Multiple infiltration and cross-species transmission of foamy viruses across Paleozoic to Cenozoic era

Foamy viruses (FVs) are complex retroviruses that can infect humans and other animals. In this study, by integrating transcriptomic and genomic data, we discovered 412 FVs from 6 lineages in amphibians, which significantly increased the known set of FVs in amphibians. Among these lineages, salamander FVs maintained a co-evolutionary pattern with their hosts that could be dated back to the Paleozoic era, while, on the contrary, frog FVs were much more likely acquired from cross-species (class level) transmission in the Cenozoic era. In addition, we found three distinct FV lineages had integrated into the genome of a salamander. Unexpectedly, we identified a potential exogenous form of FV circulated in caecilian, demonstrating the existence of exogenous form of FV besides mammals. Our discovery of rare phenomena in amphibian FVs has overturned our collective understanding of the macroevolution of the complex retrovirus. Importance Foamy viruses (FVs) represent, more so than other viruses, the best model of co-evolution between a virus and a host. This study represents so far, the largest investigation of amphibian FVs and revealed 412 FVs of 6 distinct lineages from three major orders of amphibians. Besides co-evolutionary pattern, cross-species and repeated infection were also observed during evolution of amphibian FVs. Remarkably, expressed FVs including a potential exogenous form were discovered, suggesting live FVs could be underestimated in nature. These findings revealed the multiple origin and complex evolution of amphibian FVs started from the Paleozoic era.