Env-less endogenous retroviruses are genomic superspreaders

Abstract

Endogenous retroviruses (ERVs) differ from typical retroviruses in being inherited through the host germline and therefore are a unique combination of pathogen and selfish genetic element. Some ERV lineages proliferate by infecting germline cells, as do typical retroviruses, whereas others lack the env gene required for virions to enter cells and thus behave like retrotransposons. We wished to know what factors determined the relative abundance of different ERV lineages, so we analyzed ERV loci recovered from 38 mammal genomes by in silico screening. By modeling the relationship between proliferation and replication mechanism in detail within one group, the intracisternal A-type particles (IAPs), and performing simple correlations across all ERV lineages, we show that when ERVs lose the env gene their proliferation within that genome is boosted by a factor of ∼30. We also show that ERV abundance follows the Pareto principle or 20/80 rule, with ∼20% of lineages containing 80% of the loci. This rule is observed in many biological systems, including infectious disease epidemics, where commonly ∼20% of the infected individuals are responsible for 80% of onward infection. We thus borrow simple epidemiological and ecological models and show that retrotransposition and loss of env is the trait that leads endogenous retroviruses to becoming genomic superspreaders that take over a significant proportion of their host's genome. E ndogenous retroviruses (ERVs) proliferate by the repeated integration of new viral sequences into their host's germline (1), integrations which can become fixed in the host population and have led to ERV sequences (loci) comprising 8-10% of the human and mouse genomes (2, 3) (this number also includes nonautonomous LTR-retrotransposons, which we do not analyze here). These loci form phylogenetically distinct lineages traditionally called "families" (4) (unrelated to the general use of this term in taxonomy), each of which is the result of the expansion of a founder infection of the organism's germline that can have occurred more than ∼100 million years ago (5).ERVs can replicate both as transposable elements (TEs) and viruses. Some lineages copy by an entirely intracellular mechanism and are functionally indistinguishable from the class of TEs called LTR-retrotransposons, whereas others copy within the host germline using cell reinfection in the same manner as the copying within somatic cells of exogenous retroviruses (XRVs) (6). We refer to these replication mechanisms as "retrotransposition" and "reinfection," respectively. Whether an ERV is reinfecting or retrotransposing can be determined by the integrity of its env gene, which produces the protein on the surface of the viral particle that is responsible for cell entry. We can assume that an ERV lineage with a functional env is reinfecting, whereas an ERV lineage with a disintegrated env is retrotransposing (whether reinfection can include germline cells in other host individuals of the same or other species is not known). Some retroviruses w...

Mammalian Endogenous Retroviruses

“…Alternately, the ERV might undergo a more dramatic genetic change. The evolutionary success of the superspreaders, such as IAP elements in mice, suggests the development of an intracellular replication strategy resembling the retrovirus life cycle but lacking budding from and reentering the cell, might be advantageous (23). Perhaps replication in this manner is intrinsically more efficient; alternately, it avoids host responses to infection (see below).…”

“…These entail searches for conserved sequences and/or sequence motifs organized in the same manner as exogenous retroviruses (21). Using such mining techniques, comprehensive ERV collections have been obtained from ever-increasing numbers of species (22,23). Thus, one recent paper refers to 87,750 defined ERVs identified in an analysis of 60 vertebrate genomes (24), and these numbers can only increase with time.…”

A Novel Recombinant Retrovirus in the Genomes of Modern Birds Combines Features of Avian and Mammalian Retroviruses

“…First, it is the only known class II/gammaretroviral recombinant in an avian genome. Other such recombinants have been described in mammals, including the exogenous and endogenous primate type D betaretroviruses (e.g., MPMV) (12, 29, 34), a recently described bat ERV (35), and endogenous intracisternal A particles (IAPs), which have recombined with gammaretroviral env, in the genomes of the shrew and guinea pig (36). The only previously characterized class II/gammaretroviral recombinants found outside mammals are two related ERVs of pythons (PyERV) (37).…”

Genome-Wide Screening of Retroviral Envelope Genes in the Nine-Banded Armadillo (Dasypus novemcinctus, Xenarthra) Reveals an Unfixed Chimeric Endogenous Betaretrovirus Using the ASCT2 Receptor

“…It is noteworthy that the relative fraction of betaretrovirus-like env sequences is small compared to that of gag-pol sequences of a betaretroviral origin reported by Hayward et al, i.e., 72% (10). This can be accounted for by a significant fraction of the armadillo genome being occupied by recombinant beta/gamma-type ERVs and/or by env-less betaretrovirus-like ERV families, which have been reported to expand in certain mammalian species (52) and whose quantitative importance in armadillo remains to be addressed. Finally, the abundance of env genes in the armadillo genome results largely from a small number of significant bursts of closely related ERVs (e.g., Dasy-Env5 to -Env14).…”

“…This is the case for the simian retroviruses SMRV, SRV, and MPMV (48) as well as for rabbit syncytin-Ory1-ERV, bat DrERV, possum TvERV(D), and murine MMERV-␤6, as revealed in this study. While other recombinants between betaand gamma-type retroviruses have been described (e.g., Python molurus endogenous retrovirus [PyERV] [61], intracisternal Aparticle Env-encoding proviral elements in shrew and guinea pig [52], and marsupial Opo-Env3-ERV [28]), the acquisition of a gammaretroviral env gene that specifically binds and infects cells expressing the ASCT2 receptor therefore turns out to be a frequent event. We propose that ASCT2 usage is one of the driving forces for the recombination events leading to the emergence of DnERV and of other chimeric viruses in a panel of vertebrate species.…”