Insights into the evolution of the ISG15 and UBA7 system

The genetic origins of novelty are of central interest in evolutionary biology. ISG15 and UBA7 are present only in vertebrates. The emergence and evolution of them are not clear. Phylogenetic comparisons revealed that UBA7 descends from gene duplication, and ISG15 and UBA7 arose from UBB/UBC and UBA1, respectively. Uba7 exhibits ubiquitin-activation activity in fish but not tetrapods, suggesting that the relationship of ISG15/Uba7 was promiscuous in origin but was later coopted toward higher specificity. Zebrafish Uba7 is capable of activating the ubiquitin cascade in vitro and in vivo, and it displays distinct specificity preference toward substrates and E2 enzymes compared to zebrafish Uba1. These results together provide a framework for understanding the origin and diversification of ISG15/Uba7 and may serve as a paradigmatic example in which an originally minor functionality in an old gene is made into a new high-specificity protein through random mutations and natural selection.