Repetitive Elements and Human Disorders

Repetitive sequences, consisting largely of transposable elements (TEs), comprise over 50% of the mammalian genome. Ongoing proliferation of human TEs results in a significant level of disease-causing mutations. More frequently than insertional mutagenesis, TEs participate in nonallelic recombinations that generate both germ-line and somatic mutations. Further exacerbating the deleterious nature of TEs, the protein products of some autonomous elements have been demonstrated to generate double-stranded deoxyribonucleic acid (DNA) breaks, which have themselves been established as potent inducers of genetic instability. Other repetitive genomic sequence, such as segmental duplications and microsatellites (particularly triplet repeats), also promote genetic instability resulting in disease phenotypes.

Keywords: L1; ALU; SVA; human mobile elements; insertional mutation; nonallelic homologous recombination

Figure 1. Schematic of nonallelic homologous recombination between related elements. The dark bars represent genome sequence and the arrows represent related mobile, or repetitive, elements found in that genome. These dispersed repetitive elements provide the opportunity for mispairing between different copies of the same element, resulting in an unequal, homologous recombination. This recombination can result in either a deletion of the sequences between the elements or a duplication of the same region. This same process may also occur between elements on different chromosomes, resulting in a chromosomal translocation.
close
 References
    Bailey JA, Carrel L, Chakravarti A and Eichler EE (2000) From the cover: molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis. Proceedings of the National Academy of Sciences of the USA 97: 6634–6639.
    Bailey JA and Eichler EE (2006) Primate segmental duplications: crucibles of evolution, diversity and disease. Nature Reviews Genetics 7: 552–564.
    Belancio VP, Hedges DJ and Deininger P (2006) LINE-1 RNA splicing and influences on mammalian gene expression. Nucleic Acids Research 34: 1512–1521.
    Boissinot S, Entezam A and Furano AV (2001) Selection against deleterious LINE-1-containing loci in the human lineage. Molecular Biology Evolution 18: 926–935.
    Bowater RP and Wells RD (2000) The intrinsically unstable life of DNA triplet repeats associated with human hereditary disorders. Progress in Nucleic Acid Research and Molecular Biology 66: 159–202.
    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 USA 100: 5280–5285.
    Callinan PA, Wang J, Herke SW et al. (2005) Alu retrotransposition-mediated deletion. Journal of Molecular Biology 348: 791–800.
    Chen JM, Ferec C and Cooper DN (2006) LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease: mutation detection bias and multiple mechanisms of target gene disruption. Journal of Biomedical Biotechnology 2006: 56182.
    Chen JM, Stenson PD, Cooper DN and Ferec C (2005) A systematic analysis of LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease. Human Genetics 117: 411–427.
    Chimpanzee Sequencing and Analysis Consortium (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437(7055): 69–87.
    Cordaux R, Hedges DJ, Herke SW and Batzer MA (2006) Estimating the retrotransposition rate of human Alu elements. Gene 373: 134–137.
    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.
    Eichler EE (1998) Masquerading repeats: paralogous pitfalls of the human genome. Genome Research 8: 758–762.
    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 and Cellular Biology 20: 4028–4035.
    Han K, Sen SK, Wang J et al. (2005) Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages. Nucleic Acids Research 33: 4040–4052.
    Hedges DJ and Deininger PL (2007) Inviting instability: transposable elements, double-strand breaks, and the maintenance of genome integrity. Mutation Research 616(1–2): 46–59.
    Kazazian HH Jr and Moran JV (1998) The impact of L1 retrotransposons on the human genome. Nature Genetics 19: 19–24.
    Lander ES, Linton LM, Birren B et al. (2001) Initial sequencing and analyses of the human genome. Nature 409: 860–921.
    Mine M, Chen JM, 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: 137–142.
    Muotri AR, Chu VT, Marchetto MC et al. (2005) Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435: 903–910.
    Ostertag EM, Goodier JL, Zhang Y and Kazazian HH Jr (2003) SVA elements are nonautonomous retrotransposons that cause disease in humans. American Journal of Human Genetics 73: 1444–1451.
    Pace JK 2nd and Feschotte C (2007) The evolutionary history of human DNA transposons: evidence for intense activity in the primate lineage. Genome Research 17: 422–432.
    Reiter LT, Liehr T, Rautenstrauss B, Robertson HM and Lupski JR (1999) Localization of mariner DNA transposons in the human genome by PRINS. Genome Research 9: 839–843.
    Rudiger NS, Gregersen N and Kielland-Brandt MC (1995) One short well conserved region of Alu-sequences is involved in human gene rearrangements and has homology with prokaryotic chi. Nucleic Acids Research 23: 256–260.
    Sorek R, Lev-Maor G, Reznik M et al. (2004) Minimal conditions for exonization of intronic sequences: 5¢ splice site formation in alu exons. Molecular Cell 14: 221–231.
    Urnovitz HB and Murphy WH (1996) Human endogenous retroviruses: nature, occurrence, and clinical implications in human disease. Clinical Microbiology Reviews 9: 72–99.
    other van den Hurk JA, Meij IC, Del Carmen Seleme M et al. (2007) L1 retrotransposition can occur early in human embryonic development. Human Molecular Genetics. May 4. [Epub ahead of print]
    Wang H, Xing J, Grover D et al. (2006) Emergence of primate genes by retrotransposon-mediated sequence transduction. Proceedings of the National Academy of Sciences of the USA 103: 17608–17613.
 Further Reading
    book Craig NL, Craigie R, Gellert M and Lambowitz AM (eds) (2002) Mobile DNA II. Washington, DC: American Society for Microbiology.
    Babushok DV and Kazazian HH Jr (2007) Progress in understanding the biology of the human mutagen LINE-1. Human Mutation 28: 527–539.
    Batzer MA and Deininger PL (2002) Alu repeats and human genomic diversity. Nature Reviews Genetics 3: 370–379.
    Hu X and Worton RG (1992) Partial gene duplication as a cause of human disease. Human Mutation 1: 3–12.
    Ji Y, Eichler EE, Schwartz S and Nicholls RD (2000) Structure of chromosomal duplicons and their role in mediating human genomic disorders. Genome Research 10: 597–610.
    Kazazian HHJ (1998) Mobile elements and disease. Current Opinion in Genetics and Development 8: 343–350.
    Moran JV, Holmes SE, Naas TP et al. (1996) High frequency retrotransposition in cultured mammalian cells. Cell 87: 917–927.
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Hedges, Dale J, and Deininger, Prescott L(Dec 2007) Repetitive Elements and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005493.pub2]