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Motivation: Systematically predicting gene (or protein) function based on molecular interaction networks has become an important tool in refining and enhancing the existing annotation catalogs, such as the Gene Ontology (GO) database. However, functional labels with only a few (<10) annotated genes, which constitute about half of the GO terms in yeast, mouse and human, pose a unique challenge in that any prediction algorithm that independently considers each label faces a paucity of information and thus is prone to capture non-generalizable patterns in the data, resulting in poor predictive performance. There exist a variety of algorithms for function prediction, but none properly address this ‘overfitting’ issue of sparsely annotated functions, or do so in a manner scalable to tens of thousands of functions in the human catalog.Results: We propose a novel function prediction algorithm, clusDCA, which transfers information between similar functional labels to alleviate the overfitting problem for sparsely annotated functions. Our method is scalable to datasets with a large number of annotations. In a cross-validation experiment in yeast, mouse and human, our method greatly outperformed previous state-of-the-art function prediction algorithms in predicting sparsely annotated functions, without sacrificing the performance on labels with sufficient information. Furthermore, we show that our method can accurately predict genes that will be assigned a functional label that has no known annotations, based only on the ontology graph structure and genes associated with other labels, which further suggests that our method effectively utilizes the similarity between gene functions.Availability and implementation: https://github.com/wangshenguiuc/clusDCA.Contact: jianpeng@illinois.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Motivation: Protein contact prediction is important for protein structure and functional study. Both evolutionary coupling (EC) analysis and supervised machine learning methods have been developed, making use of different information sources. However, contact prediction is still challenging especially for proteins without a large number of sequence homologs. Results: This article presents a group graphical lasso (GGL) method for contact prediction that integrates joint multi-family EC analysis and supervised learning to improve accuracy on proteins without many sequence homologs. Different from existing single-family EC analysis that uses residue coevolution information in only the target protein family, our joint EC analysis uses residue coevolution in both the target family and its related families, which may have divergent sequences but similar folds. To implement this, we model a set of related protein families using Gaussian graphical models and then coestimate their parameters by maximum-likelihood, subject to the constraint that these parameters shall be similar to some degree. Our GGL method can also integrate supervised learning methods to further improve accuracy. Experiments show that our method outperforms existing methods on proteins without thousands of sequence homologs, and that our method performs better on both conserved and family-specific contacts. Availability and implementation: See http://raptorx.uchicago.edu/ContactMap/ for a web server implementing the method.

Supplementary data are available at Bioinformatics online.

Intra-protein residue-level contact prediction has drawn a lot of attentions in recent years and made very good progress, but much fewer methods are dedicated to inter-protein contact prediction, which are important for understanding how proteins interact at structure and residue level. Direct coupling analysis (DCA) is popular for intra-protein contact prediction, but extending it to inter-protein contact prediction is challenging since it requires too many interlogs (i.e., interacting homologs) to be effective, which cannot be easily fulfilled especially for a putative interacting protein pair in eukaryotes. We show that deep learning, even trained by only intra-protein contact maps, works much better than DCA for inter-protein contact prediction. We also show that a phylogeny-based method can generate a better multiple sequence alignment for eukaryotes than existing genome-based methods and thus, lead to better inter-protein contact prediction. Our method shall be useful for protein docking, protein interaction prediction and protein interaction network construction.

Single cell technologies are rapidly generating large amounts of data that enables us to understand biological systems at single-cell resolution. However, joint analysis of datasets generated by independent labs remains challenging due to a lack of consistent terminology to describe cell types. Here, we present OnClass, an algorithm and accompanying software for automatically classifying cells into cell types that are part of the controlled vocabulary that forms the Cell Ontology. A key advantage of OnClass is its capability to classify cells into cell types not present in the training data because it uses the Cell Ontology graph to infer cell type relationships. Furthermore, OnClass can be used to identify marker genes for all the cell ontology categories, regardless of whether the cell types are present or absent in the training data, suggesting that OnClass goes beyond a simple annotation tool for single cell datasets, being the first algorithm capable to identify marker genes specific to all terms of the Cell Ontology and offering the possibility of refining the Cell Ontology using a data-centric approach.

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