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Cancer driver genes, i.e., oncogenes and tumor suppressor genes, are involved in the acquisition of important functions in tumors, providing a selective growth advantage, allowing uncontrolled proliferation and avoiding apoptosis. It is therefore important to identify these driver genes, both for the fundamental understanding of cancer and to help finding new therapeutic targets or biomarkers. Although the most frequently mutated driver genes have been identified, it is believed that many more remain to be discovered, particularly for driver genes specific to some cancer types. In this paper, we propose a new computational method called LOTUS to predict new driver genes. LOTUS is a machine-learning based approach which allows to integrate various types of data in a versatile manner, including information about gene mutations and protein-protein interactions. In addition, LOTUS can predict cancer driver genes in a pan-cancer setting as well as for specific cancer types, using a multitask learning strategy to share information across cancer types. We empirically show that LOTUS outperforms five other state-of-the-art driver gene prediction methods, both in terms of intrinsic consistency and prediction accuracy, and provide predictions of new cancer genes across many cancer types. [ABSTRACT FROM AUTHOR]

Due to continuous evolution of biomedical data, biomedical ontologies are becoming larger and more complex, which leads to the existence of many overlapping information. To support semantic inter-operability between ontology-based biomedical systems, it is necessary to identify the correspondences between these information, which is commonly known as biomedical ontology matching. However, it is a challenge to match biomedical ontologies, which dues to: (1) biomedical ontologies often possess tens of thousands of entities, (2) biomedical terminologies are complex and ambiguous. To efficiently match biomedical ontologies, in this paper, an interactive biomedical ontology matching approach is proposed, which utilizes the Evolutionary Algorithm (EA) to implement the automatic matching process, and gets a user involved in the evolving process to improve the matching efficiency. In particular, we propose an Evolutionary Tabu Search (ETS) algorithm, which can improve EA’s performance by introducing the tabu search algorithm as a local search strategy into the evolving process. On this basis, we further make the ETS-based ontology matching technique cooperate with the user in a reasonable amount of time to efficiently create high quality alignments, and make use of EA’s survival of the fittest to eliminate the wrong correspondences brought by erroneous user validations. The experiment is conducted on the Anatomy track and Large Biomedic track that are provided by the Ontology Alignment Evaluation Initiative (OAEI), and the experimental results show that our approach is able to efficiently exploit the user intervention to improve its non-interactive version, and the performance of our approach outperforms the state-of-the-art semi-automatic ontology matching systems. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) encode active retroviral proteins, which may be involved in the progression of cancer and other diseases. Matrix protein (MA), in group-specific antigen genes (gag) of retroviruses, is associated with the virus envelope glycoproteins in most mammalian retroviruses and may be involved in virus particle assembly, transport and budding. However, the amount of annotated MAs in ERVs is still at a low level so far. No computational method to predict the exact start and end coordinates of MAs in gags has been proposed yet. In this paper, a computational method to identify MAs in ERVs is proposed. A divide and conquer technique was designed and applied to the conventional prediction model to acquire better results when dealing with gene sequences with various lengths. Initiation sites and termination sites were predicted separately and then combined according to their intervals. Three different algorithms were applied and compared: weighted support vector machine (WSVM), weighted extreme learning machine (WELM) and random forest (RF). G − mean (geometric mean of sensitivity and specificity) values of initiation sites and termination sites under 5-fold cross validation generated by random forest models are 0.9869 and 0.9755 respectively, highest among the algorithms applied. Our prediction models combine RF & WSVM algorithms to achieve the best prediction results. 98.4% of all the collected ERV sequences with complete MAs (125 in total) could be predicted exactly correct by the models. 94,671 HERV sequences from 118 families were scanned by the model, 104 new putative MAs were predicted in human chromosomes. Distributions of the putative MAs and optimizations of model parameters were also analyzed. The usage of our predicting method was also expanded to other retroviruses and satisfying results were acquired. [ABSTRACT FROM AUTHOR]

Manually curating biomedical knowledge from publications is necessary to build a knowledge based service that provides highly precise and organized information to users. The process of retrieving relevant publications for curation, which is also known as document triage, is usually carried out by querying and reading articles in PubMed. However, this query-based method often obtains unsatisfactory precision and recall on the retrieved results, and it is difficult to manually generate optimal queries. To address this, we propose a machine-learning assisted triage method. We collect previously curated publications from two databases UniProtKB/Swiss-Prot and the NHGRI-EBI GWAS Catalog, and used them as a gold-standard dataset for training deep learning models based on convolutional neural networks. We then use the trained models to classify and rank new publications for curation. For evaluation, we apply our method to the real-world manual curation process of UniProtKB/Swiss-Prot and the GWAS Catalog. We demonstrate that our machine-assisted triage method outperforms the current query-based triage methods, improves efficiency, and enriches curated content. Our method achieves a precision 1.81 and 2.99 times higher than that obtained by the current query-based triage methods of UniProtKB/Swiss-Prot and the GWAS Catalog, respectively, without compromising recall. In fact, our method retrieves many additional relevant publications that the query-based method of UniProtKB/Swiss-Prot could not find. As these results show, our machine learning-based method can make the triage process more efficient and is being implemented in production so that human curators can focus on more challenging tasks to improve the quality of knowledge bases. [ABSTRACT FROM AUTHOR]

Protein-protein interaction network data provides valuable information that infers direct links between genes and their biological roles. This information brings a fundamental hypothesis for protein function prediction that interacting proteins tend to have similar functions. With the help of recently-developed network embedding feature generation methods and deep maxout neural networks, it is possible to extract functional representations that encode direct links between protein-protein interactions information and protein function. Our novel method, STRING2GO, successfully adopts deep maxout neural networks to learn functional representations simultaneously encoding both protein-protein interactions and functional predictive information. The experimental results show that STRING2GO outperforms other protein-protein interaction network-based prediction methods and one benchmark method adopted in a recent large scale protein function prediction competition. [ABSTRACT FROM AUTHOR]

Identifying protein coding regions in DNA sequences by computational methods is an active research topic. Welan gum produced by Sphingomonas sp. WG has great application potential in oil recovery and concrete construction industry. Predicting the coding regions in the Sphingomonas sp. WG genome and addressing the mechanism underlying the explanation for the synthesis of Welan gum metabolism is an important issue at present. In this study, we apply a self adaptive spectral rotation (SASR, for short) method, which is based on the investigation of the Triplet Periodicity property, to predict the coding regions of the whole-genome data of Sphingomonas sp. WG without any previous training process, and 1115 suspected gene fragments are obtained. Suspected gene fragments are subjected to a similarity search against the non-redundant protein sequences (nr) database of NCBI with blastx, and 762 suspected gene fragments have been labeled as genes in the nr database. [ABSTRACT FROM AUTHOR]

A common goal in data-analysis is to sift through a large data-matrix and detect any significant submatrices (i.e., biclusters) that have a low numerical rank. We present a simple algorithm for tackling this biclustering problem. Our algorithm accumulates information about 2-by-2 submatrices (i.e., ‘loops’) within the data-matrix, and focuses on rows and columns of the data-matrix that participate in an abundance of low-rank loops. We demonstrate, through analysis and numerical-experiments, that this loop-counting method performs well in a variety of scenarios, outperforming simple spectral methods in many situations of interest. Another important feature of our method is that it can easily be modified to account for aspects of experimental design which commonly arise in practice. For example, our algorithm can be modified to correct for controls, categorical- and continuous-covariates, as well as sparsity within the data. We demonstrate these practical features with two examples; the first drawn from gene-expression analysis and the second drawn from a much larger genome-wide-association-study (GWAS). [ABSTRACT FROM AUTHOR]

Pooled DNA from multiple unknown organisms arises in a variety of contexts, for example microbial samples from ecological or human health research. Determining the composition of pooled samples can be difficult, especially at the scale of modern sequencing data and reference databases. Here we propose a novel method for taxonomic profiling in pooled DNA that combines the speed and low-memory requirements of k-mer based pseudoalignment with a likelihood framework that uses base quality information to better resolve multiply mapped reads. We apply the method to the problem of classifying 16S rRNA reads using a reference database of known organisms, a common challenge in microbiome research. Using simulations, we show the method is accurate across a variety of read lengths, with different length reference sequences, at different sample depths, and when samples contain reads originating from organisms absent from the reference. We also assess performance in real 16S data, where we reanalyze previous genetic association data to show our method discovers a larger number of quantitative trait associations than other widely used methods. We implement our method in the software Karp, for k-mer based analysis of read pools, to provide a novel combination of speed and accuracy that is uniquely suited for enhancing discoveries in microbial studies. [ABSTRACT FROM AUTHOR]

The adaptation of the CRISPR-Cas9 system as a genome editing technique has generated much excitement in recent years owing to its ability to manipulate targeted genes and genomic regions that are complementary to a programmed single guide RNA (sgRNA). However, the efficacy of a specific sgRNA is not uniquely defined by exact sequence homology to the target site, thus unintended off-targets might additionally be cleaved. Current methods for sgRNA design are mainly concerned with predicting off-targets for a given sgRNA using basic sequence features and employ elementary rules for ranking possible sgRNAs. Here, we introduce CRISTA (CRISPR Target Assessment), a novel algorithm within the machine learning framework that determines the propensity of a genomic site to be cleaved by a given sgRNA. We show that the predictions made with CRISTA are more accurate than other available methodologies. We further demonstrate that the occurrence of bulges is not a rare phenomenon and should be accounted for in the prediction process. Beyond predicting cleavage efficiencies, the learning process provides inferences regarding patterns that underlie the mechanism of action of the CRISPR-Cas9 system. We discover that attributes that describe the spatial structure and rigidity of the entire genomic site as well as those surrounding the PAM region are a major component of the prediction capabilities. [ABSTRACT FROM AUTHOR]

In functionally diverse protein families, conservation in short signature regions may outperform full-length sequence comparisons for identifying proteins that belong to a subgroup within which one specific aspect of their function is conserved. The SIMBAL workflow (Sites Inferred by Metabolic Background Assertion Labeling) is a data-mining procedure for finding such signature regions. It begins by using clues from genomic context, such as co-occurrence or conserved gene neighborhoods, to build a useful training set from a large number of uncharacterized but mutually homologous proteins. When training set construction is successful, the YES partition is enriched in proteins that share function with the user’s query sequence, while the NO partition is depleted. A selected query sequence is then mined for short signature regions whose closest matches overwhelmingly favor proteins from the YES partition. High-scoring signature regions typically contain key residues critical to functional specificity, so proteins with the highest sequence similarity across these regions tend to share the same function. The SIMBAL algorithm was described previously, but significant manual effort, expertise, and a supporting software infrastructure were required to prepare the requisite training sets. Here, we describe a new, distributable software suite that speeds up and simplifies the process for using SIMBAL, most notably by providing tools that automate training set construction. These tools have broad utility for comparative genomics, allowing for flexible collection of proteins or protein domains based on genomic context as well as homology, a capability that can greatly assist in protein family construction. Armed with this new software suite, SIMBAL can serve as a fast and powerful in silico alternative to direct experimentation for characterizing proteins and their functional interactions. [ABSTRACT FROM AUTHOR]

The focus of analyzing data from microarray experiments has shifted from the identification of associated individual genes to that of associated biological pathways or gene sets. In bioinformatics, a feature selection algorithm is usually used to cope with the high dimensionality of microarray data. In addition to those algorithms that use the biological information contained within a gene set as a priori to facilitate the process of feature selection, various gene set analysis methods can be applied directly or modified readily for the purpose of feature selection. Significance analysis of microarray to gene-set reduction analysis (SAM-GSR) algorithm, a novel direction of gene set analysis, is one of such methods. Here, we explore the feature selection property of SAM-GSR and provide a modification to better achieve the goal of feature selection. In a multiple sclerosis (MS) microarray data application, both SAM-GSR and our modification of SAM-GSR perform well. Our results show that SAM-GSR can carry out feature selection indeed, and modified SAM-GSR outperforms SAM-GSR. Given pathway information is far from completeness, a statistical method capable of constructing biologically meaningful gene networks is of interest. Consequently, both SAM-GSR algorithms will be continuously revaluated in our future work, and thus better characterized. [ABSTRACT FROM AUTHOR]

Various types of genome and gene similarity networks along with their characteristics have been increasingly used for retracing different kinds of evolutionary and ecological relationships. Here, we present a new polynomial time algorithm and the corresponding software (BRIDES) to provide characterization of different types of paths existing in evolving (or augmented) similarity networks under the constraint that such paths contain at least one node that was not present in the original network. These different paths are denoted as Breakthroughs, Roadblocks, Impasses, Detours, Equal paths, and Shortcuts. The analysis of their distribution can allow discriminating among different evolutionary hypotheses concerning genomes or genes at hand. Our approach is based on an original application of the popular shortest path Dijkstra’s and Yen’s algorithms. The C++ and R versions of the BRIDES program are freely available at: . [ABSTRACT FROM AUTHOR]

A set of conserved binding sites recognized by a transcription factor is called a motif, which can be found by many applications of comparative genomics for identifying over-represented segments. Moreover, when numerous putative motifs are predicted from a collection of genome-wide data, their similarity data can be represented as a large graph, where these motifs are connected to one another. However, an efficient clustering algorithm is desired for clustering the motifs that belong to the same groups and separating the motifs that belong to different groups, or even deleting an amount of spurious ones. In this work, a new motif clustering algorithm, CLIMP, is proposed by using maximal cliques and sped up by parallelizing its program. When a synthetic motif dataset from the database JASPAR, a set of putative motifs from a phylogenetic foot-printing dataset, and a set of putative motifs from a ChIP dataset are used to compare the performances of CLIMP and two other high-performance algorithms, the results demonstrate that CLIMP mostly outperforms the two algorithms on the three datasets for motif clustering, so that it can be a useful complement of the clustering procedures in some genome-wide motif prediction pipelines. CLIMP is available at . [ABSTRACT FROM AUTHOR]

Recent advances in whole genome sequencing have made the technology available for routine use in microbiological laboratories. However, a major obstacle for using this technology is the availability of simple and automatic bioinformatics tools. Based on previously published and already available web-based tools we developed a single pipeline for batch uploading of whole genome sequencing data from multiple bacterial isolates. The pipeline will automatically identify the bacterial species and, if applicable, assemble the genome, identify the multilocus sequence type, plasmids, virulence genes and antimicrobial resistance genes. A short printable report for each sample will be provided and an Excel spreadsheet containing all the metadata and a summary of the results for all submitted samples can be downloaded. The pipeline was benchmarked using datasets previously used to test the individual services. The reported results enable a rapid overview of the major results, and comparing that to the previously found results showed that the platform is reliable and able to correctly predict the species and find most of the expected genes automatically. In conclusion, a combined bioinformatics platform was developed and made publicly available, providing easy-to-use automated analysis of bacterial whole genome sequencing data. The platform may be of immediate relevance as a guide for investigators using whole genome sequencing for clinical diagnostics and surveillance. The platform is freely available at: and it is the intention that it will continue to be expanded with new features as these become available. [ABSTRACT FROM AUTHOR]

Sub-cellular localisation of proteins is an essential post-translational regulatory mechanism that can be assayed using high-throughput mass spectrometry (MS). These MS-based spatial proteomics experiments enable us to pinpoint the sub-cellular distribution of thousands of proteins in a specific system under controlled conditions. Recent advances in high-throughput MS methods have yielded a plethora of experimental spatial proteomics data for the cell biology community. Yet, there are many third-party data sources, such as immunofluorescence microscopy or protein annotations and sequences, which represent a rich and vast source of complementary information. We present a unique transfer learning classification framework that utilises a nearest-neighbour or support vector machine system, to integrate heterogeneous data sources to considerably improve on the quantity and quality of sub-cellular protein assignment. We demonstrate the utility of our algorithms through evaluation of five experimental datasets, from four different species in conjunction with four different auxiliary data sources to classify proteins to tens of sub-cellular compartments with high generalisation accuracy. We further apply the method to an experiment on pluripotent mouse embryonic stem cells to classify a set of previously unknown proteins, and validate our findings against a recent high resolution map of the mouse stem cell proteome. The methodology is distributed as part of the open-source Bioconductor suite for spatial proteomics data analysis. [ABSTRACT FROM AUTHOR]