Repetitive Elements and Human Disorders

Abstract

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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References

Beck CR, Garcia‐Perez JL, Badge RM and Moran JV (2011) LINE‐1 elements in structural variation and disease. Annual Review of Genomics and Human Genetics 12: 187–215. DOI: 10.1146/annurev-genom-082509-141802.

Belancio VP, Hedges DJ and Deininger P (2006) LINE‐1 RNA splicing and influences on mammalian gene expression. Nucleic Acids Research 34 (5): 1512–1521. DOI: 10.1093/nar/gkl027.

de Boer M, van Leeuwen K, Geissler J, et al. (2014) Primary immunodeficiency caused by an exonized retroposed gene copy inserted in the CYBB gene. Human Mutation 35 (4): 486–496. DOI: 10.1002/humu.22519.

Boone PM, Liu P, Zhang F, et al. (2011) Alu‐specific microhomology‐mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia. Genetics in Medicine: Official Journal of the American College of Medical Genetics 13 (6): 582–592. DOI: 10.1097/GIM.0b013e3182106775.

Boone P, Yuan B, Campbell IM, et al. (2014) The Alu‐rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease‐associated CNV alleles. American Journal of Human Genetics 95 (2): 143–161. DOI: 10.1016/j.ajhg.2014.06.014.

Brouha B, Schustak J, Badge RM, et al. (2003) Hot L1s account for the bulk of retrotransposition in the human population. Proceedings of the National Academy of Sciences of the United States of America 100 (9): 5280–5285. DOI: 10.1073/pnas.0831042100.

Callinan PA, Wang J, Herke SW, et al. (2005) Alu retrotransposition‐mediated deletion. Journal of Molecular Biology 348 (4): 791–800. DOI: http://dx.doi.org/10.1016/j.jmb.2005.02.043.

Christensen SM and Eickbush TH (2005) R2 target‐primed reverse transcription: ordered cleavage and polymerization steps by protein subunits asymmetrically bound to the target DNA. Molecular and Cellular Biology 25 (15): 6617–6628. DOI: 10.1128/MCB.25.15.6617-6628.2005.

Clements AP and Singer MF (1998) The human LINE‐1 reverse transcriptase:effect of deletions outside the common reverse transcriptase domain. Nucleic Acids Research 26 (15): 3528–3535.

Deininger PL and Batzer MA (1999) Alu repeats and human disease. Molecular Genetics and Metabolism 67 (3): 183–193. DOI: 10.1006/mgme.1999.2864.

Deininger P (2011) Alu elements: know the SINEs. Genome Biology 12 (12): 236. DOI: 10.1186/gb-2011-12-12-236.

Denli AM, Narvaiza I, Kerman BE, et al. (2015) Primate‐specific ORF0 contributes to retrotransposon‐mediated diversity. Cell 163 (3): 583–593. DOI: 10.1016/j.cell.2015.09.025.

Dewannieux M, Esnault C and Heidmann T (2003) LINE‐mediated retrotransposition of marked Alu sequences. Nature Genetics 35 (1): 41–48.

Elliott B, Richardson C and Jasin M (2005) Chromosomal translocation mechanisms at intronic Alu elements in mammalian cells. Molecular Cell 17 (6): 885–894. DOI: 10.1016/j.molcel.2005.02.028.

Esnault C, Maestre J and Heidmann T (2000) Human LINE retrotransposons generate processed pseudogenes. Nature Genetics 24 (4): 363–367.

Ewing AD, Gacita A, Wood LD, et al. (2015) Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Research 25: 1536–1545. DOI: 10.1101/gr.196238.115.

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 and Cellular Biology 20 (11): 4028–4035.

van Gent DC, Hoeijmakers JHJ and Kanaar R (2001) Chromosomal stability and the DNA double‐stranded break connection. Nature Reviews. Genetics 2 (3): 196–206.

Goodier JL, Ostertag EM and Kazazian HH (2000) Transduction of 3′‐flanking sequences is common in L1 retrotransposition. Human Molecular Genetics 9 (4): 653–657.

Gu S, Yuan B, Campbell IM, et al. (2015) Alu‐mediated diverse and complex pathogenic copy‐number variants within human chromosome 17 at p13.3. Human Molecular Genetics 24 (14): 4061–4077. DOI: 10.1093/hmg/ddv146.

Hancks DC and Kazazian HH (2012) Active human retrotransposons: variation and disease. Current Opinion in Genetics & Development 22 (3): 191–203. DOI: 10.1016/j.gde.2012.02.006.

Hancks DC and Kazazian HH (2016) Roles for retrotransposon insertions in human disease. Mobile DNA 7: 9. DOI: 10.1186/s13100-016-0065-9.

Helman E, Lawrence MS, Stewart C, et al. (2014) Somatic retrotransposition in human cancer revealed by whole‐genome and exome sequencing. Genome Research 24 (7): 1053–1063. DOI: 10.1101/gr.163659.113.

Kazazian HH and Moran JV (1998) The impact of L1 retrotransposons on the human genome. Nature Genetics 19 (1): 19–24.

Kim S, Cho C‐S, Han K and Lee J (2016) Structural variation of Alu element and human disease. Genomics & Informatics 14 (3): 70–77. DOI: 10.5808/GI.2016.14.3.70.

Lander ES, Linton LM, Birren B, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409 (6822): 860–921. DOI: 10.1038/35057062.

Martin SL (2010) Nucleic acid chaperone properties of ORF1p from the non‐LTR retrotransposon, LINE‐1. RNA Biology 7 (6): 706–711. DOI: 10.4161/rna.7.6.13766.

Maxwell PH (2016) What might retrotransposons teach us about aging? Current Genetics 62 (2): 277–282. DOI: 10.1007/s00294-015-0538-2.

Mayer J and Meese E (2005) Human endogenous retroviruses in the primate lineage and their influence on host genomes. Cytogenetic and Genome Research 110 (1‐4): 448–456.

Meili D, Kralovicova J, Zagalak J, et al. (2009) Disease‐causing mutations improving the branch site and polypyrimidine tract: pseudoexon activation of LINE‐2 and antisense Alu lacking the poly(T)‐tail. Human Mutation 30 (5): 823–831. DOI: 10.1002/humu.20969.

Miki Y, Nishisho I, Horii A, et al. (1992) Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Research 52 (3): 643.

Miné M, Chen J‐M, Brivet M, et al. (2007) A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full‐length LINE‐1 element. Human Mutation 28 (2): 137–142. DOI: 10.1002/humu.20449.

Morales ME, White TB, Streva VA, et al. (2015) The contribution of Alu elements to mutagenic DNA double‐strand break repair. PLoS Genetics 11 (3): e1005016. DOI: 10.1371/journal.pgen.1005016.

Moran JV, Holmes SE, Naas TP, et al. (1996) High Frequency Retrotransposition in Cultured Mammalian Cells. Cell 87 (5): 917–927. DOI: 10.1016/S0092-8674(00)81998-4.

Nazaryan‐Petersen L, Bertelsen B, Bak M, et al. (2016) Germline chromothripsis driven by L1‐mediated retrotransposition and Alu/Alu homologous recombination. Human Mutation 37 (4): 385–395. DOI: 10.1002/humu.22953.

Nyström‐Lahti M, Kristo P, Nicolaides NC, et al. (1995) Founding mutations and Alu‐mediated recombination in hereditary colon cancer. Nature Medicine 1 (11): 1203–1206.

Oliveira C, Senz J, Kaurah P, et al. (2009) Germline CDH1 deletions in hereditary diffuse gastric cancer families. Human Molecular Genetics 18 (9): 1545–1555. DOI: 10.1093/hmg/ddp046.

Perepelitsa‐Belancio V and Deininger P (2003) RNA truncation by premature polyadenylation attenuates human mobile element activity. Nature Genetics 35 (4): 363–366.

Piskareva O, Ernst C, Higgins N and Schmatchenko V (2013) The carboxy‐terminal segment of the human LINE‐1 ORF2 protein is involved in RNA binding(). FEBS Open Bio 3: 433–437. DOI: 10.1016/j.fob.2013.09.005.

Raiz J, Damert A, Chira S, et al. (2012) The non‐autonomous retrotransposon SVA is trans‐mobilized by the human LINE‐1 protein machinery. Nucleic Acids Research 40 (4): 1666–1683. DOI: 10.1093/nar/gkr863.

Reilly MT, Faulkner GJ, Dubnau J, Ponomarev I and Gage FH (2013) The role of transposable elements in health and diseases of the central nervous system. The Journal of Neuroscience 33 (45): 17577–17586. DOI: 10.1523/JNEUROSCI.3369-13.2013.

Rodić N, Steranka JP, Makohon‐Moore A, et al. (2015) Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nature Medicine 21: 1060–1064. DOI: 10.1038/nm.3919.

Shukla R, Upton KR, Muñoz‐Lopez M, et al. (2013) Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 153 (1): 101–111. DOI: 10.1016/j.cell.2013.02.032.

Solyom S, Ewing AD, Hancks DC, et al. (2012) Pathogenic orphan transduction created by a non‐reference LINE‐1 retrotransposon. Human Mutation 33 (2): 369–371. DOI: 10.1002/humu.21663.

Szpakowski S, Sun X, Lage JM, et al. (2009) Loss of epigenetic silencing in tumors preferentially affects primate‐specific retroelements. Gene 448 (2): 151–167. DOI: 10.1016/j.gene.2009.08.006.

Tubio JMC, Li Y, Ju YS, et al. (2014) Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science (New York, N.Y.) 345 (6196): 1251343. DOI: 10.1126/science.1251343.

Van den Hurk JAJM, van de Pol DJR, Wissinger B, et al. (2003) Novel types of mutation in the choroideremia (CHM) gene: a full‐length L1 insertion and an intronic mutation activating a cryptic exon. Human Genetics 113 (3): 268–275. DOI: 10.1007/s00439-003-0970-0.

Vogt J, Bengesser K, Claes KBM, et al. (2014) SVA retrotransposon insertion‐associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non‐recurrent breakpoints. Genome Biology 15 (6): R80. DOI: 10.1186/gb-2014-15-6-r80.

Voineagu I, Narayanan V, Lobachev KS and Mirkin SM (2008) Replication stalling at unstable inverted repeats: interplay between DNA hairpins and fork stabilizing proteins. Proceedings of the National Academy of Sciences of the United States of America 105 (29): 9936–9941. DOI: 10.1073/pnas.0804510105.

Volkman HE and Stetson DB (2014) The enemy within: endogenous retroelements and autoimmune disease. Nature Immunology 15 (5): 415–422. DOI: 10.1038/ni.2872.

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. http://www.els.net [doi: 10.1002/9780470015902.a0005493.pub3]