Alignment of helical membrane protein sequences using AlignMe

Few sequence alignment methods have been designed specifically for integral membrane proteins, even though these important proteins have distinct evolutionary and structural properties that might affect their alignments. Existing approaches typically consider membrane-related information either by using membrane-specific substitution matrices or by assigning distinct penalties for gap creation in transmembrane and non-transmembrane regions. Here, we ask whether favoring matching of predicted transmembrane segments within a standard dynamic programming algorithm can improve the accuracy of pairwise membrane protein sequence alignments. We tested various strategies using a specifically designed program called AlignMe. An updated set of homologous membrane protein structures, called HOMEP2, was used as a reference for optimizing the gap penalties. The best of the membrane-protein optimized approaches were then tested on an independent reference set of membrane protein sequence alignments from the BAliBASE collection. When secondary structure (S) matching was combined with evolutionary information (using a position-specific substitution matrix (P)), in an approach we called AlignMePS, the resultant pairwise alignments were typically among the most accurate over a broad range of sequence similarities when compared to available methods. Matching transmembrane predictions (T), in addition to evolutionary information, and secondary-structure predictions, in an approach called AlignMePST, generally reduces the accuracy of the alignments of closely-related proteins in the BAliBASE set relative to AlignMePS, but may be useful in cases of extremely distantly related proteins for which sequence information is less informative. The open source AlignMe code is available at https://sourceforge.net/projects/alignme​/, and at http://www.forrestlab.org, along with an online server and the HOMEP2 data set

On Recursive Edit Distance Kernels with Application to Time Series Classification

This paper proposes some extensions to the work on kernels dedicated to string or time series global alignment based on the aggregation of scores obtained by local alignments. The extensions we propose allow to construct, from classical recursive definition of elastic distances, recursive edit distance (or time-warp) kernels that are positive definite if some sufficient conditions are satisfied. The sufficient conditions we end-up with are original and weaker than those proposed in earlier works, although a recursive regularizing term is required to get the proof of the positive definiteness as a direct consequence of the Haussler's convolution theorem. The classification experiment we conducted on three classical time warp distances (two of which being metrics), using Support Vector Machine classifier, leads to conclude that, when the pairwise distance matrix obtained from the training data is \textit{far} from definiteness, the positive definite recursive elastic kernels outperform in general the distance substituting kernels for the classical elastic distances we have tested.Comment: 14 page

MRFalign: Protein Homology Detection through Alignment of Markov Random Fields

Sequence-based protein homology detection has been extensively studied and so far the most sensitive method is based upon comparison of protein sequence profiles, which are derived from multiple sequence alignment (MSA) of sequence homologs in a protein family. A sequence profile is usually represented as a position-specific scoring matrix (PSSM) or an HMM (Hidden Markov Model) and accordingly PSSM-PSSM or HMM-HMM comparison is used for homolog detection. This paper presents a new homology detection method MRFalign, consisting of three key components: 1) a Markov Random Fields (MRF) representation of a protein family; 2) a scoring function measuring similarity of two MRFs; and 3) an efficient ADMM (Alternating Direction Method of Multipliers) algorithm aligning two MRFs. Compared to HMM that can only model very short-range residue correlation, MRFs can model long-range residue interaction pattern and thus, encode information for the global 3D structure of a protein family. Consequently, MRF-MRF comparison for remote homology detection shall be much more sensitive than HMM-HMM or PSSM-PSSM comparison. Experiments confirm that MRFalign outperforms several popular HMM or PSSM-based methods in terms of both alignment accuracy and remote homology detection and that MRFalign works particularly well for mainly beta proteins. For example, tested on the benchmark SCOP40 (8353 proteins) for homology detection, PSSM-PSSM and HMM-HMM succeed on 48% and 52% of proteins, respectively, at superfamily level, and on 15% and 27% of proteins, respectively, at fold level. In contrast, MRFalign succeeds on 57.3% and 42.5% of proteins at superfamily and fold level, respectively. This study implies that long-range residue interaction patterns are very helpful for sequence-based homology detection. The software is available for download at http://raptorx.uchicago.edu/download/.Comment: Accepted by both RECOMB 2014 and PLOS Computational Biolog

Algorithms in comparative genomics

The field of comparative genomics is abundant with problems of interest to computer scientists. In this thesis, the author presents solutions to three contemporary problems: obtaining better alignments for phylogeny reconstruction, identifying related RNA sequences in genomes, and ranking Single Nucleotide Polymorphisms (SNPs) in genome-wide association studies (GWAS). Sequence alignment is a basic and widely used task in bioinformatics. Its applications include identifying protein structure, RNAs and transcription factor binding sites in genomes, and phylogeny reconstruction. Phylogenetic descriptions depend not only on the employed reconstruction technique, but also on the underlying sequence alignment. The author has studied and established a simple prescription for obtaining a better phylogeny by improving the underlying alignments used in phylogeny reconstruction. This was achieved by improving upon Gotoh\u27s iterative heuristic by iterating with maximum parsimony guide-trees. This approach has shown an improvement in accuracy over standard alignment programs. A novel alignment algorithm named Probalign-RNAgenome that can identify non-coding RNAs in genomic sequences was also developed. Non-coding RNAs play a critical role in the cell such as gene regulation. It is thought that many such RNAs lie undiscovered in the genome. To date, alignment based approaches have shown to be more accurate than thermodynamic methods for identifying such non-coding RNAs. Probalign-RNAgenome employs a probabilistic consistency based approach for aligning a query RNA sequence to its homolog in a genomic sequence. Results show that this approach is more accurate on real data than the widely used BLAST and Smith- Waterman algorithms. Within the realm of comparative genomics are also a large number of recently conducted GWAS. GWAS aim to identify regions in the genome that are associated with a given disease. The support vector machine (SVM) provides a discriminative alternative to the widely used chi-square statistic in GWAS. A novel hybrid strategy that combines the chi-square statistic with the SVM was developed and implemented. Its performance was studied on simulated data and the Wellcome Trust Case Control Consortium (WTCCC) studies. Results presented in this thesis show that the hybrid strategy ranks causal SNPs in simulated data significantly higher than the chi-square test and SVM alone. The results also show that the hybrid strategy ranks previously replicated SNPs and associated regions (where applicable) of type 1 diabetes, rheumatoid arthritis, and Crohn\u27s disease higher than the chi-square, SVM, and SVM Recursive Feature Elimination (SVM-RFE)

Similarity Learning for High-Dimensional Sparse Data

A good measure of similarity between data points is crucial to many tasks in machine learning. Similarity and metric learning methods learn such measures automatically from data, but they do not scale well respect to the dimensionality of the data. In this paper, we propose a method that can learn efficiently similarity measure from high-dimensional sparse data. The core idea is to parameterize the similarity measure as a convex combination of rank-one matrices with specific sparsity structures. The parameters are then optimized with an approximate Frank-Wolfe procedure to maximally satisfy relative similarity constraints on the training data. Our algorithm greedily incorporates one pair of features at a time into the similarity measure, providing an efficient way to control the number of active features and thus reduce overfitting. It enjoys very appealing convergence guarantees and its time and memory complexity depends on the sparsity of the data instead of the dimension of the feature space. Our experiments on real-world high-dimensional datasets demonstrate its potential for classification, dimensionality reduction and data exploration.Comment: 14 pages. Proceedings of the 18th International Conference on Artificial Intelligence and Statistics (AISTATS 2015). Matlab code: https://github.com/bellet/HDS