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′ (UTR) (grey), open reading frame 1, ORF1 (purple), intergenic region, ORF2 (brown) and a 3′ UTR that ends in a (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 (FL) RNA and a variety of prematurely polyadenylated and spliced L1‐related products. Only the FLRNA 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 (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.

(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′ (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).



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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.

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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]