Repetitive Elements and Human Disorders


Repetitive sequences, consisting largely of transposable elements (TEs), comprise almost two‐thirds of the human genome. Non‐long‐terminal repeat (non‐LTR) TEs such as L1s, Alus and SVAs are still actively multiplying. Ongoing proliferation of these non‐LTR TEs results in a significant level of disease‐causing mutations through insertional mutagenesis, non‐allelic recombination (NAR) and the induction of genomic instability. NAR between Alu elements represents a major form of genetic instability leading to deletions, duplications and complex rearrangements. Between these different mechanisms, TEs have not only contributed a great deal to the evolution of the genome but also continue to generate germline mutations that cause a variety of diseases and potentially the progression of somatic diseases like cancer. With the advent of sequencing technologies, the future holds the promise of uncovering this role.

Key Concepts

  • Transposable elements (TEs) are DNA segments that are able to create new copies within the genome.
  • These TEs are known to cause a variety of germline diseases through insertional mutagenesis and mutagenic recombination.
  • TEs provide opportunities for non‐allelic recombination events to cause DNA rearrangements.
  • There is a sharp increase in TE insertions in most epithelial cancers as well as increased opportunities for non‐allelic recombination.
  • The overall impact of these TEs in a number of somatic diseases, particularly epithelial cancers, is under investigation.
  • High‐throughput sequencing approaches are being utilised to better understand mobile element biology.

Keywords: L1; ALU; SVA; human mobile elements; retrotransposition; insertional mutagenesis; nonallelic recombination; cancer

Figure 1. Structural organisation of Class I retroelements: Class I TEs (transposable elements) are flanked on either side by tandem site duplications (TSDs, white arrowheads) caused by duplication of a short segment of sequence at the site of insertion. Retroelements that are still active in humans are characterised by their absence of long‐terminal repeats (LTRs). The non‐LTR retroelement that is able to mobilise autonomously by generating its own replication and insertion factors is known as long interspersed elements (LINEs). LINEs have two open reading frames (ORF1 and ORF2) that encode for several proteins. ORF1 is an RNA binding protein, while ORF2 encodes endonuclease (EN) and reverse transcriptase. Shown is a representative LINE‐1 with an internal promoter (PR) and a 3′ end poly‐A tail. Also shown are non‐autonomous retroelements that vary in size and include short interspersed elements (SINEs)‐VNTR‐Alu also known as SVA and Alus. Because LINE‐1, SVA and Alu are the TEs that are still active in humans, they have the potential to cause human disease.
Figure 2. L1 replication cycle. L1s are transcribed off its own promoter into mRNA (messenger ribonucleic acid). Two proteins, ORF1 and ORF2, are expressed from the mRNA in the cytoplasm, which then bind to the L1 mRNA in cis preference. This ribonucleic protein re‐enters the nucleus where the EN and reverse transcriptase from ORF2 re‐inserts the L1 into the human genome through a process called target‐primed reverse transcription (TPRT).
Figure 3. Genomic rearrangements resulting from recombination between Alu elements. Alu elements are depicted as blue or gray bars. Direction of the arrowhead indicates Alu orientation. Capital letters above the thin horizontal lines refer to the flanking unique sequences. Homologues on the other strand (can be another chromatid or the homologous chromosome) are also shown. Thin diagonal lines refer to a recombination event with the results shown by numbers 1 and 2. (a) Non‐allelic homologous recombination (NAHR). Recombination between two different chromatids results in deletion and/or duplication. (b) Inverted non‐homologous end joining (NHEJ) between inverted repeats results in deletion. (c) Non‐allelic recombination (NAR) through single‐strand annealing (SSA) or microhomology‐mediated end joining (MMEJ). Several mechanisms of non‐allelic recombination between Alu elements can form a chimeric Alu element from the two flanking elements with the loss of the DNA (deoxyribonucleic acid) sequence between them.


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Further Reading

Cristofari G (ed.) (2017) Human Retrotransposons in Health and Disease, pp. 1–330. Switzerland: Springer. DOI: 10.1007/978-3-319-48344-3_11.

Goodier JL (2016) Restricting retrotransposons: a review. Mobile DNA 7 (1): 16. DOI: 10.1186/s13100-016-0070-z.

Deininger P, Morales ME, White TB, et al (2017) A comprehensive approach to expression of L1 loci. Nucleic Acids Research 45 (5): e31. DOI: 10.1093/nar/gkw1067.

O'Donnell KA and Burns KH (2010) Mobilizing diversity: transposable element insertions in genetic variation and disease. Mobile DNA 1: 21. DOI: 10.1186/1759-8753-1-21.

Ray DA and Batzer MA (2011) Reading TE leaves: new approaches to the identification of transposable element insertions. Genome Research 21 (6): 813–820. DOI: 10.1101/gr.110528.110.

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Kaul, Tiffany K, Morales, Maria E, and Deininger, Prescott L(Sep 2017) Repetitive Elements and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005493.pub3]