Large-scale investigation of zoonotic viruses in the era of high-throughput sequencing.

Zoonotic diseases considerably impact public health and socioeconomics. RNA viruses reportedly caused approximately 94% of zoonotic diseases documented from 1990 to 2010, emphasizing the importance of investigating RNA viruses in animals. Furthermore, it has been estimated that hundreds of thousands of animal viruses capable of infecting humans are yet to be discovered, warning against the inadequacy of our understanding of viral diversity. High-throughput sequencing (HTS) has enabled the identification of viral infections with relatively little bias. Viral searches using both symptomatic and asymptomatic animal samples by HTS have revealed hidden viral infections. This review introduces the history of viral searches using HTS, current analytical limitations, and future potentials. We primarily summarize recent research on large-scale investigations on viral infections reusing HTS data from public databases. Furthermore, considering the accumulation of uncultivated viruses, we discuss current studies and challenges for connecting viral sequences to their phenotypes using various approaches: performing data analysis, developing predictive modeling, or implementing high-throughput platforms of virological experiments. We believe that this article provides a future direction in large-scale investigations of potential zoonotic viruses using the HTS technology.