Network-based approach for post genome-wide association study analysis in admixed populations

Includes abstract.Includes bibliographical references.In this project, we review some existing pathway-based approaches for GWA study analyses, by exploring different implemented methods for combining effects of multiple modest genetic variants at gene and pathway levels. We then propose a graph-based method, ancGWAS, that incorporates the signal from GWA study, and the locus-specific ancestry into the human protein-protein interaction (PPI) network to identify significant sub-networks or pathways associated with the trait of interest. This network-based method applies centrality measures within linkage disequilibrium (LD) on the network to search for pathways and applies a scoring summary statistic on the resulting pathways to identify the most enriched pathways associated with complex diseases

Computing hybridization networks using agreement forests

Rooted phylogenetic trees are widely used in biology to represent the evolutionary history of certain species. Usually, such a tree is a simple binary tree only containing internal nodes of in-degree one and out-degree two representing specific speciation events. In applied phylogenetics, however, trees can contain nodes of out-degree larger than two because, often, in order to resolve some orderings of speciation events, there is only insufficient information available and the common way to model this uncertainty is to use nonbinary nodes (i.e., nodes of out-degree of at least three), also denoted as polytomies. Moreover, in addition to such speciation events, there exist certain biological events that cannot be modeled by a tree and, thus, require the more general concept of rooted phylogenetic networks or, more specifically, of hybridization networks. Examples for such reticulate events are horizontal gene transfer, hybridization, and recombination. Nevertheless, in order to construct hybridization networks, the less general concept of a phylogenetic tree can still be used as building block. More precisely, often, in a first step, phylogenetic trees for a set of species, each based on a distinctive orthologous gene, are constructed. In a second step, specific sets containing common subtrees of those trees, known as maximum acyclic agreement forests, are calculated, which are then glued together to a single hybridization network. In such a network, hybridization nodes (i.e., nodes of in-degree larger than or equal to two) can exist representing potential reticulate events of the underlying evolutionary history. As such events are considered as rare phenomena, from a biological point of view, especially those networks representing a minimum number of reticulate events, which is denoted as hybridization number, are of high interest. Consequently, in a mathematical aspect, the problem of calculating hybridization networks can be briefly described as follows. Given a set T of rooted phylogenetic trees sharing the same set of taxa, compute a hybridization network N displaying T with minimum hybridization number. In this context, we say that such a network N displays a phylogenetic tree T, if we can obtain T from N by removing as well as contracting some of its nodes and edges. Unfortunately, this is a computational hard problem (i.e., it is NP-hard), even for the simplest case given just two binary input trees. In this thesis, we present several methods tackling this NP-hard problem. Our first approach describes how to compute a representative set of minimum hybridization networks for two binary input trees. For that purpose, our approach implements the first non-naive algorithm - called allMAAFs - calculating all maximum acyclic agreement forests for two rooted binary phylogenetic trees on the same set of taxa. In a subsequent step, in order to maximize the efficiency of the algorithm allMAAFs, we have developed additionally several modifications each reducing the number of computational steps and, thus, significantly improving its practical runtime. Our second approach is an extension of our first approach making the underlying algorithm accessible to more than two binary input trees. For this purpose, our approach implements the algorithm allHNetworks being the first algorithm calculating all relevant hybridization networks displaying a set of rooted binary phylogenetic trees on the same set of taxa, which is a preferable feature when studying hybridization events. Lastly, we have developed a generalization of our second approach that can now deal with multiple nonbinary input trees. For that purpose, our approach implements the first non-naive algorithm - called allMulMAAFs - calculating a relevant set of nonbinary maximum acyclic agreement forests for two rooted (nonbinary) phylogenetic trees on the same set of taxa. Each of the algorithms above is integrated into our user friendly Java-based software package Hybroscale, which is freely available and platform independent, so that it runs on all major operating systems. Our program provides a graphical user interface for visualizing trees and networks. Moreover, it facilitates the interpretation of computed hybridization networks by adding specific features to its graphical representation and, thus, supports biologists in investigating reticulate evolution. In addition, we have implemented a method using a user friendly SQL-style modeling language for filtering the usually large amount of reported networks

Exploiting Intrinsic Clustering Structure in Discrete-Valued Data Sets for Efficient Knowledge Discovery in the Presence of Missing Data

Scalable algorithm design has become central in the era of large-scale data analysis. The vast amounts of data pouring in from a diverse set of application domains, such as bioinformatics, recommender systems, sensor systems, and social networks, cannot be analyzed efficiently using many data mining and statistical tools that were designed for a small scale setting. It is an ongoing challenge to the data mining, machine learning, and statistics communities to design new methods for efficient data analysis. Confounding this challenge is the noisy and incomplete nature of real-world data sets. Research scientists as well as practitioners in industry need to find meaningful patterns in data with missing value rates often as high as 99%, in addition to errors in the data that can obstruct accurate analyses. My contribution to this line of research is the design of new algorithms for scalable clustering, data reduction, and similarity evaluation by exploiting inherent clustering structure in the input data to overcome the challenges of significant amounts of missing entries. I demonstrate that, by focusing on underlying clustering properties of the data, we can improve the efficiency of several data analysis methods on sparse, discrete-valued data sets. I highlight new methods that I have developed with my collaborators for three diverse knowledge discovery tasks: (1) clustering genetic markers into linkage groups, (2) reducing large-scale genetic data to a much smaller, more accurate representative data set, and (3) computing similarity between users in recommender systems. In each case, I point out how the underlying clustering structure can be used to design more efficient algorithms, even when high missing value rates are present

Exploring the Non-vertical Component of Bacterial Evolution Using Network Structures

The central tree metaphor has been challenged over the last couple of decades with the observation of incongruent trees derived largely from protein-coding genes in prokaryotic genomes. There are an increasing number of evolutionary processes and entities that confuse and confound the traditional understanding of evolution. As a result, these processes and entities are very often omitted from phylogenetic studies altogether. In this thesis I attempt to uncover the importance of non-tree like evolution. I discuss the types of genes that do not adhere to vertical patterns of inheritance such as fusion genes and mobile genetic elements. Furthermore I explore the alternative of using network structures in describing the evolutionary history of bacteria. This thesis recounts two key uses of networks for revealing the less commonly noted aspects of bacterial evolution. Firstly I present each stage in the development of a new method for identifying fusions of unrelated genes from conception of the idea, through the implementation to its application to data. Secondly I use networks of gene sharing to elucidate patterns of divergence among a group of closely related bacteria that would have once formed a single species cloud. These studies reveal an abundance of the types of genes that contradict traditional tree-thinking and support the notion that a strictly vertical view of evolution is inadequate when describing bacterial relationships

'Accept no limits': imaginaries of life, responsibility and biosafety in xenobiology

Researchers in the emerging field of xenobiology aim to explore the non-canonical (or non-natural) biological world through the development of alternative genetic systems and chemistries. This discipline may help us better understand the origin of life, as well as enable the development of biological systems with built-in safety features (biocontainment). The development of xenobiology is assumed to be guided by goals, narratives, imaginaries and visions of possible futures, whose 'opening up' and examination are the central question of this thesis. This thesis combines work in science and technology studies and ‘responsible research and innovation.’ It focuses on the values, assumptions and “sociotechnical imaginaries” that drive the development of xenobiology, in terms of how xenobiologists understand and redefine life, and how they construct promises of biosafety through biocontainment. The thesis’ argument draws on semi-structured interviews with scientists in the fields of synthetic biology and xenobiology. In addition, I conducted a year-long participant observation in a xenobiology laboratory located in London. This thesis argues that two sociotechnical imaginaries lead the development of xenobiology. The first is about redefining life, or “life unbound,” according to which the biological universe is thought to include (or navigate) novel biological worlds. Second, an imaginary of ‘controllable emergence’ accounts for claims of biosafety and governance by containment, a response to the collective imagination of the public who are fearful and concerned about release, and portrays scientists as responsible by pursuing safety. As xenobiologists test the limits of what is biologically possible, they also test the limits of what is socially acceptable. I describe how xenobiologists, in order to justify research in their field, draw on existing legacies of governance, such as the Asilomar Conference, and previous controversies over genetically modified crops. These legacies are still in use because they allow scientists to turn questions about governance into questions about design and science. These assumptions, shared by science funders, help to attract resources and visibility to the field, as well as legitimize the release of genetically modified microorganisms. This thesis concludes by suggesting that xenobiology should be open to uncertainty and frameworks that give up control in exchange for deliberation and reframing of problems as technologies advance, following ideas of real-world experimentation and collective experimentation

Differential evolution of non-coding DNA across eukaryotes and its close relationship with complex multicellularity on Earth

Here, I elaborate on the hypothesis that complex multicellularity (CM, sensu Knoll) is a major evolutionary transition (sensu Szathmary), which has convergently evolved a few times in Eukarya only: within red and brown algae, plants, animals, and fungi. Paradoxically, CM seems to correlate with the expansion of non-coding DNA (ncDNA) in the genome rather than with genome size or the total number of genes. Thus, I investigated the correlation between genome and organismal complexities across 461 eukaryotes under a phylogenetically controlled framework. To that end, I introduce the first formal definitions and criteria to distinguish ‘unicellularity’, ‘simple’ (SM) and ‘complex’ multicellularity. Rather than using the limited available estimations of unique cell types, the 461 species were classified according to our criteria by reviewing their life cycle and body plan development from literature. Then, I investigated the evolutionary association between genome size and 35 genome-wide features (introns and exons from protein-coding genes, repeats and intergenic regions) describing the coding and ncDNA complexities of the 461 genomes. To that end, I developed ‘GenomeContent’, a program that systematically retrieves massive multidimensional datasets from gene annotations and calculates over 100 genome-wide statistics. R-scripts coupled to parallel computing were created to calculate >260,000 phylogenetic controlled pairwise correlations. As previously reported, both repetitive and non-repetitive DNA are found to be scaling strongly and positively with genome size across most eukaryotic lineages. Contrasting previous studies, I demonstrate that changes in the length and repeat composition of introns are only weakly or moderately associated with changes in genome size at the global phylogenetic scale, while changes in intron abundance (within and across genes) are either not or only very weakly associated with changes in genome size. Our evolutionary correlations are robust to: different phylogenetic regression methods, uncertainties in the tree of eukaryotes, variations in genome size estimates, and randomly reduced datasets. Then, I investigated the correlation between the 35 genome-wide features and the cellular complexity of the 461 eukaryotes with phylogenetic Principal Component Analyses. Our results endorse a genetic distinction between SM and CM in Archaeplastida and Metazoa, but not so clearly in Fungi. Remarkably, complex multicellular organisms and their closest ancestral relatives are characterized by high intron-richness, regardless of genome size. Finally, I argue why and how a vast expansion of non-coding RNA (ncRNA) regulators rather than of novel protein regulators can promote the emergence of CM in Eukarya. As a proof of concept, I co-developed a novel ‘ceRNA-motif pipeline’ for the prediction of “competing endogenous” ncRNAs (ceRNAs) that regulate microRNAs in plants. We identified three candidate ceRNAs motifs: MIM166, MIM171 and MIM159/319, which were found to be conserved across land plants and be potentially involved in diverse developmental processes and stress responses. Collectively, the findings of this dissertation support our hypothesis that CM on Earth is a major evolutionary transition promoted by the expansion of two major ncDNA classes, introns and regulatory ncRNAs, which might have boosted the irreversible commitment of cell types in certain lineages by canalizing the timing and kinetics of the eukaryotic transcriptome.:Cover page Abstract Acknowledgements Index 1. The structure of this thesis 1.1. Structure of this PhD dissertation 1.2. Publications of this PhD dissertation 1.3. Computational infrastructure and resources 1.4. Disclosure of financial support and information use 1.5. Acknowledgements 1.6. Author contributions and use of impersonal and personal pronouns 2. Biological background 2.1. The complexity of the eukaryotic genome 2.2. The problem of counting and defining “genes” in eukaryotes 2.3. The “function” concept for genes and “dark matter” 2.4. Increases of organismal complexity on Earth through multicellularity 2.5. Multicellularity is a “fitness transition” in individuality 2.6. The complexity of cell differentiation in multicellularity 3. Technical background 3.1. The Phylogenetic Comparative Method (PCM) 3.2. RNA secondary structure prediction 3.3. Some standards for genome and gene annotation 4. What is in a eukaryotic genome? GenomeContent provides a good answer 4.1. Background 4.2. Motivation: an interoperable tool for data retrieval of gene annotations 4.3. Methods 4.4. Results 4.5. Discussion 5. The evolutionary correlation between genome size and ncDNA 5.1. Background 5.2. Motivation: estimating the relationship between genome size and ncDNA 5.3. Methods 5.4. Results 5.5. Discussion 6. The relationship between non-coding DNA and Complex Multicellularity 6.1. Background 6.2. Motivation: How to define and measure complex multicellularity across eukaryotes? 6.3. Methods 6.4. Results 6.5. Discussion 7. The ceRNA motif pipeline: regulation of microRNAs by target mimics 7.1. Background 7.2. A revisited protocol for the computational analysis of Target Mimics 7.3. Motivation: a novel pipeline for ceRNA motif discovery 7.4. Methods 7.5. Results 7.6. Discussion 8. Conclusions and outlook 8.1. Contributions and lessons for the bioinformatics of large-scale comparative analyses 8.2. Intron features are evolutionarily decoupled among themselves and from genome size throughout Eukarya 8.3. “Complex multicellularity” is a major evolutionary transition 8.4. Role of RNA throughout the evolution of life and complex multicellularity on Earth 9. Supplementary Data Bibliography Curriculum Scientiae Selbständigkeitserklärung (declaration of authorship