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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Herniou, E. et al. Retroviral diversity and distribution in vertebrates. J. Virol. 72, 5955–5966 (1998).
Aiewsakun, P. & Katzourakis, A. Endogenous viruses: connecting recent and ancient viral evolution. Virology 479–480, 26–37 (2015).
Xu, X., Zhao, H., Gong, Z. & Han, G.-Z. Endogenous retroviruses of non-avian/mammalian vertebrates illuminate diversity and deep history of retroviruses. PLOS Pathog. 14, e1007072 (2018).
Naville, M. & Volff, J.-N. Endogenous retroviruses in fish genomes: from relics of past infections to evolutionary innovations? Front. Microbiol. 7, 1197 (2016).
Gifford, R. & Tristem, M. The evolution, distribution and diversity of endogenous retroviruses. Virus Genes 26, 291–315 (2003).
Gifford, R. J. Viral evolution in deep time: lentiviruses and mammals. Trends Genet. 28, 89–100 (2012).
Lavialle, C. et al. Paleovirology of ‘syncytins’, retroviral env genes exapted for a role in placentation. Phil. Trans. R. Soc. B Biol. Sci. 368, 20120507 (2013).
Delviks-Frankenberry, K., Cingöz, O., Coffin, J. M. & Pathak, V. K. Recombinant origin, contamination, and de-discovery of XMRV. Curr. Opin. Virol. 2, 499–507 (2012).
Groom, H. C. T. & Bishop, K. N. The tale of xenotropic murine leukemia virus-related virus. J. Gen. Virol. 93, 915–924 (2012).
Suling, K., Quinn, G., Wood, J. & Patience, C. Packaging of human endogenous retrovirus sequences is undetectable in porcine endogenous retrovirus particles produced from human cells. Virology 312, 330–336 (2003).
Young, G. R., Stoye, J. P. & Kassiotis, G. Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis. Bioessays 35, 794–803 (2013).
Babaian, A. & Mager, D. L. Endogenous retroviral promoter exaptation in human cancer. Mob. DNA 7, 24 (2016).
Mager, D. L. & Lorincz, M. C. Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses. Nat. Genet. 49, 974–975 (2017).
Young, G. R. et al. Resurrection of endogenous retroviruses in antibody-deficient mice. Nature 491, 774–778 (2012).
Stoye, J. P. & Coffin, J. M. The four classes of endogenous murine leukemia virus: structural relationships and potential for recombination. J. Virol. 61, 2659–2669 (1987).
Martinelli, S. C. & Goff, S. P. Rapid reversion of a deletion mutation in Moloney murine leukemia virus by recombination with a closely related endogenous provirus. Virology 174, 135–144 (1990).
Stoye, J. P., Moroni, C. & Coffin, J. M. Virological events leading to spontaneous AKR thymomas. J. Virol. 65, 1273–1285 (1991).
Benachenhou, F. et al. Evolutionary conservation of orthoretroviral long terminal repeats (LTRs) and ab initio detection of single LTRs in genomic data. PLOS ONE 4, e5179 (2009).
Benachenhou, F. et al. Conserved structure and inferred evolutionary history of long terminal repeats (LTRs). Mob. DNA 4, 5 (2013).
Copeland, N. G., Hutchison, K. W. & Jenkins, N. A. Excision of the DBA ecotropic provirus in dilute coat-color revertants of mice occurs by homologous recombination involving the viral LTRs. Cell 33, 379–387 (1983).
Weiss, R. A. The discovery of endogenous retroviruses. Retrovirology 3, 67 (2006).
Bannert, N. & Kurth, R. The evolutionary dynamics of human endogenous retroviral families. Annu. Rev. Genomics Hum. Genet. 7, 149–173 (2006).
Gifford, R., Kabat, P., Martin, J., Lynch, C. & Tristem, M. Evolution and distribution of class II-related endogenous retroviruses. J. Virol. 79, 6478–6486 (2005).
Belshaw, R., Katzourakis, A., Pac˘es, J., Burt, A. & Tristem, M. High copy number in human endogenous retrovirus families is associated with copying mechanisms in addition to reinfection. Mol. Biol. Evol. 22, 814–817 (2005).
Magiorkinis, G., Gifford, R. J., Katzourakis, A., De Ranter, J. & Belshaw, R. Env-less endogenous retroviruses are genomic superspreaders. Proc. Natl Acad. Sci. USA 109, 7385–7390 (2012).
Jern, P., Sperber, G. O. & Blomberg, J. Use of endogenous retroviral sequences (ERVs) and structural markers for retroviral phylogenetic inference and taxonomy. Retrovirology 2, 50 (2005).
Hayward, A., Cornwallis, C. K. & Jern, P. Pan-vertebrate comparative genomics unmasks retrovirus macroevolution. Proc. Natl Acad. Sci. USA 112, 464–469 (2015).
Bénit, L., Dessen, P. & Heidmann, T. Identification, phylogeny, and evolution of retroviral elements based on their envelope genes. J. Virol. 75, 11709–11719 (2001).
King, A. M. Q., Adams, M. J., Carstens, E. B. & Lefkowitz, E. J. (eds) Virus Taxonomy: Classification and Nomenclature of Viruses: The Ninth Report of the International Committee on Taxonomy of Viruses (Elsevier, 2011).
Gifford, R. J. et al. Nomenclature for endogenous retrovirus (ERV) loci. Retrovirology 15, 59 (2018).
Martin, J., Herniou, E., Cook, J., O’Neill, R. W. & Tristem, M. Interclass transmission and phyletic host tracking in murine leukemia virus-related retroviruses. J. Virol. 73, 2442–2449 (1999).
Hayward, A., Grabherr, M. & Jern, P. Broad-scale phylogenomics provides insights into retrovirus-host evolution. Proc. Natl Acad. Sci. USA 110, 20146–20151 (2013).
Henzy, J. E. & Johnson, W. E. Pushing the endogenous envelope. Phil. Trans. R. Soc. B Biol. Sci. 368, 20120506 (2013).
Farkašová, H. et al. Discovery of an endogenous deltaretrovirus in the genome of long-fingered bats (Chiroptera: Miniopteridae). Proc. Natl Acad. Sci. USA 114, 3145–3150 (2017). This paper is the first to identify an ERV related to modern deltaretroviruses, the genus that includes human T-lymphotropic viruses and the bovine leukaemia virus.
Hron, T. et al. Remnants of an ancient deltaretrovirus in the genomes of horseshoe bats (Rhinolophidae). Viruses 10, 185 (2018).
Katzourakis, A., Tristem, M., Pybus, O. G. & Gifford, R. J. Discovery and analysis of the first endogenous lentivirus. Proc. Natl Acad. Sci. USA 104, 6261–6265 (2007).
Gifford, R. J. et al. A transitional endogenous lentivirus from the genome of a basal primate and implications for lentivirus evolution. Proc. Natl Acad. Sci. USA 105, 20362–20367 (2008).
Gilbert, C., Maxfield, D. G., Goodman, S. M. & Feschotte, C. Parallel germline infiltration of a lentivirus in two Malagasy lemurs. PLOS Genet. 5, e1000425 (2009).
Cui, J. & Holmes, E. C. Endogenous lentiviruses in the ferret genome. J. Virol. 86, 3383–3385 (2012).
Han, G.-Z. & Worobey, M. A primitive endogenous lentivirus in a colugo: insights into the early evolution of lentiviruses. Mol. Biol. Evol. 32, 211–215 (2015).
Hron, T., Fábryová, H., Pačes, J. & Elleder, D. Endogenous lentivirus in Malayan colugo (Galeopterus variegatus), a close relative of primates. Retrovirology 11, 84 (2014).
Hron, T., Farkašová, H., Padhi, A., Pačes, J. & Elleder, D. Life history of the oldest lentivirus: characterization of ELVgv integrations in the dermopteran genome. Mol. Biol. Evol. 33, 2659–2669 (2016).
Marchi, E., Kanapin, A., Byott, M., Magiorkinis, G. & Belshaw, R. Neanderthal and Denisovan retroviruses in modern humans. Curr. Biol. 23, R994–R995 (2013).
Lee, A. et al. Novel Denisovan and Neanderthal retroviruses. J. Virol. 88, 12907–12909 (2014).
Lenz, J. HERV-K HML-2 diversity among humans. Proc. Natl Acad. Sci. USA 113, 4240–4242 (2016).
Holloway, J. R., Williams, Z. H., Freeman, M. M., Bulow, U. & Coffin, J. M. Gorillas have been infected with the HERV-K (HML-2) endogenous retrovirus much more recently than humans and chimpanzees. Proc. Natl Acad. Sci. USA 116, 1337–1346 (2019). This study uncovers multiple young ERVs in gorilla genomes related to human HERV-K(HML2), indicating recent activity in the gorilla lineage and raising the possibility that modern gorillas host an active HML-2 virus.
Goldstone, D. C. et al. Structural and functional analysis of prehistoric lentiviruses uncovers an ancient molecular interface. Cell Host Microbe 8, 248–259 (2010). This paper describes X-ray crystallography of the capsid proteins of two ancient lentiviruses in complex with host factor cyclophilin A. It also uses structures to infer phylogenetic relationships between extinct and extant lentiviruses.
Aiewsakun, P. & Katzourakis, A. Marine origin of retroviruses in the early Palaeozoic Era. Nat. Commun. 8, 13954 (2017). This paper describes the discovery and analysis of foamy-virus-like ERVs in marine vertebrates and suggests retroviruses may have originated early during vertebrate evolution.
Diehl, W. E., Patel, N., Halm, K. & Johnson, W. E. Tracking interspecies transmission and long-term evolution of an ancient retrovirus using the genomes of modern mammals. eLife 5, e12704 (2016). This paper describes the use of ERV loci to retrace the origins and global spread of an ancient gammaretrovirus among mammals between 15 million and 33 million years ago, spanning the late Oligocene and early Miocene epochs.
Katzourakis, A. et al. Discovery of prosimian and afrotherian foamy viruses and potential cross species transmissions amidst stable and ancient mammalian co-evolution. Retrovirology 11, 61 (2014).
Escalera-Zamudio, M. et al. A novel endogenous betaretrovirus in the common vampire bat (Desmodus rotundus) suggests multiple independent infection and cross-species transmission events. J. Virol. 89, 5180–5184 (2015).
Zhuo, X. & Feschotte, C. Cross-species transmission and differential fate of an endogenous retrovirus in three mammal lineages. PLOS Pathog. 11, e1005279 (2015).
Holmes, E. C. The evolution of endogenous viral elements. Cell Host Microbe 10, 368–377 (2011).
Kamath, P. L. et al. The population history of endogenous retroviruses in mule deer (Odocoileus hemionus). J. Hered. 105, 173–187 (2014).
Greenwood, A. D., Ishida, Y., O’Brien, S. P., Roca, A. L. & Eiden, M. V. Transmission, evolution, and endogenization: lessons learned from recent retroviral invasions. Microbiol. Mol. Biol. Rev. 82, e00044–17 (2018).
Lee, A., Nolan, A., Watson, J. & Tristem, M. Identification of an ancient endogenous retrovirus, predating the divergence of the placental mammals. Phil. Trans. R. Soc. B Biol. Sci. 368, 20120503 (2013).
Blanco-Melo, D., Gifford, R. J. & Bieniasz, P. D. Co-option of an endogenous retrovirus envelope for host defense in hominid ancestors. eLife 6, 11 (2017). This study uses ancestral node reconstruction to establish that an intact env gene in the human genome can mediate superinfection interference and may have functioned to restrict entry of an ancient exogenous virus.
Blanco-Melo, D., Gifford, R. J. & Bieniasz, P. D. Reconstruction of a replication-competent ancestral murine endogenous retrovirus-L. Retrovirology 15, 34 (2018). This paper reports on the resurrection and experimental investigation of an ancient, extinct retrovirus using ancestral node reconstruction. This retrovirus is the oldest ERV (ERV-L) successfully reconstructed so far.
Johnson, W. E. & Coffin, J. M. Constructing primate phylogenies from ancient retrovirus sequences. Proc. Natl Acad. Sci. USA 96, 10254–10260 (1999).
Martins, H. & Villesen, P. Improved integration time estimation of endogenous retroviruses with phylogenetic data. PLOS ONE 6, e14745 (2011).
Dangel, A. W., Baker, B. J., Mendoza, A. R. & Yu, C. Y. Complement component C4 gene intron 9 as a phylogenetic marker for primates: long terminal repeats of the endogenous retrovirus ERV-K(C4) are a molecular clock of evolution. Immunogenetics 42, 41–52 (1995).
Magiorkinis, G., Blanco-Melo, D. & Belshaw, R. The decline of human endogenous retroviruses: extinction and survival. Retrovirology 12, 8 (2015).
Wildschutte, J. H. et al. Discovery of unfixed endogenous retrovirus insertions in diverse human populations. Proc. Natl Acad. Sci. USA 113, E2326–E2334 (2016). This study capitalizes on human genomic variation captured in databases, such as the 1000 Genomes Project, to detect and describe rare, unfixed HERV-K(HML-2) loci in the human population.
Subramanian, R. P., Wildschutte, J. H., Russo, C. & Coffin, J. M. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8, 90 (2011).
Bhardwaj, N., Montesion, M., Roy, F. & Coffin, J. M. Differential expression of HERV-K (HML-2) proviruses in cells and virions of the teratocarcinoma cell line Tera-1. Viruses 7, 939–968 (2015).
Domansky, A. N. et al. Solitary HERV-K LTRs possess bi-directional promoter activity and contain a negative regulatory element in the U5 region. FEBS Lett. 472, 191–195 (2000).
Boeke, J. D., Garfinkel, D. J., Styles, C. A. & Fink, G. R. Ty elements transpose through an RNA intermediate. Cell 40, 491–500 (1985).
Heidmann, T., Heidmann, O. & Nicolas, J. F. An indicator gene to demonstrate intracellular transposition of defective retroviruses. Proc. Natl Acad. Sci. USA 85, 2219–2223 (1988).
Esnault, C. et al. APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature 433, 430–433 (2005).
Heslin, D. J. et al. A single amino acid substitution in a segment of the CA protein within Gag that has similarity to human immunodeficiency virus type 1 blocks infectivity of a human endogenous retrovirus K provirus in the human genome. J. Virol. 83, 1105–1114 (2009).
Chudak, C. et al. Identification of late assembly domains of the human endogenous retrovirus-K(HML-2). Retrovirology 10, 140 (2013).
Hanke, K. et al. Reconstitution of the ancestral glycoprotein of human endogenous retrovirus k and modulation of its functional activity by truncation of the cytoplasmic domain. J. Virol. 83, 12790–12800 (2009).
Robinson, L. R. & Whelan, S. P. J. Infectious entry pathway mediated by the human endogenous retrovirus K envelope protein. J. Virol. 90, 3640–3649 (2016).
Robinson-McCarthy, L. R. et al. Reconstruction of the cell entry pathway of an extinct virus. PLOS Pathog. 14, e1007123 (2018). This paper and that of Robinson and Whelan (2016) use an infectious rhabdovirus vesicular stomatitis virus (VSV) engineered to express an ancient Env protein in place of the VSVG protein to dissect the entry pathway of an ancient human endogenous retrovirus.
Soll, S. J., Neil, S. J. D. & Bieniasz, P. D. Identification of a receptor for an extinct virus. Proc. Natl Acad. Sci. USA 107, 19496–19501 (2010).
Kaiser, S. M., Malik, H. S. & Emerman, M. Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein. Science 316, 1756–1758 (2007).
Dewannieux, M. et al. Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. Genome Res. 16, 1548–1556 (2006).
Lee, Y. N. & Bieniasz, P. D. Reconstitution of an infectious human endogenous retrovirus. PLOS Pathog. 3, e10 (2007). This paper and that of Dewannieux et al. (2006) describe the first successful reconstructions of functional infectious human endogenous retrovirus particles, in both cases on the basis of the HERV-K(HML2) family of ERV loci.
Lee, Y. N., Malim, M. H. & Bieniasz, P. D. Hypermutation of an ancient human retrovirus by APOBEC3G. J. Virol. 82, 8762–8770 (2008).
Brady, T. et al. Integration target site selection by a resurrected human endogenous retrovirus. Genes Dev. 23, 633–642 (2009). This study describes the first global analysis of integration site preferences for an ancient, reconstituted endogenous retrovirus (HERV–Kcon), enabling direct comparison of integration site preferences to the locations of fixed HERV-K(HML2) loci in the human genome.
Gould, S. J. & Vrba, E. S. Exaptation—a missing term in the science of form. Paleobiology 8, 4–15 (2016).
McClintock, B. Controlling elements and the gene. Cold Spring Harb. Symp. Quant. Biol. 21, 197–216 (1956).
Britten, R. J. & Davidson, E. H. Gene regulation for higher cells: a theory. Science 165, 349–357 (1969).
Nethe, M., Berkhout, B. & van der Kuyl, A. C. Retroviral superinfection resistance. Retrovirology 2, 52 (2005).
Sommerfelt, M. A. & Weiss, R. A. Receptor interference groups of 20 retroviruses plating on human cells. Virology 176, 58–69 (1990).
Malfavon-Borja, R. & Feschotte, C. Fighting fire with fire: endogenous retrovirus envelopes as restriction factors. J. Virol. 89, 4047–4050 (2015).
Bolze, P.-A., Mommert, M. & Mallet, F. Contribution of syncytins and other endogenous retroviral envelopes to human placenta pathologies. Prog. Mol. Biol. Transl Sci. 145, 111–162 (2017).
Dupressoir, A., Lavialle, C. & Heidmann, T. From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta 33, 663–671 (2012).
Cornelis, G. et al. Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials. Proc. Natl Acad. Sci. USA 112, E487–E496 (2015).
Cornelis, G. et al. An endogenous retroviral envelope syncytin and its cognate receptor identified in the viviparous placental Mabuya lizard. Proc. Natl Acad. Sci. USA 114, E10991–E11000 (2017). This paper gives the first description of a syncytin in a nonmammalian species.
Dupressoir, A. et al. A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc. Natl Acad. Sci. USA 108, E1164–E1173 (2011).
Johnson, W. E. Rapid adversarial co-evolution of viruses and cellular restriction factors. Curr. Top. Microbiol. Immunol. 371, 123–151 (2013).
Meyerson, N. R. & Sawyer, S. L. Two-stepping through time: mammals and viruses. Trends Microbiol. 19, 286–294 (2011).
Robinson, H. L., Astrin, S. M., Senior, A. M. & Salazar, F. H. Host susceptibility to endogenous viruses: defective, glycoprotein-expressing proviruses interfere with infections. J. Virol. 40, 745–751 (1981).
Ikeda, H. & Odaka, T. A cell membrane ‘gp70’ associated with Fv-4 gene: immunological characterization, and tissue and strain distribution. Virology 133, 65–76 (1984).
Gardner, M. B., Kozak, C. A. & O’Brien, S. J. The Lake Casitas wild mouse: evolving genetic resistance to retroviral disease. Trends Genet. 7, 22–27 (1991).
Kozak, C. A., Gromet, N. J., Ikeda, H. & Buckler, C. E. A unique sequence related to the ecotropic murine leukemia virus is associated with the Fv-4 resistance gene. Proc. Natl Acad. Sci. USA 81, 834–837 (1984).
Inaguma, Y., Yoshida, T. & Ikeda, H. Scheme for the generation of a truncated endogenous murine leukaemia virus, the Fv-4 resistance gene. J. Gen. Virol. 73, 1925–1930 (1992).
Jung, Y. T., Lyu, M. S., Buckler-White, A. & Kozak, C. A. Characterization of a polytropic murine leukemia virus proviral sequence associated with the virus resistance gene Rmcf of DBA/2 mice. J. Virol. 76, 8218–8224 (2002).
Wu, T., Yan, Y. & Kozak, C. A. Rmcf2, a xenotropic provirus in the Asian mouse species Mus castaneus, blocks infection by polytropic mouse gammaretroviruses. J. Virol. 79, 9677–9684 (2005).
Ito, J. et al. Refrex-1, a soluble restriction factor against feline endogenous and exogenous retroviruses. J. Virol. 87, 12029–12040 (2013).
Sugimoto, J., Sugimoto, M., Bernstein, H., Jinno, Y. & Schust, D. A novel human endogenous retroviral protein inhibits cell-cell fusion. Sci. Rep. 3, 1462 (2013).
Villesen, P., Aagaard, L., Wiuf, C. & Pedersen, F. S. Identification of endogenous retroviral reading frames in the human genome. Retrovirology 1, 32 (2004).
de Parseval, N., Lazar, V., Casella, J.-F., Bénit, L. & Heidmann, T. Survey of human genes of retroviral origin: identification and transcriptome of the genes with coding capacity for complete envelope proteins. J. Virol. 77, 10414–10422 (2003).
Young, G. R. et al. HIV-1 infection of primary CD4+ T cells regulates the expression of specific human endogenous retrovirus HERV-K (HML-2) elements. J. Virol. 92, e01507–17 (2018).
Terry, S. N. et al. Expression of HERV-K108 envelope interferes with HIV-1 production. Virology 509, 52–59 (2017).
Henzy, J. E., Gifford, R. J., Kenaley, C. P. & Johnson, W. E. An intact retroviral gene conserved in Spiny-rayed fishes for over 100 My. Mol. Biol. Evol. 34, 634–639 (2017). This paper describes what may be the oldest reported intact retroviral env gene, which inserted between 109 million and 140 million years ago and is shared by thousands of species of modern fish.
Heidmann, O. et al. HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors. Proc. Natl Acad. Sci. USA 114, E6642–E6651 (2017). This paper describes the discovery and functional characterization of an unusual ERV-encoded Env expressed as a secreted protein in placental tissues and in the blood of pregnant women.
Barnett, A. L., Davey, R. A. & Cunningham, J. M. Modular organization of the Friend murine leukemia virus envelope protein underlies the mechanism of infection. Proc. Natl Acad. Sci. USA 98, 4113–4118 (2001).
Brody, B. A., Rhee, S. S. & Hunter, E. Postassembly cleavage of a retroviral glycoprotein cytoplasmic domain removes a necessary incorporation signal and activates fusion activity. J. Virol. 68, 4620–4627 (1994).
Rein, A., Mirro, J., Haynes, J. G., Ernst, S. M. & Nagashima, K. Function of the cytoplasmic domain of a retroviral transmembrane protein: p15E-p2E cleavage activates the membrane fusion capability of the murine leukemia virus Env protein. J. Virol. 68, 1773–1781 (1994).
Taylor, G. M., Gao, Y. & Sanders, D. A. Fv-4: identification of the defect in Env and the mechanism of resistance to ecotropic murine leukemia virus. J. Virol. 75, 11244–11248 (2001).
Ito, J., Baba, T., Kawasaki, J. & Nishigaki, K. Ancestral mutations acquired in refrex-1, a restriction factor against feline retroviruses, during its cooption and domestication. J. Virol. 90, 1470–1485 (2015).
Bénit, L., Calteau, A. & Heidmann, T. Characterization of the low-copy HERV-Fc family: evidence for recent integrations in primates of elements with coding envelope genes. Virology 312, 159–168 (2003).
Bonnaud, B. et al. Evidence of selection on the domesticated ERVWE1 env retroviral element involved in placentation. Mol. Biol. Evol. 21, 1895–1901 (2004).
Nakaya, Y. & Miyazawa, T. The roles of syncytin-like proteins in ruminant placentation. Viruses 7, 2928–2942 (2015).
Goff, S. P. in Fields Virology (eds Knipe, D. M. & Howley, P. M.) 6th edn 1424–1473 (Lippincott Williams and Wilkins, 2013).
Marco, A. & Marín, I. CGIN1: a retroviral contribution to mammalian genomes. Mol. Biol. Evol. 26, 2167–2170 (2009).
Best, S., Le Tissier, P., Towers, G. & Stoye, J. P. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 382, 826–829 (1996).
Pincus, T., Hartley, J. W. & Rowe, W. P. A major genetic locus affecting resistance to infection with murine leukemia viruses. I. Tissue culture studies of naturally occurring viruses. J. Exp. Med. 133, 1219–1233 (1971).
Bénit, L. et al. Cloning of a new murine endogenous retrovirus, MuERV-L, with strong similarity to the human HERV-L element and with a gag coding sequence closely related to the Fv1 restriction gene. J. Virol. 71, 5652–5657 (1997).
Boso, G., Buckler-White, A. & Kozak, C. A. Ancient evolutionary origin and positive selection of the retroviral restriction factor Fv1 in muroid rodents. J. Virol. https://doi.org/10.1128/JVI.00850-18 (2018).
Young, G. R., Yap, M. W., Michaux, J. R., Steppan, S. J. & Stoye, J. P. Evolutionary journey of the retroviral restriction gene Fv1. Proc. Natl Acad. Sci. USA 115, 10130–10135 (2018).
Yap, M. W., Colbeck, E., Ellis, S. A. & Stoye, J. P. Evolution of the retroviral restriction gene Fv1: inhibition of non-MLV retroviruses. PLOS Pathog. 10, e1003968 (2014).
Mortuza, G. B. et al. High-resolution structure of a retroviral capsid hexameric amino-terminal domain. Nature 431, 481–485 (2004).
Mura, M. et al. Late viral interference induced by transdominant Gag of an endogenous retrovirus. Proc. Natl Acad. Sci. USA 101, 11117–11122 (2004).
Arnaud, F., Murcia, P. R. & Palmarini, M. Mechanisms of late restriction induced by an endogenous retrovirus. J. Virol. 81, 11441–11451 (2007).
Monde, K., Contreras-Galindo, R., Kaplan, M. H., Markovitz, D. M. & Ono, A. Human endogenous retrovirus K Gag coassembles with HIV-1 Gag and reduces the release efficiency and infectivity of HIV-1. J. Virol. 86, 11194–11208 (2012).
Campillos, M., Doerks, T., Shah, P. K. & Bork, P. Computational characterization of multiple Gag-like human proteins. Trends Genet. 22, 585–589 (2006).
Pastuzyn, E. D. et al. The neuronal gene Arc encodes a repurposed retrotransposon Gag protein that mediates intercellular RNA transfer. Cell 172, 275–288 (2018).
Ashley, J. et al. Retrovirus-like Gag protein Arc1 binds RNA and traffics across synaptic boutons. Cell 172, 262–274 (2018). This paper and that of Pastuzyn et al. (2018) describe neuronal proteins that are related to retroviral Gag proteins and that form capsid-like structures that package RNA and are released extracellularly.
Bernard, D. et al. Identification and characterization of a novel retroviral-like aspartic protease specifically expressed in human epidermis. J. Invest. Dermatol. 125, 278–287 (2005).
Katzourakis, A., Gifford, R. J., Tristem, M., Gilbert, M. T. P. & Pybus, O. G. Macroevolution of complex retroviruses. Science 325, 1512–1512 (2009).
Frankel, W. N., Rudy, C., Coffin, J. M. & Huber, B. T. Linkage of Mls genes to endogenous mammary tumour viruses of inbred mice. Nature 349, 526–528 (1991).
Ross, S. R. Mouse mammary tumor virus molecular biology and oncogenesis. Viruses 2, 2000–2012 (2010).
Golovkina, T. V., Chervonsky, A., Dudley, J. P. & Ross, S. R. Transgenic mouse mammary tumor virus superantigen expression prevents viral infection. Cell 69, 637–645 (1992).
Mertz, J. A., Simper, M. S., Lozano, M. M., Payne, S. M. & Dudley, J. P. Mouse mammary tumor virus encodes a self-regulatory RNA export protein and is a complex retrovirus. J. Virol. 79, 14737–14747 (2005).
Hofacre, A. & Fan, H. Jaagsiekte sheep retrovirus biology and oncogenesis. Viruses 2, 2618–2648 (2010).
Grow, E. J. et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 522, 221–225 (2015).
Magin, C., Löwer, R. & Löwer, J. cORF and RcRE, the Rev/Rex and RRE/RxRE homologues of the human endogenous retrovirus family HTDV/HERV-K. J. Virol. 73, 9496–9507 (1999).
Yang, J. et al. An ancient family of human endogenous retroviruses encodes a functional homolog of the HIV-1 Rev protein. Proc. Natl Acad. Sci. USA 96, 13404–13408 (1999).
Yang, Z. & Bielawski, J. Statistical methods for detecting molecular adaptation. Trends Ecol. Evol. (Amst.) 15, 496–503 (2000).
Katzourakis, A. & Gifford, R. J. Endogenous viral elements in animal genomes. PLOS Genet. 6, e1001191 (2010).
Aswad, A. & Katzourakis, A. Paleovirology and virally derived immunity. Trends Ecol. Evol. (Amst.) 27, 627–636 (2012).
Kozak, C. A. Origins of the endogenous and infectious laboratory mouse gammaretroviruses. Viruses 7, 1–26 (2014).
Anai, Y. et al. Infectious endogenous retroviruses in cats and emergence of recombinant viruses. J. Virol. 86, 8634–8644 (2012).
Jern, P. & Coffin, J. M. Effects of retroviruses on host genome function. Annu. Rev. Genet. 42, 709–732 (2008).
Cohen, C. J., Lock, W. M. & Mager, D. L. Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene 448, 105–114 (2009).
Thompson, P. J., Macfarlan, T. S. & Lorincz, M. C. Long terminal repeats: from parasitic elements to building blocks of the transcriptional regulatory repertoire. Mol. Cell 62, 766–776 (2016).
Fuentes, D. R., Swigut, T. & Wysocka, J. Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation. eLife 7, e35989 (2018). This study uses a modified CRISPR system to induce or silence multiple HERV-K(HML2) LTRs in parallel, revealing long-range effects on expression of hundreds of genes.
Santoni, F. A., Guerra, J. & Luban, J. HERV-H RNA is abundant in human embryonic stem cells and a precise marker for pluripotency. Retrovirology 9, 111 (2012).
Kapusta, A. et al. Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLOS Genet. 9, e1003470 (2013).
Fort, A. et al. Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance. Nat. Genet. 46, 558–566 (2014).
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory activities of transposable elements: from conflicts to benefits. Nat. Rev. Genet. 18, 71–86 (2017).
Lynch, V. J. A copy-and-paste gene regulatory network. Science 351, 1029–1030 (2016).
Khodosevich, K., Lebedev, Y. & Sverdlov, E. Endogenous retroviruses and human evolution. Comp. Funct. Genomics 3, 494–498 (2002).
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016).
Wang, T. et al. Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. Proc. Natl Acad. Sci. USA 104, 18613–18618 (2007). This paper and that of Chuong et al. (2016) reveal that co-option of ERV LTRs contributed to concerted evolution of interferon-regulated gene networks and many p53 regulated genes, respectively.
Ito, J. et al. Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses. PLOS Genet. 13, e1006883 (2017).
Simonti, C. N., Pavlicev, M. & Capra, J. A. Transposable element exaptation into regulatory regions is rare, influenced by evolutionary age, and subject to pleiotropic constraints. Mol. Biol. Evol. 34, 2856–2869 (2017).
Carroll, S. B. Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134, 25–36 (2008).
Monteiro, A. & Podlaha, O. Wings, horns, and butterfly eyespots: how do complex traits evolve? PLOS Biol. 7, e37 (2009).
Lesbats, P., Engelman, A. N. & Cherepanov, P. Retroviral DNA integration. Chem. Rev. 116, 12730–12757 (2016).
Hughes, J. F. & Coffin, J. M. Human endogenous retroviral elements as indicators of ectopic recombination events in the primate genome. Genetics 171, 1183–1194 (2005).
Kijima, T. E. & Innan, H. On the estimation of the insertion time of LTR retrotransposable elements. Mol. Biol. Evol. 27, 896–904 (2010).
Trombetta, B., Fantini, G., D’Atanasio, E., Sellitto, D. & Cruciani, F. Evidence of extensive non-allelic gene conversion among LTR elements in the human genome. Sci. Rep. 6, 28710 (2016).
Schlesinger, S. & Goff, S. P. Retroviral transcriptional regulation and embryonic stem cells: war and peace. Mol. Cell. Biol. 35, 770–777 (2015).
Cullen, B. R., Lomedico, P. T. & Ju, G. Transcriptional interference in avian retroviruses — implications for the promoter insertion model of leukaemogenesis. Nature 307, 241–245 (1984).
Hughes, J. F. & Coffin, J. M. Human endogenous retrovirus K solo-LTR formation and insertional polymorphisms: implications for human and viral evolution. Proc. Natl Acad. Sci. USA 101, 1668–1672 (2004).
Belshaw, R. et al. Rate of recombinational deletion among human endogenous retroviruses. J. Virol. 81, 9437–9442 (2007).
Martin, J., Kabat, P., Herniou, E. & Tristem, M. Characterization and complete nucleotide sequence of an unusual reptilian retrovirus recovered from the order Crocodylia. J. Virol. 76, 4651–4654 (2002).
Henzy, J. E., Gifford, R. J., Johnson, W. E. & Coffin, J. M. A novel recombinant retrovirus in the genomes of modern birds combines features of avian and mammalian retroviruses. J. Virol. 88, 2398–2405 (2014).
de Souza, F. S. J., Franchini, L. F. & Rubinstein, M. Exaptation of transposable elements into novel cis-regulatory elements: is the evidence always strong? Mol. Biol. Evol. 30, 1239–1251 (2013).
Hobbs, M. et al. Long-read genome sequence assembly provides insight into ongoing retroviral invasion of the koala germline. Sci. Rep. 7, 15838 (2017).
Montesion, M., Bhardwaj, N., Williams, Z. H., Kuperwasser, C. & Coffin, J. M. Mechanisms of HERV-K (HML-2) transcription during human mammary epithelial cell transformation. J. Virol. 92, e01258–17 (2018).
Niu, D. et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science 357, 1303–1307 (2017). This paper describes the parallel inactivation of two dozen related porcine ERV (PERV) loci in a single fetal fibroblast cell using a customized CRISPR–Cas9 protocol followed by nuclear transfer to create a line of pigs free of functional PERV loci.
Ellermann, V. & Bang, O. Experimentelle leukämie bei hühnern [German]. Zentralbl. Bakteriol. Parasitenkd. Infectionskr. Hyg. Abt. Orig. 46, 595–609 (1908).
Rous, P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 13, 397–411 (1911).
Dietrich, M. R. in Evolutionary Genetics: Concepts and Case Studies (eds Wolf, J. B. & Fox, C. W.) (Oxford Univ. Press, 2006).
Krupovic, M. et al. Ortervirales: new virus order unifying five families of reverse-transcribing viruses. J. Virol. 92, e00515–18 (2018).
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).
Reviewer information
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
Rights and permissions
About this article
Cite this article
Johnson, W.E. Origins and evolutionary consequences of ancient endogenous retroviruses. Nat Rev Microbiol 17, 355–370 (2019). https://doi.org/10.1038/s41579-019-0189-2
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41579-019-0189-2
This article is cited by
-
Adaptive expansion of ERVK solo-LTRs is associated with Passeriformes speciation events
Nature Communications (2024)
-
Contrasting segregation patterns among endogenous retroviruses across the koala population
Communications Biology (2024)
-
GWAS reveals determinants of mobilization rate and dynamics of an active endogenous retrovirus of cattle
Nature Communications (2024)
-
Regulation and function of transposable elements in cancer genomes
Cellular and Molecular Life Sciences (2024)
-
Human archetypal pluripotent stem cells differentiate into trophoblast stem cells via endogenous BMP5/7 induction without transitioning through naive state
Scientific Reports (2024)