3'-UTR SIRF: A database for identifying clusters of short interspersed repeats in 3' untranslated regions

BACKGROUND:Short (~5 nucleotides) interspersed repeats regulate several aspects of post-transcriptional gene expression. Previously we developed an algorithm (REPFIND) that assigns P-values to all repeated motifs in a given nucleic acid sequence and reliably identifies clusters of short CAC-containing motifs required for mRNA localization in Xenopus oocytes.DESCRIPTION:In order to facilitate the identification of genes possessing clusters of repeats that regulate post-transcriptional aspects of gene expression in mammalian genes, we used REPFIND to create a database of all repeated motifs in the 3' untranslated regions (UTR) of genes from the Mammalian Gene Collection (MGC). The MGC database includes seven vertebrate species: human, cow, rat, mouse and three non-mammalian vertebrate species. A web-based application was developed to search this database of repeated motifs to generate species-specific lists of genes containing specific classes of repeats in their 3'-UTRs. This computational tool is called 3'-UTR SIRF (Short Interspersed Repeat Finder), and it reveals that hundreds of human genes contain an abundance of short CAC-rich and CAG-rich repeats in their 3'-UTRs that are similar to those found in mRNAs localized to the neurites of neurons. We tested four candidate mRNAs for localization in rat hippocampal neurons by in situ hybridization. Our results show that two candidate CAC-rich (Syntaxin 1B and Tubulin beta4) and two candidate CAG-rich (Sec61alpha and Syntaxin 1A) mRNAs are localized to distal neurites, whereas two control mRNAs lacking repeated motifs in their 3'-UTR remain primarily in the cell body.CONCLUSION:Computational data generated with 3'-UTR SIRF indicate that hundreds of mammalian genes have an abundance of short CA-containing motifs that may direct mRNA localization in neurons. In situ hybridization shows that four candidate mRNAs are localized to distal neurites of cultured hippocampal neurons. These data suggest that short CA-containing motifs may be part of a widely utilized genetic code that regulates mRNA localization in vertebrate cells. The use of 3'-UTR SIRF to search for new classes of motifs that regulate other aspects of gene expression should yield important information in future studies addressing cis-regulatory information located in 3'-UTRs.

Integration of relational and hierarchical network information for protein function prediction

BACKGROUND:In the current climate of high-throughput computational biology, the inference of a protein's function from related measurements, such as protein-protein interaction relations, has become a canonical task. Most existing technologies pursue this task as a classification problem, on a term-by-term basis, for each term in a database, such as the Gene Ontology (GO) database, a popular rigorous vocabulary for biological functions. However, ontology structures are essentially hierarchies, with certain top to bottom annotation rules which protein function predictions should in principle follow. Currently, the most common approach to imposing these hierarchical constraints on network-based classifiers is through the use of transitive closure to predictions.RESULTS:We propose a probabilistic framework to integrate information in relational data, in the form of a protein-protein interaction network, and a hierarchically structured database of terms, in the form of the GO database, for the purpose of protein function prediction. At the heart of our framework is a factorization of local neighborhood information in the protein-protein interaction network across successive ancestral terms in the GO hierarchy. We introduce a classifier within this framework, with computationally efficient implementation, that produces GO-term predictions that naturally obey a hierarchical 'true-path' consistency from root to leaves, without the need for further post-processing.CONCLUSION:A cross-validation study, using data from the yeast Saccharomyces cerevisiae, shows our method offers substantial improvements over both standard 'guilt-by-association' (i.e., Nearest-Neighbor) and more refined Markov random field methods, whether in their original form or when post-processed to artificially impose 'true-path' consistency. Further analysis of the results indicates that these improvements are associated with increased predictive capabilities (i.e., increased positive predictive value), and that this increase is consistent uniformly with GO-term depth. Additional in silico validation on a collection of new annotations recently added to GO confirms the advantages suggested by the cross-validation study. Taken as a whole, our results show that a hierarchical approach to network-based protein function prediction, that exploits the ontological structure of protein annotation databases in a principled manner, can offer substantial advantages over the successive application of 'flat' network-based methods.

Generalized Methods for Discovering Frequent Poly-Regions in DNA

The problem of discovering frequent poly-regions (i.e. regions of high occurrence of a set of items or patterns of a given alphabet) in a sequence is studied, and three efficient approaches are proposed to solve it. The first one is entropy-based and applies a recursive segmentation technique that produces a set of candidate segments which may potentially lead to a poly-region. The key idea of the second approach is the use of a set of sliding windows over the sequence. Each sliding window covers a sequence segment and keeps a set of statistics that mainly include the number of occurrences of each item or pattern in that segment. Combining these statistics efficiently yields the complete set of poly-regions in the given sequence. The third approach applies a technique based on the majority vote, achieving linear running time with a minimal number of false negatives. After identifying the poly-regions, the sequence is converted to a sequence of labeled intervals (each one corresponding to a poly-region). An efficient algorithm for mining frequent arrangements of intervals is applied to the converted sequence to discover frequently occurring arrangements of poly-regions in different parts of DNA, including coding regions. The proposed algorithms are tested on various DNA sequences producing results of significant biological meaning.

Learning Embeddings for Indexing, Retrieval, and Classification, with Applications to Object and Shape Recognition in Image Databases

Nearest neighbor retrieval is the task of identifying, given a database of objects and a query object, the objects in the database that are the most similar to the query. Retrieving nearest neighbors is a necessary component of many practical applications, in fields as diverse as computer vision, pattern recognition, multimedia databases, bioinformatics, and computer networks. At the same time, finding nearest neighbors accurately and efficiently can be challenging, especially when the database contains a large number of objects, and when the underlying distance measure is computationally expensive. This thesis proposes new methods for improving the efficiency and accuracy of nearest neighbor retrieval and classification in spaces with computationally expensive distance measures. The proposed methods are domain-independent, and can be applied in arbitrary spaces, including non-Euclidean and non-metric spaces. In this thesis particular emphasis is given to computer vision applications related to object and shape recognition, where expensive non-Euclidean distance measures are often needed to achieve high accuracy. The first contribution of this thesis is the BoostMap algorithm for embedding arbitrary spaces into a vector space with a computationally efficient distance measure. Using this approach, an approximate set of nearest neighbors can be retrieved efficiently - often orders of magnitude faster than retrieval using the exact distance measure in the original space. The BoostMap algorithm has two key distinguishing features with respect to existing embedding methods. First, embedding construction explicitly maximizes the amount of nearest neighbor information preserved by the embedding. Second, embedding construction is treated as a machine learning problem, in contrast to existing methods that are based on geometric considerations. The second contribution is a method for constructing query-sensitive distance measures for the purposes of nearest neighbor retrieval and classification. In high-dimensional spaces, query-sensitive distance measures allow for automatic selection of the dimensions that are the most informative for each specific query object. It is shown theoretically and experimentally that query-sensitivity increases the modeling power of embeddings, allowing embeddings to capture a larger amount of the nearest neighbor structure of the original space. The third contribution is a method for speeding up nearest neighbor classification by combining multiple embedding-based nearest neighbor classifiers in a cascade. In a cascade, computationally efficient classifiers are used to quickly classify easy cases, and classifiers that are more computationally expensive and also more accurate are only applied to objects that are harder to classify. An interesting property of the proposed cascade method is that, under certain conditions, classification time actually decreases as the size of the database increases, a behavior that is in stark contrast to the behavior of typical nearest neighbor classification systems. The proposed methods are evaluated experimentally in several different applications: hand shape recognition, off-line character recognition, online character recognition, and efficient retrieval of time series. In all datasets, the proposed methods lead to significant improvements in accuracy and efficiency compared to existing state-of-the-art methods. In some datasets, the general-purpose methods introduced in this thesis even outperform domain-specific methods that have been custom-designed for such datasets.

Spatiotemporal Gesture Segmentation

Spotting patterns of interest in an input signal is a very useful task in many different fields including medicine, bioinformatics, economics, speech recognition and computer vision. Example instances of this problem include spotting an object of interest in an image (e.g., a tumor), a pattern of interest in a time-varying signal (e.g., audio analysis), or an object of interest moving in a specific way (e.g., a human's body gesture). Traditional spotting methods, which are based on Dynamic Time Warping or hidden Markov models, use some variant of dynamic programming to register the pattern and the input while accounting for temporal variation between them. At the same time, those methods often suffer from several shortcomings: they may give meaningless solutions when input observations are unreliable or ambiguous, they require a high complexity search across the whole input signal, and they may give incorrect solutions if some patterns appear as smaller parts within other patterns. In this thesis, we develop a framework that addresses these three problems, and evaluate the framework's performance in spotting and recognizing hand gestures in video. The first contribution is a spatiotemporal matching algorithm that extends the dynamic programming formulation to accommodate multiple candidate hand detections in every video frame. The algorithm finds the best alignment between the gesture model and the input, and simultaneously locates the best candidate hand detection in every frame. This allows for a gesture to be recognized even when the hand location is highly ambiguous. The second contribution is a pruning method that uses model-specific classifiers to reject dynamic programming hypotheses with a poor match between the input and model. Pruning improves the efficiency of the spatiotemporal matching algorithm, and in some cases may improve the recognition accuracy. The pruning classifiers are learned from training data, and cross-validation is used to reduce the chance of overpruning. The third contribution is a subgesture reasoning process that models the fact that some gesture models can falsely match parts of other, longer gestures. By integrating subgesture reasoning the spotting algorithm can avoid the premature detection of a subgesture when the longer gesture is actually being performed. Subgesture relations between pairs of gestures are automatically learned from training data. The performance of the approach is evaluated on two challenging video datasets: hand-signed digits gestured by users wearing short sleeved shirts, in front of a cluttered background, and American Sign Language (ASL) utterances gestured by ASL native signers. The experiments demonstrate that the proposed method is more accurate and efficient than competing approaches. The proposed approach can be generally applied to alignment or search problems with multiple input observations, that use dynamic programming to find a solution.