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Analysis of Viral, Cellular Proteomes Indicates Ancient Cellular Origin for Viruses

NEW YORK (GenomeWeb) – Viruses deserve a place on a universal tree of life, according to a new proteomic and phylogenomic analysis of cells and viruses.

A pair of researchers from the University of Illinois analyzed more than 5,000 viral and cellular proteomes to uncover nearly 2,000 protein fold superfamilies, including ones shared by cells and viruses and ones unique to viruses.

"This tells you that you can build a tree of life because you've found a multitude of features in viruses that have all the properties that cells have," Gustavo Caetano-Anollés, a professor of genomic biology at the university, said in a statement. "Viruses also have unique components besides the components that are shared with cells."

Through this and other analyses, the researchers found that viruses likely had an ancient cellular origin, arose more than once, and developed in parallel with the ancestors of modern cells, as they reported today in Science Advances.

Caetano-Anollés and his graduate student, Arshan Nasir, now at the COMSATS Institute of Information Technology in Pakistan, analyzed 5,080 completely sequenced proteomes from cells and viruses. This set included 1,620 proteomes representing the Archaea, Bacteria, and Eukarya superkingdoms  as well as the proteomes of 1,629 double-stranded DNA, 534 single-stranded DNA, 166 double-stranded RNA, 991 single-stranded RNA, and 120 retrotranscribing viruses.

Among the 11 million or so proteins the researchers analyzed, they uncovered 1,995 significant fold superfamily domains, about two-thirds of which were unique to cells. Some 440 fold superfamilies were found across Archaea, Bacteria, Eukarya, and viruses, which they dubbed the ABEV group. Sixty-six fold superfamilies, though, were specific to viruses.

By focusing on protein folds, the duo argued that they could better trace the evolutionary history of viruses, which undergo frequent sequence-level mutations, but whose protein structures change less frequently.

These viral-specific fold superfamilies suggested to Caetano-Anollés and Nasir that viruses haven't just obtained their genetic diversity from host cells, but have generated such variation themselves.

In addition, they noted that viruses that infect all three superkingdoms share a core of 68 fold superfamilies that perform crucial metabolic functions and are widespread in viral proteomes. The researchers added that this indicates that viruses have an ancient origin and that they co-existed with ancient cells.

The researchers reconstructed phylogenomic trees of domains to characterize the evolution of those 1,995 fold superfamilies domains from the 5,080 sampled proteomes. Based on this, they found that most viral fold superfamilies originated very early in evolutionary time.

The most ancient group on this tree was the ABEV group that includes 442 fold superfamilies encoded by both cells and viruses. The next oldest group was the ABE group, which includes fold superfamilies encoded by Achaea, Bacteria, and Eukarya.

Fold superfamilies unique to the superkingdoms and viral supergroups arose later, the researchers noted. Viral-specific fold superfamilies, they added, cropped up at about the same time that modern cells began to diversify.

According to Caetano-Anollés and Nasir, this means that viral-specific fold superfamilies represent the time when proto-virocells were under genome reduction pressure and lost their cellular nature to become dependent on the emerging modern cells for their reproduction.

This, they added, points to two key phases in viral evolution: an early cell-like existence and a transition to the viral mode, as seen today.

Through phylogenomic trees of domains, Ariadne's threads, trees of proteomes, and other analyses, the researchers reported that RNA viral proteomes appear to be more ancient that DNA viral proteomes. The most basal viral group included minus-ssRNA viruses and dsRNA viruses with segmented genomes. This suggests that proto-virocells had segmented RNA genomes that could 'mate' by combining with other RNA segments, much like how the influenza virus evolves, the researchers said.

The universal tree of life also indicated that viruses likely have a polyphyletic origin, as spherical and filamentous virions appear to be unrelated. This then indicated that the viral way of life has arisen more than once, though always before the divergence of modern cells.

All together, Caetano-Anollés and Nasir said their data indicates that viruses originated from multiple ancient cells with segmented RNA genomes and that these virocells coexisted with the ancestors of modern cells. Then, under pressure to reduce their genome and particle sizes, these virocells lost their cellular makeup to become modern viruses. They regain that cellular nature, the researchers added, when they take over the machinery of modern cells.

"Viruses now merit a place in the tree of life," Caetano-Anollés said. "Obviously, there is much more to viruses than we once thought."