BIOINFORMATICS Additional Gene Ontology Structure for Improved Biological Rea- soning

Motivation: The Gene Ontology (GO) is a widely used terminology for gene product characterisation in e.g. interpretation of biology underlying microarray experiments. The current GO defines term relationships within each of the independent subontologies: molecu-lar function, biological process and cellular component. However, it is evident that there also exist biological relationships between terms of different subontologies. Our aim was to connect the three subon-tologies to enable GO to cover more biological knowledge, enable a more consistent use of GO, and provide new opportunities for bio-logical reasoning. Results: We propose a new structure, the Sec-ond Gene Ontology Layer, capturing biological relations not directly reflected in the present ontology structure. Given molecular func-tions, these paths identify biological processes where the molecular functions are involved and cellular components where they are ac-tive. The current Second Layer contains 6271 validated paths, cov-ering 54 % of the molecular functions of GO and can be used to render existing gene annotation sets more complete and consistent. Applying Second Layer paths to a set of 4223 human genes, in-creased biological process annotations by 24 % compared to publicly available annotations and reproduced 30 % of them. Availability: The Second Gene Ontology is publicly available through the G