Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they occupy up to 8% of the human genome. ERVs are a subclass of a type of gene called a transposon, which can be packaged and moved within the genome to serve a vital role in gene expression and in regulation. Researchers have suggested that retroviruses evolved from a type of transposable gene called a retrotransposon, which includes ERVs; these genes can mutate and instead of moving to another location in the genome they can become exogenous or pathogenic. This means that all ERVs may not have originated as an insertion by a retrovirus but that some may have been the source for the genetic information in the retroviruses they resemble.
The replication cycle of a retrovirus entails the insertion ("integration") of a DNA copy of the viral genome into the nuclear genome of the host cell. Most retroviruses infect somatic cells, but occasional infection of germline cells (cells that produce eggs and sperm) can also occur. Rarely, retroviral integration may occur in a germline cell that goes on to develop into a viable organism. This organism will carry the inserted retroviral genome as an integral part of its own genome—an "endogenous" retrovirus (ERV) that may be inherited by its offspring as a novel allele. Many ERVs have persisted in the genome of their hosts for millions of years. However, most of these have acquired inactivating mutations during host DNA replication and are no longer capable of producing virus. ERVs can also be partially excised from the genome by a process known as recombinational deletion, in which recombination between the identical sequences that flank newly integrated retroviruses results in deletion of the internal, protein-coding regions of the viral genome.
Role in genome evolution
Endogenous retroviruses can play an active role in shaping genomes. Most studies in this area have focused on the genomes of humans and higher primates, but other vertebrates, such as mice and sheep, have also been studied in depth. The long terminal repeat (LTR) sequences that flank ERV genomes frequently act as alternate promoters and enhancers, often contributing to the transcriptome by producing tissue-specific variants. In addition, the retroviral proteins themselves have been co-opted to serve novel host functions, particularly in reproduction and development. Recombination between homologous retroviral sequences has also contributed to gene shuffling and the generation of genetic variation. Furthermore, in the instance of potentially antagonistic effects of retroviral sequences, repressor genes have co-evolved to combat them.
Solo LTRs and LTRs associated with complete retroviral sequences have been shown to act as transcriptional elements on host genes. Their range of action is mainly by insertion into the 5’ UTRs of protein coding genes; however, they have been known to act upon genes up to 70–100 kb away. The majority of these elements are inserted in the sense direction to their corresponding genes, but there has been evidence of LTRs acting in the antisense direction and as a bidirectional promoter for neighboring genes. In a few cases, the LTR functions as the major promoter for the gene. For example, in humans AMY1C has a complete ERV sequence in its promoter region; the associated LTR confers salivary specific expression of the digestive enzyme amylase. Also, the primary promoter for bile acid-CoA:amino acid N-acyltransferase (BAAT), which codes for an enzyme that is integral in bile metabolism, is of LTR origin.
The insertion of a solo ERV-9 LTR may have produced a functional open reading frame (ORF), causing the rebirth of the human immunity related GTPase gene (IRGM). ERV insertions have also been shown to generate alternative splice sites either by direct integration into the gene, as with the human leptin hormone receptor, or driven by the expression of an upstream LTR, as with the phospholipase A-2 like protein.
Most of the time, however, the LTR functions as one of many alternate promoters, often conferring tissue-specific expression related to reproduction and development. In fact, 64% of known LTR-promoted transcription variants are expressed in reproductive tissues. For example, the gene CYP19 codes for aromatase P450, an important enzyme for estrogen synthesis, that is normally expressed in the brain and reproductive organs of most mammals. However, in primates, an LTR-promoted transcriptional variant confers expression to the placenta and is responsible for controlling estrogen levels during pregnancy. Furthermore, the neuronal apoptosis inhibitory protein (NAIP), normally widespread, has an LTR of the HERV-P family acting as a promoter that confers expression to the testis and prostate. Other proteins, such as nitric acid synthase 3 (NOS3), interleukin-2 receptor B (IL2RB), and another mediator of estrogen synthesis, HSD17B1, are also alternatively regulated by LTRs that confer placental expression, but their specific functions are not yet known. The high degree of reproductive expression is thought to be an aftereffect of the method by which they were endogenized; however, this also may be due to a lack of DNA methylation in germ-line tissues.
The best-characterized instance of placental protein expression comes not from an alternatively promoted host gene but from a complete co-option of a retroviral protein. Retroviral fusogenic env proteins, which play a role in the entry of the virion into the host cell, have had an important impact on the development of mammalian placenta. In mammals, intact env proteins called syncytins are responsible for the formation and function of syncytiotrophoblasts. These multinucleated cells are mainly responsible for maintaining nutrient exchange and separating the fetus from the mother's immune system. It has been suggested that the selection and fixation of these proteins for this function have played a critical role in the evolution of viviparity.
In addition, the insertion of ERVs and their respective LTRs has the potential to induce chromosomal rearrangement due to recombination between viral sequences at inter-chromosomal loci. These rearrangements have been shown to induce gene duplications and deletions that largely contribute to genome plasticity and dramatically change the dynamic of gene function. Furthermore, retroelements in general are largely prevalent in rapidly evolving, mammal-specific gene families whose function is largely related to the response to stress and external stimuli. In particular, both human class I and class II MHC genes have a high density of HERV elements as compared to other multi-locus-gene families. It has been shown that HERVs have contributed to the formation of extensively duplicated duplicon blocks that make up the HLA class 1 family of genes. More specifically, HERVs primarily occupy regions within and between the break points between these blocks, suggesting that considerable duplication and deletions events, typically associated with unequal crossover, facilitated their formation. The generation of these blocks, inherited as immunohaplotypes, act as a protective polymorphism against a wide range of antigens that may have imbued humans with an advantage over other primates.
Finally, the insertion of ERVs or ERV elements into genic regions of host DNA, or overexpression of their transcriptional variants, has a much higher potential to produce deleterious effects than positive ones. Their appearance into the genome has created a host-parasite co-evolutionary dynamic that proliferated the duplication and expansion of repressor genes. The most clear-cut example of this involves the rapid duplication and proliferation of tandem zinc-finger genes in mammal genomes. Zinc-finger genes, particularly those that include a KRAB domain, exist in high copy number in vertebrate genomes, and their range of functions are limited to transcriptional roles. It has been shown in mammals, however, that the diversification of these genes was due to multiple duplication and fixation events in response to new retroviral sequences or their endogenous copies to repress their transcription.
Role in disease
The majority of ERVs that occur in vertebrate genomes are ancient, inactivated by mutation, and have reached genetic fixation in their host species. For these reasons, they are extremely unlikely to have negative effects on their hosts except under unusual circumstances. Nevertheless, it is clear from studies in birds and non-human mammal species including mice, cats and koalas, that younger (i.e., more recently integrated) ERVs can be associated with disease. This has led researchers to propose a role for ERVs in several forms of human cancer and autoimmune disease, although conclusive evidence is lacking.
In humans, ERVs have been proposed to be involved in multiple sclerosis (MS). A specific association between MS and the ERVWE1, or "syncytin", gene, which is derived from an ERV insertion, has been reported, along with the presence of an "MS-associated retrovirus" (MSRV), in patients with the disease. Human ERVs (HERVs) have also been implicated in ALS.
In 2004 it was reported that antibodies to HERVs were found in greater frequency in the sera of people with schizophrenia. Additionally, the cerebrospinal fluid of people with recent onset schizophrenia contained levels of a retroviral marker, reverse transcriptase, four times higher than control subjects. Researchers continue to look at a possible link between HERVs and schizophrenia, with the additional possibility of a triggering infection inducing schizophrenia.
Human endogenous retroviruses
Human endogenous retroviruses (HERV) proviruses comprise a significant part of the human genome, with approximately 98,000 ERV elements and fragments making up nearly 8%. According to a study published in 2005, no HERVs capable of replication had been identified; all appeared to be defective, containing major deletions or nonsense mutations. This is because most HERVs are merely traces of original viruses, having first integrated millions of years ago.
Nevertheless one family of viruses has been active since the divergence of humans and chimpanzees. This family, termed HERV-K (HML2), makes up less than 1% of HERV elements but is one of the most studied. There are indications it has even been active in the past few hundred thousand years, e.g., some human individuals carry more copies of HML2 than others. Traditionally, age estimates of HERVs are performed by comparing the 5' and 3' LTR of a HERV; however, this method is only relevant for full-length HERVs. A recent method, called cross-sectional dating, uses variations within a single LTR to estimate the ages of HERV insertions. This method is more precise in estimating HERV ages and can be used for any HERV insertions. Cross-sectional dating has been used to suggest that two members of HERV-K(HML2), HERV-K106 and HERV-K116, were active in the last 800,000 years and that HERV-K106 may have infected modern humans 150,000 years ago. However, the absence of known infectious members of the HERV-K(HML2) family, and the lack of elements with a full coding potential within the published human genome sequence, suggests to some that the family is less likely to be active at present. In 2006 and 2007, researchers working independently in France and the US recreated functional versions of HERV-K(HML2).
Immunological studies have shown some evidence for T cell immune responses against HERVs in HIV-infected individuals. The hypothesis that HIV induces HERV expression in HIV-infected cells led to the proposal that a vaccine targeting HERV antigens could specifically eliminate HIV-infected cells. The potential advantage of this novel approach is that, by using HERV antigens as surrogate markers of HIV-infected cells, it could circumvent the difficulty inherent in directly targeting notoriously diverse and fast-mutating HIV antigens.
There are a few classes of human endogenous retroviruses that still have intact open reading frames. For example, the expression of HERV-K, a biologically active family of HERV, produces proteins found in placenta. Furthermore, the expression of the envelope genes of HERV-W (ERVW-1)and HERV-FRD (ERVFRD-1) produces syncytins which are important for the generation of the syncytiotrophoblast cell layer during placentogenesis by inducing cell-cell fusion. The HUGO Gene Nomenclature Committee (HGNC) approves gene symbols for transcribed human ERVs.
- Endogenous viral element
- Jaagsiekte sheep retrovirus (JSRV)
- Mouse mammary tumor virus (MMTV)
- Murine leukemia virus (MLV) and xenotropic murine leukemia virus-related virus (XMRV)
- Koala retrovirus (KoRV)
- Avian sarcoma leukosis virus (ASLV)
- Horizontal gene transfer
- Belshaw R, Pereira V, Katzourakis A, Talbot G, Paces J, Burt A, Tristem M (Apr 2004). "Long-term reinfection of the human genome by endogenous retroviruses". Proc Natl Acad Sci USA 101 (14): 4894–99. Bibcode:2004PNAS..101.4894B. doi:10.1073/pnas.0307800101. PMC 387345. PMID 15044706.
- Nelson, PN; Hooley, P and Molecular Immunology Research Group (October 2004). "Human endogenous retroviruses: Transposable elements with potential ?". Clinical and Experimental Immunology 138 (138(1)): 1–9. doi:10.1111/j.1365-2249.2004.02592.x. PMC 1809191. PMID 15373898. Retrieved 2014-02-01.
- Khodosevich, Konstantin; Lebedev, L; Sverdolv, E. (October 2002). "Endogenous retroviruses and human evolution". Comparative and Functional Genomics (3): 494–98. doi:10.1002/cfg.216.
- Emergence of vertebrate retroviruses and envelope capture Felix J. Kim, Jean-Luc Battini, Nicolas Manel, and Marc Sitbon Virology (2004) 318: 183
- Cotton, J. (2001). "Retroviruses from retrotransposons". Genome Biology 2 (2): 6.
It appears that the transition from nonviral retrotransposon to retrovirus has occurred independently at least eight times, and the source of the envelope gene responsible for infectious ability can now be traced to a virus in at least four of these instances. This suggests that potentially, any LTR retrotransposon can become a virus through the acquisition of existing viral genes.
- Li J, Akagi K, Hu Y, Trivett AL, Hlynialuk CJ, Swing DA, Volfovsky N, Morgan TC, Golubeva Y, Stephens RM, Smith DE, Symer DE (Mar 2012). "Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance". Genome Res 22 (5): 870–84. doi:10.1101/gr.130740.111. PMC 3337433. PMID 22367191.
- Spencer TE, Palmarini M (2012). "Endogenous retroviruses of sheep: a model system for understanding physiological adaptation to an evolving ruminant genome". J Reprod Dev 58 (1): 33–7. doi:10.1262/jrd.2011-026. PMID 22450282.
- Black SG, Arnaud F, Palmarini M, Spencer TE (2010). "Endogenous Retroviruses in Trophoblast Differentiation and Placental Development". American Journal of Reproductive Immunology 64 (4): 255–264. doi:10.1111/j.1600-0897.2010.00860.x. PMID 20528833.
- Ryan FP (December 2004). "Human endogenous retroviruses in health and disease: a symbiotic perspective". Journal of the Royal Society of Medicine 97 (12): 560–5. doi:10.1258/jrsm.97.12.560. PMC 1079666. PMID 15574851.
- Pi W, Zhu X, Wu M, Wang Y, Fulzele S, Eroglu A, Ling J, Tuan D (July 2010). "Long-range function of an intergenic retrotransposon". PNAS 107 (29): 12992–12997. Bibcode:2010PNAS..10712992P. doi:10.1073/pnas.1004139107. PMC 2919959. PMID 20615953.
- van de Lagemaat LN, Landry JR, Mager DL, Medstrand P (Oct 2003). "Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions". Trends Genet 19 (10): 530–6. doi:10.1016/j.tig.2003.08.004. PMID 14550626.
- Kovalskaya E, Buzdin A, Gogvadze E, Vinogradova T, Sverdlov E (2006). "Functional human endogenous retroviral LTR transcription start sites are located between the R and U5 regions". Virology 346 (2): 373–8. doi:10.1016/j.virol.2005.11.007. PMID 16337666.
- Dunn CA, Romanish MT, Gutierrez LE, van de Lagemaat LN, Mager DL (2006). "Transcription of two human genes from a bidirectional endogenous retrovirus promoter". Gene 366 (2): 335–42. doi:10.1016/j.gene.2005.09.003. PMID 16288839.
- Gogvadze E, Stukacheva E, Buzdin A, Sverdlov E (2009). "Human-specific modulation of transcriptional activity provided by endogenous retroviral insertions". J Virol 83 (12): 6098–105. doi:10.1128/JVI.00123-09. PMC 2687385. PMID 19339349.
- Ting CN, Rosenberg MP, Snow CM, Samuelson LC, Meisler MH (1992). "Endogenous retroviral sequences are required for tissue-specific expression of a human salivary amylase gene". Genes Dev 6 (8): 1457–1465. doi:10.1101/gad.6.8.1457. PMID 1379564.
- Cohen CJ, Lock WM, Mager DL (2009). "Endogenous retroviral LTRs as promoters for human genes: a critical assessment". Gene 448 (2): 105–14. doi:10.1016/j.gene.2009.06.020. PMID 19577618.
- Bekpen C, Marques-Bonet T, Alkan C, Antonacci F, Leogrande MB, Ventura M, Kidd JM, Siswara P, Howard JC, Eichler EE (2009). "Death and resurrection of the human IRGM gene". PLoS Genet 5 (3): e1000403. doi:10.1371/journal.pgen.1000403. PMC 2644816. PMID 19266026.
- Jern P, Coffin JM (2008). "Effects of Retroviruses on Host Genome Function". Annu Rev Genet 42: 709–32. doi:10.1146/annurev.genet.42.110807.091501. PMID 18694346.
- Oliver KR, Greene WK (2011). "Mobile DNA and the TE-Thrust hypothesis: supporting evidence from the primates". Mob DNA 2 (1): 8. doi:10.1186/1759-8753-2-8. PMC 3123540. PMID 21627776.
- Romanish MT, Lock WM, van de Lagemaat LN, Dunn CA, Mager DL (2007). "Repeated recruitment of LTR retrotransposons as promoters by the anti- apoptotic locus NAIP during mammalian evolution". PLoS Genet 3 (1): e10. doi:10.1371/journal.pgen.0030010. PMC 1781489. PMID 17222062.
- Huh JW, Ha HS, Kim DS, Kim HS (2008). "Placenta-restricted expression of LTR- derived NOS3". Placenta 29 (7): 602–608. doi:10.1016/j.placenta.2008.04.002. PMID 18474398.
- Villarreal LP. On viruses, sex, and motherhood (1997). "On viruses, sex, and motherhood". J Virol 71 (2): 859–865. PMC 191132. PMID 8995601.
- Hughes, J and Coffin, JM (2001). "Evidence for Genomic Rearrangements Mediated by Human Endogenous Retroviruses during Primate Evolution". Nat Genet 29 (4): 487–92. doi:10.1038/ng775.
- Dawkins R, Leelayuwat C, Gaudieri S, Tay G, Hui J, Cattley S, Martinez P, Kulski J (1999). "Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease". Immunol Rev 167: 275–304. doi:10.1111/j.1600-065X.1999.tb01399.x. PMID 10319268.
- Doxiadis GG, de Groot N, Bontrop RE (2008). "Impact of Endogenous Intronic Retroviruses on Major Histocompatibility Complex Class II Diversity and Stability". J Virol 82 (13): 6667–6677. doi:10.1128/JVI.00097-08. PMC 2447082. PMID 18448532.
- Thomas JH, Schneider S (2011). "Coevolution of retroelements and tandem zinc finger genes". Genome Res 21 (11): 1800–12. doi:10.1101/gr.121749.111. PMC 3205565. PMID 21784874.
- Bannert, Norbert and Kurth, Reinhard (Oct 2004). "Retroelements and the human genome: New perspectives on an old relation". Proc Natl Acad Sci U S A. 101 (Suppl 2): 14572–14579. Bibcode:2004PNAS..10114572B. doi:10.1073/pnas.0404838101. PMC 521986. PMID 15310846.
- Nelson PN, Carnegie PR, Martin J, Davari Ejtehadi H, Hooley P, Roden D, Rowland-Jones S, Warren P, Astley J (2003). "Demystified . . . Human endogenous retroviruses". Molecular Pathology 56 (1): 11–18. doi:10.1136/mp.56.1.11. PMC 1187282. PMID 12560456.
- Singh SK (June 2007). "Endogenous retroviruses: suspects in the disease world". Future Microbiology 2 (3): 269–75. doi:10.2217/174609184.108.40.2069. PMID 17661701.
- Mameli G, Astone V, Arru G, Marconi S, Lovato L, Serra C, Sotgiu S, Bonetti B, Dolei A (Jan 2007). "Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not human herpesvirus 6". J Gen Virol. 88 (Pt 1): 264–74. doi:10.1099/vir.0.81890-0. PMID 17170460.
- Serra C, Mameli G, Arru G, Sotgiu S, Rosati G, Dolei A (Dec 2003). "In vitro modulation of the multiple sclerosis (MS)-associated retrovirus by cytokines: implications for MS pathogenesis". J Neurovirol. 9 (6): 637–43. doi:10.1080/714044485. PMID 14602576.
- "Reactivated Virus May Contribute to ALS".
- Yolken R (Jun 2004). "Viruses and schizophrenia: a focus on herpes simplex virus". Herpes 11 (Suppl 2): 83A–88A. PMID 15319094.
- Fox D (2010). "The Insanity Virus". Discover. Retrieved 2011-02-17.
- Belshaw R, Dawson AL, Woolven-Allen J, Redding J, Burt A, Tristem M (Oct 2005). "Genomewide Screening Reveals High Levels of Insertional Polymorphism in the Human Endogenous Retrovirus Family HERV-K(HML2): Implications for Present-Day Activity". J Virol. 79 (19): 12507–14. doi:10.1128/JVI.79.19.12507-12514.2005. PMC 1211540. PMID 16160178.
- Jha AR, Pillai SK, York VA, Sharp ER, Storm EC, Wachter DJ, Martin JN, Deeks SG, Rosenberg MG, Nixon DF, Garrison KE (Aug 2009). "Cross-Sectional Dating of Novel Haplotypes of HERV-K 113 and HERV-K 115 Indicate These Proviruses Originated in Africa before Homo sapiens". Mol Biol Evol 26 (11): 2617–2626. doi:10.1093/molbev/msp180. PMC 2760466. PMID 19666991.
- Jha AR, Nixon DF, Rosenberg MG, Martin JN, Deeks SG, Hudson RR, Garrison KE, Pillai SK (May 2011). "Human Endogenous Retrovirus K106 (HERV-K106) Was Infectious after the Emergence of Anatomically Modern Humans". PLoS ONE 6 (5): e20234. Bibcode:2011PLoSO...620234J. doi:10.1371/journal.pone.0020234. PMC 3102101. PMID 21633511.
- Bieniasz, Paul; Lee, Young Nam (Jan 2007). "Reconstitution of an infectious human endogenous retrovirus.". PLoS Pathog. 3 (1): e10. doi:10.1371/journal.ppat.0030010. PMC 1781480. PMID 17257061.
- Dewannieux M, Harper F, Richaud A, Letzelter C, Ribet D, Pierron G, Heidmann T (Dec 2006). "Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements". Genome Res. 16 (12): 1548–56. doi:10.1101/gr.5565706. PMC 1665638. PMID 17077319. Lay summary – ScienceNOW Daily News.
- Garrison KE, Jones RB, Meiklejohn DA, Anwar N, Ndhlovu LC, Chapman JM, Erickson AL, Agrawal A, Spotts G, Hecht FM, Rakoff-Nahoum S, Lenz J, Ostrowski MA, Nixon DF (Nov 2007). "T cell responses to human endogenous retroviruses in HIV-1 infection". PLoS Pathog. 3 (11): e165. doi:10.1371/journal.ppat.0030165. PMC 2065876. PMID 17997601.
- "The Transmembrane Protein of the Human Endogenous Retrovirus - K (HERV-K) Modulates Cytokine Release and Gene Expression"
- Mayer, J; Blomberg, J; Seal, RL (May 4, 2011). "A revised nomenclature for transcribed human endogenous retroviral loci.". Mobile DNA 2 (1): 7. doi:10.1186/1759-8753-2-7. PMC 3113919. PMID 21542922.
- Löwer R, Löwer J, Kurth R (May 1996). "The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences". Proc Natl Acad Sci USA. 93 (11): 5177–84. Bibcode:1996PNAS...93.5177L. doi:10.1073/pnas.93.11.5177. PMC 39218. PMID 8643549.
- Molès JP, Tesniere A, Guilhou JJ (Jul 2005). "A new endogenous retroviral sequence is expressed in skin of patients with psoriasis". Br J Dermatol. 153 (1): 83–89. doi:10.1111/j.1365-2133.2005.06555.x. PMID 16029331.
- Seifarth W, Frank O, Zeilfelder U, Spiess B, Greenwood AD, Hehlmann R, Leib-Mösch C (Jan 2005). "Comprehensive analysis of human endogenous retrovirus transcriptional activity in human tissues with a retrovirus-specific microarray". J Virol. 79 (1): 341–52. doi:10.1128/JVI.79.1.341-352.2005. PMC 538696. PMID 15596828.
- Knerr I, Beinder E, Rascher W (Feb 2002). "Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome". Am J Obstet Gynecol. 186 (2): 210–13. doi:10.1067/mob.2002.119636. PMID 11854637.
- Gifford R, Tristem M (May 2003). "The evolution, distribution and diversity of endogenous retroviruses" (PDF). Virus Genes 26 (3): 291–315. doi:10.1023/A:1024455415443. PMID 12876457.
- Endogenous Retroviruses at the US National Library of Medicine Medical Subject Headings (MeSH)
- HERVd—human endogenous retrovirus database