Discovery and Analysis of Aligned Pattern Clusters from Protein Family Sequences
Lee, En-Shiun Annie
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Protein sequences are essential for encoding molecular structures and functions. Consequently, biologists invest substantial resources and time discovering functional patterns in proteins. Using high-throughput technologies, biologists are generating an increasing amount of data. Thus, the major challenge in biosequencing today is the ability to conduct data analysis in an effi cient and productive manner. Conserved amino acids in proteins reveal important functional domains within protein families. Conversely, less conserved amino acid variations within these protein sequence patterns reveal areas of evolutionary and functional divergence. Exploring protein families using existing methods such as multiple sequence alignment is computationally expensive, thus pattern search is used. However, at present, combinatorial methods of pattern search generate a large set of solutions, and probabilistic methods require richer representations. They require biological ground truth of the input sequences, such as gene name or taxonomic species, as class labels based on traditional classi fication practice to train a model for predicting unknown sequences. However, these algorithms are inherently biased by mislabelling and may not be able to reveal class characteristics in a detailed and succinct manner. A novel pattern representation called an Aligned Pattern Cluster (AP Cluster) as developed in this dissertation is compact yet rich. It captures conservations and variations of amino acids and covers more sequences with lower entropy and greatly reduces the number of patterns. AP Clusters contain statistically signi cant patterns with variations; their importance has been confi rmed by the following biological evidences: 1) Most of the discovered AP Clusters correspond to binding segments while their aligned columns correspond to binding sites as verifi ed by pFam, PROSITE, and the three-dimensional structure. 2) By compacting strong correlated functional information together, AP Clusters are able to reveal class characteristics for taxonomical classes, gene classes and other functional classes, or incorrect class labelling. 3) Co-occurrence of AP Clusters on the same homologous protein sequences are spatially close in the protein's three-dimensional structure. These results demonstrate the power and usefulness of AP Clusters. They bring in similar statistically signifi cance patterns with variation together and align them to reveal protein regional functionality, class characteristics, binding and interacting sites for the study of protein-protein and protein-drug interactions, for diff erentiation of cancer tumour types, targeted gene therapy as well as for drug target discovery.
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