Comparative analysis of genome-encoded viral sequences reveals the evolutionary history of Flaviviridae

The flaviviruses (family Flaviviridae) are a group of positive-strand RNA viruses, many of which pose serious risks to human health on a global scale. Here, we calibrate the timeline of flavivirus evolution using flavivirus-derived DNA sequences identified in animal genomes. We demonstrate that the family is at least 100 million years old and show that this timing can be integrated with dates inferred from co-phylogenetic analysis and paleontological records to produce a cohesive overview of flavivirus evolution in which the main subgroups originate early in animal evolution and broadly co-diverge with animal phyla. In addition, we show that the arthropod-borne classical flaviviruses first evolved from tick-specific viruses, and only later adapted to become insect-borne. Our findings demonstrate that the biological properties of flaviviruses have been acquired over many millions of years of evolution, implying that broad-scale comparative analysis can reveal fundamental insights into flavivirus biology. We implement a novel approach to computational genomic studies of viruses that can support these efforts by enabling more efficient utilization of evolution-related domain knowledge in virus research. SignificanceUnderstanding how pathogenic viruses evolved can provide vital insights into their biology. In this study we use genomic data to show that flaviviruses - a group of viruses that includes important pathogens such as Dengue virus and hepatitis C virus - arose through an extended history of evolutionary interaction with host and vector species. Our findings show that comparative studies can productively utilise genomic data to reveal insights into flavivirus biology, which will help to facilitate the development of more effective antiviral treatments and strategies.