Graph Kernels and Applications in Bioinformatics

In recent years, machine learning has emerged as an important discipline. However, despite the popularity of machine learning techniques, data in the form of discrete structures are not fully exploited. For example, when data appear as graphs, the common choice is the transformation of such structures into feature vectors. This procedure, though convenient, does not always effectively capture topological relationships inherent to the data; therefore, the power of the learning process may be insufficient. In this context, the use of kernel functions for graphs arises as an attractive way to deal with such structured objects. On the other hand, several entities in computational biology applications, such as gene products or proteins, may be naturally represented by graphs. Hence, the demanding need for algorithms that can deal with structured data poses the question of whether the use of kernels for graphs can outperform existing methods to solve specific computational biology problems. In this dissertation, we address the challenges involved in solving two specific problems in computational biology, in which the data are represented by graphs. First, we propose a novel approach for protein function prediction by modeling proteins as graphs. For each of the vertices in a protein graph, we propose the calculation of evolutionary profiles, which are derived from multiple sequence alignments from the amino acid residues within each vertex. We then use a shortest path graph kernel in conjunction with a support vector machine to predict protein function. We evaluate our approach under two instances of protein function prediction, namely, the discrimination of proteins as enzymes, and the recognition of DNA binding proteins. In both cases, our proposed approach achieves better prediction performance than existing methods. Second, we propose two novel semantic similarity measures for proteins based on the gene ontology. The first measure directly works on the gene ontology by combining the pairwise semantic similarity scores between sets of annotating terms for a pair of input proteins. The second measure estimates protein semantic similarity using a shortest path graph kernel to take advantage of the rich semantic knowledge contained within ontologies. Our comparison with other methods shows that our proposed semantic similarity measures are highly competitive and the latter one outperforms state-of-the-art methods. Furthermore, our two methods are intrinsic to the gene ontology, in the sense that they do not rely on external sources to calculate similarities

Human protein function prediction: application of machine learning for integration of heterogeneous data sources

Experimental characterisation of protein cellular function can be prohibitively expensive and take years to complete. To address this problem, this thesis focuses on the development of computational approaches to predict function from sequence. For sequences with well characterised close relatives, annotation is trivial, orphans or distant homologues present a greater challenge. The use of a feature based method employing ensemble support vector machines to predict individual Gene Ontology classes is investigated. It is found that different combinations of feature inputs are required to recognise different functions. Although the approach is applicable to any human protein sequence, it is restricted to broadly descriptive functions. The method is well suited to prioritisation of candidate functions for novel proteins rather than to make highly accurate class assignments. Signatures of common function can be derived from different biological characteristics; interactions and binding events as well as expression behaviour. To investigate the hypothesis that common function can be derived from expression information, public domain human microarray datasets are assembled. The questions of how best to integrate these datasets and derive features that are useful in function prediction are addressed. Both co-expression and abundance information is represented between and within experiments and investigated for correlation with function. It is found that features derived from expression data serve as a weak but significant signal for recognising functions. This signal is stronger for biological processes than molecular function categories and independent of homology information. The protein domain has historically been coined as a modular evolutionary unit of protein function. The occurrence of domains that can be linked by ancestral fusion events serves as a signal for domain-domain interactions. To exploit this information for function prediction, novel domain architecture and fused architecture scores are developed. Architecture scores rather than single domain scores correlate more strongly with function, and both architecture and fusion scores correlate more strongly with molecular functions than biological processes. The final study details the development of a novel heterogeneous function prediction approach designed to target the annotation of both homologous and non-homologous proteins. Support vector regression is used to combine pair-wise sequence features with expression scores and domain architecture scores to rank protein pairs in terms of their functional similarities. The target of the regression models represents the continuum of protein function space empirically derived from the Gene Ontology molecular function and biological process graphs. The merit and performance of the approach is demonstrated using homologous and non-homologous test datasets and significantly improves upon classical nearest neighbour annotation transfer by sequence methods. The final model represents a method that achieves a compromise between high specificity and sensitivity for all human proteins regardless of their homology status. It is expected that this strategy will allow for more comprehensive and accurate annotations of the human proteome

Large-scale automated protein function prediction

Includes bibliographical references.2016 Summer.Proteins are the workhorses of life, and identifying their functions is a very important biological problem. The function of a protein can be loosely defined as everything it performs or happens to it. The Gene Ontology (GO) is a structured vocabulary which captures protein function in a hierarchical manner and contains thousands of terms. Through various wet-lab experiments over the years scientists have been able to annotate a large number of proteins with GO categories which reflect their functionality. However, experimentally determining protein functions is a highly resource-intensive task, and a large fraction of proteins remain un-annotated. Recently a plethora automated methods have emerged and their reasonable success in computationally determining the functions of proteins using a variety of data sources – by sequence/structure similarity or using various biological network data, has led to establishing automated function prediction (AFP) as an important problem in bioinformatics. In a typical machine learning problem, cross-validation is the protocol of choice for evaluating the accuracy of a classifier. But, due to the process of accumulation of annotations over time, we identify the AFP as a combination of two sub-tasks: making predictions on annotated proteins and making predictions on previously unannotated proteins. In our first project, we analyze the performance of several protein function prediction methods in these two scenarios. Our results show that GOstruct, an AFP method that our lab has previously developed, and two other popular methods: binary SVMs and guilt by association, find it hard to achieve the same level of accuracy on these two tasks compared to the performance evaluated through cross-validation, and that predicting novel annotations for previously annotated proteins is a harder problem than predicting annotations for uncharacterized proteins. We develop GOstruct 2.0 by proposing improvements which allows the model to make use of information of a protein's current annotations to better handle the task of predicting novel annotations for previously annotated proteins. Experimental results on yeast and human data show that GOstruct 2.0 outperforms the original GOstruct, demonstrating the effectiveness of the proposed improvements. Although the biomedical literature is a very informative resource for identifying protein function, most AFP methods do not take advantage of the large amount of information contained in it. In our second project, we conduct the first ever comprehensive evaluation on the effectiveness of literature data for AFP. Specifically, we extract co-mentions of protein-GO term pairs and bag-of-words features from the literature and explore their effectiveness in predicting protein function. Our results show that literature features are very informative of protein function but with further room for improvement. In order to improve the quality of automatically extracted co-mentions, we formulate the classification of co-mentions as a supervised learning problem and propose a novel method based on graph kernels. Experimental results indicate the feasibility of using this co-mention classifier as a complementary method that aids the bio-curators who are responsible for maintaining databases such as Gene Ontology. This is the first study of the problem of protein-function relation extraction from biomedical text. The recently developed human phenotype ontology (HPO), which is very similar to GO, is a standardized vocabulary for describing the phenotype abnormalities associated with human diseases. At present, only a small fraction of human protein coding genes have HPO annotations. But, researchers believe that a large portion of currently unannotated genes are related to disease phenotypes. Therefore, it is important to predict gene-HPO term associations using accurate computational methods. In our third project, we introduce PHENOstruct, a computational method that directly predicts the set of HPO terms for a given gene. We compare PHENOstruct with several baseline methods and show that it outperforms them in every respect. Furthermore, we highlight a collection of informative data sources suitable for the problem of predicting gene-HPO associations, including large scale literature mining data

Design and development of learning model for compression and processing of deoxyribonucleic acid genome sequence

Owing to the substantial volume of human genome sequence data files (from 30-200 GB exposed) Genomic data compression has received considerable traction and storage costs are one of the major problems faced by genomics laboratories. This involves a modern technology of data compression that reduces not only the storage but also the reliability of the operation. There were few attempts to solve this problem independently of both hardware and software. A systematic analysis of associations between genes provides techniques for the recognition of operative connections among genes and their respective yields, as well as understandings into essential biological events that are most important for knowing health and disease phenotypes. This research proposes a reliable and efficient deep learning system for learning embedded projections to combine gene interactions and gene expression in prediction comparison of deep embeddings to strong baselines. In this paper we preform data processing operations and predict gene function, along with gene ontology reconstruction and predict the gene interaction. The three major steps of genomic data compression are extraction of data, storage of data, and retrieval of the data. Hence, we propose a deep learning based on computational optimization techniques which will be efficient in all the three stages of data compression

Predicting gene function using hierarchical multi-label decision tree ensembles

<p>Abstract</p> <p>Background</p> <p><it>S. cerevisiae</it>, <it>A. thaliana </it>and <it>M. musculus </it>are well-studied organisms in biology and the sequencing of their genomes was completed many years ago. It is still a challenge, however, to develop methods that assign biological functions to the ORFs in these genomes automatically. Different machine learning methods have been proposed to this end, but it remains unclear which method is to be preferred in terms of predictive performance, efficiency and usability.</p> <p>Results</p> <p>We study the use of decision tree based models for predicting the multiple functions of ORFs. First, we describe an algorithm for learning hierarchical multi-label decision trees. These can simultaneously predict all the functions of an ORF, while respecting a given hierarchy of gene functions (such as FunCat or GO). We present new results obtained with this algorithm, showing that the trees found by it exhibit clearly better predictive performance than the trees found by previously described methods. Nevertheless, the predictive performance of individual trees is lower than that of some recently proposed statistical learning methods. We show that ensembles of such trees are more accurate than single trees and are competitive with state-of-the-art statistical learning and functional linkage methods. Moreover, the ensemble method is computationally efficient and easy to use.</p> <p>Conclusions</p> <p>Our results suggest that decision tree based methods are a state-of-the-art, efficient and easy-to-use approach to ORF function prediction.</p

FFPred: an integrated feature-based function prediction server for vertebrate proteomes

One of the challenges of the post-genomic era is to provide accurate function annotations for large volumes of data resulting from genome sequencing projects. Most function prediction servers utilize methods that transfer existing database annotations between orthologous sequences. In contrast, there are few methods that are independent of homology and can annotate distant and orphan protein sequences. The FFPred server adopts a machine-learning approach to perform function prediction in protein feature space using feature characteristics predicted from amino acid sequence. The features are scanned against a library of support vector machines representing over 300 Gene Ontology (GO) classes and probabilistic confidence scores returned for each annotation term. The GO term library has been modelled on human protein annotations; however, benchmark performance testing showed robust performance across higher eukaryotes. FFPred offers important advantages over traditional function prediction servers in its ability to annotate distant homologues and orphan protein sequences, and achieves greater coverage and classification accuracy than other feature-based prediction servers. A user may upload an amino acid and receive annotation predictions via email. Feature information is provided as easy to interpret graphics displayed on the sequence of interest, allowing for back-interpretation of the associations between features and function classes