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Retroviruses Are Some 500 Million Years Old, Phylogenetic Analysis Shows

NEW YORK (GenomeWeb) – Retroviruses are some 500 million years old and likely originated in the ocean, a new genomic analysis has suggested.

A pair of researchers from the University of Oxford examined foamy-like endogenous retroviruses (FLERVs) — which resemble foamy viruses that have integrated into host genomes — from within fish and amphibian genomes. As the duo reported today in Nature Communications, their phylogenetic analyses suggest that the FLERVs they identified largely co-speciated with their hosts and could trace their origin back to the early Paleozoic Era.

Retroviruses, which include HIV, are found throughout vertebrates, but were only thought to be 100 million years old. "These findings show that this medically important group of viruses is at least up to half a billion years in age — far older than previously thought," Oxford's Aris Katzourakis said in a statement. "They date back to the origins of vertebrates, and this gives us the context in which we should consider their present-day activity and interactions with their hosts."

With a reverse transcriptase probe based on RT proteins from known FLERVs, Katzourakis and his colleague Pakorn Aiewsakun fished out retroviral sequences from within amphibian and fish genomes housed in GenBank. Overall, they identified 193 sequences from 32 vertebrate species as FLERVs.

A phylogeny based on their RT sequences indicated that these new FLERVs were closely related to known ones and to foamy viruses. It further supported monophyletic clades for salamander, lobe-finned fish, and ray-finned fish FLERVs, while shark FLERVs formed two clades, one of which also contained frog FLERVs. In addition, they noted that mammalian foamy viruses, salamander FLERVs, and lobe-finned fish FLERVs clustered together, and that ray-finned fish and shark FLERVs were basal to this clade.

Katzourakis and Aiewsakun identified potentially full-length FLERVs from the eastern newt (Notophthalmus viridescens), midas cichlid (Amphilophus citrinellus), and annual killifish (Austrofundulus limnaeus) genomes, which they respectively dubbed NviFLERV, AciFLERV, and AliFLERV.

As many of these full-length FLERVs elements had paired long terminal repeats, the researchers used changes in these sequences to estimate the age of the elements. For instance, they noted the pairwise distance between LTRs of one NviFLERV element to be 4.4 percent, and given the synonymous substitution rate of the amphibian genome, they gauged that element to be about 14 million years old. They similarly estimated the oldest AciFLERV and AliFLERV elements to be 0.377 million years and 1.68 million years old, respectively. This young age led the researchers to suggest that these FLERVs might still be active.

To more closely examine the relationship between foamy viruses and FLERVs, Katzourakis and Aiewsakun also constructed a phylogeny based on their Pol protein alignments. Like the RT-based phylogeny, the ray-finned fish, lobe-finned fish, and salamander FLERVs and mammalian foamy viruses all formed monophyletic clades. But, the Pol phylogeny instead showed shark FLERVs to be paraphyletic, rather than forming two clades.

FLERVs like those from ray-finned fish and salamander co-diverged with their hosts, the researchers also found. Mammalian foamy viruses were most closely related to lobe-finned fish FLERVs, with salamander FLERVs located basal to that clade. However, that is not what the host phylogeny shows. Instead, the researchers suggested that this indicates that there were ancient transmissions of foamy virus-like viruses between tetrapods.

By combining this phylogeny with time-dependent rate phenomenon model, the researchers estimated that the salamander FLERVs branched off some 342 million to 348 million years ago, similar to the divergence timing of their amphibian hosts. In addition, the researchers gauged the split between foamy viruses and FLERVs to have occurred 455 million to 473 million years ago, also reflecting the timing of the split of jawed vertebrates. This timeframe indicates the viruses originated with their jawed vertebrate hosts in the ancient ocean, the researchers added.

"Our new research shows that retroviruses are at least 450 million years old, if not older, and that they must have originated together with, if not before, their vertebrate hosts in the early Paleozoic era," Katzourakis said. "Furthermore, they would have been present in our vertebrate ancestors prior to the colonization of land and have accompanied their hosts throughout this transition from sea to land, all the way up until the present day."