Targeted exploration and analysis of large cross-platform human transcriptomic compendia.

We present SEEK (search-based exploration of expression compendia; http://seek.princeton.edu/), a query-based search engine for very large transcriptomic data collections, including thousands of human data sets from many different microarray and high-throughput sequencing platforms. SEEK uses a query-level cross-validation-based algorithm to automatically prioritize data sets relevant to the query and a robust search approach to identify genes, pathways and processes co-regulated with the query. SEEK provides multigene query searching with iterative metadata-based search refinement and extensive visualization-based analysis options.

Functional knowledge transfer for high-accuracy prediction of under-studied biological processes.

A key challenge in genetics is identifying the functional roles of genes in pathways. Numerous functional genomics techniques (e.g. machine learning) that predict protein function have been developed to address this question. These methods generally build from existing annotations of genes to pathways and thus are often unable to identify additional genes participating in processes that are not already well studied. Many of these processes are well studied in some organism, but not necessarily in an investigator's organism of interest. Sequence-based search methods (e.g. BLAST) have been used to transfer such annotation information between organisms. We demonstrate that functional genomics can complement traditional sequence similarity to improve the transfer of gene annotations between organisms. Our method transfers annotations only when functionally appropriate as determined by genomic data and can be used with any prediction algorithm to combine transferred gene function knowledge with organism-specific high-throughput data to enable accurate function prediction. We show that diverse state-of-art machine learning algorithms leveraging functional knowledge transfer (FKT) dramatically improve their accuracy in predicting gene-pathway membership, particularly for processes with little experimental knowledge in an organism. We also show that our method compares favorably to annotation transfer by sequence similarity. Next, we deploy FKT with state-of-the-art SVM classifier to predict novel genes to 11,000 biological processes across six diverse organisms and expand the coverage of accurate function predictions to processes that are often ignored because of a dearth of annotated genes in an organism. Finally, we perform in vivo experimental investigation in Danio rerio and confirm the regulatory role of our top predicted novel gene, wnt5b, in leftward cell migration during heart development. FKT is immediately applicable to many bioinformatics techniques and will help biologists systematically integrate prior knowledge from diverse systems to direct targeted experiments in their organism of study.

IMP: a multi-species functional genomics portal for integration, visualization and prediction of protein functions and networks.

Integrative multi-species prediction (IMP) is an interactive web server that enables molecular biologists to interpret experimental results and to generate hypotheses in the context of a large cross-organism compendium of functional predictions and networks. The system provides a framework for biologists to analyze their candidate gene sets in the context of functional networks, as they expand or focus these sets by mining functional relationships predicted from integrated high-throughput data. IMP integrates prior knowledge and data collections from multiple organisms in its analyses. Through flexible and interactive visualizations, researchers can compare functional contexts and interpret the behavior of their gene sets across organisms. Additionally, IMP identifies homologs with conserved functional roles for knowledge transfer, allowing for accurate function predictions even for biological processes that have very few experimental annotations in a given organism. IMP currently supports seven organisms (Homo sapiens, Mus musculus, Rattus novegicus, Drosophila melanogaster, Danio rerio, Caenorhabditis elegans and Saccharomyces cerevisiae), does not require any registration or installation and is freely available for use at http://imp.princeton.edu.