GOReverseLookup: A gene ontology reverse lookup tool

The Gene Ontology (GO) project has been pivotal in providing a structured framework for characterizing genes and annotating them to specific biological concepts. While traditional gene annotation primarily focuses on mapping genes to GO terms, descriptors of biological concepts, there is a growing need for tools facilitating reverse querying. This paper introduces GOReverseLookup, a novel tool designed to identify over- or underrepresented genes in researcher-defined states of interest (phenotypes), described by sets of GO terms. GOReverseLookup supplements the existing power of Gene Ontology by the possibility of orthologous gene querying across several databases, such as Ensembl and UniProtKB. This combination allows for a more nuanced identification of significant genes across a range of cross-species research contexts.

GOReverseLookup queries genes associated with input GO terms. Bundles of GO terms encapsulate user-defined states of interest, e.g., angiogenesis. In the second stage of the analysis, all GO terms associated with each gene are fetched, and finally, the statistical relevance of the genes being involved in one (or all) of the defined states of interests is computed.

The two presented use cases illustrate its utility in discovering genes related to rheumatoid arthritis and genes linked with chronic inflammation and tumorigenesis. In both cases, GOReverseLookup discovered a substantial number of genes significantly associated with the aforementioned states of interest.

GOReverseLookup proves to be a valuable resource for unraveling the genetic basis of phenotypes, with diverse practical potentials in functional genomics, systems biology, and drug discovery. We anticipate that GOReverseLookup will significantly aid in identifying potential gene targets during the initial research phases.