Since the discovery of transposons, their sheer abundance in host genomes has puzzled many. While historically viewed as largely harmless ‘parasitic’ DNAs during evolution, transposons are not a mere record of ancient genome invasion. Instead, nearly every element of transposon biology has been integrated into host biology. Here we review how host genome sequences introduced by transposon activities provide raw material for genome innovation and document the distinct evolutionary path of each species.
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McClintock, B. The origin and behavior of mutable loci in maize. Proc. Natl Acad. Sci. USA 36, 344–355 (1950).
Britten, R. J. & Davidson, E. H. Gene regulation for higher cells: a theory. Science 165, 349–357 (1969).
Nurk, S. et al. The complete sequence of a human genome. Science 376, 44–53 (2022).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Craig Venter, J. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).
Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).
Wicker, T. et al. A unified classification system for eukaryotic transposable elements. Nat. Rev. Genet. 8, 973–982 (2007).
Jangam, D., Feschotte, C. & Betrán, E. Transposable element domestication as an adaptation to evolutionary conflicts. Trends Genet. 33, 817–831 (2017).
Feschotte, C. & Pritham, E. J. DNA transposons and the evolution of eukaryotic genomes. Annu Rev. Genet. 41, 331–368 (2007).
Levin, H. L. & Moran, J. V. Dynamic interactions between transposable elements and their hosts. Nat. Rev. Genet. 12, 615–627 (2011).
Doolittle, W. F. & Sapienza, C. Selfish genes, the phenotype paradigm and genome evolution. Nature 284, 601–603 (1980).
Capy, P. Taming, domestication and exaptation: trajectories of transposable elements in genomes. Cells 10, 3590 (2021).
Polak, P. & Domany, E. Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes. BMC Genomics 7, 133–148 (2006).
Gifford, W. D., Pfaff, S. L. & Macfarlan, T. S. Transposable elements as genetic regulatory substrates in early development. Trends Cell Biol. 23, 218–226 (2013).
Garcia-Perez, J. R., Widmann, T. J. & Adams, I. R. The impact of transposable elements on mammalian development. Development 143, 4101–4114 (2016).
van de Lagemaat, L. N., Landry, J.-R., Mager, D. L. & Medstrand, P. Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions. Trends Genet. 19, 530–536 (2003).
Simonti, C. N., Pavličev, 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).
Miyawaki, S. et al. The mouse Sry locus harbors a cryptic exon that is essential for male sex determination. Science 370, 121–124 (2020).
Flemr, M. et al. A retrotransposon-driven dicer isoform directs endogenous small interfering RNA production in mouse oocytes. Cell 155, 807–816 (2013).
Sakashita, A. et al. Endogenous retroviruses drive species-specific germline transcriptomes in mammals. Nat. Struct. Mol. Biol. 27, 967–977 (2020).
Modzelewski, A. J. et al. A mouse-specific retrotransposon drives a conserved Cdk2ap1 isoform essential for development. Cell 184, 5541–5558.e22 (2021).
Senft, A. D. & Macfarlan, T. S. Transposable elements shape the evolution of mammalian development. Nat. Rev. Genet. 22, 691–711 (2021).
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory activities of transposable elements: from conflicts to benefits. Nat. Rev. Genet. 18, 71–86 (2017).
Ito, J. et al. Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses. PLoS Genet. 13, e1006883 (2017).
Notwell, J. H., Chung, T., Heavner, W. & Bejerano, G. A family of transposable elements co-opted into developmental enhancers in the mouse neocortex. Nat. Commun. 6, 6644 (2015).
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016).
Ye, M. et al. Specific subfamilies of transposable elements contribute to different domains of T lymphocyte enhancers. Proc. Natl Acad. Sci. USA 117, 7905–7916 (2020).
Peaston, A. E. et al. Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Dev. Cell 7, 597–606 (2004).
Macfarlan, T. S. et al. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature 487, 57–63 (2012).
Franke, V. et al. Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes. Genome Res. 27, 1384–1394 (2017).
Hasuwa, H. et al. Production of functional oocytes requires maternally expressed PIWI genes and piRNAs in golden hamsters. Nat. Cell Biol. 23, 1002–1012 (2021).
Gerlo, S., Davis, J. R. E., Mager, D. L. & Kooijman, R. Prolactin in man: a tale of two promoters. BioEssays 28, 1051–1055 (2006).
Emera, D. et al. Convergent evolution of endometrial prolactin expression in primates, mice, and elephants through the independent recruitment of transposable elements. Mol. Biol. Evol. 29, 239–247 (2012).
Davis, M. P. et al. Transposon-driven transcription is a conserved feature of vertebrate spermatogenesis and transcript evolution. EMBO Rep. 18, 1231–1247 (2017).
Beyer, U., Moll-Rocek, J., Moll, U. M. & Dobbelstein, M. Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes. Proc. Natl Acad. Sci. USA 108, 3624–3629 (2011).
Pi, W. et al. The LTR enhancer of ERV-9 human endogenous retrovirus is active in oocytes and progenitor cells in transgenic zebrafish and humans. Proc. Natl Acad. Sci. USA 101, 805–810 (2004).
Hu, T. et al. Long non-coding RNAs transcribed by ERV-9 LTR retrotransposon act in cis to modulate long-range LTR enhancer function. Nucleic Acids Res. 45, 4479–4492 (2017).
Feschotte, C. Transposable elements and the evolution of regulatory networks. Nat. Rev. Genet. 9, 397–405 (2008).
Sundaram, V. & Wysocka, J. Transposable elements as a potent source of diverse cis-regulatory sequences in mammalian genomes. Philos. Trans. R. Soc. Lond. B 375, 20190347 (2020).
Xie, M. et al. DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape. Nat. Genet. 45, 836–841 (2013).
Pehrsson, E. C., Choudhary, M. N. K., Sundaram, V. & Wang, T. The epigenomic landscape of transposable elements across normal human development and anatomy. Nat. Commun. 10, 5640 (2019).
Miao, B. et al. Tissue-specific usage of transposable element-derived promoters in mouse development. Genome Biol. 21, 255–280 (2020).
Bourque, G. et al. Evolution of the mammalian transcription factor binding repertoire via transposable elements. Genome Res. 18, 1752–1762 (2008).
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).
Kunarso, G. et al. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat. Genet. 42, 631–634 (2010).
Schmidt, D. et al. Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. Cell 148, 335–348 (2012).
Sundaram, V. et al. Widespread contribution of transposable elements to the innovation of gene regulatory networks. Genome Res 24, 1963–1976 (2014).
Sundaram, V. et al. Functional cis-regulatory modules encoded by mouse-specific endogenous retrovirus. Nat. Commun. 8, 14550 (2017).
Choudhary, M. N. K. et al. Co-opted transposons help perpetuate conserved higher-order chromosomal structures. Genome Biol. 21, 16 (2020).
Xia, B. et al. The genetic basis of tail-loss evolution in humans and apes. Preprint at bioRxiv https://doi.org/10.1101/2021.09.14.460388 (2021).
Mayr, C. Regulation by 3′-untranslated regions. Annu. Rev. Genet. 51, 171–194 (2017).
Kelley, D. & Rinn, J. Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol. 13, R107 (2012).
Jachowicz, J. W. et al. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat. Genet. 49, 1502–1510 (2017).
Lu, X. et al. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat. Struct. Mol. Biol. 21, 423–425 (2014).
Percharde, M. et al. A LINE1–nucleolin partnership regulates early development and ESC identity. Cell 174, 391–405.e19 (2018).
Zhao, Y. et al. Transposon-triggered innate immune response confers cancer resistance to the blind mole rat. Nat. Immunol. 22, 1219–1230 (2021).
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).
Ueda, M. T. et al. Comprehensive genomic analysis reveals dynamic evolution of endogenous retroviruses that code for retroviral-like protein domains. Mob. DNA 11, 29–46 (2020).
Campillos, M., Doerks, T., Shah, P. K. & Bork, P. Computational characterization of multiple Gag-like human proteins. Trends Genet. 22, 585–589 (2006).
Zhang, W. et al. Structural basis of Arc binding to synaptic proteins: implications for cognitive disease. Neuron 86, 490–500 (2015).
Pastuzyn, E. D. et al. The neuronal gene Arc encodes a repurposed retrotransposon Gag protein that mediates intercellular RNA transfer. Cell 172, 275–288.e18 (2018).
Ashley, J. et al. Retrovirus-like Gag protein Arc1 binds RNA and traffics across synaptic boutons. Cell 172, 262–274.e11 (2018).
Kedrov, A. V., Durymanov, M. & Anokhin, K. V. The Arc gene: retroviral heritage in cognitive functions. Neurosci. Biobehav Rev. 99, 275–281 (2019).
Okuno, H. et al. Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIβ. Cell 149, 886–898 (2012).
Ono, R. et al. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nat. Genet. 38, 101–106 (2005).
Clark, M. B. et al. Mammalian gene PEG10 expresses two reading frames by high efficiency –1 frameshifting in embryonic-associated tissues. J. Biol. Chem. 282, 37359–37369 (2007).
Abed, M. et al. The Gag protein PEG10 binds to RNA and regulates trophoblast stem cell lineage specification. PLoS ONE 14, e0214110 (2019).
Segel, M. et al. Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery. Science 373, 882–889 (2021).
Sha, M. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403, 785–789 (2000).
Esnault, C., Cornelis, G., Heidmann, O. & Heidmann, T. Differential evolutionary fate of an ancestral primate endogenous retrovirus envelope gene, the EnvV syncytin, captured for a function in placentation. PLoS Genet. 9, e1003400 (2013).
Dupressoir, A. et al. Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene. Proc. Natl Acad. Sci. USA 106, 12127–12132 (2009).
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).
Mangeney, M. et al. Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc. Natl Acad. Sci. USA 104, 20534–20539 (2007).
Marco, A. & Marín, I. CGIN1: a retroviral contribution to mammalian genomes. Mol. Biol. Evol. 26, 2167–2170 (2009).
Lloréns, C. & Marín, I. A mammalian gene evolved from the integrase domain of an LTR retrotransposon. Mol. Biol. Evol. 18, 1597–1600 (2001).
Shiura, H. et al. PEG10 viral aspartic protease domain is essential for the maintenance of fetal capillary structure in the mouse placenta. Development 148, dev199564 (2021).
Kitazawa, M., Tamura, M., Kaneko-Ishino, T. & Ishino, F. Severe damage to the placental fetal capillary network causes mid- to late fetal lethality and reduction in placental size in Peg11/Rtl1 KO mice. Genes Cells 22, 174–188 (2017).
McLaughlin, R. N. et al. Positive selection and multiple losses of the LINE-1-derived L1TD1 gene in mammals suggest a dual role in genome defense and pluripotency. PLoS Genet. 10, e1004531 (2014).
Huang, S. et al. Discovery of an active RAG transposon illuminates the origins of V(D)J recombination. Cell 166, 102–114 (2016).
Ruiz, M. et al. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia. Hum. Mol. Genet. 24, 7159–7170 (2015).
Dejosez, M. et al. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 133, 1162–1174 (2008).
Majumdar, S., Singh, A. & Rio, D. C. The human THAP9 gene encodes an active P-element DNA transposase. Science 339, 446–448 (2013).
Cosby, R. L. et al. Recurrent evolution of vertebrate transcription factors by transposase capture. Science 371, eabc6405 (2021).
Koonin, E. V. & Krupovic, M. Evolution of adaptive immunity from transposable elements combined with innate immune systems. Nat. Rev. Genet.16, 184–192 (2014).
Kapitonov, V. V., Makarova, K. S. & Koonin, E. V. ISC, a novel group of bacterial and archaeal DNA transposons that encode Cas9 homologs. J. Bacteriol. 198, 797–807 (2015).
Altae-Tran, H. et al. The widespread IS200/IS605 transposon family encodes diverse programmable RNA-guided endonucleases. Science 374, 57–65 (2021).
Malfavon-Borja, R. & Feschotte, C. Fighting fire with fire: endogenous retrovirus envelopes as restriction factors. J. Virol. 89, 4047–4050 (2015).
Blanco-Melo, D., Gifford, R. J. & Bieniasz, P. D. Co-option of an endogenous retrovirus envelope for host defense in hominid ancestors. eLife 6, e22519 (2017).
Grow, E. J. et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 522, 221–225 (2015).
Frank, J. A. et al. Antiviral activity of a human placental protein of retroviral origin. Preprint at bioRxiv https://doi.org/10.1101/2020.08.23.263665 (2020).
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).
Horikoshi, M. et al. Positional cloning of the mouse retrovirus restriction gene Fvl. Nature 382, 826–829 (1996).
Jin, Y., Tam, O. H., Paniagua, E. & Hammell, M. TEtranscripts: a package for including transposable elements in differential expression analysis of RNA-seq datasets. Bioinformatics 31, 3593–3599 (2015).
Yang, W. R., Ardeljan, D., Pacyna, C. N., Payer, L. M. & Burns, K. H. SQuIRE reveals locus-specific regulation of interspersed repeat expression. Nucleic Acids Res. 47, e27 (2019).
Bendall, M. L. et al. Telescope: characterization of the retrotranscriptome by accurate estimation of transposable element expression. PLoS Comput. Biol. 15, e1006453 (2019).
Miga, K. H. et al. Telomere-to-telomere assembly of a complete human X chromosome. Nature 585, 79–84 (2020).
Miga, K. H. & Wang, T. The need for a human pangenome reference sequence. Annu Rev. Genomics Hum. Genet 22, 81–102 (2021).
Rhie, A. et al. Towards complete and error-free genome assemblies of all vertebrate species. Nature 592, 737–746 (2021).
Stoye, J. P. Koala retrovirus: a genome invasion in real time. Genome Biol. 7, 241 (2006).
Dupuy, A. J., Akagi, K., Largaespada, D. A., Copeland, N. G. & Jenkins, N. A. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436, 221–226 (2005).
Ding, S. et al. Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122, 473–483 (2005).
Zamore, P. D., Tuschl, T., Sharp, P. A. & Bartel, D. P. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25–33 (2000).
Jinek, M. et al. RNA-programmed genome editing in human cells. eLife 2013, e00471 (2013).
Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).
Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
Casacuberta, E. Drosophila: retrotransposons making up telomeres. Viruses 9, 192–208 (2017).
Abad, J. P. et al. TAHRE, a novel telomeric retrotransposon from Drosophila melanogaster, reveals the origin of Drosophila telomeres. Mol. Biol. Evol. 21, 1620–1624 (2004).
Levis, R. W., Ganesan, R., Houtchens, K., Tolar, L. A. & Sheen, F. Miin Transposons in place of telomeric repeats at a Drosophila telomere. Cell 75, 1083–1093 (1993).
We are grateful to L. B. King for editing and proofreading this review. A.J.M. is supported by NIH (R00HD096108) and the Siebel Stem Cell Institute. T.W. is supported by NIH (R01HG007175, U24ES026699, U01CA200060, U01HG009391, U41HG010972 and U24HG012070). L.H. is a Thomas and Stacey Siebel Distinguished Chair Professor, and a Chan-Zuckerberg Biohub Investigator, supported by an HHMI Faculty Scholar award, a Bakar Fellow award and NIH grants (1R01GM114414, R01CA139067, 1R21OD027053, GRANT12095758, 1R01HD106809 and R01NS120287).
The authors declare no competing interests.
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Modzelewski, A.J., Gan Chong, J., Wang, T. et al. Mammalian genome innovation through transposon domestication. Nat Cell Biol 24, 1332–1340 (2022). https://doi.org/10.1038/s41556-022-00970-4