A clique-based method for the edit distance between unordered trees and its application to analysis of glycan structures

[Background]Measuring similarities between tree structured data is important for analysis of RNA secondary structures, phylogenetic trees, glycan structures, and vascular trees. The edit distance is one of the most widely used measures for comparison of tree structured data. However, it is known that computation of the edit distance for rooted unordered trees is NP-hard. Furthermore, there is almost no available software tool that can compute the exact edit distance for unordered trees. [Results]In this paper, we present a practical method for computing the edit distance between rooted unordered trees. In this method, the edit distance problem for unordered trees is transformed into the maximum clique problem and then efficient solvers for the maximum clique problem are applied. We applied the proposed method to similar structure search for glycan structures. The result suggests that our proposed method can efficiently compute the edit distance for moderate size unordered trees. It also suggests that the proposed method has the accuracy comparative to those by the edit distance for ordered trees and by an existing method for glycan search. [Conclusions]The proposed method is simple but useful for computation of the edit distance between unordered trees. The object code is available upon request

Tree Echo State Networks

In this paper we present the Tree Echo State Network (TreeESN) model, generalizing the paradigm of Reservoir Computing to tree structured data. TreeESNs exploit an untrained generalized recursive reservoir, exhibiting extreme efficiency for learning in structured domains. In addition, we highlight through the paper other characteristics of the approach: First, we discuss the Markovian characterization of reservoir dynamics, extended to the case of tree domains, that is implied by the contractive setting of the TreeESN state transition function. Second, we study two types of state mapping functions to map the tree structured state of TreeESN into a fixed-size feature representation for classification or regression tasks. The critical role of the relation between the choice of the state mapping function and the Markovian characterization of the task is analyzed and experimentally investigated on both artificial and real-world tasks. Finally, experimental results on benchmark and real-world tasks show that the TreeESN approach, in spite of its efficiency, can achieve comparable results with state-of-the-art, although more complex, neural and kernel based models for tree structured data

Tree Edit Distance Learning via Adaptive Symbol Embeddings

Metric learning has the aim to improve classification accuracy by learning a distance measure which brings data points from the same class closer together and pushes data points from different classes further apart. Recent research has demonstrated that metric learning approaches can also be applied to trees, such as molecular structures, abstract syntax trees of computer programs, or syntax trees of natural language, by learning the cost function of an edit distance, i.e. the costs of replacing, deleting, or inserting nodes in a tree. However, learning such costs directly may yield an edit distance which violates metric axioms, is challenging to interpret, and may not generalize well. In this contribution, we propose a novel metric learning approach for trees which we call embedding edit distance learning (BEDL) and which learns an edit distance indirectly by embedding the tree nodes as vectors, such that the Euclidean distance between those vectors supports class discrimination. We learn such embeddings by reducing the distance to prototypical trees from the same class and increasing the distance to prototypical trees from different classes. In our experiments, we show that BEDL improves upon the state-of-the-art in metric learning for trees on six benchmark data sets, ranging from computer science over biomedical data to a natural-language processing data set containing over 300,000 nodes.Comment: Paper at the International Conference of Machine Learning (2018), 2018-07-10 to 2018-07-15 in Stockholm, Swede

Linear-time algorithms for the subpath kernel

The subpath kernel is a useful positive definite kernel, which takes arbitrary rooted trees as input, no matter whether they are ordered or unordered, We first show that the subpath kernel can exhibit excellent classification performance in combination with SVM through an intensive experiment. Secondly, we develop a theory of irreducible trees, and then, using it as a rigid mathematical basis, reconstruct a bottom-up linear-time algorithm for the subtree kernel, which is a correction of an algorithm well-known in the literature. Thirdly, we show a novel top-down algorithm, with which we can realize a linear-time parallel-computing algorithm to compute the subpath kernel

Cross-species network and transcript transfer

Metabolic processes, signal transduction, gene regulation, as well as gene and protein expression are largely controlled by biological networks. High-throughput experiments allow the measurement of a wide range of cellular states and interactions. However, networks are often not known in detail for specific biological systems and conditions. Gene and protein annotations are often transferred from model organisms to the species of interest. Therefore, the question arises whether biological networks can be transferred between species or whether they are specific for individual contexts. In this thesis, the following aspects are investigated: (i) the conservation and (ii) the cross-species transfer of eukaryotic protein-interaction and gene regulatory (transcription factor- target) networks, as well as (iii) the conservation of alternatively spliced variants. In the simplest case, interactions can be transferred between species, based solely on the sequence similarity of the orthologous genes. However, such a transfer often results either in the transfer of only a few interactions (medium/high sequence similarity threshold) or in the transfer of many speculative interactions (low sequence similarity threshold). Thus, advanced network transfer approaches also consider the annotations of orthologous genes involved in the interaction transfer, as well as features derived from the network structure, in order to enable a reliable interaction transfer, even between phylogenetically very distant species. In this work, such an approach for the transfer of protein interactions is presented (COIN). COIN uses a sophisticated machine-learning model in order to label transferred interactions as either correctly transferred (conserved) or as incorrectly transferred (not conserved). The comparison and the cross-species transfer of regulatory networks is more difficult than the transfer of protein interaction networks, as a huge fraction of the known regulations is only described in the (not machine-readable) scientific literature. In addition, compared to protein interactions, only a few conserved regulations are known, and regulatory elements appear to be strongly context-specific. In this work, the cross-species analysis of regulatory interaction networks is enabled with software tools and databases for global (ConReg) and thousands of context-specific (CroCo) regulatory interactions that are derived and integrated from the scientific literature, binding site predictions and experimental data. Genes and their protein products are the main players in biological networks. However, to date, the aspect is neglected that a gene can encode different proteins. These alternative proteins can differ strongly from each other with respect to their molecular structure, function and their role in networks. The identification of conserved and species-specific splice variants and the integration of variants in network models will allow a more complete cross-species transfer and comparison of biological networks. With ISAR we support the cross-species transfer and comparison of alternative variants by introducing a gene-structure aware (i.e. exon-intron structure aware) multiple sequence alignment approach for variants from orthologous and paralogous genes. The methods presented here and the appropriate databases allow the cross-species transfer of biological networks, the comparison of thousands of context-specific networks, and the cross-species comparison of alternatively spliced variants. Thus, they can be used as a starting point for the understanding of regulatory and signaling mechanisms in many biological systems.In biologischen Systemen werden Stoffwechselprozesse, Signalübertragungen sowie die Regulation von Gen- und Proteinexpression maßgeblich durch biologische Netzwerke gesteuert. Hochdurchsatz-Experimente ermöglichen die Messung einer Vielzahl von zellulären Zuständen und Wechselwirkungen. Allerdings sind für die meisten Systeme und Kontexte biologische Netzwerke nach wie vor unbekannt. Gen- und Proteinannotationen werden häufig von Modellorganismen übernommen. Demnach stellt sich die Frage, ob auch biologische Netzwerke und damit die systemischen Eigenschaften ähnlich sind und übertragen werden können. In dieser Arbeit wird: (i) Die Konservierung und (ii) die artenübergreifende Übertragung von eukaryotischen Protein-Interaktions- und regulatorischen (Transkriptionsfaktor-Zielgen) Netzwerken, sowie (iii) die Konservierung von Spleißvarianten untersucht. Interaktionen können im einfachsten Fall nur auf Basis der Sequenzähnlichkeit zwischen orthologen Genen übertragen werden. Allerdings führt eine solche Übertragung oft dazu, dass nur sehr wenige Interaktionen übertragen werden können (hoher bis mittlerer Sequenzschwellwert) oder dass ein Großteil der übertragenden Interaktionen sehr spekulativ ist (niedriger Sequenzschwellwert). Verbesserte Methoden berücksichtigen deswegen zusätzlich noch die Annotationen der Orthologen, Eigenschaften der Interaktionspartner sowie die Netzwerkstruktur und können somit auch Interaktionen auf phylogenetisch weit entfernte Arten (zuverlässig) übertragen. In dieser Arbeit wird ein solcher Ansatz für die Übertragung von Protein-Interaktionen vorgestellt (COIN). COIN verwendet Verfahren des maschinellen Lernens, um Interaktionen als richtig (konserviert) oder als falsch übertragend (nicht konserviert) zu klassifizieren. Der Vergleich und die artenübergreifende Übertragung von regulatorischen Interaktionen ist im Vergleich zu Protein-Interaktionen schwieriger, da ein Großteil der bekannten Regulationen nur in der (nicht maschinenlesbaren) wissenschaftlichen Literatur beschrieben ist. Zudem sind im Vergleich zu Protein-Interaktionen nur wenige konservierte Regulationen bekannt und regulatorische Elemente scheinen stark kontextabhängig zu sein. In dieser Arbeit wird die artenübergreifende Analyse von regulatorischen Netzwerken mit Softwarewerkzeugen und Datenbanken für globale (ConReg) und kontextspezifische (CroCo) regulatorische Interaktionen ermöglicht. Regulationen wurden dafür aus Vorhersagen, experimentellen Daten und aus der wissenschaftlichen Literatur abgeleitet und integriert. Grundbaustein für viele biologische Netzwerke sind Gene und deren Proteinprodukte. Bisherige Netzwerkmodelle vernachlässigen allerdings meist den Aspekt, dass ein Gen verschiedene Proteine kodieren kann, die sich von der Funktion, der Proteinstruktur und der Rolle in Netzwerken stark voneinander unterscheiden können. Die Identifizierung von konservierten und artspezifischen Proteinprodukten und deren Integration in Netzwerkmodelle würde einen vollständigeren Übertrag und Vergleich von Netzwerken ermöglichen. In dieser Arbeit wird der artenübergreifende Vergleich von Proteinprodukten mit einem multiplen Sequenzalignmentverfahren für alternative Varianten von paralogen und orthologen Genen unterstützt, unter Berücksichtigung der bekannten Exon-Intron-Grenzen (ISAR). Die in dieser Arbeit vorgestellten Verfahren, Datenbanken und Softwarewerkzeuge ermöglichen die Übertragung von biologischen Netzwerken, den Vergleich von tausenden kontextspezifischen Netzwerken und den artenübergreifenden Vergleich von alternativen Varianten. Sie können damit die Ausgangsbasis für ein Verständnis von Kommunikations- und Regulationsmechanismen in vielen biologischen Systemen bilden

Metric Learning for Structured Data

Paaßen B. Metric Learning for Structured Data. Bielefeld: Universität Bielefeld; 2019.Distance measures form a backbone of machine learning and information retrieval in many application fields such as computer vision, natural language processing, and biology. However, general-purpose distances may fail to capture semantic particularities of a domain, leading to wrong inferences downstream. Motivated by such failures, the field of metric learning has emerged. Metric learning is concerned with learning a distance measure from data which pulls semantically similar data closer together and pushes semantically dissimilar data further apart. Over the past decades, metric learning approaches have yielded state-of-the-art results in many applications. Unfortunately, these successes are mostly limited to vectorial data, while metric learning for structured data remains a challenge. In this thesis, I present a metric learning scheme for a broad class of sequence edit distances which is compatible with any differentiable cost function, and a scalable, interpretable, and effective tree edit distance learning scheme, thus pushing the boundaries of metric learning for structured data. Furthermore, I make learned distances more useful by providing a novel algorithm to perform time series prediction solely based on distances, a novel algorithm to infer a structured datum from edit distances, and a novel algorithm to transfer a learned distance to a new domain using only little data and computation time. Finally, I apply these novel algorithms to two challenging application domains. First, I support students in intelligent tutoring systems. If a student gets stuck before completing a learning task, I predict how capable students would proceed in their situation and guide the student in that direction via edit hints. Second, I use transfer learning to counteract disturbances for bionic hand prostheses to make these prostheses more robust in patients' everyday lives

Cross-species network and transcript transfer

Metabolic processes, signal transduction, gene regulation, as well as gene and protein expression are largely controlled by biological networks. High-throughput experiments allow the measurement of a wide range of cellular states and interactions. However, networks are often not known in detail for specific biological systems and conditions. Gene and protein annotations are often transferred from model organisms to the species of interest. Therefore, the question arises whether biological networks can be transferred between species or whether they are specific for individual contexts. In this thesis, the following aspects are investigated: (i) the conservation and (ii) the cross-species transfer of eukaryotic protein-interaction and gene regulatory (transcription factor- target) networks, as well as (iii) the conservation of alternatively spliced variants. In the simplest case, interactions can be transferred between species, based solely on the sequence similarity of the orthologous genes. However, such a transfer often results either in the transfer of only a few interactions (medium/high sequence similarity threshold) or in the transfer of many speculative interactions (low sequence similarity threshold). Thus, advanced network transfer approaches also consider the annotations of orthologous genes involved in the interaction transfer, as well as features derived from the network structure, in order to enable a reliable interaction transfer, even between phylogenetically very distant species. In this work, such an approach for the transfer of protein interactions is presented (COIN). COIN uses a sophisticated machine-learning model in order to label transferred interactions as either correctly transferred (conserved) or as incorrectly transferred (not conserved). The comparison and the cross-species transfer of regulatory networks is more difficult than the transfer of protein interaction networks, as a huge fraction of the known regulations is only described in the (not machine-readable) scientific literature. In addition, compared to protein interactions, only a few conserved regulations are known, and regulatory elements appear to be strongly context-specific. In this work, the cross-species analysis of regulatory interaction networks is enabled with software tools and databases for global (ConReg) and thousands of context-specific (CroCo) regulatory interactions that are derived and integrated from the scientific literature, binding site predictions and experimental data. Genes and their protein products are the main players in biological networks. However, to date, the aspect is neglected that a gene can encode different proteins. These alternative proteins can differ strongly from each other with respect to their molecular structure, function and their role in networks. The identification of conserved and species-specific splice variants and the integration of variants in network models will allow a more complete cross-species transfer and comparison of biological networks. With ISAR we support the cross-species transfer and comparison of alternative variants by introducing a gene-structure aware (i.e. exon-intron structure aware) multiple sequence alignment approach for variants from orthologous and paralogous genes. The methods presented here and the appropriate databases allow the cross-species transfer of biological networks, the comparison of thousands of context-specific networks, and the cross-species comparison of alternatively spliced variants. Thus, they can be used as a starting point for the understanding of regulatory and signaling mechanisms in many biological systems.In biologischen Systemen werden Stoffwechselprozesse, Signalübertragungen sowie die Regulation von Gen- und Proteinexpression maßgeblich durch biologische Netzwerke gesteuert. Hochdurchsatz-Experimente ermöglichen die Messung einer Vielzahl von zellulären Zuständen und Wechselwirkungen. Allerdings sind für die meisten Systeme und Kontexte biologische Netzwerke nach wie vor unbekannt. Gen- und Proteinannotationen werden häufig von Modellorganismen übernommen. Demnach stellt sich die Frage, ob auch biologische Netzwerke und damit die systemischen Eigenschaften ähnlich sind und übertragen werden können. In dieser Arbeit wird: (i) Die Konservierung und (ii) die artenübergreifende Übertragung von eukaryotischen Protein-Interaktions- und regulatorischen (Transkriptionsfaktor-Zielgen) Netzwerken, sowie (iii) die Konservierung von Spleißvarianten untersucht. Interaktionen können im einfachsten Fall nur auf Basis der Sequenzähnlichkeit zwischen orthologen Genen übertragen werden. Allerdings führt eine solche Übertragung oft dazu, dass nur sehr wenige Interaktionen übertragen werden können (hoher bis mittlerer Sequenzschwellwert) oder dass ein Großteil der übertragenden Interaktionen sehr spekulativ ist (niedriger Sequenzschwellwert). Verbesserte Methoden berücksichtigen deswegen zusätzlich noch die Annotationen der Orthologen, Eigenschaften der Interaktionspartner sowie die Netzwerkstruktur und können somit auch Interaktionen auf phylogenetisch weit entfernte Arten (zuverlässig) übertragen. In dieser Arbeit wird ein solcher Ansatz für die Übertragung von Protein-Interaktionen vorgestellt (COIN). COIN verwendet Verfahren des maschinellen Lernens, um Interaktionen als richtig (konserviert) oder als falsch übertragend (nicht konserviert) zu klassifizieren. Der Vergleich und die artenübergreifende Übertragung von regulatorischen Interaktionen ist im Vergleich zu Protein-Interaktionen schwieriger, da ein Großteil der bekannten Regulationen nur in der (nicht maschinenlesbaren) wissenschaftlichen Literatur beschrieben ist. Zudem sind im Vergleich zu Protein-Interaktionen nur wenige konservierte Regulationen bekannt und regulatorische Elemente scheinen stark kontextabhängig zu sein. In dieser Arbeit wird die artenübergreifende Analyse von regulatorischen Netzwerken mit Softwarewerkzeugen und Datenbanken für globale (ConReg) und kontextspezifische (CroCo) regulatorische Interaktionen ermöglicht. Regulationen wurden dafür aus Vorhersagen, experimentellen Daten und aus der wissenschaftlichen Literatur abgeleitet und integriert. Grundbaustein für viele biologische Netzwerke sind Gene und deren Proteinprodukte. Bisherige Netzwerkmodelle vernachlässigen allerdings meist den Aspekt, dass ein Gen verschiedene Proteine kodieren kann, die sich von der Funktion, der Proteinstruktur und der Rolle in Netzwerken stark voneinander unterscheiden können. Die Identifizierung von konservierten und artspezifischen Proteinprodukten und deren Integration in Netzwerkmodelle würde einen vollständigeren Übertrag und Vergleich von Netzwerken ermöglichen. In dieser Arbeit wird der artenübergreifende Vergleich von Proteinprodukten mit einem multiplen Sequenzalignmentverfahren für alternative Varianten von paralogen und orthologen Genen unterstützt, unter Berücksichtigung der bekannten Exon-Intron-Grenzen (ISAR). Die in dieser Arbeit vorgestellten Verfahren, Datenbanken und Softwarewerkzeuge ermöglichen die Übertragung von biologischen Netzwerken, den Vergleich von tausenden kontextspezifischen Netzwerken und den artenübergreifenden Vergleich von alternativen Varianten. Sie können damit die Ausgangsbasis für ein Verständnis von Kommunikations- und Regulationsmechanismen in vielen biologischen Systemen bilden

Annotation and comparative analysis of fungal genomes: a hitchhiker's guide to genomics

This thesis describes several genome-sequencing projects such as those from the fungi Laccaria bicolor S238N-H82, Glomus intraradices DAOM 197198, Melampsora laricis-populina 98AG31, Puccinia graminis, Pichia pastoris GS115 and Candida bombicola, as well as the one of the haptophyte Emiliania huxleyi CCMP1516. These species are important organisms in many aspects, for instance: L. bicolor and G. intraradices are symbiotic fungi growing associate with trees and present an important ecological niches for promoting tree growth; M. laricis- populina and P. graminis are two devastating fungi threating plants; the tiny yeast P. pastoris is the major protein production platform in the pharmaceutical industry; the biosurfactant production yeast C. bombicola is likely to provide a low ecotoxicity detergent and E. huxleyi places in a unique phylogeny position of chromalveolate and contributes to the global carbon cycle system. The completion of the genome sequence and the subsequent functional studies broaden our understanding of these complex biological systems and promote the species as possible model organisms. However, it is commonly observed that the genome sequencing projects are launched with lots of enthusiasm but often frustratingly difficult to finish. Part of the reason are the ever-increasing expectations regarding quality delivery (both with respect to data and analyses). The Introductory Chapter aims to provide an overview of how best to conduct a genome sequencing project. It explains the importance of understanding the basic biology and genetics of the target organism. It also discusses the latest developments in new (next) generation high throughput sequencing (HTS) technologies, how to handle the data and their applications. The emergence of the new HTS technologies brings the whole biology research into a new frontier. For instance, with the help of the new sequencing technologies, we were able to sequence the genome of our interest, namely Pichia pastoris. This tiny yeast, the analysis of which forms the bulk of this thesis, is an important heterologous production platform because its methanol assimilation properties makes it ideally suitable for large scale industrial production. The unique protein assembly pathway of P. pastoris also attracts much basic research interests. We used the new HTS method to sequence and assemble the GS115 genome into four chromosomes and made it publicly available to the research community (Chapter 2 and Chapter 3). The public release of the GS115 brought broader interests on the comparison of GS115 and its parental strains. By sequencing the parental strain of GS115 with different new sequencing platforms, we identified several point mutations in the coding genes that likely contribute to the higher protein translocation efficiency in GS115. The sequence divergence and copy number variation of rDNA between strains also explains the difference of protein production efficiency (Chapter 4). Before 2008, the Sanger sequencing method was the only technology to obtain high quality complete genomes of eukaryotes. Because of the high cost of the Sanger method, regarding the other genome projects discussed in this thesis, it was necessary to team up with many other partners and to rely on the U.S. Department of Energy Joint Genome Institute (DOE-JGI) and the Broad Institute to generate the genome sequence. The M. larici-populina srain 98AG31 and the Puccinia graminis f. sp. tritici strain CRL 75-36-700-3 are two devastating basidiomycete ‘rusts’ that infect poplar and wheat. Lineage-specific gene family expansions in these two rusts highlight the possible role in their obligate biotrophic life-style. Two large sets of effector-like small-secreted proteins with different pri- mary sequence structures were identified in each organism. The in planta-induced transcriptomic data showed upregulation of these lineage-specific genes and they are likely involved in the establishing of the rust-host interaction. An additional immunolocalization study on M. larici-populina confirmed the accumulation of some candidate effectors in the haustoria and infection hyphae, which is described in Chapter 5