MondrianMap: Navigating Gene Set Hierarchies with Multi-Resolution Enrichment Maps

Abstract

Gene Ontology encodes genes as a hierarchy, yet every enrichment visualization flattens it into a ranked list, discarding the ability to view the same process at different levels of abstraction. We present MondrianMap, a free interactive web application (https://mondrianmap.smartdrugdiscovery.org/) that organizes enrichment results into 13 semantically principled layers derived from the GOALS framework and renders them as color-encoded rectangular maps where block area reflects significance, color encodes effect direction, and spatial proximity preserves semantic relations, all within an interactive interface. Three case studies across the NIH Common Fund Data Ecosystem demonstrate that visualization facilitates recognition of patterns that are difficult to discern in flat outputs: (1) LINCS CRISPR perturbations reveal that TP53 and KRAS knockouts produce opposite color maps at a single semantic layer, the same immune recruitment processes suppressed by TP53 loss are activated by KRAS disruption; (2) GTEx aging signatures expose the inflammaging paradox as an immediate visual phenomenon, identical antimicrobial defense programs appear uniformly upregulated in aging blood yet uniformly downregulated in aging liver at matched semantic resolution; and (3) MoTrPAC exercise data capture temporal dynamics as color transitions where brown adipose tissue undergoes a threshold switch from two enriched terms to thirty-four at a single molecular layer, while cardiac tissue reverses from uniformly activated to uniformly suppressed glycolytic metabolism as adaptation progresses. MondrianMap facilitates hierarchical visual reasoning, complementing statistical enrichment reporting for biological discovery. HIGHLIGHTSO_LIMondrianMap provides multi-resolution enrichment visualization for Gene Ontology C_LIO_LILayer-specific views reveal directional oppositions difficult to discern in flat term lists C_LIO_LINavigating layers organizes one enrichment into a multi-scale biological narrative C_LIO_LIDemonstrated on cancer, aging, and exercise data across three CFDE programs C_LI IN BRIEFMondrianMap is a web application that transforms gene set enrichment results into layered visualizations encoding regulation, significance, and semantic hierarchy. Across cancer, aging, and exercise datasets, viewing enrichment at defined semantic layers exposes directional inversions, temporal switches, and multi-scale biological narratives that are difficult to extract from conventional flat enrichment outputs. THE BIGGER PICTUREWhen researchers measure gene expression changes in disease, aging, or drug response, they rely on enrichment analysis to translate thousands of molecular measurements into interpretable biological themes. The standard output is a ranked list of processes sorted by statistical significance. This format served the field well when studies examined a single condition; however, modern genomics routinely compares dozens of tissues, timepoints, and perturbations, each generating hundreds of enriched terms. The critical limitation is not statistical power; however, interpretive structure: a flat list cannot show whether two conditions activate the same biological process in opposite directions, whether a process visible at one level of abstraction disappears or transforms at another, or how a tissues functional response evolves across time. These are precisely the questions that define contemporary systems biology. Does a tumor suppressor gene silence the same immune program that an oncogene activates? Does aging drive the same defense pathway upward in the blood and downward in the liver? Does an exercise response flip from activation to suppression as the tissue adapts? Answering these questions requires a visualization framework that preserves hierarchy, encodes direction, and enables comparison at matched levels of biological resolution. MondrianMap provides this framework by organizing Gene Ontology terms into quantitatively defined semantic layers and rendering enrichment as color-encoded rectangular maps navigable from molecular mechanism to system-level theme. The result is a tool that extends enrichment analysis from a reporting step into an interactive framework for biological reasoning, hypothesis generation, and cross-dataset discovery.