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1. deepNF: deep network fusion for protein function prediction

   https://doi.org/10.1093/bioinformatics/bty440  

   Gligorijević, Vladimir ; Barot, Meet ; Bonneau, Richard ; Wren, ed., Jonathan ( June 2018 , Bioinformatics)

   The prevalence of high-throughput experimental methods has resulted in an abundance of large-scale molecular and functional interaction networks. The connectivity of these networks provides a rich source of information for inferring functional annotations for genes and proteins. An important challenge has been to develop methods for combining these heterogeneous networks to extract useful protein feature representations for function prediction. Most of the existing approaches for network integration use shallow models that encounter difficulty in capturing complex and highly non-linear network structures. Thus, we propose deepNF, a network fusion method based on Multimodal Deep Autoencoders to extract high-level features of proteins from multiple heterogeneous interaction networks.

   We apply this method to combine STRING networks to construct a common low-dimensional representation containing high-level protein features. We use separate layers for different network types in the early stages of the multimodal autoencoder, later connecting all the layers into a single bottleneck layer from which we extract features to predict protein function. We compare the cross-validation and temporal holdout predictive performance of our method with state-of-the-art methods, including the recently proposed method Mashup. Our results show that our method outperforms previous methods for both human and yeast STRING networks. We also show substantial improvement in the performance of our method in predicting gene ontology terms of varying type and specificity.

   deepNF is freely available at: https://github.com/VGligorijevic/deepNF.

   Supplementary data are available at Bioinformatics online.

    

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2. NetQuilt: deep multispecies network-based protein function prediction using homology-informed network similarity

   https://doi.org/10.1093/bioinformatics/btab098  

   Barot, Meet ; Gligorijević, Vladimir ; Cho, Kyunghyun ; Bonneau, Richard ( February 2021 , Bioinformatics)

   Martelli, Pier Luigi (Ed.)

   Abstract Motivation Transferring knowledge between species is challenging: different species contain distinct proteomes and cellular architectures, which cause their proteins to carry out different functions via different interaction networks. Many approaches to protein functional annotation use sequence similarity to transfer knowledge between species. These approaches cannot produce accurate predictions for proteins without homologues of known function, as many functions require cellular context for meaningful prediction. To supply this context, network-based methods use protein-protein interaction (PPI) networks as a source of information for inferring protein function and have demonstrated promising results in function prediction. However, most of these methods are tied to a network for a single species, and many species lack biological networks. Results In this work, we integrate sequence and network information across multiple species by computing IsoRank similarity scores to create a meta-network profile of the proteins of multiple species. We use this integrated multispecies meta-network as input to train a maxout neural network with Gene Ontology terms as target labels. Our multispecies approach takes advantage of more training examples, and consequently leads to significant improvements in function prediction performance compared to two network-based methods, a deep learning sequence-based method and the BLAST annotation method used in the Critial Assessment of Functional Annotation. We are able to demonstrate that our approach performs well even in cases where a species has no network information available: when an organism’s PPI network is left out we can use our multi-species method to make predictions for the left-out organism with good performance. Availability and implementation The code is freely available at https://github.com/nowittynamesleft/NetQuilt. The data, including sequences, PPI networks and GO annotations are available at https://string-db.org/. Supplementary information Supplementary data are available at Bioinformatics online. 

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3. 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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4. Prediction of evolutionary constraint by genomic annotations improves functional prioritization of genomic variants in maize

   https://doi.org/10.1186/s13059-022-02747-2  

   Ramstein, Guillaume P. ; Buckler, Edward S. ( September 2022 , Genome Biology)

   Crop improvement through cross-population genomic prediction and genome editing requires identification of causal variants at high resolution, within fewer than hundreds of base pairs. Most genetic mapping studies have generally lacked such resolution. In contrast, evolutionary approaches can detect genetic effects at high resolution, but they are limited by shifting selection, missing data, and low depth of multiple-sequence alignments. Here we use genomic annotations to accurately predict nucleotide conservation across angiosperms, as a proxy for fitness effect of mutations.

   Using only sequence analysis, we annotate nonsynonymous mutations in 25,824 maize gene models, with information from bioinformatics and deep learning. Our predictions are validated by experimental information: within-species conservation, chromatin accessibility, and gene expression. According to gene ontology and pathway enrichment analyses, predicted nucleotide conservation points to genes in central carbon metabolism. Importantly, it improves genomic prediction for fitness-related traits such as grain yield, in elite maize panels, by stringent prioritization of fewer than 1% of single-site variants.

   Our results suggest that predicting nucleotide conservation across angiosperms may effectively prioritize sites most likely to impact fitness-related traits in crops, without being limited by shifting selection, missing data, and low depth of multiple-sequence alignments. Our approach—Prediction of mutation Impact by Calibrated Nucleotide Conservation (PICNC)—could be useful to select polymorphisms for accurate genomic prediction, and candidate mutations for efficient base editing. The trained PICNC models and predicted nucleotide conservation at protein-coding SNPs in maize are publicly available in CyVerse (https://doi.org/10.25739/hybz-2957).

    

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5. Assessing Bayesian Phylogenetic Information Content of Morphological Data Using Knowledge From Anatomy Ontologies

   https://doi.org/10.1093/sysbio/syac022  

   Porto, Diego S. ; Dahdul, Wasila M. ; Lapp, Hilmar ; Balhoff, James P. ; Vision, Todd J. ; Mabee, Paula M. ; Uyeda, Josef ( March 2022 , Systematic Biology)

   Morphology remains a primary source of phylogenetic information for many groups of organisms, and the only one for most fossil taxa. Organismal anatomy is not a collection of randomly assembled and independent “parts”, but instead a set of dependent and hierarchically nested entities resulting from ontogeny and phylogeny. How do we make sense of these dependent and at times redundant characters? One promising approach is using ontologies—structured controlled vocabularies that summarize knowledge about different properties of anatomical entities, including developmental and structural dependencies. Here, we assess whether evolutionary patterns can explain the proximity of ontology-annotated characters within an ontology. To do so, we measure phylogenetic information across characters and evaluate if it matches the hierarchical structure given by ontological knowledge—in much the same way as across-species diversity structure is given by phylogeny. We implement an approach to evaluate the Bayesian phylogenetic information (BPI) content and phylogenetic dissonance among ontology-annotated anatomical data subsets. We applied this to data sets representing two disparate animal groups: bees (Hexapoda: Hymenoptera: Apoidea, 209 chars) and characiform fishes (Actinopterygii: Ostariophysi: Characiformes, 463 chars). For bees, we find that BPI is not substantially explained by anatomy since dissonance is often high among morphologically related anatomical entities. For fishes, we find substantial information for two clusters of anatomical entities instantiating concepts from the jaws and branchial arch bones, but among-subset information decreases and dissonance increases substantially moving to higher-level subsets in the ontology. We further applied our approach to address particular evolutionary hypotheses with an example of morphological evolution in miniature fishes. While we show that phylogenetic information does match ontology structure for some anatomical entities, additional relationships and processes, such as convergence, likely play a substantial role in explaining BPI and dissonance, and merit future investigation. Our work demonstrates how complex morphological data sets can be interrogated with ontologies by allowing one to access how information is spread hierarchically across anatomical concepts, how congruent this information is, and what sorts of processes may play a role in explaining it: phylogeny, development, or convergence. [Apidae; Bayesian phylogenetic information; Ostariophysi; Phenoscape; phylogenetic dissonance; semantic similarity.]

    

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