Agentic AI uncovers conserved cross-tissue protein co-abundance programs inaccessible to single-dataset analysis

원문 초록

Protein co-abundance clusters preserved across tissues can nominate shared disease mechanisms and therapeutic targets, particularly where proteins implicated in organ-confined diseases converge in other tissues. Yet cross-tissue proteomic studies have examined pre-selected tissue pairs, leaving most combinations, and non-obvious relationships among them, unexplored. Exhaustive comparison requires consistently assessing thousands of candidate clusters from hundreds of tissue-pair networks across heterogeneous evidence, a scale beyond manual curation. We present an LLM-agent framework for large-scale, evidence-grounded comparison of tissue-specific protein co-abundance networks. From sample-level proteomic data, it constructs tissue networks, derives conserved clusters for each tissue pair, integrates evidence from expression atlases, interaction and complex databases, pathways, disease associations and the literature, and proposes mechanistic hypotheses in which every conclusion cites its evidence. Applied to all 231 pairs among 22 human tissues and sample groups, it identified 1,825 conserved clusters in 216 tissue pairs. Co-abundance relationships were shared beyond chance in 76% of pairs, including unrelated organs, and shared clusters were only weakly associated with abundance similarity. Clusters were enriched 3.7- to 6.9-fold for known interactions and complex memberships, and 379 of 793 testable clusters replicated in independent CPTAC proteomes. Some clusters pointed to relationships absent from current databases: one shared by liver and bone marrow linked three genes causing inherited white matter disorders, suggesting a common mechanism via the integrated stress response. Conserved co-abundance clusters thus offer a hypothesis-generating resource for studying disease proteins beyond the affected organ. Code: https://github.com/jacob20030316-crypto/Protein_Co_Abundance_Agent