Divergent Viruses Discovered in Arthropods and Vertebrates Revise the Evolutionary History of the Flaviviridae and Related Viruses.
Viruses of the family Flaviviridae are important pathogens of humans and other animals and are currently classified into four genera. To better understand their diversity, evolutionary history, and genomic flexibility, we used transcriptome sequencing (RNA-seq) to search for the viruses related to the Flaviviridae in a range of potential invertebrate and vertebrate hosts. Accordingly, we recovered the full genomes of five segmented jingmenviruses and 12 distant relatives of the known Flaviviridae ("flavi-like" viruses) from a range of arthropod species. Although these viruses are highly divergent, they share a similar genomic plan and common ancestry with the Flaviviridae in the NS3 and NS5 regions. Remarkably, although these viruses fill in major gaps in the phylogenetic diversity of the Flaviviridae, genomic comparisons reveal important changes in genome structure, genome size, and replication/gene regulation strategy during evolutionary history. In addition, the wide diversity of flavi-like viruses found in invertebrates, as well as their deep phylogenetic positions, suggests that they may represent the ancestral forms from which the vertebrate-infecting viruses evolved. For the vertebrate viruses, we expanded the previously mammal-only pegivirus-hepacivirus group to include a virus from the graceful catshark (Proscyllium habereri), which in turn implies that these viruses possess a larger host range than is currently known. In sum, our data show that the Flaviviridae infect a far wider range of hosts and exhibit greater diversity in genome structure than previously anticipated.


OBJECTIVE
The family Flaviviridae of RNA viruses contains several notorious human pathogens, including dengue virus, West Nile virus, and hepatitis C virus. To date, however, our understanding of the biodiversity and evolution of the Flaviviridae has largely been directed toward vertebrate hosts and their blood-feeding arthropod vectors. Therefore, we investigated an expanded group of potential arthropod and vertebrate host species that have generally been ignored by surveillance programs. Remarkably, these species contained diverse flaviviruses and related viruses that are characterized by major changes in genome size and genome structure, such that these traits are more flexible than previously thought. More generally, these data suggest that arthropods may be the ultimate reservoir of the Flaviviridae and related viruses, harboring considerable genetic and phenotypic diversity. In sum, this study revises the traditional view on the evolutionary history, host range, and genomic structures of a major group of RNA viruses.
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Biological Sciences and Sydney Medical School, The University of Sydney, Sydney, Australia.
Mang
M
Shi
Wenzhou Center for Disease Control and Prevention, Wenzhou, China.
Xian-Dan
XD
Lin
Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA.
Nikos
N
Vasilakis
Wuhan Center for Disease Control and Prevention, Wuhan, China.
Jun-Hua
JH
Tian
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Ci-Xiu
CX
Li
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Liang-Jun
LJ
Chen
Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA.
Gillian
G
Eastwood
Veterinary Station, Jiulingtuan of Wushi, Bole, China.
Xiu-Nian
XN
Diao
Veterinary Station, Jiushi, Emin, China.
Ming-Hui
MH
Chen
Guangxi Mangrove Research Center, Beihai, China.
Xiao
X
Chen
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Xin-Cheng
XC
Qin
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Steven G
SG
Widen
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Thomas G
TG
Wood
Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA.
Robert B
RB
Tesh
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Jianguo
J
Xu
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Biological Sciences and Sydney Medical School, The University of Sydney, Sydney, Australia.
Edward C
EC
Holmes
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China zhangyongzhen@icdc.cn.
Yong-Zhen
YZ
Zhang
D000818:Animals; D001181:Arthropods / Q000821:virology*; D019143:Evolution, Molecular; D018067:Flaviviridae / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D014644:Genetic Variation; D016679:Genome, Viral; D058507:Host Specificity; D006801:Humans; D010802:Phylogeny; D026801:Synteny; D014714:Vertebrates / Q000821:virology*