Locus‐Specific Convergent Evolution and Interchromosomal Rearrangements Contribute to the Diversification of Amniote Type I Interferons

Type I interferons (IFNs) play essential roles in antiviral immune responses. The extensive diversification of type I IFNs into various subtypes and duplicated gene copies has posed significant challenges for evolutionary reconstruction. To address this, we developed the type I IFN sequence composition and structure (IFN‐SCOPE) model and gene‐network graph degree centrality (GENE‐GRADE) algorithm, which transform the discovery of type I IFN evolutionary trajectories into computing the node centrality in its gene networks. Through synteny‐guided analysis, we verified that three previously reported evolutionarily conserved type I IFN loci (HACD4, MOB3B, and UBAP2) have maintained chromosomal colocalization across all major amniote lineages. While the MOB3B locus maintained a single IFN‐κ ortholog, the HACD4 (IFN‐HA) and UBAP2 (IFN‐UB) loci showed lineage‐specific expansion patterns: IFN‐HA proliferated in mammals/reptiles but remained single‐copy in birds, whereas IFN‐UB expanded in birds but not in other lineages. A phylogenetic analysis revealed that these independently evolved multicopy genes nevertheless clustered into two conserved subgroups (IFN‐HA2/HA1 and IFN‐UB2/UB1), suggesting convergent functional specialization. Within the IFN‐HA and IFN‐UB clusters, the single‐copy IFN‐HA2 and IFN‐UB2 genes, positioned at the ancestral ends of their respective genomic arrays, likely represent the progenitor sequences of each locus, where the poorly characterized IFN‐ν (rather than IFN‐β) is the ancestral form of mammalian IFN‐HA subtypes. Furthermore, wet lab evidence revealed type I IFN genes at noncanonical loci resulting from interchromosomal duplication events in tortoises and diving ducks and provided clear evidence that interchromosomal duplications contributed to type I IFN gene diversity. These discoveries advance our understanding of the evolutionary mechanisms that shape type I IFN genes in amniotes and are potentially beneficial for the development of novel type I IFN‐based antiviral treatments through comparative immunological approaches.