Cross-Species Genome-Wide Analysis Reveals Molecular and Functional Diversity of the Unconventional Interferon-? Subtype

Shields, Lauren E.; Jennings, Jordan; Liu, Qinfang; Lee, Jinhwa; Ma, Wenjun; Blecha, Frank; Miller, Laura C.; Sang, Yongming

Innate immune interferons (IFNs), consisting of type I IFNs and type III IFNs, are key in regulating antiviral immunity, antitumor activity, and cell proliferation (1) (2) (3) (4) (5) (6) . In contrast to the single type II IFN (IFN-γ), which is primarily involved in adaptive immunity, type I IFNs are remarkable for their molecular and functional diversity. However, to date only a few subtypes (e.g., IFN-α and IFN-β) have been well characterized, even in humans and mice (1, 2, 4) . Thus, there are significant knowledge gaps considering the evolutionarily diversified 20-60 IFN-coding genes of multiple subtypes in each mammalian species (2, (7) (8) (9) (10) . Interferon genes most likely emerged during tetrapod evolution from fish (2, (10) (11) (12) . The common ancestor genes of IFNs were originally identified in jawed fish, which almost coincides with the emergence of animal adaptive immunity (2, 4) . Fish only have a few ancestral introncontaining IFN genes, but more than a dozen IFN genes in each amniote species are mostly intronless (6) (7) (8) (9) (10) 12) . The intronless type I IFNs in amniotes appear to have arisen from a retroposition event that is assumed to have replaced the original IFN locus by integration of intron-spliced RNA and, thus, favored subsequent gene duplication and family expansion adaptable to rapidly evolving viruses and functional divergence (8) (9) (10) (11) . We have examined IFN genes across the genome sequences of 120 animal species, and we specifically characterized the emergence and expansion of intronless IFNs in amphibians (10) . In mammals, intronless type I IFNs have evolved through a subtype expansion resulting in at least nine subtypes, which include IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω commonly found in most mammalian species as well as IFN-δ (pigs), IFN-ζ (mice), and IFN-τ (cattle) only detected in some species. Moreover, subtypes including IFN-α, IFN-ω, IFN-δ, IFN-ζ, and IFN-τ have further diversified into multi-gene sub-clusters (7) (8) (9) (10) (11) (12) .