Circular sequence comparison: algorithms and applications

Background: Sequence comparison is a fundamental step in many important tasks in bioinformatics; from phylogenetic reconstruction to the reconstruction of genomes. Traditional algorithms for measuring approximation in sequence comparison are based on the notions of distance or similarity, and are generally computed through sequence alignment techniques. As circular molecular structure is a common phenomenon in nature, a caveat of the adaptation of alignment techniques for circular sequence comparison is that they are computationally expensive, requiring from super-quadratic to cubic time in the length of the sequences. Results: In this paper, we introduce a new distance measure based on q-grams, and show how it can be applied effectively and computed efficiently for circular sequence comparison. Experimental results, using real DNA, RNA, and protein sequences as well as synthetic data, demonstrate orders-of-magnitude superiority of our approach in terms of efficiency, while maintaining an accuracy very competitive to the state of the art

Robust and Efficient Algorithms for Protein 3-D Structure Alignment and Genome Sequence Comparison

Sequence analysis and structure analysis are two of the fundamental areas of bioinformatics research. This dissertation discusses, specifically, protein structure related problems including protein structure alignment and query, and genome sequence related problems including haplotype reconstruction and genome rearrangement. It first presents an algorithm for pairwise protein structure alignment that is tested with structures from the Protein Data Bank (PDB). In many cases it outperforms two other well-known algorithms, DaliLite and CE. The preliminary algorithm is a graph-theory based approach, which uses the concept of \stars to reduce the complexity of clique-finding algorithms. The algorithm is then improved by introducing \double-center stars in the graph and applying a self-learning strategy. The updated algorithm is tested with a much larger set of protein structures and shown to be an improvement in accuracy, especially in cases of weak similarity. A protein structure query algorithm is designed to search for similar structures in the PDB, using the improved alignment algorithm. It is compared with SSM and shows better performance with lower maximum and average Q-score for missing proteins. An interesting problem dealing with the calculation of the diameter of a 3-D sequence of points arose and its connection to the sublinear time computation is discussed. The diameter calculation of a 3-D sequence is approximated by a series of sublinear time deterministic, zero-error and bounded-error randomized algorithms and we have obtained a series of separations about the power of sublinear time computations. This dissertation also discusses two genome sequence related problems. A probabilistic model is proposed for reconstructing haplotypes from SNP matrices with incomplete and inconsistent errors. The experiments with simulated data show both high accuracy and speed, conforming to the theoretically provable e ciency and accuracy of the algorithm. Finally, a genome rearrangement problem is studied. The concept of non-breaking similarity is introduced. Approximating the exemplar non-breaking similarity to factor n1..f is proven to be NP-hard. Interestingly, for several practical cases, several polynomial time algorithms are presented

Algorithmic Techniques in Gene Expression Processing. From Imputation to Visualization

The amount of biological data has grown exponentially in recent decades. Modern biotechnologies, such as microarrays and next-generation sequencing, are capable to produce massive amounts of biomedical data in a single experiment. As the amount of the data is rapidly growing there is an urgent need for reliable computational methods for analyzing and visualizing it. This thesis addresses this need by studying how to efficiently and reliably analyze and visualize high-dimensional data, especially that obtained from gene expression microarray experiments. First, we will study the ways to improve the quality of microarray data by replacing (imputing) the missing data entries with the estimated values for these entries. Missing value imputation is a method which is commonly used to make the original incomplete data complete, thus making it easier to be analyzed with statistical and computational methods. Our novel approach was to use curated external biological information as a guide for the missing value imputation. Secondly, we studied the effect of missing value imputation on the downstream data analysis methods like clustering. We compared multiple recent imputation algorithms against 8 publicly available microarray data sets. It was observed that the missing value imputation indeed is a rational way to improve the quality of biological data. The research revealed differences between the clustering results obtained with different imputation methods. On most data sets, the simple and fast k-NN imputation was good enough, but there were also needs for more advanced imputation methods, such as Bayesian Principal Component Algorithm (BPCA). Finally, we studied the visualization of biological network data. Biological interaction networks are examples of the outcome of multiple biological experiments such as using the gene microarray techniques. Such networks are typically very large and highly connected, thus there is a need for fast algorithms for producing visually pleasant layouts. A computationally efficient way to produce layouts of large biological interaction networks was developed. The algorithm uses multilevel optimization within the regular force directed graph layout algorithm.Siirretty Doriast

Computational methods and tools for protein phosphorylation analysis

Signaling pathways represent a central regulatory mechanism of biological systems where a key event in their correct functioning is the reversible phosphorylation of proteins. Protein phosphorylation affects at least one-third of all proteins and is the most widely studied posttranslational modification. Phosphorylation analysis is still perceived, in general, as difficult or cumbersome and not readily attempted by many, despite the high value of such information. Specifically, determining the exact location of a phosphorylation site is currently considered a major hurdle, thus reliable approaches are necessary for the detection and localization of protein phosphorylation. The goal of this PhD thesis was to develop computation methods and tools for mass spectrometry-based protein phosphorylation analysis, particularly validation of phosphorylation sites. In the first two studies, we developed methods for improved identification of phosphorylation sites in MALDI-MS. In the first study it was achieved through the automatic combination of spectra from multiple matrices, while in the second study, an optimized protocol for sample loading and washing conditions was suggested. In the third study, we proposed and evaluated the hypothesis that in ESI-MS, tandem CID and HCD spectra of phosphopeptides can be accurately predicted and used in spectral library searching. This novel strategy for phosphosite validation and identification offered accuracy that outperformed the other currently existing popular methods and proved applicable to complex biological samples. And finally, we significantly improved the performance of our command-line prototype tool, added graphical user interface, and options for customizable simulation parameters and filtering of selected spectra, peptides or proteins. The new software, SimPhospho, is open-source and can be easily integrated in a phosphoproteomics data analysis workflow. Together, these bioinformatics methods and tools enable confident phosphosite assignment and improve reliable phosphoproteome identification and reportin