How to understand the cell by breaking it: network analysis of gene perturbation screens

Modern high-throughput gene perturbation screens are key technologies at the forefront of genetic research. Combined with rich phenotypic descriptors they enable researchers to observe detailed cellular reactions to experimental perturbations on a genome-wide scale. This review surveys the current state-of-the-art in analyzing perturbation screens from a network point of view. We describe approaches to make the step from the parts list to the wiring diagram by using phenotypes for network inference and integrating them with complementary data sources. The first part of the review describes methods to analyze one- or low-dimensional phenotypes like viability or reporter activity; the second part concentrates on high-dimensional phenotypes showing global changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio

A hierarchical Bayesian model for predicting ecological interactions using scaled evolutionary relationships

Identifying undocumented or potential future interactions among species is a challenge facing modern ecologists. Recent link prediction methods rely on trait data, however large species interaction databases are typically sparse and covariates are limited to only a fraction of species. On the other hand, evolutionary relationships, encoded as phylogenetic trees, can act as proxies for underlying traits and historical patterns of parasite sharing among hosts. We show that using a network-based conditional model, phylogenetic information provides strong predictive power in a recently published global database of host-parasite interactions. By scaling the phylogeny using an evolutionary model, our method allows for biological interpretation often missing from latent variable models. To further improve on the phylogeny-only model, we combine a hierarchical Bayesian latent score framework for bipartite graphs that accounts for the number of interactions per species with the host dependence informed by phylogeny. Combining the two information sources yields significant improvement in predictive accuracy over each of the submodels alone. As many interaction networks are constructed from presence-only data, we extend the model by integrating a correction mechanism for missing interactions, which proves valuable in reducing uncertainty in unobserved interactions.Comment: To appear in the Annals of Applied Statistic

Compact Integration of Multi-Network Topology for Functional Analysis of Genes

The topological landscape of molecular or functional interaction networks provides a rich source of information for inferring functional patterns of genes or proteins. However, a pressing yet-unsolved challenge is how to combine multiple heterogeneous networks, each having different connectivity patterns, to achieve more accurate inference. Here, we describe the Mashup framework for scalable and robust network integration. In Mashup, the diffusion in each network is first analyzed to characterize the topological context of each node. Next, the high-dimensional topological patterns in individual networks are canonically represented using low-dimensional vectors, one per gene or protein. These vectors can then be plugged into off-the-shelf machine learning methods to derive functional insights about genes or proteins. We present tools based on Mashup that achieve state-of-the-art performance in three diverse functional inference tasks: protein function prediction, gene ontology reconstruction, and genetic interaction prediction. Mashup enables deeper insights into the struct ure of rapidly accumulating and diverse biological network data and can be broadly applied to other network science domains. Keywords: interactome analysis; network integration; heterogeneous networks; dimensionality reduction; network diffusion; gene function prediction; genetic interaction prediction; gene ontology reconstruction; drug response predictionNational Institutes of Health (U.S.) (Grant R01GM081871

SIFTER search: a web server for accurate phylogeny-based protein function prediction.

We are awash in proteins discovered through high-throughput sequencing projects. As only a minuscule fraction of these have been experimentally characterized, computational methods are widely used for automated annotation. Here, we introduce a user-friendly web interface for accurate protein function prediction using the SIFTER algorithm. SIFTER is a state-of-the-art sequence-based gene molecular function prediction algorithm that uses a statistical model of function evolution to incorporate annotations throughout the phylogenetic tree. Due to the resources needed by the SIFTER algorithm, running SIFTER locally is not trivial for most users, especially for large-scale problems. The SIFTER web server thus provides access to precomputed predictions on 16 863 537 proteins from 232 403 species. Users can explore SIFTER predictions with queries for proteins, species, functions, and homologs of sequences not in the precomputed prediction set. The SIFTER web server is accessible at http://sifter.berkeley.edu/ and the source code can be downloaded

Automated data integration for developmental biological research

In an era exploding with genome-scale data, a major challenge for developmental biologists is how to extract significant clues from these publicly available data to benefit our studies of individual genes, and how to use them to improve our understanding of development at a systems level. Several studies have successfully demonstrated new approaches to classic developmental questions by computationally integrating various genome-wide data sets. Such computational approaches have shown great potential for facilitating research: instead of testing 20,000 genes, researchers might test 200 to the same effect. We discuss the nature and state of this art as it applies to developmental research

Transforming Graph Representations for Statistical Relational Learning

Relational data representations have become an increasingly important topic due to the recent proliferation of network datasets (e.g., social, biological, information networks) and a corresponding increase in the application of statistical relational learning (SRL) algorithms to these domains. In this article, we examine a range of representation issues for graph-based relational data. Since the choice of relational data representation for the nodes, links, and features can dramatically affect the capabilities of SRL algorithms, we survey approaches and opportunities for relational representation transformation designed to improve the performance of these algorithms. This leads us to introduce an intuitive taxonomy for data representation transformations in relational domains that incorporates link transformation and node transformation as symmetric representation tasks. In particular, the transformation tasks for both nodes and links include (i) predicting their existence, (ii) predicting their label or type, (iii) estimating their weight or importance, and (iv) systematically constructing their relevant features. We motivate our taxonomy through detailed examples and use it to survey and compare competing approaches for each of these tasks. We also discuss general conditions for transforming links, nodes, and features. Finally, we highlight challenges that remain to be addressed