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Supervised machine learning is widely used in biology and deserves more scrutiny. We present a set of community-wide recommendations (DOME) aiming to help establish standards of supervised machine learning validation in biology. Formulated as questions, the DOME recommendations improve the assessment and reproducibility of papers when included as supplementary material. The work of the Machine Learning Focus Group was funded by ELIXIR, the research infrastructure for life-science data. IW was funded by the A*STAR Career Development Award (project no. C210112057) from the Agency for Science, Technology and Research (A*STAR), Singapore. D.F. was supported by Estonian Research Council grants (PRG1095, PSG59 and ERA-NET TRANSCAN-2 (BioEndoCar)); Project No 2014-2020.4.01.16-0271, ELIXIR and the European Regional Development Fund through EXCITE Center of Excellence. S.C.E.T. has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie Grant agreements No. 778247 and No. 823886, and Italian Ministry of University and Research PRIN 2017 grant 2017483NH8. Peer Reviewed "Article signat per 8 autors més 28 autors/es de l' ELIXIR Machine Learning Focus Group: Emidio Capriotti, Rita Casadio, Salvador Capella-Gutierrez, Davide Cirillo, Alessio Del Conte, Alexandros C. Dimopoulos, Victoria Dominguez Del Angel, Joaquin Dopazo, Piero Fariselli, José Maria Fernández, Florian Huber, Anna Kreshuk, Tom Lenaerts, Pier Luigi Martelli, Arcadi Navarro, Pilib Ó Broin, Janet Piñero, Damiano Piovesan, Martin Reczko, Francesco Ronzano, Venkata Satagopam, Castrense Savojardo, Vojtech Spiwok, Marco Antonio Tangaro, Giacomo Tartari, David Salgado, Alfonso Valencia & Federico Zambelli"

Protein sequences, directly translated from genomic data, need functional and structural annotation. Together with molecular function and biological process, subcellular localization is an important feature necessary for understanding the protein role and the compartment where the mature protein is active. In the case of mitochondrial proteins, their precursor sequences translated by the ribosome machinery include specific patterns from which it is possible not only to recognize their final destination within the organelle but also which of the mitochondrial subcompartments the protein is intended for. Four compartments are routinely discriminated, including the inner and the outer membranes, the intermembrane space, and the matrix. Here we discuss to which extent it is feasible to develop computational methods for detecting mitochondrial targeting peptides in the precursor sequence and todiscriminate their final destination in the organelle. We benchmark two of our methods on the general task of recognizing human mitochondrial proteins endowed with an experimentally characterized targeting peptide (TPpred3) and predicting which submitochondrial compartment is the final destination (DeepMito). We describe how to adopt our web servers in order to discriminate which human proteins are endowed with mitochondrial targeting peptides, the position of cleavage sites, and which submitochondrial compartment are intended for. By this, we add some other 1788 human proteins to the 450 ones already manually annotated in UniProt with a mitochondrial targeting peptide, providing for each of them also the characterization of the suborganellar localization.

Background The prediction of protein subcellular localization is a key step of the big effort towards protein functional annotation. Many computational methods exist to identify high-level protein subcellular compartments such as nucleus, cytoplasm or organelles. However, many organelles, like mitochondria, have their own internal compartmentalization. Knowing the precise location of a protein inside mitochondria is crucial for its accurate functional characterization. We recently developed DeepMito, a new method based on a 1-Dimensional Convolutional Neural Network (1D-CNN) architecture outperforming other similar approaches available in literature. Results Here, we explore the adoption of DeepMito for the large-scale annotation of four sub-mitochondrial localizations on mitochondrial proteomes of five different species, including human, mouse, fly, yeast and Arabidopsis thaliana. A significant fraction of the proteins from these organisms lacked experimental information about sub-mitochondrial localization. We adopted DeepMito to fill the gap, providing complete characterization of protein localization at sub-mitochondrial level for each protein of the five proteomes. Moreover, we identified novel mitochondrial proteins fishing on the set of proteins lacking any subcellular localization annotation using available state-of-the-art subcellular localization predictors. We finally performed additional functional characterization of proteins predicted by DeepMito as localized into the four different sub-mitochondrial compartments using both available experimental and predicted GO terms. All data generated in this study were collected into a database called DeepMitoDB (available at http://busca.biocomp.unibo.it/deepmitodb), providing complete functional characterization of 4307 mitochondrial proteins from the five species. Conclusions DeepMitoDB offers a comprehensive view of mitochondrial proteins, including experimental and predicted fine-grain sub-cellular localization and annotated and predicted functional annotations. The database complements other similar resources providing characterization of new proteins. Furthermore, it is also unique in including localization information at the sub-mitochondrial level. For this reason, we believe that DeepMitoDB can be a valuable resource for mitochondrial research.

Motivation The correct localization of proteins in cell compartments is a key issue for their function. Particularly, mitochondrial proteins are physiologically active in different compartments and their aberrant localization contributes to the pathogenesis of human mitochondrial pathologies. Many computational methods exist to assign protein sequences to subcellular compartments such as nucleus, cytoplasm and organelles. However, a substantial lack of experimental evidence in public sequence databases hampered so far a finer grain discrimination, including also intra-organelle compartments. Results We describe DeepMito, a novel method for predicting protein sub-mitochondrial cellular localization. Taking advantage of powerful deep-learning approaches, such as convolutional neural networks, our method is able to achieve very high prediction performances when discriminating among four different mitochondrial compartments (matrix, outer, inner and intermembrane regions). The method is trained and tested in cross-validation on a newly generated, high-quality dataset comprising 424 mitochondrial proteins with experimental evidence for sub-organelle localizations. We benchmark DeepMito towards the only one recent approach developed for the same task. Results indicate that DeepMito performances are superior. Finally, genomic-scale prediction on a highly-curated dataset of human mitochondrial proteins further confirms the effectiveness of our approach and suggests that DeepMito is a good candidate for genome-scale annotation of mitochondrial protein subcellular localization. Availability and implementation The DeepMito web server as well as all datasets used in this study are available at http://busca.biocomp.unibo.it/deepmito. A standalone version of DeepMito is available on DockerHub at https://hub.docker.com/r/bolognabiocomp/deepmito. DeepMito source code is available on GitHub at https://github.com/BolognaBiocomp/deepmito Supplementary information Supplementary data are available at Bioinformatics online.