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1. MUNDO: protein function prediction embedded in a multispecies world

   https://doi.org/10.1093/bioadv/vbab025  

   Arsenescu, Victor; Devkota, Kapil; Erden, Mert; Shpilker, Polina; Werenski, Matthew; Cowen, Lenore J (January 2022, Bioinformatics Advances)

   Mulder, Nicola (Ed.)

   Abstract Motivation Leveraging cross-species information in protein function prediction can add significant power to network-based protein function prediction methods, because so much functional information is conserved across at least close scales of evolution. We introduce MUNDO, a new cross-species co-embedding method that combines a single-network embedding method with a co-embedding method to predict functional annotations in a target species, leveraging also functional annotations in a model species network. Results Across a wide range of parameter choices, MUNDO performs best at predicting annotations in the mouse network, when trained on mouse and human protein–protein interaction (PPI) networks, in the human network, when trained on human and mouse PPIs, and in Baker’s yeast, when trained on Fission and Baker’s yeast, as compared to competitor methods. MUNDO also outperforms all the cross-species methods when predicting in Fission yeast when trained on Fission and Baker’s yeast; however, in this single case, discarding the information from the other species and using annotations from the Fission yeast network alone usually performs best. Availability and implementation All code is available and can be accessed here: github.com/v0rtex20k/MUNDO. Supplementary information Supplementary data are available at Bioinformatics Advances online. Additional experimental results are on our github site. 

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2. GLIDER: function prediction from GLIDE-based neighborhoods

   https://doi.org/10.1093/bioinformatics/btac322  

   Devkota, Kapil; Schmidt, Henri; Werenski, Matt; Murphy, James M.; Erden, Mert; Arsenescu, Victor; Cowen, Lenore J.; Valencia, ed., Alfonso (May 2022, Bioinformatics)

   Abstract MotivationProtein function prediction, based on the patterns of connection in a protein–protein interaction (or association) network, is perhaps the most studied of the classical, fundamental inference problems for biological networks. A highly successful set of recent approaches use random walk-based low-dimensional embeddings that tend to place functionally similar proteins into coherent spatial regions. However, these approaches lose valuable local graph structure from the network when considering only the embedding. We introduce GLIDER, a method that replaces a protein–protein interaction or association network with a new graph-based similarity network. GLIDER is based on a variant of our previous GLIDE method, which was designed to predict missing links in protein–protein association networks, capturing implicit local and global (i.e. embedding-based) graph properties. ResultsGLIDER outperforms competing methods on the task of predicting GO functional labels in cross-validation on a heterogeneous collection of four human protein–protein association networks derived from the 2016 DREAM Disease Module Identification Challenge, and also on three different protein–protein association networks built from the STRING database. We show that this is due to the strong functional enrichment that is present in the local GLIDER neighborhood in multiple different types of protein–protein association networks. Furthermore, we introduce the GLIDER graph neighborhood as a way for biologists to visualize the local neighborhood of a disease gene. As an application, we look at the local GLIDER neighborhoods of a set of known Parkinson’s Disease GWAS genes, rediscover many genes which have known involvement in Parkinson’s disease pathways, plus suggest some new genes to study. Availability and implementationAll code is publicly available and can be accessed here: https://github.com/kap-devkota/GLIDER. Supplementary informationSupplementary data are available at Bioinformatics online. 

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3. Specialization Restricts the Evolutionary Paths Available to Yeast Sugar Transporters

   https://doi.org/10.1093/molbev/msae228  

   Crandall, Johnathan_G; Zhou, Xiaofan; Rokas, Antonis; Hittinger, Chris_Todd; Townsend, ed., Jeffrey (November 2024, Molecular Biology and Evolution)

   Abstract Functional innovation at the protein level is a key source of evolutionary novelties. The constraints on functional innovations are likely to be highly specific in different proteins, which are shaped by their unique histories and the extent of global epistasis that arises from their structures and biochemistries. These contextual nuances in the sequence–function relationship have implications both for a basic understanding of the evolutionary process and for engineering proteins with desirable properties. Here, we have investigated the molecular basis of novel function in a model member of an ancient, conserved, and biotechnologically relevant protein family. These Major Facilitator Superfamily sugar porters are a functionally diverse group of proteins that are thought to be highly plastic and evolvable. By dissecting a recent evolutionary innovation in an α-glucoside transporter from the yeast Saccharomyces eubayanus, we show that the ability to transport a novel substrate requires high-order interactions between many protein regions and numerous specific residues proximal to the transport channel. To reconcile the functional diversity of this family with the constrained evolution of this model protein, we generated new, state-of-the-art genome annotations for 332 Saccharomycotina yeast species spanning ∼400 My of evolution. By integrating phylogenetic and phenotypic analyses across these species, we show that the model yeast α-glucoside transporters likely evolved from a multifunctional ancestor and became subfunctionalized. The accumulation of additive and epistatic substitutions likely entrenched this subfunction, which made the simultaneous acquisition of multiple interacting substitutions the only reasonably accessible path to novelty. 

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4. Disentangled Network Alignment with Matching Explainability

   https://doi.org/10.1109/INFOCOM.2019.8737411  

   Zhou, Fan; Wen, Zijing; Trajcevski, Goce; Zhang, Kunpeng; Zhong, Ting; Liu, Fang (April 2019, 2019 {IEEE} Conference on Computer Communications, {INFOCOM} 2019, Paris, France, April 29 - May 2, 2019)

   Network alignment (NA) is a fundamental problem in many application domains – from social networks, through biology and communications, to neuroscience. The main objective is to identify common nodes and most similar connections across multiple networks (resp. graphs). Many of the existing efforts focus on efficient anchor node linkage by leveraging various features and optimizing network mapping functions with the pairwise similarity between anchor nodes. Despite the recent advances, there still exist two kinds of challenges: (1) entangled node embeddings, arising from the contradictory goals of NA: embedding proximal nodes in a closed form for representation in a single network vs. discriminating among them when mapping the nodes across networks; and (2) lack of interpretability about the node matching and alignment, essential for understanding prediction tasks. We propose dNAME (disentangled Network Alignment with Matching Explainability) – a novel solution for NA in heterogeneous networks settings, based on a matching technique that embeds nodes in a disentangled and faithful manner. The NA task is cast as an adversarial optimization problem which learns a proximity-preserving model locally around the anchor nodes, while still being discriminative. We also introduce a method to explain our semi-supervised model with the theory of robust statistics, by tracing the importance of each anchor node and its explanations on the NA performance. This is extensible to many other NA methods, as it provides model interpretability. Experiments conducted on several public datasets show that dNAME outperforms the state-of-the-art methods in terms of both network alignment precision and node matching ranking. 

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5. HFSP: high speed homology-driven function annotation of proteins

   https://doi.org/10.1093/bioinformatics/bty262  

   Mahlich, Yannick; Steinegger, Martin; Rost, Burkhard; Bromberg, Yana (June 2018, Bioinformatics)

   Abstract MotivationThe rapid drop in sequencing costs has produced many more (predicted) protein sequences than can feasibly be functionally annotated with wet-lab experiments. Thus, many computational methods have been developed for this purpose. Most of these methods employ homology-based inference, approximated via sequence alignments, to transfer functional annotations between proteins. The increase in the number of available sequences, however, has drastically increased the search space, thus significantly slowing down alignment methods. ResultsHere we describe homology-derived functional similarity of proteins (HFSP), a novel computational method that uses results of a high-speed alignment algorithm, MMseqs2, to infer functional similarity of proteins on the basis of their alignment length and sequence identity. We show that our method is accurate (85% precision) and fast (more than 40-fold speed increase over state-of-the-art). HFSP can help correct at least a 16% error in legacy curations, even for a resource of as high quality as Swiss-Prot. These findings suggest HFSP as an ideal resource for large-scale functional annotation efforts. Supplementary informationSupplementary data are available at Bioinformatics online. 

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