PT  - JOURNAL ARTICLE
AU  - Anastasia Baryshnikova
TI  - Systematic Functional Annotation and Visualization of Biological Networks
AID  - 10.1101/030551
DP  - 2015 Jan 01
TA  - bioRxiv
PG  - 030551
4099  - http://biorxiv.org/content/early/2015/11/03/030551.short
4100  - http://biorxiv.org/content/early/2015/11/03/030551.full
AB  - Large-scale biological networks map functional relationships between most genes in the genome and can potentially uncover high level organizing principles governing cellular functions. Despite the availability of an incredible wealth of network data, our current understanding of their functional organization is very limited and essentially opaque to biologists. To facilitate the discovery and the interpretation of network functional structure, I developed a systematic quantitative approach to determine which functions are represented in a network, which parts of the network they are associated with and how they are related to one another. This method, named Spatial Analysis of Functional Enrichment (SAFE), detects network regions that are statistically overrepresented for a functional group or a quantitative phenotype of interest, and provides a visual representation of their relative positioning within the network. This visual representation is remarkably intuitive to biologists and maps the connection between a network and a set of functions with unprecedented clarity. By systematically annotating the genetic interaction similarity network from Saccharomyces cerevisiae with Gene Ontology (GO) biological process terms, SAFE proved to be accurate and robust to several sources of variation. In addition to GO, SAFE successfully annotated the network with other types of functional information, including quantitative chemical genomics and genetic interaction data. The union of these annotations produced a global view of the yeast cellular response to chemical treatment, which recapitulated known modes-of-action of chemical compounds and identified a potentially novel mechanism of resistance to the anti-cancer drug bortezomib. Finally, SAFE annotated the yeast protein-protein interaction network and revealed that, despite the lack of any visible topological structure on a global scale, the network presents a clear functional structure. These results demonstrate that SAFE is a powerful new tool for systematically annotating biological networks and investigating the global wiring diagram of the cell.