Škorjanc Aljoša, Smrkolj Vladimir, Umek Nejc
Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova 2, Ljubljana, Slovenia.
Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova 2, Ljubljana, Slovenia; National Institute of Chemistry, Hajdrihova ulica 19, Ljubljana, Slovenia.
Comput Biol Med. 2025 Jun;191:110185. doi: 10.1016/j.compbiomed.2025.110185. Epub 2025 Apr 15.
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.
基因本体论（GO）项目在提供用于表征基因并将其注释到特定生物学概念的结构化框架方面发挥了关键作用。虽然传统的基因注释主要侧重于将基因映射到GO术语（生物学概念的描述符），但对促进反向查询的工具的需求日益增长。本文介绍了GOReverseLookup，这是一种新颖的工具，旨在识别由GO术语集描述的研究人员定义的感兴趣状态（表型）中过度或不足表达的基因。GOReverseLookup通过跨多个数据库（如Ensembl和UniProtKB）进行直系同源基因查询的可能性，补充了基因本体论的现有功能。这种结合使得在一系列跨物种研究背景下能够更细致地识别重要基因。
GOReverseLookup查询与输入GO术语相关的基因。GO术语束封装了用户定义的感兴趣状态，例如血管生成。在分析的第二阶段，获取与每个基因相关的所有GO术语，最后计算基因参与一个（或所有）定义的感兴趣状态的统计相关性。
所展示的两个用例说明了其在发现与类风湿性关节炎相关的基因以及与慢性炎症和肿瘤发生相关的基因方面的效用。在这两种情况下，GOReverseLookup都发现了大量与上述感兴趣状态显著相关的基因。
GOReverseLookup被证明是揭示表型遗传基础的宝贵资源，在功能基因组学、系统生物学和药物发现中具有多种实际潜力。我们预计GOReverseLookup将在初始研究阶段显著帮助识别潜在的基因靶点。
