Evolutionary analysis reveals repeated diversification events in immune metabolic pathways
Evolution. Evolutionary Analysis. Immune System. Immune Surveillance.
The human immune system represents an integrated network of cellular and molecular components essential for pathogen defense, tumor cell surveillance, and tissue homeostasis. Traditionally categorized into two arms, innate immunity (rapid response) and adaptive immunity (antigen-specific with memory), its function relies on intricate cooperation regulated by metabolic pathways that sustain immune responses. However, the evolutionary scenario of immune-metabolic pathway diversification remains poorly explored. Moreover, an integrated understanding of the relationship between the evolutionary emergence of malignant tumors and the establishment of the immune system as observed in humans is still lacking. In this study, we employed 1,209 genes involved in 21 immune metabolic pathways (KEGG Pathway) and 1,124 cancer-related genes (OncoKB/COSMIC). Orthology information for these gene lists was acquired from the STRING database and subsequently processed using the R package GeneBridge, which infers the most probable last common ancestor for each orthologous group (OG) within a reference phylogenetic tree containing 476 eukaryotic species. We identified four clades with significant emergence of immune OGs: Metamonada, SAR, Choanoflagellata, and Actinopterygii. In contrast to cancer-associated OGs, which showed greater diversification during the origin of multicellularity, immune OGs exhibited multiple expansion events, particularly during the radiation of jawed vertebrates. Our results indicate that human immune metabolic pathways underwent successive adaptive waves, with marked complexity increase in jawed vertebrates. We propose that the emergence of malignant neoplasms and epithelium-immune system coevolution represented additional selective pressures, driving progressive refinement of immune surveillance mechanisms in this group.