Yeast Protein-protein Interaction Networks Research Articles

IsoGloVe: A New Count-based Graph Embedding Method based on Geodesic Distance

Graph embedding techniques have gained increasing attention for their ability to encode the complex structural information of networks into low-dimensional vectors. Existing graph embedding methods have achieved considerable success in various applications. However, these methods have limitations in capturing global graph topology information and fail to provide insights into the underlying mechanisms of network function. In this paper, we propose IsoGloVe, a count-based method that encodes graph topology into vectors using the co-occurrence statistics of fixed-size routes in random walks. IsoGloVe calculates the final embeddings based on the geodesic distances of the node’s neighbors on a manifold. This representation in geodesic space allows for the analysis of node interactions and contributes to a better understanding of complex network structure and function. The performance of IsoGloVe is evaluated on various protein-protein interactions (PPI) using graph reconstruction, node classification, and visualization. The findings reveal that IsoGloVe surpasses other comparable methods with a 30% increase in MAP for graph reconstruction and a 25% increase in model scores for node classification in the Yeast PPI network. In addition, IsoGloVe demonstrated a 6.9% increase in MAP for graph reconstruction on the Human PPI network.

A Tri-Gene Ontology Migration Operator for Improving the Performance of Meta-heuristics in Complex Detection Problems

Detecting protein complexes in protein-protein interaction (PPI) networks is a challenging problem in computational biology. To uncover a PPI network into a complex structure, different meta-heuristic algorithms have been proposed in the literature. Unfortunately, many of such methods, including evolutionary algorithms (EAs), are based solely on the topological information of the network rather than on biological information. Despite the effectiveness of EAs over heuristic methods, more inherent biological properties of proteins are rarely investigated and exploited in these approaches. In this paper, we proposed an EA with a new mutation operator for complex detection problems. The proposed mutation operator is formulated under four expressions depending on the type of gene sub-ontology. To demonstrate the performance of the proposed evolutionary based complex detection algorithm, the Saccharomyces Cerevisiae (yeast) PPI network is used in the evaluation. The results reveal that the proposed algorithm achieves more accurate complex structures than the counterpart heuristic algorithms and the canonical evolutionary algorithm based on the topological-aware mutation operator.

Cost-based Feature Selection for Network Model Choice

Selecting a small set of informative features from a large number of possibly noisy candidates is a challenging problem with many applications in machine learning and approximate Bayesian computation. In practice, the cost of computing informative features also needs to be considered. This is particularly important for networks because the computational costs of individual features can span several orders of magnitude. We addressed this issue for the network model selection problem using two approaches. First, we adapted nine feature selection methods to account for the cost of features. We show for two classes of network models that the cost can be reduced by two orders of magnitude without considerably affecting classification accuracy (proportion of correctly identified models). Second, we selected features using pilot simulations with smaller networks. This approach reduced the computational cost by a factor of 50 without affecting classification accuracy. To demonstrate the utility of our approach, we applied it to three different yeast protein interaction networks and identified the best-fitting duplication divergence model. Supplementary materials, including computer code to reproduce our results, are available online.

Inference of pan-cancer related genes by orthologs matching based on enhanced LSTM model.

Many disease-related genes have been found to be associated with cancer diagnosis, which is useful for understanding the pathophysiology of cancer, generating targeted drugs, and developing new diagnostic and treatment techniques. With the development of the pan-cancer project and the ongoing expansion of sequencing technology, many scientists are focusing on mining common genes from The Cancer Genome Atlas (TCGA) across various cancer types. In this study, we attempted to infer pan-cancer associated genes by examining the microbial model organism Saccharomyces Cerevisiae (Yeast) by homology matching, which was motivated by the benefits of reverse genetics. First, a background network of protein-protein interactions and a pathogenic gene set involving several cancer types in humans and yeast were created. The homology between the human gene and yeast gene was then discovered by homology matching, and its interaction sub-network was obtained. This was undertaken following the principle that the homologous genes of the common ancestor may have similarities in expression. Then, using bidirectional long short-term memory (BiLSTM) in combination with adaptive integration of heterogeneous information, we further explored the topological characteristics of the yeast protein interaction network and presented a node representation score to evaluate the node ability in graphs. Finally, homologous mapping for human genes matched the important genes identified by ensemble classifiers for yeast, which may be thought of as genes connected to all types of cancer. One way to assess the performance of the BiLSTM model is through experiments on the database. On the other hand, enrichment analysis, survival analysis, and other outcomes can be used to confirm the biological importance of the prediction results. You may access the whole experimental protocols and programs at https://github.com/zhuyuan-cug/AI-BiLSTM/tree/master.

Rule-Based Pruning and In Silico Identification of Essential Proteins in Yeast PPIN.

Proteins are vital for the significant cellular activities of living organisms. However, not all of them are essential. Identifying essential proteins through different biological experiments is relatively more laborious and time-consuming than the computational approaches used in recent times. However, practical implementation of conventional scientific methods sometimes becomes challenging due to poor performance impact in specific scenarios. Thus, more developed and efficient computational prediction models are required for essential protein identification. An effective methodology is proposed in this research, capable of predicting essential proteins in a refined yeast protein–protein interaction network (PPIN). The rule-based refinement is done using protein complex and local interaction density information derived from the neighborhood properties of proteins in the network. Identification and pruning of non-essential proteins are equally crucial here. In the initial phase, careful assessment is performed by applying node and edge weights to identify and discard the non-essential proteins from the interaction network. Three cut-off levels are considered for each node and edge weight for pruning the non-essential proteins. Once the PPIN has been filtered out, the second phase starts with two centralities-based approaches: (1) local interaction density (LID) and (2) local interaction density with protein complex (LIDC), which are successively implemented to identify the essential proteins in the yeast PPIN. Our proposed methodology achieves better performance in comparison to the existing state-of-the-art techniques.

A Novel Method for Predicting Essential Proteins by Integrating Multidimensional Biological Attribute Information and Topological Properties

Background: Essential proteins are indispensable to the maintenance of life activities and play essential roles in the areas of synthetic biology. Identification of essential proteins by computational methods has become a hot topic in recent years because of its efficiency. Objective: Identification of essential proteins is of important significance and practical use in the areas of synthetic biology, drug targets, and human disease genes. Method: In this paper, a method called EOP (Edge clustering coefficient -Orthologous-Protein) is proposed to infer potential essential proteins by combining Multidimensional Biological Attribute Information of proteins with Topological Properties of the protein-protein interaction network. Results: The simulation results on the yeast protein interaction network show that the number of essential proteins identified by this method is more than the number identified by the other 12 methods (DC, IC, EC, SC, BC, CC, NC, LAC, PEC, CoEWC, POEM, DWE). Especially compared with DC (Degree Centrality), the SN (sensitivity) is 9% higher, when the candidate protein is 1%, the recognition rate is 34% higher, when the candidate protein is 5%, 10%, 15%, 20%, 25% the recognition rate is 36%, 22%, 15%, 11%, 8% higher, respectively. Conclusion: Experimental results show that our method can achieve satisfactory prediction results, which may provide references for future research.

Predicting Essential Proteins Based on Integration of Local Fuzzy Fractal Dimension and Subcellular Location Information

Essential proteins are indispensable to cells’ survival and development. Prediction and analysis of essential proteins are crucial for uncovering the mechanisms of cells. With the help of computer science and high-throughput technologies, forecasting essential proteins by protein–protein interaction (PPI) networks has become more efficient than traditional approaches (expensive experimental methods are generally used). Many computational algorithms were employed to predict the essential proteins; however, they have various restrictions. To improve the prediction accuracy, by introducing the Local Fuzzy Fractal Dimension (LFFD) of complex networks into the analysis of the PPI network, we propose a novel algorithm named LDS, which combines the LFFD of the PPI network with the protein subcellular location information. By testing the proposed LDS algorithm on three different yeast PPI networks, the experimental results show that LDS outperforms some state-of-the-art essential protein-prediction techniques.

Super.Complex: A supervised machine learning pipeline for molecular complex detection in protein-interaction networks.

Characterization of protein complexes, i.e. sets of proteins assembling into a single larger physical entity, is important, as such assemblies play many essential roles in cells such as gene regulation. From networks of protein-protein interactions, potential protein complexes can be identified computationally through the application of community detection methods, which flag groups of entities interacting with each other in certain patterns. Most community detection algorithms tend to be unsupervised and assume that communities are dense network subgraphs, which is not always true, as protein complexes can exhibit diverse network topologies. The few existing supervised machine learning methods are serial and can potentially be improved in terms of accuracy and scalability by using better-suited machine learning models and parallel algorithms. Here, we present Super.Complex, a distributed, supervised AutoML-based pipeline for overlapping community detection in weighted networks. We also propose three new evaluation measures for the outstanding issue of comparing sets of learned and known communities satisfactorily. Super.Complex learns a community fitness function from known communities using an AutoML method and applies this fitness function to detect new communities. A heuristic local search algorithm finds maximally scoring communities, and a parallel implementation can be run on a computer cluster for scaling to large networks. On a yeast protein-interaction network, Super.Complex outperforms 6 other supervised and 4 unsupervised methods. Application of Super.Complex to a human protein-interaction network with ~8k nodes and ~60k edges yields 1,028 protein complexes, with 234 complexes linked to SARS-CoV-2, the COVID-19 virus, with 111 uncharacterized proteins present in 103 learned complexes. Super.Complex is generalizable with the ability to improve results by incorporating domain-specific features. Learned community characteristics can also be transferred from existing applications to detect communities in a new application with no known communities. Code and interactive visualizations of learned human protein complexes are freely available at: https://sites.google.com/view/supercomplex/super-complex-v3-0.

A Cross-entropy-based Method for Essential Protein Identification in Yeast Protein-protein Interaction Network

Background: Research has shown that essential proteins play important roles in the development and survival of organisms. Because of the high costs of traditional biological experiments, several computational prediction methods based on known protein-protein interactions (PPIs) have been recently proposed to detect essential proteins. Objective: Here, a novel prediction model called IoMCD is proposed to identify essential proteins by combining known PPIs with a variety of biological information about proteins, including gene expression data and homologous information of proteins. Methods: Compared to the traditional state-of-the-art prediction models, IoMCD involves two kinds of weights that are obtained, respectively, by extracting topological features of proteins from the original known protein–protein interaction (PPI) networks and calculating the Pearson correlation coefficients (PCCs) between the gene expression data of proteins. Based on these two kinds of weights and adopting a cross-entropy method, a unique weight is assigned to each protein. Subsequently, the homologous information of proteins is used to calculate an initial score for each protein. Finally, based on the unique weights and initial score of proteins, an iterative method is designed to measure the essentialities of proteins. Results: Intensive experiments were performed, and simulation results showed that the prediction accuracy of IoMCD, based on the dataset downloaded from the DIP and Gavin databases, was 92.16% and 89.71%, respectively, in the top 1% of the predicted essential proteins. Conclusion: Both simulation results demonstrated that IoMCD can achieve excellent prediction accuracy and could be an effective method for essential protein prediction.

An engineered protein-phosphorylation toggle network with implications for endogenous network discovery.

Synthetic biological networks comprising fast, reversible reactions could enable engineering of new cellular behaviors that are not possible with slower regulation. Here, we created a bistable toggle switch in Saccharomyces cerevisiae using a cross-repression topology comprising 11 protein-protein phosphorylation elements. The toggle is ultrasensitive, can be induced to switch states in seconds, and exhibits long-term bistability. Motivated by our toggle's architecture and size, we developed a computational framework to search endogenous protein pathways for other large and similar bistable networks. Our framework helped us to identify and experimentally verify five formerly unreported endogenous networks that exhibit bistability. Building synthetic protein-protein networks will enable bioengineers to design fast sensing and processing systems, allow sophisticated regulation of cellular processes, and aid discovery of endogenous networks with particular functions.

Building synthetic protein–based switches

Synthetic Biology Synthetic circuits can potentially help to control complex biological processes, but systems based on regulating gene expression respond to stimuli at the minute to the hour time scale. Working in yeast cells, Mishra et al. report synthetic regulatory circuits based on protein phosphorylation reactions that respond to inputs within seconds (see the Perspective by Kholodenko and Okada). Multicomponent logic gates allowed ultrasensitive and stable switching between states. After validating their effective synthetic circuit, the authors searched known yeast protein interaction networks for similar regulatory motifs and found previously unrecognized circuits that function as native toggle switches in yeast. Science , aav0780, this issue p. [eaav0780][1]; see also abj5028, p. [25][2] [1]: /lookup/doi/10.1126/science.aav0780 [2]: /lookup/doi/10.1126/science.abj5028

GLIDE: combining local methods and diffusion state embeddings to predict missing interactions in biological networks.

MotivationOne of the core problems in the analysis of biological networks is the link prediction problem. In particular, existing interactions networks are noisy and incomplete snapshots of the true network, with many true links missing because those interactions have not yet been experimentally observed. Methods to predict missing links have been more extensively studied for social than for biological networks; it was recently argued that there is some special structure in protein–protein interaction (PPI) network data that might mean that alternate methods may outperform the best methods for social networks. Based on a generalization of the diffusion state distance, we design a new embedding-based link prediction method called global and local integrated diffusion embedding (GLIDE). GLIDE is designed to effectively capture global network structure, combined with alternative network type-specific customized measures that capture local network structure. We test GLIDE on a collection of three recently curated human biological networks derived from the 2016 DREAM disease module identification challenge as well as a classical version of the yeast PPI network in rigorous cross validation experiments.ResultsWe indeed find that different local network structure is dominant in different types of biological networks. We find that the simple local network measures are dominant in the highly connected network core between hub genes, but that GLIDE’s global embedding measure adds value in the rest of the network. For example, we make GLIDE-based link predictions from genes known to be involved in Crohn’s disease, to genes that are not known to have an association, and make some new predictions, finding support in other network data and the literature.Availability and implementationGLIDE can be downloaded at https://bitbucket.org/kap_devkota/glide.Supplementary information Supplementary data are available at Bioinformatics online.

Inferring essential proteins from centrality in interconnected multilayer networks

Computational tool for inferring essential genes and their coding essential proteins based on its topological features in biological network is crucial for insights into vital and disease mechanism of organisms. The problem of how to quantify this correspondence via network centralities in an incomplete protein interaction network (PIN), such as that of human, remains open. Here we develop Random Walk Occupation (RWO) augmented method in interconnected multilayer network model to disclose topological characteristics of essential proteins. The peculiar non-hub essential proteins can be revealed in yeast–human interconnected networks. Statistically RWO augmented method performs well, and improves the prediction results in incomplete human PIN and maintains noticeable performance in well-tested yeast PIN. Biologically, the detected non-hub essential proteins really participate in some vital biological function. Overall, we present a systematic method for deeper understanding and effective identification of essential proteins.

A Novel Computational Approach for Identifying Essential Proteins From Multiplex Biological Networks.

The identification of essential proteins can help in understanding the minimum requirements for cell survival and development. Ever-increasing amounts of high-throughput data provide us with opportunities to detect essential proteins from protein interaction networks (PINs). Existing network-based approaches are limited by the poor quality of the underlying PIN data, which exhibits high rates of false positive and false negative results. To overcome this problem, researchers have focused on the prediction of essential proteins by combining PINs with other biological data, which has led to the emergence of various interactions between proteins. It remains challenging, however, to use aggregated multiplex interactions within a single analysis framework to identify essential proteins. In this study, we created a multiplex biological network (MON) by initially integrating PINs, protein domains, and gene expression profiles. Next, we proposed a new approach to discover essential proteins by extending the random walk with restart algorithm to the tensor, which provides a data model representation of the MON. In contrast to existing approaches, the proposed MON approach considers for the importance of nodes and the different types of interactions between proteins during the iteration. MON was implemented to identify essential proteins within two yeast PINs. Our comprehensive experimental results demonstrated that MON outperformed 11 other state-of-the-art approaches in terms of precision-recall curve, jackknife curve, and other criteria.

The Influence of Three Statistical Variables on Self-Similarity in Complex Networks

The reason for the self-similarity property of complex network is still an open issue. In this paper, we focus on the influence of degree, betweenness, and coreness on self-similarity of complex network. Some nodes are removed from the original network based on the definitions of degree, betweenness, and coreness in the ascending and descending order. And then, some new networks are obtained after removing nodes. The self-similarities of original network and new networks are compared. Moreover, two real networks are used for numerical simulation, including aUSAirnetwork and the yeast protein interaction (YPI) network. The effects of the three statistical variables on the two real networks are considered. The results reveal that the nodes with large degree and betweenness have great effects on self-similarity, and the influence of coreness on self-similarity is small.

Using Alias Sampling Strategy Based on Network Embeddings to Detect Protein Complexes

Detecting protein complexes from available protein-protein interaction (PPI) data will help to deeply understand the mechanism of the biological activities. In recent years, various computational methods have been developed for identifying protein complexes from PPI networks. Almost all the basic computational methods mainly depend on the association of topological analysis of PPI networks. However, most of them fail to satisfactorily capture the global and local topological structures of the PPI networks, as well as the diversity of connectivity patterns between individual nodes at the same time. To solve this problem, in this work we propose a node embedding based alias sampling extension method to detect protein complexes. More specifically, for a given set of seed nodes, it first uses the alias sampling strategy based on protein node embedding similarities to select potential addable nodes. Then it makes use of a new conductance measure, which could better quantify the likelihood of a subgraph being a protein complex, to decide whether to extend the current candidate subgraph in order to find protein complexes. Evaluated on six real yeast PPI networks, our method outperforms state-of-the-art methods in detecting protein complexes. Furthermore, the experimental results demonstrate the protein complexes predicted by our method have higher biological significance.

Link clustering explains non-central and contextually essential genes in protein interaction networks

Recent studies have shown that many essential genes (EGs) change their essentiality across various contexts. Finding contextual EGs in pathogenic conditions may facilitate the identification of therapeutic targets. We propose link clustering as an indicator of contextual EGs that are non-central in protein-protein interaction (PPI) networks. In various human and yeast PPI networks, we found that 29–47% of EGs were better characterized by link clustering than by centrality. Importantly, non-central EGs were prone to change their essentiality across different human cell lines and between species. Compared with central EGs and non-EGs, non-central EGs had intermediate levels of expression and evolutionary conservation. In addition, non-central EGs exhibited a significant impact on communities at lower hierarchical levels, suggesting that link clustering is associated with contextual essentiality, as it depicts locally important nodes in network structures.

Adaptive Large Neighborhood Search Enhances Global Network Alignment

Aligning protein-protein interaction networks from different species is a useful mechanism for figuring out orthologous proteins, predicting/verifying protein unknown functions or constructing evolutionary relationships. The network alignment problem is proved to be NP-hard, requiring exponential-time algorithms, which is not feasible for the fast growth of biological data. In this paper, we present a novel protein-protein interaction global network alignment algorithm, which is enhanced with an extended large neighborhood search heuristics. Evaluated on benchmark datasets of yeast, fly, human and worm, the proposed algorithm outperforms state-of-the-art. Furthermore, the complexity of ours is polynomial, thus being scalable to large biological networks in practice.
 Keywords
 Heuristic, Protein-protein interaction networks, network alignment, neighborhood search
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Topological and functional comparison of community detection algorithms in biological networks

BackgroundCommunity detection algorithms are fundamental tools to uncover important features in networks. There are several studies focused on social networks but only a few deal with biological networks. Directly or indirectly, most of the methods maximize modularity, a measure of the density of links within communities as compared to links between communities.ResultsHere we analyze six different community detection algorithms, namely, Combo, Conclude, Fast Greedy, Leading Eigen, Louvain and Spinglass, on two important biological networks to find their communities and evaluate the results in terms of topological and functional features through Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology term enrichment analysis. At a high level, the main assessment criteria are 1) appropriate community size (neither too small nor too large), 2) representation within the community of only one or two broad biological functions, 3) most genes from the network belonging to a pathway should also belong to only one or two communities, and 4) performance speed. The first network in this study is a network of Protein-Protein Interactions (PPI) in Saccharomyces cerevisiae (Yeast) with 6532 nodes and 229,696 edges and the second is a network of PPI in Homo sapiens (Human) with 20,644 nodes and 241,008 edges. All six methods perform well, i.e., find reasonably sized and biologically interpretable communities, for the Yeast PPI network but the Conclude method does not find reasonably sized communities for the Human PPI network. Louvain method maximizes modularity by using an agglomerative approach, and is the fastest method for community detection. For the Yeast PPI network, the results of Spinglass method are most similar to the results of Louvain method with regard to the size of communities and core pathways they identify, whereas for the Human PPI network, Combo and Spinglass methods yield the most similar results, with Louvain being the next closest.ConclusionsFor Yeast and Human PPI networks, Louvain method is likely the best method to find communities in terms of detecting known core pathways in a reasonable time.

A Novel Core-Attachment-Based Method to Identify Dynamic Protein Complexes Based on Gene Expression Profiles and PPI Networks.

Cellular functions are always performed by protein complexes. At present, many approaches have been proposed to identify protein complexes from protein-protein interaction (PPI) networks. Some approaches focus on detecting local dense subgraphs in PPI networks which are regarded as protein-complex cores, then identify protein complexes by including local neighbors. However, from gene expression profiles at different time points or tissues it is known that proteins are dynamic. Therefore, identifying dynamic protein complexes should become very important and meaningful. In this study, a novel core-attachment-based method named CO-DPC to detect dynamic protein complexes is presented. First, CO-DPC selects active proteins according to gene expression profiles and the 3-sigma principle, and constructs dynamic PPI networks based on the co-expression principle and PPI networks. Second, CO-DPC detects local dense subgraphs as the cores of protein complexes and then attach close neighbors of these cores to form protein complexes. In order to evaluate the method, the method and the existing algorithms are applied to yeast PPI networks. The experimental results show that CO-DPC performs much better than the existing methods. In addition, the identified dynamic protein complexes can match very well and thus become more meaningful for future biological study.