Review Article | Published:

Origins and evolutionary consequences of ancient endogenous retroviruses

Abstract

Retroviruses infect a broad range of vertebrate hosts that includes amphibians, reptiles, fish, birds and mammals. In addition, a typical vertebrate genome contains thousands of loci composed of ancient retroviral sequences known as endogenous retroviruses (ERVs). ERVs are molecular remnants of ancient retroviruses and proof that the ongoing relationship between retroviruses and their vertebrate hosts began hundreds of millions of years ago. The long-term impact of retroviruses on vertebrate evolution is twofold: first, as with other viruses, retroviruses act as agents of selection, driving the evolution of host genes that block viral infection or that mitigate pathogenesis, and second, through the phenomenon of endogenization, retroviruses contribute an abundance of genetic novelty to host genomes, including unique protein-coding genes and cis-acting regulatory elements. This Review describes ERV origins, their diversity and their relationships to retroviruses and discusses the potential for ERVs to reveal virus–host interactions on evolutionary timescales. It also describes some of the many examples of cellular functions, including protein-coding genes and regulatory elements, that have evolved from ERVs.

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Acknowledgements

The author thanks J. Butler, B. Howell and the organizers of the 2018 Boston College Intersections Villa Faculty Writing Retreat for the opportunity to complete major portions of this manuscript; R. Gifford, L. Mulder and J. Henzy for helpful discussions; S. Whelan and V. Simon for providing offices for writing while on sabbatical leave at Harvard Medical School and the Icahn School of Medicine at Mount Sinai, respectively. Work in the author’s laboratory is supported by grants from the US National Institutes of Health (AI083118) and the US Department of Defense/Congressionally Directed Medical Research Programs (PR172274).

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Nature Reviews Microbiology thanks A. Dupressoir, C. Feschotte, J. Frank and other anonymous reviewer(s) for their contribution to the peer review of this work.

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The author declares no competing interests.

Correspondence to Welkin E. Johnson.

Glossary

Endogenous retrovirus

(ERV). Heritable retrovirus-derived sequence elements found in the genomes of most or all vertebrates; ERVs usually originate as proviruses integrated into germline DNA.

Loss

Refers to the case when an allelic variant of a locus disappears from the population over time.

Fixation

Refers to the case in which an allelic variant of a locus achieves a frequency of 100% in the population, thereby displacing all other alleles at that locus.

Random genetic drift

Refers to the change in frequency of an allele over time owing to random chance (in the absence of selection).

Long-terminal repeats

(LTRs). Direct identical repeats found at the 5ʹ and 3ʹ ends of a DNA provirus generated during reverse transcription of the retroviral RNA genome.

CAAT box

A cis-acting transcription-factor-binding site frequently found upstream of eukaryotic promoters and in retroviral long-terminal repeats.

Accessory genes

Viral genes that are dispensable for the essential steps of the viral replication cycle but that provide one or more functions that contribute to optimal viral fitness in vivo, such as antagonizing intrinsic and innate immune defences or modifying the metabolic state of the host cell.

Solo-LTRs

Solitary long-terminal repeats (LTRs) lacking any other proviral sequence that usually arise by homologous recombination between the 5ʹ and 3ʹ LTRs of an ERV locus.

Retrotransposition

The amplification of a genomic DNA sequence by reverse transcription of an RNA intermediate followed by integration of the new DNA copies.

Segmental duplications

Stretches of initially identical or nearly identical genomic sequences that arise by DNA duplication.

Exaptation

A trait that evolved on the basis of one function that has subsequently evolved to provide a different function.

Superinfection interference

A phenomenon by which prior infection of a cell renders it resistant to reinfection by retroviruses using the same entry receptor; often mediated by the viral Env glycoprotein.

Syncytins

Glycoproteins of retroviral origin that fulfil cellular functions involving receptor-mediated membrane fusion; thus far, all reported syncytins function as placental syncytins.

Syncytiotrophoblast

A multinuclear layer that forms through fusion of mononuclear cytotrophoblasts.

Restriction factors

Host-encoded factors that have evolved by natural selection to suppress or prevent viral replication at the cellular level.

Purifying selection

A component of natural selection; refers to selection that eliminates deleterious or suboptimal variants of a gene or sequence that arise by mutation.

R peptides

The last 17–20 residues of the cytoplasmic carboxyl termini of gammaretroviral Env proteins, which are cleaved off by the viral protease during virion maturation to activate fusogenic potential.

ERV-L elements

An ancient family of related endogenous retrovirus (ERV) elements found in the genomes of all mammals; distantly related to spumaretroviruses.

Exogenous virus

A horizontally transmitted virus, as distinguished from endogenous viruses.

Positive selection

The selection that favours fixation of changes in a gene, such as when a virus escapes from virus-specific antibodies through changes in a target epitope.

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Fig. 1: Random genetic drift, natural selection and the early stages of endogenous retrovirus evolution in a host population.
Fig. 2: Features of a typical DNA provirus.
Fig. 3: Reconstructing and analysing ancient endogenous retrovirus genes.
Fig. 4: Env exaptation and the relationship between ancient viral functions and current genome functions.
Fig. 5: The effects of drift and selection on endogenous retrovirus genes.