Retrotransposons and Human Disease


Retrotransposition is a ‘copy‐and‐paste’ mechanism whereby a retrotransposable element is copied from one genomic location and inserted into another genomic location, using a ribonucleic acid intermediate. The consequences of the retrotransposon‐associated alterations of the genomic landscape range from silent events to changes contributing to species‐specific and individual differences as well as a broad spectrum of diseases. Retrotransposon‐induced genetic variation can lead to inactivation or alteration of expression of critical genes via insertional mutagenesis, loss of genomic sequences through nonallelic homologous recombination or in association with de novo integration. In addition to these well‐recognised mutagenic events, some retroelements such as LINE‐1 can induce deoxyribonucleic acid double‐strand breaks that, if repaired unfaithfully, may lead to mutations. Moreover, retroelements have also contributed to generation of novel genes or functions through pseudogene formation, exonisation or shuffling of genetic material during retrotransposition. Thus, a complete understanding of their cumulative effect on any given genome or on genome evolution remains elusive.

Key Concepts:

  • Retroelements are currently active in the human genome, but only a limited number of functional loci are retrotranspositionally competent.

  • Retrotransposition is a multistep process that requires LINE‐1 proteins and cellular factors.

  • Human retrotransposons (LINE‐1, Alu and SVA) contribute to disease through several mechanisms.

  • LINE‐1 ORF2 protein induces DNA double‐strand breaks, but their contribution to human disease is not yet characterised.

  • LINE‐1 expression varies among germ line, normal somatic tissues and cancer.

  • Retrotransposition can occur in the germ line, normal somatic tissues and cancer.

  • There is variation in the rate of LINE‐1, Alu and SVA retrotransposition.

  • The estimated frequency of LINE‐1‐, Alu‐ and SVA‐associated diseases is likely an underestimation of their contribution to human disease.

Keywords: retrotransposons; L1 elements; alu elements; insertional mutagenesis; unequal homologous recombination; double‐strand breaks; DNA damage

Figure 1.

Simplified schematic of the proposed mechanism of L1 retrotransposition. A full‐length active L1 element has a 5′ untranslated region (UTR) (grey), open reading frame 1, ORF1 (purple), intergenic region, ORF2 (brown) and a 3′ UTR that ends in a polyadenylation (pA) signal and an A tail. (1) A full‐length active L1 element in the genome is first transcribed using an internal promoter to generate full‐length L1 (FL) RNA and a variety of prematurely polyadenylated and spliced L1‐related products. Only the FL‐RNA will generate new L1 inserts. (2) The L1 transcript translation in the cytoplasm generates ORF1 and ORF2 proteins. Experimental evidence shows that some of the processed transcripts are able to generate functional ORF2 protein (dashed arrow). (3) The ORF1 and ORF2 proteins preferentially bind the L1 RNA molecule that encoded them (cis preference) to form an RNP (ribonucleoprotein) complex. Through an unknown mechanism, the L1 RNP returns to the nucleus. (4) In the nucleus the L1 ORF2‐encoded endonuclease (EN) makes a first strand cleavage in the host DNA at the EN recognition site. The L1 cDNA is generated by the ORF2 reverse transcriptase and integrated into the genome by target‐primed reverse transcription (TPRT). At this step, usually the process of insertion is incomplete generating a 5′ truncated or rearranged L1 copy. The inserted L1 sequence is a copy of the original L1 element at a new genomic location. Note that the target site duplications flanking the original L1 element will differ from the target site duplications flanking the L1 copy at a new genomic location.

Figure 2.

Target‐primed reverse transcription (TPRT). The L1 retrotransposon is thought to integrate by TPRT. (1) During L1 TPRT, the retrotransposon's endonuclease cleaves one strand of genomic DNA at the target site (grey box) cleaving at the endonuclease consensus site 5′‐TT/AAAA‐3′: 3′‐AA/TTTT‐5′, producing a 3′ hydroxyl (OH) at the nick. (2) The retrotransposon RNA base pairs with the exposed genomic DNA strand containing Ts at the nick. (3) The retrotransposon's reverse transcriptase uses the free 3′ OH to prime reverse transcription. Reverse transcription proceeds, producing a cDNA of the retrotransposon RNA. (4) A second break occurs in the other DNA strand of the target site to produce a staggered break. (5) Insertion of the cDNA into the break is completed by an unknown mechanism. (6) Removal of RNA and completion of DNA synthesis produces a complete insertion flanked by target site duplications (TSDs, grey boxes).



An W, Han JS, Wheelan SJ et al. (2006) Active retrotransposition by a synthetic L1 element in mice. Proceedings of the National Academy of Sciences of the USA 103: 18662–18667.

Babushok DV and Kazazian HH Jr (2007) Progress in understanding the biology of the human mutagen LINE‐1. Human Mutation 28: 527–539.

Beck CR, Collier P, Macfarlane C et al. (2010) LINE‐1 retrotransposition activity in human genomes. Cell 25: 1159–1170.

Belancio VP, Hedges DJ and Deininger P (2008) Mammalian non‐LTR retrotransposons: for better or worse, in sickness and in health. Genome Research 18: 343–358.

Belancio VP, Roy‐Engel AM and Deininger PL (2010a) All y'all need to know'bout retroelements in cancer. Seminars in Cancer Biology 20: 200–210.

Belancio VP, Roy‐Engel AM, Pochampally RR and Deininger P (2010b) Somatic expression of LINE‐1 elements in human tissues. Nucleic Acids Research 38: 3909–3922.

Burwinkel B and Kilimann MW (1998) Unequal homologous recombination between LINE‐1 elements as a mutational mechanism in human genetic disease. Journal of Molecular Biology 277: 513–517.

Chow JC, Ciaudo C, Fazzari MJ et al. (2010) LINE‐1 activity in facultative heterochromatin formation during X chromosome inactivation. Cell 11: 956–969.

Cordaux R and Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nature Reviews Genetics 10: 691–703.

Cordaux R, Hedges DJ, Herke SW and Batzer MA (2006) Estimating the retrotransposition rate of human Alu elements. Gene 373: 134–137.

Coufal NG, Garcia‐Perez JL, Peng GE et al. (2009) L1 retrotransposition in human neural progenitor cells. Nature 460: 1127–1131.

Deininger PL and Batzer MA (1999) Alu repeats and human disease. Molecular Genetics and Metabolism 67: 183–193.

Dewannieux M, Esnault C and Heidmann T (2003) LINE‐mediated retrotransposition of marked Alu sequences. Nature Genetics 35: 41–48.

Doucet AJ, Hulme AE, Sahinovic E et al. (2010) Characterization of LINE‐1 ribonucleoprotein particles. PloS Genetics 6: e1001150.

Ergun S, Buschmann C, Heukeshoven J et al. (2004) Cell type‐specific expression of LINE‐1 open reading frames 1 and 2 in fetal and adult human tissues. Journal Biological Chemistry 279: 27753–27763.

Esnault C, Maestre J and Heidmann T (2000) Human LINE retrotransposons generate processed pseudogenes. Nature Genetics 24: 363–367.

Ewing AD and Kazazian HH Jr (2011) Whole‐genome resequencing allows detection of many rare LINE‐1 insertion alleles in humans. Genome Research 21: 985–990.

Gasior SL, Preston G, Hedges DJ et al. (2007) Characterization of pre‐insertion loci of the novo L1 insertions. Gene 390: 190–198.

Gasior SL, Roy‐Engel AM and Deininger PL (2008) ERCC1/XPF limits L1 retrotransposition. DNA Repair (Amsterdam) 7: 983–989.

Gasior SL, Wakeman TP, Xu B and Deininger PL (2006) The human LINE‐1 retrotransposon creates DNA double‐strand breaks. Journal of Molecular Biology 357: 1383–1393.

Gebow D, Miselis N and Liber HL (2000) Homologous and nonhomologous recombination resulting in deletion: effects of p53 status, microhomology, and repetitive DNA length and orientation. Molecular Cell Biology 20: 4028–4035.

Gilbert N, Lutz S, Morrish TA and Moran JV (2005) Multiple fates of L1 retrotransposition intermediates in cultured human cells. Molecular Cell Biology 25: 7780–7795.

Han JS and Boeke JD (2005) LINE‐1 retrotransposons: modulators of quantity and quality of mammalian gene expression? Bioessays 27: 775–784.

Hedges DJ and Belancio VP (2011) Restless genomes humans as a model organism for understanding host‐retrotransposable element dynamics. Advances in Genetics 73: 219–262.

Hedges DJ and Deininger PL (2007) Inviting instability: transposable elements, double‐strand breaks, and the maintenance of genome integrity. Mutation Research 616: 46–59.

Huang CR, Schneider AM, Lu Y et al. (2010) Mobile interspersed repeats are major structural variants in the human genome. Cell 141: 1171–1182.

International Human Genome Sequencing Consortium (2001) The human genome: initial sequencing and analysis. Nature 409: 860–921.

Iskow RC, McCabe MT, Mills RE et al. (2010) Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 19: R131–136.

Jurka J (1997) Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons. Proceedings of the National Academy of Sciences of the USA 94: 1872–1877.

Kano H, Godoy I, Courtney C et al. (2009) L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes and Development 23: 1303–1312.

Kazazian HH Jr (1999) An estimated frequency of endogenous insertional mutations in humans. Nature Genetics 22: 130.

Kazazian HH Jr, Wong C, Youssoufian H et al. (1988) Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332: 164–166.

Kolosha VO and Martin SL (1997) In vitro properties of the first ORF protein from mouse LINE‐1 support its role in ribonucleoprotein particle formation during retrotransposition. Proceedings of the National Academy of Sciences of the USA 94: 10155–10160.

Konkel MK and Batzer MA (2010) A mobile threat to genome stability: The impact of non‐LTR retrotransposons upon the human genome. Seminars in Cancer Biology 20: 211–221.

Kroutter EN, Belancio VP, Wagstaff BJ and Roy‐Engel AM (2009) The RNA polyerase dictates ORF1 requirement and timing of LINE and SINE retrotransposition. PloS Genetics 5: e1000458.

Lengauer C, Kinzler KW and Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396: 643–649.

Luan DD, Korman MH, Jakubczak JL and Eickbush TH (1993) 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.

Mitchell GA, Labuda D, Fontaine G et al. (1991) Splice mediated insertion of an Alu sequence inactivates ornithine δ‐aminotransferase: a role for Alu elements in human mutation. Proceedings of the National Academy of Sciences of the USA 88: 815–819.

Moran JV, Holmes SE, Naas TP et al. (1996) High frequency retrotransposition in cultured mammalian cells. Cell 87: 917–927.

Muotri AR, Chu VT, Marchetto MC et al. (2005) Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435: 903–910.

Pickeral OK, Makalowski W, Boguski MS and Boeke JD (2000) Frequent human genomic DNA transduction driven by LINE‐1 retrotransposition. Genome Research 10: 411–415.

Sassaman DM, Dombroski BA, Moran JV et al. (1997) Many human L1 elements are capable of retrotransposition. Nature Genetics 16: 37–43.

Segal Y, Peissel B, Renieri A et al. (1999) LINE‐1 elements at the sites of molecular rearrangements in Alport syndrome‐diffuse leiomyomatosis. American Journal of Human Genetics 64: 62–69.

Seleme MC, Vetter MR, Cordaux R et al. (2006) Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. Proceedings of the National Academy of Sciences of the USA 103: 661–6616.

Stenglein MD and Harris RS (2006) APOBEC3B and APOBEC3F inhibit L1 retrotransposition by a DNA deamination‐independent mechanism. Journal of Biological Chemistry 281: 16837–16841.

Suzuki J, Yamaguchi K, Kajikawa M et al. (2009) Genetic evidence that the non‐homologous end‐joining repair pathway is involved in LINE retrotransposition. PloS Genetics 5: e1000461.

Wei W, Gilbert N, Ooi SL et al. (2001) Human L1 retrotransposition: cis‐preference vs. trans‐complementation. Molecular and Cellular Biology 21: 1429–1439.

Xing J, Wang H, Belancio VP et al. (2006) Emergence of primate gens by retrotransposon‐mediated sequence transduction. Proceedings of the National Academy of Sciences of the USA 103: 17608–17613.

Xing J, Zhang Y, Han K et al. (2007) Mobile elements create structural variation: analysis of a complete human genome. Genome Research 19: 1516–1526.

Further Reading

Boissinot S, Davis J, Entezam A, Petrov D and Furano AV (2006) Fitness cost of LINE‐1 (L1) activity in humans. Proceedings of the National Academy of Sciences of the USA 103: 9590–9594.

Crow MK (2010) Long interspersed nuclear elements (LINE‐1): potential triggers of systemic autoimmune disease. Autoimmunity 43: 7–16.

Deininger PL, Moran JV, Batzer MA and Kazazian HH Jr (2003) Mobile elements and mammalian genome evolution. Current Opinion in Genetics and Development 13: 651–658.

Lin C, Yang L, Tanasa B et al. (2009) Nuclear receptor‐induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 141: 956–969.

Maraia RJ (1995) Alu elements as a source of genomic variation: deleterious effects and evolutionary novelties. In: Maraia RJ (ed.) The Impact of Short Interspersed Elements (SINEs) on the Host Genome, pp. 1–24. Georgetown, TX: Landes Bioscience.

Soifer HS (2006) Do small RNAs interfere with LINE‐1? Journal of Biomedicine and Biotechnology 2006: 29049.

St Laurent G 3rd, Hammell N and McCaffrey TA (2010) A LINE‐1 component to human aging: do LINE elements exact a longevity cost for evolutionary advantage? Mechanisms of Ageing and Development 131: 299–305.

Web Links

Repbase that contains sequence annotations for eukaryotic DNA repeats from the Genetic Information Research Institute (GIRI).

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Roy‐Engel, Astrid M, and Belancio, Victoria P(Sep 2011) Retrotransposons and Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005492.pub2]