Unexpected Inheritance: Multiple Integrations of Ancient Bornavirus and Ebolavirus/Marburgvirus Sequences in Vertebrate Genomes

Abstract

Vertebrate genomes contain numerous copies of retroviral sequences, acquired over the course of evolution. Until recently they were thought to be the only type of RNA viruses to be so represented, because integration of a DNA copy of their genome is required for their replication. In this study, an extensive sequence comparison was conducted in which 5,666 viral genes from all known non-retroviral families with single-stranded RNA genomes were matched against the germline genomes of 48 vertebrate species, to determine if such viruses could also contribute to the vertebrate genetic heritage. In 19 of the tested vertebrate species, we discovered as many as 80 high-confidence examples of genomic DNA sequences that appear to be derived, as long ago as 40 million years, from ancestral members of 4 currently circulating virus families with single strand RNA genomes. Surprisingly, almost all of the sequences are related to only two families in the Order Mononegavirales: the Bornaviruses and the Filoviruses, which cause lethal neurological disease and hemorrhagic fevers, respectively. Based on signature landmarks some, and perhaps all, of the endogenous virus-like DNA sequences appear to be LINE element-facilitated integrations derived from viral mRNAs. The integrations represent genes that encode viral nucleocapsid, RNA-dependent-RNA-polymerase, matrix and, possibly, glycoproteins. Integrations are generally limited to one or very few copies of a related viral gene per species, suggesting that once the initial germline integration was obtained (or selected), later integrations failed or provided little advantage to the host. The conservation of relatively long open reading frames for several of the endogenous sequences, the virus-like protein regions represented, and a potential correlation between their presence and a species' resistance to the diseases caused by these pathogens, are consistent with the notion that their products provide some important biological advantage to the species. In addition, the viruses could also benefit, as some resistant species (e.g. bats) may serve as natural reservoirs for their persistence and transmission. Given the stringent limitations imposed in this informatics search, the examples described here should be considered a low estimate of the number of such integration events that have persisted over evolutionary time scales. Clearly, the sources of genetic information in vertebrate genomes are much more diverse than previously suspected.

Endogenous hepadnaviruses, bornaviruses and circoviruses in snakes

“…A future challenge in palaeovirology studies will be to test whether EVEs could have played and/or still play a role at the RNA level, notably in antiviral immunity [66][67][68][69]. Finally, our study provides yet another stunning illustration of the fact that, in spite of the extremely high mutation rates characterizing most modern viruses, the fossils of ancient viral genomes can be identified in their host genomes even after millions, or tens of millions of years [1,12,15]. As observed in previous studies [17,26,70,71], the long-term substitution rates we have inferred for hepadnaviruses and circoviruses (between 1.2 Â 10 28 and 7.7 Â 10 28 subst.…”

Epidemiology and host spectrum of Borna disease virus infections

“…The most commonly found EBL resembled the N gene (EBLN), and was the only EBL found in primates as well as in guinea pig, squirrel, lamprey and a few exotic animal species. In the genomes of lemur, mouse, rat, microbat, wallaby and a few fish species, however, either the L or M gene was detected in addition to or instead of the N gene (Belyi et al, 2010). These results suggest that endogenization was an ancient event in vertebrate evolution.…”

“…In 2010, EBL sequences (EBLs) were detected in the genomes of humans and several other vertebrates (Belyi et al, 2010;Horie et al, 2010). The most commonly found EBL resembled the N gene (EBLN), and was the only EBL found in primates as well as in guinea pig, squirrel, lamprey and a few exotic animal species.…”

“…In humans, numerous neuropsychiatric entities have been reported to be associated with potential markers of BDV infection, but the evidence remains inconclusive and the true prevalence and causative role are questionable (reviewed by Planz et al, 2002;Lipkin et al 2011). This association has become even more intriguing since the recent observation of endogenization of ancient bornavirus genes in vertebrate genomes (Belyi et al, 2010;Horie et al, 2010).…”

Guest list or black list: heritable small RNAs as immunogenic memories

“…While the underlying mechanisms are unknown, it was discovered that the human genome contains bits and pieces of non-retrovirus RNA viruses [55,56]. A clue to the mechanism might be found in Drosophila, where in cells such integration was shown to be achieved by the reverse transcriptase activity of transposons, resulting in establishment of an anti-viral RNAi response [57].…”