Computational identification of eukaryotic promoters based on cascaded deep capsule neural networks.

A promoter is a region in the DNA sequence that defines where the transcription of a gene by RNA polymerase initiates, which is typically located proximal to the transcription start site (TSS). How to correctly identify the gene TSS and the core promoter is essential for our understanding of the transcriptional regulation of genes. As a complement to conventional experimental methods, computational techniques with easy-to-use platforms as essential bioinformatics tools can be effectively applied to annotate the functions and physiological roles of promoters. In this work, we propose a deep learning-based method termed Depicter (Deep learning for predicting promoter), for identifying three specific types of promoters, i.e. promoter sequences with the TATA-box (TATA model), promoter sequences without the TATA-box (non-TATA model), and indistinguishable promoters (TATA and non-TATA model). Depicter is developed based on an up-to-date, species-specific dataset which includes Homo sapiens, Mus musculus, Drosophila melanogaster and Arabidopsis thaliana promoters. A convolutional neural network coupled with capsule layers is proposed to train and optimize the prediction model of Depicter. Extensive benchmarking and independent tests demonstrate that Depicter achieves an improved predictive performance compared with several state-of-the-art methods. The webserver of Depicter is implemented and freely accessible at https://depicter.erc.monash.edu/.

Porpoise: a new approach for accurate prediction of RNA pseudouridine sites.

Pseudouridine is a ubiquitous RNA modification type present in eukaryotes and prokaryotes, which plays a vital role in various biological processes. Almost all kinds of RNAs are subject to this modification. However, it remains a great challenge to identify pseudouridine sites via experimental approaches, requiring expensive and time-consuming experimental research. Therefore, computational approaches that can be used to perform accurate in silico identification of pseudouridine sites from the large amount of RNA sequence data are highly desirable and can aid in the functional elucidation of this critical modification. Here, we propose a new computational approach, termed Porpoise, to accurately identify pseudouridine sites from RNA sequence data. Porpoise builds upon a comprehensive evaluation of 18 frequently used feature encoding schemes based on the selection of four types of features, including binary features, pseudo k-tuple composition, nucleotide chemical property and position-specific trinucleotide propensity based on single-strand (PSTNPss). The selected features are fed into the stacked ensemble learning framework to enable the construction of an effective stacked model. Both cross-validation tests on the benchmark dataset and independent tests show that Porpoise achieves superior predictive performance than several state-of-the-art approaches. The application of model interpretation tools demonstrates the importance of PSTNPs for the performance of the trained models. This new method is anticipated to facilitate community-wide efforts to identify putative pseudouridine sites and formulate novel testable biological hypothesis.

Comprehensive assessment of machine learning-based methods for predicting antimicrobial peptides.

Antimicrobial peptides (AMPs) are a unique and diverse group of molecules that play a crucial role in a myriad of biological processes and cellular functions. AMP-related studies have become increasingly popular in recent years due to antimicrobial resistance, which is becoming an emerging global concern. Systematic experimental identification of AMPs faces many difficulties due to the limitations of current methods. Given its significance, more than 30 computational methods have been developed for accurate prediction of AMPs. These approaches show high diversity in their data set size, data quality, core algorithms, feature extraction, feature selection techniques and evaluation strategies. Here, we provide a comprehensive survey on a variety of current approaches for AMP identification and point at the differences between these methods. In addition, we evaluate the predictive performance of the surveyed tools based on an independent test data set containing 1536 AMPs and 1536 non-AMPs. Furthermore, we construct six validation data sets based on six different common AMP databases and compare different computational methods based on these data sets. The results indicate that amPEPpy achieves the best predictive performance and outperforms the other compared methods. As the predictive performances are affected by the different data sets used by different methods, we additionally perform the 5-fold cross-validation test to benchmark different traditional machine learning methods on the same data set. These cross-validation results indicate that random forest, support vector machine and eXtreme Gradient Boosting achieve comparatively better performances than other machine learning methods and are often the algorithms of choice of multiple AMP prediction tools.

Anthem: a user customised tool for fast and accurate prediction of binding between peptides and HLA class I molecules.

Neopeptide-based immunotherapy has been recognised as a promising approach for the treatment of cancers. For neopeptides to be recognised by CD8+ T cells and induce an immune response, their binding to human leukocyte antigen class I (HLA-I) molecules is a necessary first step. Most epitope prediction tools thus rely on the prediction of such binding. With the use of mass spectrometry, the scale of naturally presented HLA ligands that could be used to develop such predictors has been expanded. However, there are rarely efforts that focus on the integration of these experimental data with computational algorithms to efficiently develop up-to-date predictors. Here, we present Anthem for accurate HLA-I binding prediction. In particular, we have developed a user-friendly framework to support the development of customisable HLA-I binding prediction models to meet challenges associated with the rapidly increasing availability of large amounts of immunopeptidomic data. Our extensive evaluation, using both independent and experimental datasets shows that Anthem achieves an overall similar or higher area under curve value compared with other contemporary tools. It is anticipated that Anthem will provide a unique opportunity for the non-expert user to analyse and interpret their own in-house or publicly deposited datasets.

iLearnPlus: a comprehensive and automated machine-learning platform for nucleic acid and protein sequence analysis, prediction and visualization.

Sequence-based analysis and prediction are fundamental bioinformatic tasks that facilitate understanding of the sequence(-structure)-function paradigm for DNAs, RNAs and proteins. Rapid accumulation of sequences requires equally pervasive development of new predictive models, which depends on the availability of effective tools that support these efforts. We introduce iLearnPlus, the first machine-learning platform with graphical- and web-based interfaces for the construction of machine-learning pipelines for analysis and predictions using nucleic acid and protein sequences. iLearnPlus provides a comprehensive set of algorithms and automates sequence-based feature extraction and analysis, construction and deployment of models, assessment of predictive performance, statistical analysis, and data visualization; all without programming. iLearnPlus includes a wide range of feature sets which encode information from the input sequences and over twenty machine-learning algorithms that cover several deep-learning approaches, outnumbering the current solutions by a wide margin. Our solution caters to experienced bioinformaticians, given the broad range of options, and biologists with no programming background, given the point-and-click interface and easy-to-follow design process. We showcase iLearnPlus with two case studies concerning prediction of long noncoding RNAs (lncRNAs) from RNA transcripts and prediction of crotonylation sites in protein chains. iLearnPlus is an open-source platform available at https://github.com/Superzchen/iLearnPlus/ with the webserver at http://ilearnplus.erc.monash.edu/.

Computational analysis and prediction of PE_PGRS proteins using machine learning.

Mycobacterium tuberculosis genome comprises approximately 10% of two families of poorly characterised genes due to their high GC content and highly repetitive nature. The largest sub-group, the proline-glutamic acid polymorphic guanine-cytosine-rich sequence (PE_PGRS) family, is thought to be involved in host response and disease pathogenicity. Due to their high genetic variability and complexity of analysis, they are typically disregarded for further research in genomic studies. There are currently limited online resources and homology computational tools that can identify and analyse PE_PGRS proteins. In addition, they are computational-intensive and time-consuming, and lack sensitivity. Therefore, computational methods that can rapidly and accurately identify PE_PGRS proteins are valuable to facilitate the functional elucidation of the PE_PGRS family proteins. In this study, we developed the first machine learning-based bioinformatics approach, termed PEPPER, to allow users to identify PE_PGRS proteins rapidly and accurately. PEPPER was built upon a comprehensive evaluation of 13 popular machine learning algorithms with various sequence and physicochemical features. Empirical studies demonstrated that PEPPER achieved significantly better performance than alignment-based approaches, BLASTP and PHMMER, in both prediction accuracy and speed. PEPPER is anticipated to facilitate community-wide efforts to conduct high-throughput identification and analysis of PE_PGRS proteins.

An Interpretable Prediction Model for Identifying N7-Methylguanosine Sites Based on XGBoost and SHAP.

Recent studies have increasingly shown that the chemical modification of mRNA plays an important role in the regulation of gene expression. N7-methylguanosine (m7G) is a type of positively-charged mRNA modification that plays an essential role for efficient gene expression and cell viability. However, the research on m7G has received little attention to date. Bioinformatics tools can be applied as auxiliary methods to identify m7G sites in transcriptomes. In this study, we develop a novel interpretable machine learning-based approach termed XG-m7G for the differentiation of m7G sites using the XGBoost algorithm and six different types of sequence-encoding schemes. Both 10-fold and jackknife cross-validation tests indicate that XG-m7G outperforms iRNA-m7G. Moreover, using the powerful SHAP algorithm, this new framework also provides desirable interpretations of the model performance and highlights the most important features for identifying m7G sites. XG-m7G is anticipated to serve as a useful tool and guide for researchers in their future studies of mRNA modification sites.

Procleave: Predicting Protease-specific Substrate Cleavage Sites by Combining Sequence and Structural Information.

Proteases are enzymes that cleave and hydrolyse the peptide bonds between two specific amino acid residues of target substrate proteins. Protease-controlled proteolysis plays a key role in the degradation and recycling of proteins, which is essential for various physiological processes. Thus, solving the substrate identification problem will have important implications for the precise understanding of functions and physiological roles of proteases, as well as for therapeutic target identification and pharmaceutical applicability. Consequently, there is a great demand for bioinformatics methods that can predict novel substrate cleavage events with high accuracy by utilizing both sequence and structural information. In this study, we present Procleave, a novel bioinformatics approach for predicting protease-specific substrates and specific cleavage sites by taking into account both their sequence and 3D structural information. Structural features of known cleavage sites were represented by discrete values using a LOWESS data-smoothing optimization method, which turned out to be critical for the performance of Procleave. The optimal approximations of all structural parameter values were encoded in a conditional random field (CRF) computational framework, alongside sequence and chemical group-based features. Here, we demonstrate the outstanding performance of Procleave through extensive benchmarking and independent tests. Procleave is capable of correctly identifying most cleavage sites in the case study. Importantly, when applied to the human structural proteome encompassing 17,628 protein structures, Procleave suggests a number of potential novel target substrates and their corresponding cleavage sites of different proteases. Procleave is implemented as a webserver and is freely accessible at http://procleave.erc.monash.edu/.