A phylogenomic data-driven exploration of viral origins and evolution

Nasir, Arshan; Caetano-Anollés, Gustavo

The search for a "fourth" domain of life is not new [for example, (74, 75) ]. It has been the subject of intense debate in evolutionary biology [refer to (76) (77) (78) (79) (80) (81) (82) (83) and references therein]. Here, we put forth the bold conjecture of a universal tree of life (uToL) that describes the evolution of cellular and viral proteomes (Figs. 7 and 8 ). Formally placing viruses in uToL is a daring task because many scientists even question whether viruses are living entities mainly because of (i) the lack of true viral metabolism and (ii) their inability to reproduce on their own (76, 84) . However, counterarguments have recently gained popularity, especially inspired by the study of "virus factories," which are intracellular structures formed by many giant viruses inside infected cells (85) . Virus factories are "cell-like organisms" [sensu (86) ] that are compartmentalized by a membrane, have ribosomes, obtain energy from mitochondria, and contain full information to successfully produce numerous virions (85) . They are strikingly similar to many intracellular parasitic bacteria that also depend on host metabolism to reproduce. For these reasons, it has been argued that the true "self" of a virus is the intracellular virus factory of infected cells, which is metabolically active and should be contrasted with the extracellular and metabolically inert virion state. Specifically, virocells produce viral gametes (virions) that are functionally analogous to cellular gametes of sexually reproducing species, which fuse during fertilization. These viral gametes can then fertilize (infect) other cells [sensu (86) ]. Thus, viruses should be considered "living" organisms that simply survive by means of an atypical reproduction method that requires infecting a cell [similar to obligate parasitism (87) ].