Key Points
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Many transposable elements (TEs) use highly specific mechanisms to direct their integration to sites in the host genome that lack coding information. This minimizes the damage to the host genome that occurs during integration.
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Second-generation DNA sequencing has allowed the identification of a saturated map of targeted integration sites in Schizosaccharomyces pombe.
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Host organisms have evolved various mechanisms to combat TE activity. Examples include DNA methylation of TEs, small interfering RNA (siRNA)-based degradation of TE mRNA and apolipoprotein B mRNA-editing enzyme (APOBEC)-mediated cytidine deamination of TE sequences.
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Studies of diverse human populations have revealed significantly higher numbers of active long interspersed element 1 (L1) elements than exist in the human genome reference sequence.
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Recent experiments unexpectedly discovered TE integration in somatic cells. These include insertions of L1 in non-small-cell lung tumours. Several lines of evidence suggest that somatic L1 retrotransposition may also occur in the mammalian nervous system.
Abstract
Transposable elements (TEs) have a unique ability to mobilize to new genomic locations, and the major advance of second-generation DNA sequencing has provided insights into the dynamic relationship between TEs and their hosts. It now is clear that TEs have adopted diverse strategies — such as specific integration sites or patterns of activity — to thrive in host environments that are replete with mechanisms, such as small RNAs or epigenetic marks, that combat TE amplification. Emerging evidence suggests that TE mobilization might sometimes benefit host genomes by enhancing genetic diversity, although TEs are also implicated in diseases such as cancer. Here, we discuss recent findings about how, where and when TEs insert in diverse organisms.
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References
McClintock, B. The origin and behavior of mutable loci in maize. Proc. Natl Acad. Sci. USA 36, 344–355 (1950).
Levis, R. W., Ganesan, R., Houtchens, K., Tolar, L. A. & Sheen, F. M. Transposons in place of telomeric repeats at a Drosophila telomere. Cell 75, 1083–1093 (1993).
Agrawal, A., Eastman, Q. M. & Schatz, D. G. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394, 744–751 (1998).
Feschotte, C. Transposable elements and the evolution of regulatory networks. Nature Rev. Genet. 9, 397–405 (2008).
Beck, C. R., Garcia-Perez, J. L., Badge, R. M. & Moran, J. V. LINE-1 elements in structural variation and disease. Annu. Rev. Genomics Hum. Genet. 18 Jul 2011 (doi:10.1146/annurev-genom-082509-141802).
Orgel, L. E., Crick, F. H. & Sapienza, C. Selfish DNA. Nature 288, 645–646 (1980).
Doolittle, W. F. & Sapienza, C. Selfish genes, the phenotype paradigm and genome evolution. Nature 284, 601–603 (1980).
Bestor, T. H. Sex brings transposons and genomes into conflict. Genetica 107, 289–295 (1999).
Hickey, D. A. Selfish DNA: a sexually-transmitted nuclear parasite. Genetics 101, 519–531 (1982).
Goodier, J. L. & Kazazian, H. H. Jr. Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135, 23–35 (2008).
Moran, J. V. et al. High frequency retrotransposition in cultured mammalian cells. Cell 87, 917–927 (1996).
Iskow, R. C. et al. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141, 1253–1261 (2010).
Beck, C. R. et al. LINE-1 retrotransposition activity in human genomes. Cell 141, 1159–1170 (2010).
Huang, C. R. et al. Mobile interspersed repeats are major structural variants in the human genome. Cell 141, 1171–1182 (2010).
Witherspoon, D. J. et al. Mobile element scanning (ME-Scan) by targeted high-throughput sequencing. BMC Genomics 11, 410 (2010).
Hormozdiari, F. et al. Alu repeat discovery and characterization within human genomes. Genome Res. 21, 840–849 (2011).
Ewing, A. D. & Kazazian, H. H. Jr. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 20, 1262–1270 (2010).
Ewing, A. D. & Kazazian, H. H. Jr. Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans. Genome Res. 21, 985–990 (2011).
Garcia-Perez, J. L. et al. LINE-1 retrotransposition in human embryonic stem cells. Hum. Mol. Genet. 16, 1569–1577 (2007).
van den Hurk, J. A. et al. L1 retrotransposition can occur early in human embryonic development. Hum. Mol. Genet. 16, 1587–1592 (2007).
Kano, H. et al. L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev. 23, 1303–1312 (2009). References 19–21 provide evidence that L1s can retrotranspose during early embryonic development.
Miki, Y. et al. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 52, 643–645 (1992).
Coufal, N. G. et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009).
Muotri, A. R. et al. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903–910 (2005).
Sandmeyer, S. Integration by design. Proc. Natl Acad. Sci. USA 100, 5586–5588 (2003).
Leem, Y. E. et al. Retrotransposon Tf1 is targeted to pol II promoters by transcription activators. Mol. Cell 30, 98–107 (2008). This paper demonstrates a mechanism by which the S. pombe Tf1 retrotransposon can target RNA polymerase II-transcribed genes.
Devine, S. E. & Boeke, J. D. Integration of the yeast retrotransposon Ty1 is targeted to regions upstream of genes transcribed by RNA polymerase III. Genes Dev. 10, 620–633 (1996).
Eickbush, T. H. in Mobile DNA II (eds Craig, N. L., Craigie, R., Gellert, M. & Lambowitz, A. M.) 813–835 (ASM Press, Washington DC, 2002).
Winckler, T., Dingermann, T. & Glockner, G. Dictyostelium mobile elements: strategies to amplify in a compact genome. Cell. Mol. Life Sci. 59, 2097–2111 (2002).
Malone, C. D. & Hannon, G. J. Small RNAs as guardians of the genome. Cell 136, 656–668 (2009).
Bestor, T. H. & Bourc'his, D. Transposon silencing and imprint establishment in mammalian germ cells. Cold Spring Harb. Symp. Quant. Biol. 69, 381–387 (2004).
Golden, D. E., Gerbasi, V. R. & Sontheimer, E. J. An inside job for siRNAs. Mol. Cell 31, 309–312 (2008).
Chiu, Y. L. & Greene, W. C. The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu. Rev. Immunol. 26, 317–353 (2008).
Sehgal, A., Lee, C. Y. & Espenshade, P. J. SREBP controls oxygen-dependent mobilization of retrotransposons in fission yeast. PLoS Genet. 3, e131 (2007).
Dai, J., Xie, W., Brady, T. L., Gao, J. & Voytas, D. F. Phosphorylation regulates integration of the yeast Ty5 retrotransposon into heterochromatin. Mol. Cell 27, 289–299 (2007). This paper demonstrates that TEs can respond to stress by changing their target sites. When cells lack access to nitrogen, Ty5 no longer integrates into heterochromatin but instead targets coding sequences in the genome.
Grandbastien, M. A. et al. Stress activation and genomic impact of Tnt1 retrotransposons in Solanaceae. Cytogenet. Genome Res. 110, 229–241 (2005).
Hirochika, H. Activation of tobacco retrotransposons during tissue culture. EMBO J. 12, 2521–2528 (1993).
Courtial, B. et al. Tnt1 transposition events are induced by in vitro transformation of Arabidopsis thaliana, and transposed copies integrate into genes. Mol. Genet. Genomics 265, 32–42 (2001).
McClintock, B. The significance of responses of the genome to challenge. Science 226, 792–801 (1984).
Craig, N. L., Craigie, R., Gellert, M. & Lambowitz, A. M. (eds) Mobile DNA II (ASM Press, Washington DC, 2002).
Kleckner, N. Regulation of transposition in bacteria. Annu. Rev. Cell Biol. 6, 297–327 (1990).
Garfinkel, D. J., Boeke, J. D. & Fink, G. R. Ty element transposition: reverse transcriptase and virus-like particles. Cell 42, 507–517 (1985).
Boeke, J. D., Garfinkel, D. J., Styles, C. A. & Fink, G. R. Ty elements transpose through an RNA intermediate. Cell 40, 491–500 (1985).
Eichinger, D. J. & Boeke, J. D. The DNA intermediate in yeast Ty1 element transposition copurifies with virus-like particles: cell-free Ty1 transposition. Cell 54, 955–966 (1988).
Luan, D. D., Korman, M. H., Jakubczak, J. L. & Eickbush, T. H. Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell 72, 595–605 (1993).
Kajikawa, M. & Okada, N. LINEs mobilize SINEs in the eel through a shared 3′ sequence. Cell 111, 433–444 (2002).
Dewannieux, M., Esnault, C. & Heidmann, T. LINE-mediated retrotransposition of marked Alu sequences. Nature Genet. 35, 41–48 (2003).
Hancks, D. C., Goodier, J. L., Mandal, P. K., Cheung, L. E. & Kazazian, H. H. Jr. Retrotransposition of marked SVA elements by human L1s in cultured cells. Hum. Mol. Genet. 2 Jun 2011 (doi:10.1093/hmg/ddr245).
Garcia-Perez, J. L., Doucet, A. J., Bucheton, A., Moran, J. V. & Gilbert, N. Distinct mechanisms for trans-mediated mobilization of cellular RNAs by the LINE-1 reverse transcriptase. Genome Res. 17, 602–611 (2007).
Gilbert, N., Lutz, S., Morrish, T. A. & Moran, J. V. Multiple fates of L1 retrotransposition intermediates in cultured human cells. Mol. Cell. Biol. 25, 7780–7795 (2005).
Buzdin, A. et al. A new family of chimeric retrotranscripts formed by a full copy of U6 small nuclear RNA fused to the 3′ terminus of L1. Genomics 80, 402–406 (2002).
Weber, M. J. Mammalian small nucleolar RNAs are mobile genetic elements. PLoS Genet. 2, e205 (2006).
Wei, W. et al. Human L1 retrotransposition: cis preference versus trans complementation. Mol. Cell. Biol. 21, 1429–1439 (2001).
Esnault, C., Maestre, J. & Heidmann, T. Human LINE retrotransposons generate processed pseudogenes. Nature Genet. 24, 363–367 (2000).
Reznikoff, W. S. Tn5 transposition: a molecular tool for studying protein structure-function. Biochem. Soc. Trans. 34, 320–323 (2006).
Peters, J. E. & Craig, N. L. Tn7: smarter than we thought. Nature Rev. Mol. Cell Biol. 2, 806–814 (2001).
Rio, D. C. in Mobile DNA II (eds Craig, N. L., Craigie, R., Gellert, M. & Lambowitz, A. M.) 484–518 (ASM Press, Washington DC, 2002).
Plasterk, R. H. The Tc1/mariner transposon family. Curr. Top. Microbiol. Immunol. 204, 125–143 (1996).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Ray, D. A., Pagan, H. J., Thompson, M. L. & Stevens, R. D. Bats with hATs: evidence for recent DNA transposon activity in genus Myotis. Mol. Biol. Evol. 24, 632–639 (2007).
Pritham, E. J. & Feschotte, C. Massive amplification of rolling-circle transposons in the lineage of the bat Myotis lucifugus. Proc. Natl Acad. Sci. USA 104, 1895–1900 (2007).
Ray, D. A. et al. Multiple waves of recent DNA transposon activity in the bat, Myotis lucifugus. Genome Res. 18, 717–728 (2008). References 60–62 reveal that certain DNA transposons are active in the Myotis genus of bats.
Bowen, N. J. & McDonald, J. F. Drosophila euchromatic LTR retrotransposons are much younger than the host species in which they reside. Genome Res. 11, 1527–1540 (2001).
Schnable, P. S. et al. The B73 maize genome: complexity, diversity, and dynamics. Science 326, 1112–1115 (2009).
SanMiguel, P. et al. Nested retrotransposons in the intergenic regions of the maize genome. Science 274, 765–768 (1996).
Maksakova, I. A. et al. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet. 2, e2 (2006).
Moyes, D., Griffiths, D. J. & Venables, P. J. Insertional polymorphisms: a new lease of life for endogenous retroviruses in human disease. Trends Genet. 23, 326–333 (2007).
Badge, R. M., Alisch, R. S. & Moran, J. V. ATLAS: a system to selectively identify human-specific L1 insertions. Am. J. Hum. Genet. 72, 823–838 (2003).
Sheen, F. M. et al. Reading between the LINEs: human genomic variation induced by LINE-1 retrotransposition. Genome Res. 10, 1496–1508 (2000).
Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).
Kidd, J. M. et al. A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 143, 837–847 (2010).
Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).
Durbin, R. M. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Mills, R. E. et al. Mapping copy number variation by population-scale genome sequencing. Nature 470, 59–65 (2011). References 12–18 and 70–74 used second-generation DNA sequencing and/or modern genomic approaches to demonstrate that TEs continue to have an ongoing impact on human genome structural variation.
Kuduvalli, P. N., Rao, J. E. & Craig, N. L. Target DNA structure plays a critical role in Tn7 transposition. EMBO J. 20, 924–932 (2001).
Craig, N. L. in Mobile DNA II (eds Craig, N. L., Craigie, R., Gellert, M. & Lambowitz, A. M.) 423–456 (ASM Press, Washington DC, 2002).
Wolkow, C. A., DeBoy, R. T. & Craig, N. L. Conjugating plasmids are preferred targets for Tn7. Genes Dev. 10, 2145–2157 (1996).
Peters, J. E. & Craig, N. L. Tn7 transposes proximal to DNA double-strand breaks and into regions where chromosomal DNA replication terminates. Mol. Cell 6, 573–582 (2000).
Bellen, H. J. et al. The Drosophila gene disruption project: progress using transposons with distinctive site-specificities. Genetics 188, 731–743 (2011).
Feng, Q., Moran, J., Kazazian, H. & Boeke, J. D. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87, 905–916 (1996).
Feng, Q., Schumann, G. & Boeke, J. D. Retrotransposon R1Bm endonuclease cleaves the target sequence. Proc. Natl Acad. Sci. USA 95, 2083–2088 (1998).
Yang, J., Malik, H. S. & Eickbush, T. H. Identification of the endonuclease domain encoded by R2 and other site-specific, non-long terminal repeat retrotransposable elements. Proc. Natl Acad. Sci. USA 96, 7847–7852 (1999).
Bushman, F. D. Targeting survival: integration site selection by retroviruses and LTR-retrotransposons. Cell 115, 135–138 (2003).
Lesage, P. & Todeschini, A. L. Happy together: the life and times of Ty retrotransposons and their hosts. Cytogenet. Genome Res. 110, 70–90 (2005).
Kirchner, J., Connolly, C. M. & Sandmeyer, S. B. Requirement of RNA polymerase III transcription factors for in vitro position-specific integration of a retroviruslike element. Science 267, 1488–1491 (1995).
Chalker, D. L. & Sandmeyer, S. B. Ty3 integrates within the region of RNA polymerase III transcription initiation. Genes Dev. 6, 117–128 (1992).
Yieh, L., Hatzis, H., Kassavetis, G. & Sandmeyer, S. B. Mutational analysis of the transcription factor IIIB-DNA target of Ty3 retroelement integration. J. Biol. Chem. 277, 25920–25928 (2002).
Yieh, L., Kassavetis, G., Geiduschek, E. P. & Sandmeyer, S. B. The Brf and TATA-binding protein subunits of the RNA polymerase III transcription factor IIIB mediate position-specific integration of the gypsy-like element, Ty3. J. Biol. Chem. 275, 29800–29807 (2000).
Bachman, N., Eby, Y. & Boeke, J. D. Local definition of Ty1 target preference by long terminal repeats and clustered tRNA genes. Genome Res. 14, 1232–1247 (2004).
Bachman, N., Gelbart, M. E., Tsukiyama, T. & Boeke, J. D. TFIIIB subunit Bdp1p is required for periodic integration of the Ty1 retrotransposon and targeting of Isw2p to S. cerevisiae tDNAs. Genes Dev. 19, 955–964 (2005).
Bolton, E. C. & Boeke, J. D. Transcriptional interactions between yeast tRNA genes, flanking genes and Ty elements: a genomic point of view. Genome Res. 13, 254–263 (2003).
Kinsey, P. T. & Sandmeyer, S. B. Adjacent pol II and pol III promoters: transcription of the yeast retrotransposon Ty3 and a target tRNA gene. Nucleic Acids Res. 19, 1317–1324 (1991).
Hofmann, J. et al. Transfer RNA genes from Dictyostelium discoideum are frequently associated with repetitive elements and contain consensus boxes in their 5′ and 3′-flanking regions. J. Mol. Biol. 222, 537–552 (1991).
Chung, T., Siol, O., Dingermann, T. & Winckler, T. Protein interactions involved in tRNA gene-specific integration of Dictyostelium discoideum non-long terminal repeat retrotransposon TRE5-A. Mol. Cell. Biol. 27, 8492–8501 (2007).
Behrens, R., Hayles, J. & Nurse, P. Fission yeast retrotransposon Tf1 integration is targeted to 5′ ends of open reading frames. Nucleic Acids Res. 28, 4709–4716 (2000).
Guo, Y. & Levin, H. L. High-throughput sequencing of retrotransposon integration provides a saturated profile of target activity in Schizosaccharomyces pombe. Genome Res. 20, 239–248 (2010). This study describes the sequencing of a saturated set of insertion sites that are actively targeted by a TE.
Singleton, T. L. & Levin, H. L. A long terminal repeat retrotransposon of fission yeast has strong preferences for specific sites of insertion. Eukaryotic Cell 1, 44–55 (2002).
Neely, L. A. & Hoffman, C. S. Protein kinase A and mitogen-activated protein kinase pathways antagonistically regulate fission yeast fbp1 transcription by employing different modes of action at two upstream activation sites. Mol. Cell. Biol. 20, 6426–6434 (2000).
Majumdar, A., Chatterjee, A. G., Ripmaster, T. L. & Levin, H. L. The determinants that specify the integration pattern of retrotransposon Tf1 in the fbp1 promoter of Schizosaccharomyces pombe. J. Virol. 85, 519–529 (2010).
Chen, D. et al. Global transcriptional responses of fission yeast to environmental stress. Mol. Biol. Cell 14, 214–229 (2003).
Malik, H. S., Henikoff, S. & Eickbush, T. H. Poised for contagion: evolutionary origins of the infectious abilities of invertebrate retroviruses. Genome Res. 10, 1307–1318 (2000).
Mitchell, R. S. et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2, e234 (2004).
Ciuffi, A. Mechanisms governing lentivirus integration site selection. Curr. Gene Ther. 8, 419–429 (2008).
Ciuffi, A. & Bushman, F. D. Retroviral DNA integration: HIV and the role of LEDGF/p75. Trends Genet. 22, 388–395 (2006).
Engelman, A. & Cherepanov, P. The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication. PLoS Pathog. 4, e1000046 (2008).
Poeschla, E. M. Integrase, LEDGF/p75 and HIV replication. Cell. Mol. Life Sci. 65, 1403–1424 (2008).
Malik, H. S. & Eickbush, T. H. Modular evolution of the integrase domain in the Ty3/Gypsy class of LTR retrotransposons. J. Virol. 73, 5186–5190 (1999).
Gao, X., Hou, Y., Ebina, H., Levin, H. L. & Voytas, D. F. Chromodomains direct integration of retrotransposons to heterochromatin. Genome Res. 18, 359–369 (2008).
Zou, S. & Voytas, D. F. Silent chromatin determines target preference of the Saccharomyces retrotransposon Ty5. Proc. Natl Acad. Sci. USA 94, 7412–7416 (1997).
Zou, S., Wright, D. A. & Voytas, D. F. The Saccharomyces Ty5 retrotransposon family is associated with origins of DNA replication at the telomeres and the silent mating locus HMR. Proc. Natl Acad. Sci. USA 92, 920–924 (1995).
Zou, S., Ke, N., Kim, J. M. & Voytas, D. F. The Saccharomyces retrotransposon Ty5 integrates preferentially into regions of silent chromatin at the telomeres and mating loci. Genes Dev. 10, 634–645 (1996).
Gai, X. & Voytas, D. F. A single amino acid change in the yeast retrotransposon Ty5 abolishes targeting to silent chromatin. Mol. Cell 1, 1051–1055 (1998).
Xie, W. et al. Targeting of the yeast Ty5 retrotransposon to silent chromatin is mediated by interactions between integrase and Sir4p. Mol. Cell. Biol. 21, 6606–6614 (2001).
Zhu, Y., Dai, J., Fuerst, P. G. & Voytas, D. F. Controlling integration specificity of a yeast retrotransposon. Proc. Natl Acad. Sci. USA 100, 5891–5895 (2003).
Brady, T. L., Fuerst, P. G., Dick, R. A., Schmidt, C. & Voytas, D. F. Retrotransposon target site selection by imitation of a cellular protein. Mol. Cell. Biol. 28, 1230–1239 (2008).
George, J. A., Traverse, K. L., DeBaryshe, P. G., Kelley, K. J. & Pardue, M. L. Evolution of diverse mechanisms for protecting chromosome ends by Drosophila TART telomere retrotransposons. Proc. Natl Acad. Sci. USA 107, 21052–21057 (2010).
Biessmann, H. et al. HeT-A, a transposable element specifically involved in “healing” broken chromosome ends in Drosophila melanogaster. Mol. Cell. Biol. 12, 3910–3918 (1992).
Fujiwara, H., Osanai, M., Matsumoto, T. & Kojima, K. K. Telomere-specific non-LTR retrotransposons and telomere maintenance in the silkworm, Bombyx mori. Chromosome Res. 13, 455–467 (2005).
Gladyshev, E. A. & Arkhipova, I. R. A subtelomeric non-LTR retrotransposon Hebe in the bdelloid rotifer Adineta vaga is subject to inactivation by deletions but not 5′ truncations. Mob. DNA 1, 12 (2010).
Morrish, T. A. et al. Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres. Nature 446, 208–212 (2007).
Morrish, T. A. et al. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nature Genet. 31, 159–165 (2002).
Gladyshev, E. A. & Arkhipova, I. R. Telomere-associated endonuclease-deficient Penelope-like retroelements in diverse eukaryotes. Proc. Natl Acad. Sci. USA 104, 9352–9357 (2007). References 120 and 122 reveal pathways by which retrotransposons can use telomeric sequences as integration substrates.
Gilbert, N., Lutz-Prigge, S. & Moran, J. V. Genomic deletions created upon LINE-1 retrotransposition. Cell 110, 315–325 (2002).
Symer, D. E. et al. Human L1 retrotransposition is associated with genetic instability in vivo. Cell 110, 327–338 (2002).
Harrow, J. et al. GENCODE: producing a reference annotation for ENCODE. Genome Biol. 7 (Suppl. 1), 4 (2006).
Coffey, A. J. et al. The GENCODE exome: sequencing the complete human exome. Eur. J. Hum. Genet. 19, 827–831 (2011).
Jurka, J. Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons. Proc. Natl Acad. Sci. USA 94, 1872–1877 (1997).
Cost, G. J. & Boeke, J. D. Targeting of human retrotransposon integration is directed by the specificity of the L1 endonuclease for regions of unusual DNA structure. Biochemistry 37, 18081–18093 (1998).
Korenberg, J. R. & Rykowski, M. C. Human genome organization: Alu, LINES, and the molecular structure of metaphase chromosome bands. Cell 53, 391–400 (1988).
Brookfield, J. F. Selection on Alu sequences? Curr. Biol. 11, R900–R901 (2001).
Boissinot, S., Entezam, A. & Furano, A. V. Selection against deleterious LINE-1-containing loci in the human lineage. Mol. Biol. Evol. 18, 926–935 (2001).
Boissinot, S., Davis, J., Entezam, A., Petrov, D. & Furano, A. V. Fitness cost of LINE-1 (L1) activity in humans. Proc. Natl Acad. Sci. USA 103, 9590–9594 (2006).
Han, J. S., Szak, S. T. & Boeke, J. D. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature 429, 268–274 (2004).
Perepelitsa-Belancio, V. & Deininger, P. RNA truncation by premature polyadenylation attenuates human mobile element activity. Nature Genet. 35, 363–366 (2003).
Conley, M. E., Partain, J. D., Norland, S. M., Shurtleff, S. A. & Kazazian, H. H. Jr. Two independent retrotransposon insertions at the same site within the coding region of BTK. Hum. Mutat. 25, 324–325 (2005).
Halling, K. C. et al. Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene. Hum. Hered. 49, 97–102 (1999).
Vidaud, D. et al. Haemophilia B due to a de novo insertion of a human-specific Alu subfamily member within the coding region of the factor IX gene. Eur. J. Hum. Genet. 1, 30–36 (1993).
Cost, G. J., Golding, A., Schlissel, M. S. & Boeke, J. D. Target DNA chromatinization modulates nicking by L1 endonuclease. Nucleic Acids Res. 29, 573–577 (2001).
Selker, E. U. et al. The methylated component of the Neurospora crassa genome. Nature 422, 893–897 (2003).
Yoder, J. A., Walsh, C. P. & Bestor, T. H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13, 335–340 (1997).
Goll, M. G. & Bestor, T. H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).
Schaefer, C. B., Ooi, S. K., Bestor, T. H. & Bourc'his, D. Epigenetic decisions in mammalian germ cells. Science 316, 398–399 (2007).
Maksakova, I. A., Mager, D. L. & Reiss, D. Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell. Mol. Life Sci. 65, 3329–3347 (2008).
Tsukahara, S. et al. Bursts of retrotransposition reproduced in Arabidopsis. Nature 461, 423–426 (2009). This paper used modern genomic approaches to reveal that certain classes of LTR retrotransposon are mobilized in a DDM1 (decrease in DNA methylation 1) mutant background. It provides an example of how epigenetic changes can lead to TE mobility.
Bourc'his, D. & Bestor, T. H. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431, 96–99 (2004).
Law, J. A. & Jacobsen, S. E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nature Rev. Genet. 11, 204–220 (2010).
van Rij, R. P. & Berezikov, E. Small RNAs and the control of transposons and viruses in Drosophila. Trends Microbiol. 17, 163–171 (2009).
Ghildiyal, M. & Zamore, P. D. Small silencing RNAs: an expanding universe. Nature Rev. Genet. 10, 94–108 (2009).
Slotkin, R. K. & Martienssen, R. Transposable elements and the epigenetic regulation of the genome. Nature Rev. Genet. 8, 272–285 (2007).
Czech, B. & Hannon, G. J. Small RNA sorting: matchmaking for Argonautes. Nature Rev. Genet. 12, 19–31 (2011).
Aravin, A. A., Hannon, G. J. & Brennecke, J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318, 761–764 (2007).
Fischer, S. E. Small RNA-mediated gene silencing pathways in C. elegans. Int. J. Biochem. Cell Biol. 42, 1306–1315 (2010).
Sijen, T. & Plasterk, R. H. Transposon silencing in the Caenorhabditis elegans germ line by natural RNAi. Nature 426, 310–314 (2003).
Tabara, H. et al. The rde-1 gene, RNA interference, and transposon silencing in C. elegans. Cell 99, 123–132 (1999).
Malone, C. D. et al. Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137, 522–535 (2009).
Olivieri, D., Sykora, M. M., Sachidanandam, R., Mechtler, K. & Brennecke, J. An in vivo RNAi assay identifies major genetic and cellular requirements for primary piRNA biogenesis in Drosophila. EMBO J. 29, 3301–3317 (2010).
Zamore, P. D. Somatic piRNA biogenesis. EMBO J. 29, 3219–3221 (2010).
Brennecke, J. et al. An epigenetic role for maternally inherited piRNAs in transposon silencing. Science 322, 1387–1392 (2008).
Slotkin, R. K. et al. Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell 136, 461–472 (2009). References 155, 156, 158 and 159 highlight some pathways by which small RNAs can inhibit TE mobility in either the germ line or soma.
Yang, N. & Kazazian, H. H. Jr. L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nature Struct. Mol. Biol. 13, 763–771 (2006).
Kuramochi-Miyagawa, S. et al. DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev. 22, 908–917 (2008).
Reuter, M. et al. Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile. Nature Struct. Mol. Biol. 16, 639–646 (2009).
Soper, S. F. et al. Mouse maelstrom, a component of nuage, is essential for spermatogenesis and transposon repression in meiosis. Dev. Cell 15, 285–297 (2008). References 161–163 highlight how the small RNA machinery influences the expression, and perhaps mobility, of certain TEs in mammalian cells.
Matsuda, E. & Garfinkel, D. J. Posttranslational interference of Ty1 retrotransposition by antisense RNAs. Proc. Natl Acad. Sci. USA 106, 15657–15662 (2009). This paper reveals a novel RNA-based mechanism that inhibits Ty1 retrotransposition in S. cerevisiae.
Crow, Y. J. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nature Genet. 38, 917–920 (2006).
Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. TREX1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).
Grimaldi, G. & Singer, M. F. Members of the KpnI family of long interspersed repeated sequences join and interrupt alpha-satellite in the monkey genome. Nucleic Acids Res. 11, 321–338 (1983).
Eickbush, T. H. & Jamburuthugoda, V. K. The diversity of retrotransposons and the properties of their reverse transcriptases. Virus Res. 134, 221–234 (2008).
Babushok, D. V. & Kazazian, H. H. Jr. Progress in understanding the biology of the human mutagen LINE-1. Hum. Mutat. 28, 527–539 (2007).
Suzuki, J. et al. Genetic evidence that the non-homologous end-joining repair pathway is involved in LINE retrotransposition. PLoS Genet. 5, e1000461 (2009).
Gasior, S. L., Roy-Engel, A. M. & Deininger, P. L. ERCC1/XPF limits L1 retrotransposition. DNA Repair (Amst.) 7, 983–989 (2008).
Garcia-Perez, J. L. et al. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature 466, 769–773 (2010). This paper describes a host mechanism that is able to epigenetically silence reporter genes delivered into genomic DNA by L1 retrotransposition.
Rio, D. C. Regulation of Drosophila P element transposition. Trends Genet. 7, 282–287 (1991).
Pelisson, A. et al. Gypsy transposition correlates with the production of a retroviral envelope-like protein under the tissue-specific control of the Drosophila flamenco gene. EMBO J. 13, 4401–4411 (1994).
Prud'homme, N., Gans, M., Masson, M., Terzian, C. & Bucheton, A. Flamenco, a gene controlling the gypsy retrovirus of Drosophila melanogaster. Genetics 139, 697–711 (1995).
Branciforte, D. & Martin, S. L. Developmental and cell type specificity of LINE-1 expression in mouse testis: implications for transposition. Mol. Cell. Biol. 14, 2584–2592 (1994).
Trelogan, S. A. & Martin, S. L. Tightly regulated, developmentally specific expression of the first open reading frame from LINE-1 during mouse embryogenesis. Proc. Natl Acad. Sci. USA 92, 1520–1524 (1995).
Georgiou, I. et al. Retrotransposon RNA expression and evidence for retrotransposition events in human oocytes. Hum. Mol. Genet. 18, 1221–1228 (2009).
Ostertag, E. M. et al. A mouse model of human L1 retrotransposition. Nature Genet. 32, 655–660 (2002).
Macia, A. et al. Epigenetic control of retrotransposon expression in human embryonic stem cells. Mol. Cell. Biol. 31, 300–316 (2011).
Federoff, N. in Mobile DNA II (eds. Craig, N. L., Craigie, R., Gellert, M. & Lambowitz, A. M.) 997–1007 (ASM Press, Washington DC, 2002).
Emmons, S. W. & Yesner, L. High-frequency excision of transposable element Tc1 in the nematode Caenorhabditis elegans is limited to somatic cells. Cell 36, 599–605 (1984).
Fernandez, L., Torregrosa, L., Segura, V., Bouquet, A. & Martinez-Zapater, J. M. Transposon-induced gene activation as a mechanism generating cluster shape somatic variation in grapevine. Plant J. 61, 545–557 (2010).
Swergold, G. D. Identification, characterization, and cell specificity of a human LINE-1 promoter. Mol. Cell. Biol. 10, 6718–6729 (1990).
Muotri, A. R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010). References 23, 24 and 185 suggest that engineered human L1s, and perhaps endogenous L1s, can retrotranspose in somatic cells of the mammalian nervous system.
Rehen, S. K. et al. Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc. Natl Acad. Sci. USA 98, 13361–13366 (2001).
Westra, J. W. et al. Neuronal DNA content variation (DCV) with regional and individual differences in the human brain. J. Comp. Neurol. 518, 3981–4000 (2010).
Belancio, V. P., Roy-Engel, A. M. & Deininger, P. L. All y'all need to know 'bout retroelements in cancer. Semin. Cancer Biol. 20, 200–210 (2010).
Alves, G., Tatro, A. & Fanning, T. Differential methylation of human LINE-1 retrotransposons in malignant cells. Gene 176, 39–44 (1996).
Asch, H. L. et al. Comparative expression of the LINE-1 p40 protein in human breast carcinomas and normal breast tissues. Oncol. Res. 8, 239–247 (1996).
Kubo, S. et al. L1 retrotransposition in nondividing and primary human somatic cells. Proc. Natl Acad. Sci. USA 103, 8036–8041 (2006).
Shi, X., Seluanov, A. & Gorbunova, V. Cell divisions are required for L1 retrotransposition. Mol. Cell. Biol. 27, 1264–1270 (2007).
Acknowledgements
We thank J. Kim, J. Garcia-Perez and members of the Moran laboratory for critical reading of the manuscript. H.L.L. was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. He received additional support from the Intramural AIDS Targeted Antiviral Program. J.V.M. was supported in part by grants from the NIH (GM060518 and GM082970) and is an Investigator of the Howard Hughes Medical Institute.
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John V. Moran is a named inventor on the following patent: Kazazian, H.H., Boeke, J.D., Moran, J.V. and Dombroski, B.A. Compositions and methods of use of human retrotransposons. Application number 60/006,831; patent number 6,150,160. Granted 21 November 2000. He has not received any money from this patent. Henry L. Levin declares no competing financial interests.
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Glossary
- Long terminal repeat
-
(LTR). A terminal repeated sequence present at the ends of LTR retrotransposons. The LTR contains cis-acting sequences that allow the transcription and polyadenylation of retrotransposon mRNA. LTRs also have crucial roles in the reverse transcription of LTR retrotransposon mRNA.
- Short interspersed elements
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(SINEs). A family of non-autonomous retrotransposons that require functional proteins encoded by long interspersed elements (LINEs) to mediate their retrotransposition.
- hAT elements
-
A family of transposons named after the hobo, Activator and Tam3 elements.
- LINE-1
-
(L1). An abundant family of autonomous, long interspersed element (LINE) non-LTR retrotransposons in mammalian genomes. In humans, L1 elements comprise ~17% of genomic DNA. The vast majority of L1s are inactive; however, it is estimated that an average human genome contains ~80–100 active elements.
- Long interspersed elements
-
(LINEs). A family of autonomous non-long terminal repeat (non-LTR) retrotransposons that mobilize by retrotransposition.
- Alu
-
An abundant class of short interspersed elements (SINEs) that comprise ~10% of human genomic DNA. Alu elements require the endonuclease and reverse transcriptase activities contained within the long interspersed element 1 (L1) ORF2-encoded protein to mediate their mobility. Some Alu elements remain active in the human genome.
- SINE-R–VNTR–Alu elements
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(SVA elements). Composite, non-autonomous retrotransposons that also require long interspersed element 1 (L1)-encoded proteins to mediate their mobility. SVA elements are less abundant than Alu elements, and certain families of SVA elements remain active in the human genome.
- Target-site-primed reverse transcription
-
(TPRT). The mechanism of mobility that is generally used by long interspersed elements (LINEs) and short interspersed elements (SINEs). An endonuclease, encoded by the LINE, nicks genomic DNA to expose a 3′-OH at the target site that can be used as a primer to initiate the reverse transcription of the retrotransposon RNA by a LINE-encoded reverse transcriptase.
- Desmoid tumours
-
Soft tissue tumours that can arise in the abdomen as well as in other parts of the body. They are typically benign and grow slowly.
- RNA-directed DNA methylation
-
(RdDM). A pathway in which 24 nucleotide small RNAs interact with a de novo methyltransferase to mediate the methylation and transcriptional silencing of homologous genomic loci in plants.
- Small interfering RNAs
-
(siRNAs). Small (~21–24 nucleotide) RNAs that are generated from dsRNA 'triggers' by Dicer-dependent and Dicer-independent mechanisms. They bind to Argonaute proteins and guide the resultant complex to complementary mRNAs to mediate silencing.
- PIWI-interacting RNAs
-
(piRNAs). A family of small (~24–35 nucleotide) RNAs that are processed from piRNA precursor mRNAs. The mature piRNAs interact with specialized Argonaute proteins (from the PIWI clade), to mediate RNA silencing.
- Dicer
-
A family of RNase III proteins that possess an endonuclease activity that can process dsRNA 'triggers' into small interfering RNAs (siRNAs) or microRNAs (miRNAs).
- Argonaute proteins
-
Proteins that bind to small RNAs and are the defining component of the RNA-induced silencing complex (RISC); they have an ssRNA binding domain (PAZ) and a ribonuclease domain (PIWI). The small RNAs guide Argonaute proteins to target mRNAs in order to mediate post-transcriptional degradation and/or translational silencing.
- PIWI clade of proteins
-
A specialized class of Argonaute proteins that interact with PIWI-interacting RNAs (piRNAs) to mediate transposable element silencing. Members include: PIWI, Aubergine and Argonaute 3 in D. melanogaster; MIWI1, MIWI2 and MILI in mice, and HIWI1, HIWI2, HIWI3 and HILI in humans.
- piRNA cluster
-
A genomic DNA locus that encodes PIWI-interacting RNA (piRNA) precursor RNAs. Many piRNA clusters contain sense and antisense sequences that are derived from mobile genetic elements.
- Aicardi–Goutieres syndrome
-
A rare, autosomal recessive genetic disorder that leads to brain dysfunction as well as other symptoms. The early onset form of the disease can be caused by mutations in the TREX1 gene and is usually fatal.
- Hybrid dysgenesis
-
In Drosophila melanogaster, a sterility-inducing syndrome that is induced by the mobilization of P elements in crosses between females lacking P elements and males carrying P elements.
- Virus-like particle
-
(VLP). A cytoplasmic particle that comprises long terminal repeat (LTR) retrotransposon mRNA, the LTR retrotransposon-encoded proteins and host factors that are required for reverse transcription of LTR retrotransposon mRNA. LTR retrotransposon mRNA is reverse transcribed into a double-stranded cDNA within VLPs.
- X-linked choroideraemia
-
A recessive degenerative retinal disease.
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Levin, H., Moran, J. Dynamic interactions between transposable elements and their hosts. Nat Rev Genet 12, 615–627 (2011). https://doi.org/10.1038/nrg3030
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DOI: https://doi.org/10.1038/nrg3030
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