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

across the genome sequences of more than 110 animal species, and specifically characterized the emergence and expansion of intronless IFNs in amphibians (Figure 1 ) (10, 12) . Further subtype-diversification of intronless type I IFNs in ungulates, especially in livestock species including pigs and cattle, comprises other evolutionary surges of IFN gene expansions (8, 9) . Swine and bovine species thus contain a large gene number of IFNs including several multi-gene IFN subtypes such as IFN-δ, -ω, and -τ , which represent an apex of IFN gene expansion in mammalian species (1) (2) (3) (4) (5) (6) (7) (8) (9) . In contrast to the surges of IFN genes in amphibians, chickens, bats, mice, and especially in pigs and cattle, we also observed intriguing reduction of IFN genes in wild birds and underground rodent species (such as naked mole-rats) (Figure 1) . These findings support a species/lineageindependent "bouncing" model of IFN molecular evolution and subtype-diversification across vertebrates (2, 10, 12, 40) . The porcine (and bovine) IFN complex thus symbolizes a significant surge in IFN molecular evolution, which is distinguished by the expansion of multi-gene IFN subtypes beyond the classical IFN-α subtype (Figure 1 ) (8, 9) . As the emergence and rapid expansion of intronless IFNs in amphibians were ascribed to cope with dramatic environmental changes during terrestrial adaption (10, 12) , we interpret that most species-dependent evolution surges or retreats in IFN gene numbers are related to increased or decreased chances in pathogenic exposure (particularly intracellular ones like viruses) in their ambient habitats (1-7). The obvious IFN gene expansion such as in chickens, mice, pigs and cattle are likely relevant to their "domestic" process with humans, which are implicated by the increasing IFN gene numbers along three bovine species, i.e., wild yak (Bos mutus), zebu cattle (Bos indicus), and cows (Bos taurus) (Figure 1 ) (2, 41) . Although amphibians such as Xenopus have diversified 20-30 of intronless IFN molecules, these amphibian IFNs seem to have evolved independently and share little molecular phylogeny (<45%) to IFN subtypes in mammals (2, 10, 12) . The early FIGURE 10 | Signal peptides of swine and bovine IFN peptides were examined using PrediSi (http://www.predisi.de) to determine the secretory potency of relevant IFN mature peptides, indicating the evolution of intracellular IFNs (indicated by arrows, signal peptide prediction score 0-0.5) in each subgroup, particularly of unconventional IFN subtypes such as IFN-δ and IFN-ω subtypes that undergoing multi-gene expansion such as in pigs and cattle (2, 9) . IFN-ω-like genes (also potentially to be progenitors of IFN-β or -κ) were determined in reptiles and clearly in some avian species (2) . Similar to the diversification of other unconventional IFN subtypes, IFN-ω subtype is common in almost all mammalian species and rapidly evolved into multi-gene IFN subtype in ungulate, bats and some carnivore species, with the exception of rodents. Human and other primate species only have one IFN-ω molecule in each species (Figures 1, 2) (2). Human IFN-ω was demonstrated to be a leukocyte interferon, which had antiviral, anti-proliferation, and antitumor activities that are similar (but more broadly active) to those of IFN-α (20) . Previous studies in feline IFN-ω explored them as a therapeutic option for some autoimmune diseases or retroviral infections in humans and other animals. So