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

Abstract

Innate immune interferons (IFNs), particularly type I IFNs, are primary mediators regulating animal antiviral, antitumor, and cell-proliferative activity. These antiviral cytokines have evolved remarkable molecular and functional diversity to confront ever-evolving viral threats and physiological regulation. We have annotated IFN gene families across 110 animal genomes, and showed that IFN genes, after originating in jawed fishes, had several significant evolutionary surges in vertebrate species of amphibians, bats and ungulates, particularly pigs and cattle. For example, pigs have the largest but still expanding type I IFN family consisting of nearly 60 IFN-coding genes that encode seven IFN subtypes including multigene subtypes of IFN-α, -δ, and -ω. Whereas, subtypes such as IFN-α and -β have been widely studied in many species, the unconventional subtypes such as IFN-ω have barely been investigated. We have cross-species defined the IFN evolution, and shown that unconventional IFN subtypes particularly the IFN-ω subtype have evolved several novel features including: (1) being a signature multi-gene subtype expanding primarily in mammals such as bats and ungulates, (2) emerging isoforms that have superior antiviral potency than typical IFN-α, (3) highly cross-species antiviral (but little anti-proliferative) activity exerted in cells of humans and other mammalian species, and (4) demonstrating potential novel molecular and functional properties. This study focused on IFN-ω to investigate the immunogenetic evolution and functional diversity of unconventional IFN subtypes, which may further IFN-based novel antiviral design pertinent to their cross-species high antiviral and novel activities.

Egyptian Rousette IFN-ω Subtypes Elicit Distinct Antiviral Effects and Transcriptional Responses in Conspecific Cells

“…Based on previous observations of the large expansion in the type I IFN-ω subfamily in the Egyptian rousette (19), we sought to examine members of this family to gain insight into the contributions of these proteins to Egyptian rousette antiviral immunity and to ask whether the considerable duplications in the IFN locus may have functional relevance for antiviral responses. In species with multiple IFN-ω genes, like Sus scrofa (pig) and Bos taurus (cow), differences in induction and antiviral potency among IFN-ω paralogs have been observed (23,(35)(36)(37). Consistent with this work, we found functional differences between two rousette IFN-ω subtypes, supporting the hypothesis that the IFN-ω subtypes are not interchangeable.…”

“…In humans and other species, IFN-ω is induced by viral infection and has potent antiviral activity against various RNA viruses, including vesicular stomatitis virus (VSV), bovine viral diarrhea virus, yellow fever virus, West Nile virus, and influenza A virus (20)(21)(22)(23)(24). Multiple subtypes of porcine IFN-ω are expressed after viral infection and have dramatic differences in activity despite very few single nucleotide polymorphisms (23). The ISGs induced specifically by these IFN-ω proteins, however, are not known.…”

Xenopus Interferon Complex: Inscribing the Amphibiotic Adaption and Species-Specific Pathogenic Pressure in Vertebrate Evolution?

“…Our annotation of the current genome assemblies at NCBI and Xenbase not only determined intronless IFNs in frogs for the first time, but also discovered several more intron-containing IFNs, which were not revealed in previous studies. We therefore updated the current repertoire of IFN gene loci in X. tropicalis: The co-existence of 14 Figure 1) [13]. A new study in a Tibet frog species (Nanorana parkeri) reinforced the co-existence of both intron-containing and intronless IFN genes in amphibians [16].…”

“…A new study discovered ancestral IFN orthologs of all three IFN types in a cartilaginous fish, and hence resolved that three types of IFNs were ramified before the bony fish [12]. We annotated IFN gene families across 110 vertebrate genomes, and showed that IFN genes, after originating in jawed fishes, had several significant evolutionary surges regarding the numbers of IFN-coding genes and subtypes in some species of amphibians, bats, and ungulates (particularly pigs and cattle of livestock) [13][14][15]. Here, we review the newly identified IFN molecular evolution and expansion in amphibians [12,13,16].…”

“…The evolution of intronless (or single-exon) IFN genes and further molecular diversification in amniotes are signature events in IFN evolution [11][12][13][14][15][16]. However, our understanding of this Figure 1.…”