Evolutionary insights into Interleukin-12 family targets across 405 species

Weibin Wang¹Dawei Li¹Kaiyong Luo¹Chen Baozheng¹Xuzhen Li¹Tingting Hao¹Dazhong Guo¹Yang Dong^1*Ya Ning^1,2*

• ¹Yunnan Agricultural University, Kunming, China
• ²The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China

This study investigated the evolutionary history and functional divergence of the IL-12 family ligand subunits (IL-12s) and its receptor subunits (IL-12Rs) across over 400 animal species. IL-12s and IL-12Rs play a critical role in immune regulation and are implicated in autoimmune disorders and cancer progression. Using phylogenetic reconstruction, synteny analysis, and sequence alignment, we traced the origins of IL-12Rs to ancient periods, with potential roots before the mollusk era, about 514-686.2 million years ago (Mya). In contrast, ligands p19 and p28 have evolved more recently, emerging during the mammalian and avian epoch (180-225.0 Mya). Our analysis identified three highly conserved signature sequences within the fn3 domain that are critical for maintaining structural integrity and biological activity, as well as other cross-species ultra-conserved residues and motifs. Through comprehensive cross-species sequence analysis, we also performed a systematic re-characterization of IL-12s and IL-12Rs. These findings provide insights into the evolutionary conservation and functional divergence of the IL-12 family and highlight potential therapeutic targets for developing precision immunotherapies. The conserved signature sequences and recently evolved ligands p19 and p28 offer opportunities for cross-species drug development and disease control strategies with implications for human health, agriculture, and aquaculture.