with a review of the field and an overview of the technologies and protocols used to generate and analyse high throughput sequencing data. I apply some of the discussed techniques to show that there is evidence of a selective advantage of pathogenic de novo mutations in the Fibroblast Growth Factor Receptor 3 gene in the male germ line of humans. Furthermore, I use some of the methods to generate a map of genome-wide sequence variation in Western chimpanzees. Ever since Darwin [Darwin, 1871] and Huxley [Huxley, 1863] postulated more than a century ago that African great apes are our closest living evolutionary relatives, the study of chimpanzee individuals is of great scientific interest from an evolutionary point of view, as comparisons between the genomes of human and chimpanzee offer the potential to help to understand the molecular basis for similarities and differences between the two species. I use the generated data to explore the breadth of the nucleotide diversity in the chimpanzee genome in order to shed light on whether or not the local variation in mutation rate has been conserved since the divergence of the two species and to place human nucleotide diversity into perspective with an evolutionary closely related species. I explore the relationship of nucleotide diversity in chimpanzees with specific large-scale genome features to reveal a number of highly significant correlations which explain over 40% of the observed variation. I use data from the 1000 Genomes Project to examine the occurrence of ancestral polymorphisms shared between human and chimpanzee on a genome-wide scale. These ancestral polymorphisms do not only influence fine-scale divergence rates across the genome in very closely related species, they are also good candidates for regions under balancing selection and thus, they are a useful tool to study long-time population demographics and speciation. Using these variants, I postulate that long-term balancing selection may be more common than previously believed. I conclude with a discussion of the results contained in the body of the thesis and suggest a number of areas for future research.
40
Khoo, Choon-Kiat. "Chicken genome variations and selection : from sequences to consequences". Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28934.
Abstract (sommario):
Chicken is a major protein source and intensively selected for economically important traits by humans. As such, this generated a huge range of phenotypes that representing a diverse spectrum of genetic variation. Understanding the functional basis of the genetic variants that underlie these traits, however, remains a formidable endeavour particularly for complex traits. Nonetheless, molecular phenotyping of an organism from sequenced data is doable with the advances in bioinformatics analysis and unparalleled surveys of genome wide genetic variants. This provides the opportunity to gain insights into the genome architecture and assists in identifying chromosomal regions underlying selection through a “sequences to consequences” approach. Combining a whole genome re-sequencing (WGS) approach with the knowledge of selection history, this thesis aimed to study the chromosomal regions and genetic variants underlying traits of interest in various selected chicken populations. To achieve this, genetic (quantitative and population genetics), genomic and bioinformatics approaches were employed and integrated to investigate the genome wide selection signatures in a number of different lines of chicken selected for different complex traits. This includes analysing: (i) divergently selected broilers for fatness traits (Chapter 2), (ii) a closed population of layer chickens (Chapter 3), (iii) selection signatures unique to broiler or layer chickens (Chapter 4) and (iv) selection signatures in colony stimulating factor 1 (CSF1) associated with gene expression differences in broiler and layer populations (Chapter 5). Candidate genes and nucleotides underlying potential selection regions were identified, and attempts were made to further elucidate the potential interplay between genes and the biological pathways involved in regulating traits in these selected chicken lines. Incorporating integrative approaches, variants within selection signatures were annotated to provide further evidence of their functional consequences. Overall, non-coding regions were enriched in selection signatures implied that causative variants may have regulatory roles. Capitalising on the millions of genetic variants discovered from WGS, chromosomal regions subject to selection were detected using a number of population genetics statistics. In broiler chicken lines divergently selected for very low-density plasma lipoprotein (VLDL) (Chapter 2), incorporating signatures of selection helped to improve the resolution of previously mapped quantitative traits loci (QTL) intervals. This research demonstrated that the integration of the analysis of selection signatures with functional annotation of genetic variants enabled refinement and characterisation of the QTL for fatness traits. In a closed population of brown leghorn layers (Chapter 3), evidence of selection signatures was found through Tajima’s D analysis. The analysis unravelled selection signatures encoding genes involved in numerous pathways and genes having key roles such as in behaviour, including feather pecking. Combining population differentiation statistic (FST) and Tajima’s D, a number of regions subject to divergent selection between broilers and white egg layers were identified (Chapter 4). Selection signatures were found to harbour mutations involved in cellular and tissue development, including genes having important roles in growth, fatness, egg shell strength and muscle development. These regions and the overlapping genes thereby may be potentially contributing to the different phenotypic variations observed between broilers and layers. In Chapter 5, a revised gene model for colony stimulating factor 1 (CSF1) showing complex pattern of alternate transcripts was predicted from transcriptome analysis of RNA isolated from 21 different tissues. In parallel, selection signatures analysis with the FST statistic, identified selection signatures that differentiate broilers to white egg layers (3 regions) or brown egg layers to white egg layers (4 regions). All these selection signatures were located within non-coding regions, indicating potential divergent selection of CSF1 within regulatory regions. Overall, the results presented in this thesis using the “sequences to consequences” approach, link several genomic regions and genes to phenotypic variation in domesticated chicken lines. The work reported here serves as a foundation for further study to decipher the relationship between “genotype and phenotype” and its functional consequences due to selection.
41
Taleb, Robin I. "Preparation, optimisation and characterisation of sequence selective compounds". Thesis, View thesis, 2008. http://handle.uws.edu.au:8081/1959.7/38214.
Abstract (sommario):
DNA is the pharmacological target for most platinum drugs; however, the majority of these drugs show little or no specificity for particular base pairs. Considerable progress has been made in the design of sequence selective compounds, such that an antiparallel association of a polyamide can have high affinity for selected DNA base pairs. Hairpin polyamides have distinct advantages as they achieve affinities and specificities that are comparable to that of DNA-binding proteins. Platinum(II) hairpin polyamides are expected to display antitumour activity and target specific sequences of DNA. Five DNA-sequence-selective hairpin polyamide platinum(II) complexes, containing pyrrole (Py) and imidazole (Im) heterocyclic rings, have been synthesised using a combination of solid and solution phase chemistry. One mononuclear sequence selective complex, β-Ala-PyPyPy-L4-ImImIm-L4-Pt (HLSP-6) [β-Ala is β-alanine, L4 is 4-(Fmoc-amino)butyric acid and Pt is transplatin], and two dinuclear sequence selective complexes, β-Ala-PyPyPy-L4-ImImIm-L6'-Pt-(Pt) (DNHLSP-6) [L6' is 2,6-Fmoc-Lysine-(Fmoc)-OH] and β-Ala-PyPyImImIm-L4'-PyPyPyPyPy-L6'-Pt-(Pt) (DNHLSP-10) (L4' is 2-Boc-4-Fmoc-L-diaminobutyric acid), were synthesised entirely using solid phase chemistry. Two mononuclear sequence selective complexes, Pt-L6-β-Ala-Py-L4-Im (HSP-2) and Pt-L6-β-Ala-PyPyPy-L4-ImImIm (HSP-6), were synthesised using a combination of solid and solution phase chemistry. The synthesis of a trinuclear sequence selective polyamide was also attempted using a combination of solid and solution phase chemistry. The polyamides were synthesised in a series of reaction steps. Each heterocyclic ring and linker was coupled through solid phase chemistry using 2-(1H-benzotriazole-1-y1)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). Once the organic components were assembled, the platinum(II) group/s was/were added using either solid or solution phase chemistry. The polyamide sequence of PyPyPy-L4-ImImIm was designed to target the guanine rich telomere region of DNA. The metal complexes reported in this study will span sequences between 2, 5 or 7 DNA base pairs (depending on their length), which include 5'-(A/T)GGG(A/T)-3' and 5'-(A/T)(A/T)(A/T)GGG(A/T)-3'. All complexes were characterised using 1H and 195Pt NMR, high resolution mass spectrometry and elemental analysis. The binding of HLSP-6 and DNHLSP-6 to guanosine was also monitored by 1H NMR.
42
Taleb, Robin I. "Preparation, optimisation and characterisation of sequence selective compounds". View thesis, 2008. http://handle.uws.edu.au:8081/1959.7/38214.
Abstract (sommario):
Thesis (Ph.D.)--University of Western Sydney, 2008."A thesis presented to the University of Western Sydney, College of Health and Science, School of Biomedical and Health Sciences in fulfilment of the requirements for the degree of Doctor of Philosophy." Includes bibliography.
43
Tonidandel, Sandra Maria Rudella. "Superando obstáculos no ensino e na aprendizagem da evolução biológica: o desenvolvimento da argumentação dos alunos no uso de dados como evidências da seleção natural numa sequência didática baseada em investigação". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/48/48134/tde-18122014-100501/.
Abstract (sommario):
A educação científica tem se voltado para atividades pedagógicas que utilizam a prática investigativa de alunos. Um dos objetivos é que os estudantes se apropriem não apenas dos conceitos científicos, mas também das práticas específicas da atividade científica. Uma das pretensões é que os alunos desenvolvam a competência da argumentação científica. Esta investigação pretende compreender como os alunos desenvolvem sua argumentação escrita, analisando a utilização que fazem dos dados como evidências da seleção natural de forma a sustentar suas conclusões na resolução de questões investigativas sobre evolução biológica. Elaboramos uma sequência didática cuja arquitetura estabelece os alicerces para a ação pedagógica do professor e promove uma atuação investigativa dos alunos. A arquitetura da sequência tem duas bases integradoras: a) a educação científica baseada em investigação e b) a matriz de construção histórica da investigação de Darwin sobre a seleção natural como mecanismo da evolução biológica. Para investigar como seria o ensino da evolução biológica que recupera o viés da matriz investigativa utilizada por Darwin, nossa questão-problema foi construída com dois grandes focos: a) como articular intenções conceituais e metodológicas características da natureza das ciências biológicas com a abordagem dos principais obstáculos da construção histórica do conceito de seleção natural numa sequência didática baseada em investigação e b) de como é a utilização de dadosT como evidências da seleção natural na composição da estrutura argumentativa escrita de alunos de ensino médio durante a aplicação de uma Sequência de Ensino de Biologia Baseada em Investigação (SEEBI) para o ensino de evolução biológica. Para investigar nossa questão, elaboramos a SEBBI que foi aplicada por uma professora da rede pública para 125 alunos da 3ª série do ensino médio de uma escola pública estadual de São Paulo. Nossa metodologia é de abordagem qualitativa integrada a uma abordagem quantitativa. Nossos dados compõem-se de: a) materiais (apostilas, modelos experimentais, elementos audiovisuais utilizados nas aulas) e b) apostilas com respostas escritas pelos alunos após as atividades propostas. As análises foram realizadas a partir das apostilas escritas dos alunos, dos materiais elaborados e disponibilizados na SEBBI e na transcrição que realizamos. Os resultados mostram que a SEBBI tem alicerces em intenções conceituais e metodológicas características da biologia. Além disso, os resultados apontam para uma superação de obstáculos conceituais pelos alunos, como a teleologia cósmica e o fixismo, para a construção do conceito de seleção natural. Os resultados das análises apresentam uma melhora na capacidade argumentativa dos alunos, uma forte correlação entre o uso de dados de evolução biológica com a construção de argumentos de maior qualidade pelos alunos, pelo uso de justificativa (garantia e apoio) alicerçada em conhecimento científico. Há evidências da ampliação da construção de argumentos, tanto no aumento do número de componentes utilizados quanto na qualidade dos componentes campos-dependentes da ciência, como o apoio e evidências. Os argumentos construídos passam a apresentar a sustentação baseada em apoio conceitual específico do paradigma das ciências biológicas como a seleção natural, validando as conclusões a partir do uso de dadosT de Toulmin da investigação realizada pelos alunos.The scientific education has focused on pedagogical activities that use students investigative practice. One of the objectives is so that students not only obtain the scientific concepts, but also the specific practices of science activity. It is a pretention that students develop their scientific argumentation competence. This investigation aims at understanding how students develop their written argumentation, analyzing their use of data as evidence of natural selection in order to sustain their conclusions about biological evolution investigative questions. We made a didactic sequence, which architecture establishes the foundation to the teachers pedagogical actions, and promotes students investigative actions. The sequence lies on two integrative bases: a) an investigation based scientific education and b) Darwins investigation on the natural selection as a mechanism of the historical construction matrix of biological evolution. In order to examine how would it be the biological evolution teaching based in Darwins investigative structure, our problem question was built with two main focuses: a) how could we articulate conceptual and methodological intentions, characteristic to biological sciences, with the approach of the main historical obstacles of natural selection in evolving into the concept of the mechanism of biological evolution in a didactic sequence based upon inquiry and b) how it is the use of data as evidence of natural selection in the high school students written argumentative structure during the application of Inquiry Based Biology Teaching Sequence (SEEBI, in Portuguese) to biological evolution teaching. To investigate our task, we developed a SEEBI that was applied by a public networks teacher to 125 high schools senior year students in a public school of São Paulo. Our methodology has qualitative and quantitative approaches. Our data consists of: a) materials (textbooks, experimental models, audio-visual resources used in class) and b) booklets with answers written by the students after the proposed activities. The data analyses were based upon these booklets, with students written answers, materials elaborated and posted in the SEEBI and also in the transcription we did. The results show that SEEBI has its foundation lied on conceptual and methodological intentions, characteristic to Biology. Furthermore, the results indicate an overcoming of conceptual obstacles as well, such as cosmic teleology and fixism, therefore, building the concept of natural selection as a mechanism of biological evolution. The study of the consequences presents an improvement in students argumentative ability, a strong correlation between the use of data from biological evolution with the construction of higher quality arguments by the students, using justifications (warranty and theoretical support) grounded in scientific knowledge. Theres evidence of an expansion of the arguments construction, both increasing the number of used components as well as the field-dependent components of sciences quality, such as support and evidence. The arguments constructed shall provide support based on specific conceptual assistance in paradigms of Biology, like natural selection, validating the findings from the use of data (Toulmin, 2006) in researches conducted by students.
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Margolin, Yelena 1977. "Analysis of sequence-selective guanine oxidation by biological agents". Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/42381.
Abstract (sommario):
Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, February 2008.Vita.
Includes bibliographical references.
Oxidatively damaged DNA has been strongly associated with cancer, chronic degenerative diseases and aging. Guanine is the most frequently oxidized base in the DNA, and generation of a guanine radical cation (G'") as an intermediate in the oxidation reaction leads to migration of a resulting cationic hole through the DNA n-stack until it is trapped at the lowest-energy sites. These sites reside at runs of guanines, such as 5'-GG-3' sequences, and are characterized by the lowest sequence-specific ionization potentials (IPs). The charge transfer mechanism suggests that hotspots of oxidative DNA damage induced by electron transfer reagents can be predicted based on the primary DNA sequence. However, preliminary data indicated that nitrosoperoxycarbonate (ONOOCO2"), a mediator of chronic inflammation and a one-electron oxidant, displayed unusual guanine oxidation properties that were the focus of present work. As a first step in our study, we determined relative levels of guanine oxidation, induced by ONOOCO2 in all possible three-base sequence contexts (XGY) within double-stranded oligonucleotides. These levels were compared to the relative oxidation induced within the same guanines by photoactivated riboflavin, a one-electron reagent. We found that, in agreement with previous studies, photoactivated riboflavin was selective for guanines of lowest IPs located within 5'-GG-3' sequences. In contrast, ONOOCO2" preferentially reacted with guanines located within 5'-GC-3' sequences characterized by the highest IPs. This demonstrated that that sequence-specific IP was not a determinant of guanine reactivity with ONOOCO2". Sequence selectivities for both reagents were double-strand specific. Selectivity of ONOOCO2 for 5'-GC-3' sites was also observed in human genomic DNA after ligation-mediated PCR analysis.
(cont.) Relative yields of different guanine lesions produced by both ONOOCO2" and riboflavin varied 4- to 5-fold across all sequence contexts. To assess the role of solvent exposure in mediating guanine oxidation by ONOOCO2", relative reactivities of mismatched guanines with ONOOCO2" were measured. The majority of the mismatches displayed an increased reactivity with ONOOCO2 as compared to the fully matched G-C base-pairs. The extent of reactivity enhancement was sequence context-dependent, and the greatest levels of enhancement were observed for the conformationally flexible guanine- guanine (G-G) mismatches and for guanines located across from a synthetic abasic site. To test the hypothesis that the negative charge of an oxidant influences its reactivity with guanines in DNA, sequence-selective guanine oxidation by a negatively charged reagent, Fe+2-EDTA, was assessed and compared to guanine oxidation produced by a neutral oxidant, y-radiation. Because both of these agents cause high levels of deoxyribose oxidation, a general method to quantify sequence-specific nucleobase oxidation in the presence of direct strand breaks was developed. This method exploited activity of exonuclease III (Exo III), a 3' to 5' exonuclease, and utilized phosphorothioate-modified synthetic oligonucleotides that were resistant to Exo III activity. This method was employed to determine sequence-selective guanine oxidation by Fe+2-EDTA complex and y-radiation and to show that both agents produced identical guanine oxidation pattems and were equally reactive with all guanines, irrespective of their sequence-specific IPs or sequence context.
(cont.) This showed that negative charge was not a determinant of Fe+2-EDTA-mediated guanine oxidation. Finally, the role of oxidant binding on nucleobase damage was assessed by studying sequence-selective oxidation produced by DNA-bound Fe+2 ions in the presence of H202. We found that the major oxidation targets were thymines located within 5'-TGG-3' motifs, demonstrating that while guanines were a required element for coordination of Fe+2 to DNA, they were not oxidized. Our results suggest that factors other than sequence-specific IPs can act as major determinants of sequence-selective guanine oxidation, and that current models of guanine oxidation and charge transfer in DNA cannot be used to adequately predict the location and identity of mutagenic lesions in the genome.
by Yelena Margolin.
Ph.D.
45
Serres-Giardi, Laurana. "Diversité et évolution des paysages nucléotidiques des plantes". Thesis, Montpellier, SupAgro, 2012. http://www.theses.fr/2012NSAM0045/document.
Abstract (sommario):
Le paysage nucléotidique – la manière dont la composition nucléotidique varie le long du génome – est une caractéristique marquante de l'organisation des génomes et varie fortement entre espèces. Plusieurs hypothèses émergent des nombreux débats autour des mécanismes évolutifs à l'origine de ces hétérogénéités du taux de GC, parmi lesquelles la conversion génique biaisée vers G et C (BGC) et la sélection sur l'usage du code (SUC). La BGC est un processus neutre associé à la recombinaison qui favorise les allèles en G ou C au détriment des allèles en A ou T. La SUC est une force de sélection qui favorise les codons dits « préférés », ceux dont la traduction serait la plus efficace. Contrairement à ceux des vertébrés, les paysages nucléotidiques des plantes sont peu connus. La plupart des études ont été consacrées au génome d'Arabidopsis thaliana, pauvre en GC et homogène, et à celui du riz, riche en GC et hétérogène. Le contraste entre ces deux génomes a souvent été généralisé comme une dichotomie entre dicotylédones et monocotylédones, mais cette vision est clairement phylogénétiquement biaisée.Les objectifs de ce travail de thèse sont de caractériser les paysages nucléotidiques des angiospermes à une large échelle phylogénétique et de mieux comprendre quels sont les mécanismes évolutifs jouant sur l'évolution de ces paysages nucléotidiques. Comment varient les paysages nucléotidiques le long de la phylogénie des angiospermes ? SUC et BGC façonnent-elles ces paysages nucléotidiques ? Les différents taxons sont-ils affectés avec la même intensité ?Pour répondre à ces questions, j'ai utilisé une approche de génomique comparative basée sur l'analyse de données EST chez plus de 230 espèces d'angiospermes et de gymnospermes. L'exploration des paysages nucléotidiques de ce large éventail de plantes a montré que les patrons d'hétérogénéité des paysages nucléotidiques suivent un continuum le long de la phylogénie, avec des groupes particulièrement riches et hétérogènes en GC, les graminées par exemple. Mes résultats suggèrent que les paysages nucléotidiques des plantes pourraient avoir été façonnés par la BGC et, dans une moindre mesure, par la SUC. Des épisodes indépendants d'enrichissement et d'appauvrissement en GC ont vraisemblablement eu lieu au cours de l'évolution des plantes, et pourraient être expliqués par des variations d'intensité de ces mécanismes. En utilisant une prédiction du degré d'expression des EST, j'ai également mis en évidence une diversité dans les codons préférés entre espèces. Les préférences d'usage des codons se sont révélées plus labiles au cours de l'évolution pour les codons des acides aminés au code quatre et six fois dégénéré. J'ai pu lier l'évolution des préférences d'usage des codons à l'évolution de la composition nucléotidique des génomes. Mes résultats suggèrent que la composition en base des génomes, affectée en partie par la BGC, orienterait la coévolution entre préférence d'usage du code et ARNtThe nucleotide landscape – the way base composition varies along a genome – is a striking feature of genome organization and is highly variable between species. The evolutionary causes of such heterogeneity in GC content have been much debated. Biased gene conversion towards G and C (BGC) and selection on codon usage (SCU) are thought to be main forces. BGC is a neutral process associated with recombination favouring G and C alleles over A and T ones. SCU is a selection process favouring the so-called “preferred” codons, i.e., those whose translation is the most efficient. Contrary to vertebrates, plant nucleotide landscapes are still poorly known. Most studies focused on the GC-poor and homogeneous Arabidopsis thaliana genome and on the GC-rich and heterogeneous rice genome. The contrast between these two genomes was often generalized as a dicot/monocot dichotomy but this vision is clearly phylogenetically biased.The objectives of this study are to characterize angiosperm nucleotide landscapes on a wide phylogenetic scale and to better understand the evolutionary mechanisms acting upon the evolution of nucleotide landscapes. To what extent do nucleotide landscapes vary across angiosperm phylogeny? Are nucleotide landscapes shaped by BGC and SCU? Are taxa affected with the same intensity?To tackle these issues, I used a comparative genomic approach relying on EST data analysis on over 230 angiosperm and gymnosperm species. Through the nucleotide landscape survey for such a wide range of species I found a continuum of GC-heterogeneity patterns across phylogeny, some taxa such as Poaceae being strikingly GC-rich and heterogeneous. My results suggest that nucleotide landscapes could have been shaped by BGC and, to a lesser extent, by SCU. GC-content enrichment and impoverishment are likely to have occurred several times independently during plant evolution and could be explained by intensity variations of BGC and SCU. Using a proxy for EST expression level, I also characterized the diversity of preferred codons between species. Codon usage preferences were shown to be evolutionarily more unstable for four- and six-fold degenerate codon families. Finally, I could link the evolution of codon usage preferences to the evolution of genome base composition. My results suggest that genome base composition, partially shaped by BGC, seems to drive the coevolution between codon usage preferences and tRNAs
46
Vázquez, García Ignacio. "Molecular evolution of biological sequences". Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/284174.
Abstract (sommario):
Evolution is an ubiquitous feature of living systems. The genetic composition of a population changes in response to the primary evolutionary forces: mutation, selection and genetic drift. Organisms undergoing rapid adaptation acquire multiple mutations that are physically linked in the genome, so their fates are mutually dependent and selection only acts on these loci in their entirety. This aspect has been largely overlooked in the study of asexual or somatic evolution and plays a major role in the evolution of bacterial and viral infections and cancer. In this thesis, we put forward a theoretical description for a minimal model of evolutionary dynamics to identify driver mutations, which carry a large positive fitness effect, among passenger mutations that hitchhike on successful genomes. We examine the effect this mode of selection has on genomic patterns of variation to infer the location of driver mutations and estimate their selection coefficient from time series of mutation frequencies. We then present a probabilistic model to reconstruct genotypically distinct lineages in mixed cell populations from DNA sequencing. This method uses Hidden Markov Models for the deconvolution of genetically diverse populations and can be applied to clonal admixtures of genomes in any asexual population, from evolving pathogens to the somatic evolution of cancer. To understand the effects of selection on rapidly adapting populations, we constructed sequence ensembles in a recombinant library of budding yeast (S. cerevisiae). Using DNA sequencing, we characterised the directed evolution of these populations under selective inhibition of rate-limiting steps of the cell cycle. We observed recurrent patterns of adaptive mutations and characterised common mutational processes, but the spectrum of mutations at the molecular level remained stochastic. Finally, we investigated the effect of genetic variation on the fate of new mutations, which gives rise to complex evolutionary dynamics. We demonstrate that the fitness variance of the population can set a selective threshold on new mutations, setting a limit to the efficiency of selection. In summary, we combined statistical analyses of genomic sequences, mathematical models of evolutionary dynamics and experiments in molecular evolution to advance our understanding of rapid adaptation. Our results open new avenues in our understanding of population dynamics that can be translated to a range of biological systems.
47
Millan, Kelly M. "The development and application of a sequence-selective DNA sensor". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq25910.pdf.
48
Waterloh, Kerstin. "The effects of sequence selective antitumour antibiotics on DNA structure". Thesis, University of Southampton, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385333.
49
Doherty, Aidan Joseph. "Studies on the sequence-selective nuclease, bovine pancreatic DNase I". Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359221.
50
Lin, S. "Molecular and cellular evaluation of novel DNA sequence selective polyamides". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1403138/.
Abstract (sommario):
Pyrrole (P)-Imidazole (I) containing polyamides are small synthetic molecules which can target predetermined DNA sequences with high affinity and modulate gene expression by interfering with the binding of transcription factors to DNA. Hairpin and H-pin analogues show enhanced DNA binding affinity and selectivity compared to monomers, but are associated with poor cellular uptake. To address this problem, a new class of unlinked polyamide precursors containing appropriately designed pendant reactive and biocompatible functional groups is presented in this thesis. The ability of these agents to interact in situ and potentially form either H-pin or Hairpin conjugates was tested with DNase I footprinting analysis. The effects of modification on the formamido-imidazole-pyrrole-imidazole (f-IPI) polyamide and related analogues, by the addition of an amino group, on DNA binding affinity and sequence selectivity were also evaluated. Dbf4 is the regulatory subunit of Cdc7 kinase, which is essential for the initiation of DNA replication. Human Cdc7/Dbf4 (HuCdc7/Dbf4) kinase activity is critical for cell proliferation and high expression levels occur in multiple solid human malignancies. F-IPI can target the MIuI Cell cycle Box (MCB) sequence 5’-ACGCGT-3’which is the critical site for transcription factor binding and activation of expression of the HuCdc7/Dbf4 core gene in mammalian cells. DNA sequence selective binding of f-IPI to the MCB sequence was shown in DNase I footrpinting experiments. A f-IPI-induced, dose-dependent inhibition of protein binding to the MCB was demonstrated in an Electrophoretic Mobility Shift Assay (EMSA). RT-PCR and immunoblotting analysis confirmed the inhibitory effects of f-IPI on HuDbf4 in MDA-MB231 cells. Small interfering RNA-mediated depletion of HuDbf4 decreased cell survival and proliferation, and induced G1 arrest in MDA-MB231 cells. F-IPI treatments also showed a dose-dependent reduction of cell survival and proliferation and induced G1 arrest. Although the f-IPI H-pin analogue exhibited better DNA binding affinity and protein inhibition, no marked effects at mRNA and protein levels were detected in cells, likely attributed to its large size. The unlinked f-IPI analogues containing reactive groups [i.e f-IP(C3NH2)I and f-IP(C3Cl)I] able to interact in situ and form H-pin were tested in the Dbf4 promoter model system. f-IP(C3NH2)I presented the same DNA binding affinity and protein inhibition to the MCB as the combination of f-IP(C3NH2)I and f-IP(C3Cl)I (potential hybrid) but it produced much higher effects than f-IP(C3Cl)I. RT-PCR and immunoblotting analysis showed that the potential hybrid produced greater reduction of HuDbf4 mRNA and protein levels than either f-IP(C3NH2)I or f-IP(C3Cl)I. In addition, the potential hybrid demonstrated greater G1 arrest than each polyamide alone. Finally, a series of fluorescent f-IPI analogues are presented, providing an intrinsic probe for monitoring the cellular uptake of polyamides. Aza-Hx-PI was shown to target the same sequence as f-IPI (DNase I footprinting), inhibit protein binding (EMSA) and reduce the levels of HuDbf4 in cells. Time and dose-dependent nuclear localisation was detected by confocal microscopy. Overall the data presented in this thesis highlight the potential of small molecule polyamides as modulators of gene expression.