Long interspersed nuclear element

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Long interspersed nuclear element
1vyb bio r 500.jpg
Identifiers
ChemSpider
  • none
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Genetic structure of murine LINE1 and SINEs. Bottom: proposed structure of L1 RNA-protein (RNP) complexes. ORF1 proteins form trimers, exhibiting RNA binding and nucleic acid chaperone activity.

Long interspersed nuclear elements (LINEs)[1] (also known as Long interspersed nucleotide elements[2] or Long interspersed elements[3]) are a group of non-LTR (long terminal repeat) retrotransposons which are widespread in the genome of many eukaryotes.[4][5] They make up around 21.1% of the human genome.[6][7][8] LINEs make up a family of transposons, where each LINE is about 7000 base pairs long. LINEs are transcribed into mRNA and translated into protein that acts as a reverse transcriptase. The reverse transcriptase makes a DNA copy of the LINE RNA that can be integrated into the genome at a new site. The only abundant LINE in humans is LINE-1. Our genome contains an estimated 100,000 truncated and 4,000 full-length LINE-1 elements.[9] Due to the accumulation of random mutations, the sequence of many LINEs has degenerated to the extent that they are no longer transcribed or translated. Comparisons of LINE DNA sequences can be used to date transposon insertion in the genome.

History of discovery[edit]

The first description of an approximately 6.4 kb long LINE-derived sequence was published by J. Adams et al. in 1980.[10]

Types[edit]

Based on structural features and the phylogeny of its key enzyme, the reverse transcriptase (RT), LINEs are grouped into five main groups, called L1, RTE, R2, I and Jockey, which can be subdivided into at least 28 clades.[11]

In plant genomes, so far only LINEs of the L1 and RTE clade have been reported.[12][13][14] Whereas L1 elements diversify into several subclades, RTE-type LINEs are highly conserved, often constituting a single family.[15][16]

In fungi, Tad, L1, CRE, Deceiver and Inkcap-like elements have been identified,[17] with Tad-like elements appearing exclusively in fungal genomes.[18]

All LINEs encode a least one protein, ORF2, which contains an RT and an endonuclease (EN) domains. Except for the evolutionary ancient R2 and RTE superfamilies, LINEs usually encode for another protein named ORF1. LINE elements are relatively rare compared to LTR-retrotransposons in plants, fungi or insects, but are dominant in vertebrates and especially in mammals, where they represent around 20% of the genome.

L1 element[edit]

The LINE-1/L1-element is the only element that is still active in the human genome today. It is found in all mammals.[19]

L2 and L3 elements[edit]

Remnants of L2 and L3 elements are found in the human genome.[8] It is estimated, that L2 and L3 elements were active ~200-300 million years ago. Unlike L1 elements, L2 and L3 elements lack flanking target site duplications.[20]

Incidence[edit]

In human[edit]

In the first human genome draft the fraction of LINE elements of the human genome was given as 21% and their copy number as 850,000. Of these, L1, L2 and L3 elements made up 516,000, 315,000 and 37,000 copies, respectively. The non-autonomous SINE elements which depend on L1 elements for their proliferation make up 13% of the human genome and have a copy number of around 1.5 million.[8] Recent estimates show the typical human genome contains on average 100 L1 elements with potential for mobilization, however there is a fair amount of variation and some individuals may contain a larger number of active L1 elements, making these individuals more prone to L1-induced mutagenesis.[21]

Increased L1 copy numbers have also been found in the brains of people with schizophrenia, indicating that LINE elements may play a role in some neuronal diseases.[22]

Mechanism of target-primed reverse transcription (TPRT), directly at the site of integration: L1 RNP recognize AAAATT hexanucleotides and ORF2 endonuclease activity cleaves the DNA first-strand. L1 polyA tail associate with TTTT overhang and the host DNA is used as a primer to initiate reverse-transcription. ORF2 probably also mediate second-strand cleavage and attachment of newly synthesized cDNA to the DNA template, using again host DNA as a primer for second-strand synthesis.

Propagation[edit]

LINE elements propagate by a so-called target primed reverse transcription mechanism (TPRT), which was first described for the R2 element from the silkworm Bombyx mori.

ORF2 (and ORF1 when present) proteins primarily associate in cis with their encoding mRNA, forming a ribonucleoprotein (RNP) complex, likely composed of two ORF2s and an unknown number of ORF1 trimers.[23] The complex is transported back into the nucleus, where the ORF2 endonuclease domain opens the DNA (at TTAAAA hexanucleotide motifs in mammals[24]). Thus, a 3'OH group is freed for the reverse transcriptase to prime reverse transcription of the LINE RNA transcript. Following the reverse transcription the target strand is cleaved and the newly created cDNA is integrated[25]

New insertions create short TSDs, and the majority of new inserts are severely 5’-truncated (average insert size of 900pb in humans) and often inverted (Szak et al., 2002). Because they lack their 5’UTR, most of new inserts are non functional.

Regulation of LINE activity[edit]

It has been shown that host cells regulate L1 retrotransposition activity, for example through epigenetic silencing. For example, the RNA interference (RNAi) mechanism of small interfering RNAs derived from L1 sequences can cause suppression of L1 retrotransposition.[26]

In plant genomes, epigenetic modification of LINEs can lead to expression changes of nearby genes and even to phenotypic changes: In the oil palm genome, methylation of a Karma-type LINE underlies the somaclonal, 'mantled' variant of this plant, responsible for drastic yield loss.[27]

Human APOBEC3C mediated restriction of LINE-1 elements were reported and it is due to the interaction between A3C with the ORF1p that affects the reverse transcriptase activity.[28]

Association with disease[edit]

A historic example of L1-conferred disease is Haemophilia A, which is caused by insertional mutagenesis.[29] There are nearly 100 examples of known diseases caused by retroelement insertions, including some types of cancer and neurological disorders.[30] Correlation between L1 mobilization and oncogenesis has been reported for epithelial cell cancer (carcinoma).[31] Shift work sleep disorder[32] is associated with increased cancer risk because light exposure at night reduces melatonin, a hormone that has been shown to reduce L1-induced genome instability.[33]

References[edit]

  1. ^ Ewing, Adam D.; Kazazian, Haig H. (2011-06-01). "Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans". Genome Research. 21 (6): 985–990. doi:10.1101/gr.114777.110. ISSN 1549-5469. PMC 3106331Freely accessible. PMID 20980553. 
  2. ^ Huang, Xiaolan; Su, Gaixiu; Wang, Zhen; Shangguan, Shaofang; Cui, Xiaodai; Zhu, Jia; Kang, Min; Li, Shengnan; Zhang, Ting (2014-03-01). "Hypomethylation of long interspersed nucleotide element-1 in peripheral mononuclear cells of juvenile systemic lupus erythematosus patients in China". International Journal of Rheumatic Diseases. 17 (3): 280–290. doi:10.1111/1756-185X.12239. ISSN 1756-185X. PMID 24330152. 
  3. ^ Rodić, Nemanja; Burns, Kathleen H. (2013-03-01). "Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms?". PLoS Genetics. 9 (3): e1003402. doi:10.1371/journal.pgen.1003402. ISSN 1553-7404. PMC 3610623Freely accessible. PMID 23555307. 
  4. ^ Singer, MF (1982). "SINEs and LINEs: highly repeated short and long interspersed sequences in mammalian genomes". Cell. 28 (3): 433–434. doi:10.1016/0092-8674(82)90194-5. PMID 6280868. 
  5. ^ Jurka, J. (1998). "Repeats in genomic DNA: Mining and meaning". Current Opinion in Structural Biology. 8 (3): 333–337. doi:10.1016/S0959-440X(98)80067-5. 
  6. ^ Lindblad-Toh, Kerstin; Wade, Claire M.; Mikkelsen, Tarjei S.; Karlsson, Elinor K.; Jaffe, David B.; Kamal, Michael; Clamp, Michele; Chang, Jean L.; Kulbokas, Edward J. (2005-12-08). "Genome sequence, comparative analysis and haplotype structure of the domestic dog". Nature. 438 (7069): 803–819. doi:10.1038/nature04338. ISSN 1476-4687. PMID 16341006. 
  7. ^ Schumann, Gerald G.; Gogvadze, Elena V.; Osanai-Futahashi, Mizuko; Kuroki, Azusa; Münk, Carsten; Fujiwara, Haruko; Ivics, Zoltan; Buzdin, Anton A. (2010-01-01). "Unique functions of repetitive transcriptomes". International Review of Cell and Molecular Biology. International Review of Cell and Molecular Biology. 285: 115–188. doi:10.1016/B978-0-12-381047-2.00003-7. ISBN 9780123810472. ISSN 1937-6448. PMID 21035099. 
  8. ^ a b c Lander ES, Linton LM, Birren B, et al. (February 2001). "Initial sequencing and analysis of the human genome". Nature. 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011. 
  9. ^ Sheen, F. M.; Sherry, S. T.; Risch, G. M.; Robichaux, M.; Nasidze, I.; Stoneking, M.; Batzer, M. A.; Swergold, G. D. (October 2000). "Reading between the LINEs: human genomic variation induced by LINE-1 retrotransposition". Genome Research. 10 (10): 1496–1508. doi:10.1101/gr.149400. ISSN 1088-9051. PMC 310943Freely accessible. PMID 11042149. 
  10. ^ Adams, J. W.; Kaufman, R. E.; Kretschmer, P. J.; Harrison, M.; Nienhuis, A. W. (1980). "A family of long reiterated DNA sequences, one copy of which is next to the human beta globin gene". Nucleic Acids Research. 8 (24): 6113–6128. doi:10.1093/nar/8.24.6113. 
  11. ^ Kapitonov, VV; Tempel, S; Jurka, J (15 December 2009). "Simple and fast classification of non-LTR retrotransposons based on phylogeny of their RT domain protein sequences". Gene. 448 (2): 207–13. doi:10.1016/j.gene.2009.07.019. PMC 2829327Freely accessible. PMID 19651192. 
  12. ^ Heitkam, Tony; Schmidt, Thomas (2009-09-01). "BNR - a LINE family fromBeta vulgaris- contains a RRM domain in open reading frame 1 and defines a L1 sub-clade present in diverse plant genomes". The Plant Journal. 59 (6): 872–882. doi:10.1111/j.1365-313x.2009.03923.x. ISSN 1365-313X. 
  13. ^ Zupunski, V; Gubensek, F; Kordis, D (October 2001). "Evolutionary dynamics and evolutionary history in the RTE clade of non-LTR retrotransposons". Molecular Biology and Evolution. 18 (10): 1849–63. doi:10.1093/oxfordjournals.molbev.a003727. PMID 11557792. 
  14. ^ Komatsu, M; Shimamoto, K; Kyozuka, J (August 2003). "Two-step regulation and continuous retrotransposition of the rice LINE-type retrotransposon Karma". The Plant Cell. 15 (8): 1934–44. doi:10.1105/tpc.011809. PMC 167180Freely accessible. PMID 12897263. 
  15. ^ Heitkam, T; Holtgräwe, D; Dohm, JC; Minoche, AE; Himmelbauer, H; Weisshaar, B; Schmidt, T (August 2014). "Profiling of extensively diversified plant LINEs reveals distinct plant-specific subclades". The Plant Journal. 79 (3): 385–97. doi:10.1111/tpj.12565. PMID 24862340. 
  16. ^ Smyshlyaev, G; Voigt, F; Blinov, A; Barabas, O; Novikova, O (10 December 2013). "Acquisition of an Archaea-like ribonuclease H domain by plant L1 retrotransposons supports modular evolution". Proceedings of the National Academy of Sciences of the United States of America. 110 (50): 20140–5. doi:10.1073/pnas.1310958110. PMC 3864347Freely accessible. PMID 24277848. 
  17. ^ Novikova, O; Fet, V; Blinov, A (February 2009). "Non-LTR retrotransposons in fungi". Functional & Integrative Genomics. 9 (1): 27–42. doi:10.1007/s10142-008-0093-8. PMID 18677522. 
  18. ^ Malik, HS; Burke, WD; Eickbush, TH (June 1999). "The age and evolution of non-LTR retrotransposable elements". Molecular Biology and Evolution. 16 (6): 793–805. doi:10.1093/oxfordjournals.molbev.a026164. PMID 10368957. 
  19. ^ Warren, W. C.; Hillier, L. W.; Marshall Graves, J. A.; Birney, E.; Ponting, C. P.; Grützner, F.; Belov, K.; Miller, W.; Clarke, L.; Chinwalla, A. T.; Yang, S. P.; Heger, A.; Locke, D. P.; Miethke, P.; Waters, P. D.; Veyrunes, F. D. R.; Fulton, L.; Fulton, B.; Graves, T.; Wallis, J.; Puente, X. S.; López-Otín, C.; Ordóñez, G. R.; Eichler, E. E.; Chen, L.; Cheng, Z.; Deakin, J. E.; Alsop, A.; Thompson, K.; Kirby, P. (2008). "Genome analysis of the platypus reveals unique signatures of evolution". Nature. 453 (7192): 175–183. doi:10.1038/nature06936. PMC 2803040Freely accessible. PMID 18464734. 
  20. ^ Kapitonov, Vladimir V.; Pavlicek, Adam; Jurka, Jerzy (2006-01-01). Anthology of Human Repetitive DNA. Wiley-VCH Verlag GmbH & Co. KGaA. doi:10.1002/3527600906.mcb.200300166. ISBN 9783527600908. 
  21. ^ Streva, Vincent (21 March 2015). "Sequencing, identification and mapping of primed L1 elements (SIMPLE) reveals significant variation in full length L1 elements between individuals". BMC Genomics. 16 (220): 220. doi:10.1186/s12864-015-1374-y. PMC 4381410Freely accessible. PMID 25887476. 
  22. ^ Bundo M, Toyoshima M, Okada Y, et al. (22 January 2014). "Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia". Neuron. 81 (2): 306–313. doi:10.1016/j.neuron.2013.10.053. PMID 24389010. 
  23. ^ Babushok, Daria V.; Ostertag, Eric M.; Courtney, Christine E.; Choi, Janice M.; Kazazian, Haig H. (2006-02-01). "L1 integration in a transgenic mouse model". Genome Research. 16 (2): 240–250. doi:10.1101/gr.4571606. ISSN 1088-9051. PMC 1361720Freely accessible. PMID 16365384. 
  24. ^ Jurka, Jerzy (1997-03-04). "Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons". Proceedings of the National Academy of Sciences of the United States of America. 94 (5): 1872–1877. doi:10.1073/pnas.94.5.1872. ISSN 0027-8424. PMC 20010Freely accessible. PMID 9050872. 
  25. ^ Luan, D. D.; Korman, M. H.; Jakubczak, J. L.; Eickbush, T. H. (1993). "Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: A mechanism for non-LTR retrotransposition". Cell. 72 (4): 595–605. doi:10.1016/0092-8674(93)90078-5. PMID 7679954. 
  26. ^ Yang, N; Kazazian Jr, H. H. (2006). "L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells". Nature Structural & Molecular Biology. 13 (9): 763–71. doi:10.1038/nsmb1141. PMID 16936727. 
  27. ^ Ong-Abdullah, M; Ordway, JM; Jiang, N; Ooi, SE; Kok, SY; Sarpan, N; Azimi, N; Hashim, AT; Ishak, Z; Rosli, SK; Malike, FA; Bakar, NA; Marjuni, M; Abdullah, N; Yaakub, Z; Amiruddin, MD; Nookiah, R; Singh, R; Low, ET; Chan, KL; Azizi, N; Smith, SW; Bacher, B; Budiman, MA; Van Brunt, A; Wischmeyer, C; Beil, M; Hogan, M; Lakey, N; Lim, CC; Arulandoo, X; Wong, CK; Choo, CN; Wong, WC; Kwan, YY; Alwee, SS; Sambanthamurthi, R; Martienssen, RA (24 September 2015). "Loss of Karma transposon methylation underlies the mantled somaclonal variant of oil palm". Nature. 525 (7570): 533–7. doi:10.1038/nature15365. PMC 4857894Freely accessible. PMID 26352475. 
  28. ^ Horn, AV; Klawitter, S; Held, U; Berger, A; Vasudevan, AA; Bock, A; Hofmann, H; Hanschmann, KM; Trösemeier, JH; Flory, E; Jabulowsky, RA; Han, JS; Löwer, J; Löwer, R; Münk, C; Schumann, GG (January 2014). "Human LINE-1 restriction by APOBEC3C is deaminase independent and mediated by an ORF1p interaction that affects LINE reverse transcriptase activity". Nucleic Acids Research. 42 (1): 396–416. doi:10.1093/nar/gkt898. PMC 3874205Freely accessible. PMID 24101588. 
  29. ^ Kazazian, H. H.; Wong, C.; Youssoufian, H.; Scott, A. F.; Phillips, D. G.; Antonarakis, S. E. (1988-03-10). "Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man". Nature. 332 (6160): 164–166. doi:10.1038/332164a0. ISSN 0028-0836. PMID 2831458. 
  30. ^ Solyom, Szilvia; Kazazian, Haig H. (2012-02-24). "Mobile elements in the human genome: implications for disease". Genome Medicine. 4 (2): 12. doi:10.1186/gm311. ISSN 1756-994X. PMC 3392758Freely accessible. PMID 22364178. 
  31. ^ Carreira PE1, Richardson SR, Faulkner GJ (2014). "L1 retrotransposons, cancer stem cells and oncogenesis". FEBS Journal. 281 (1): 63–67. doi:10.1111/febs.12601. PMC 4160015Freely accessible. PMID 24286172. 
  32. ^ Spadafora, C (2015). "A LINE-1-encoded reverse transcriptase-dependent regulatory mechanism is active in embryogenesis and tumorigenesis". Ann N Y Acad Sci. 1341 (1): 164–71. doi:10.1111/nyas.12637. 
  33. ^ deHaro D, Kines KJ, Sokolowski M, Dauchy RT, Streva VA, Hill SM, Hanifin JP, Brainard GC, Blask DE, Belancio VP (2014). "Regulation of L1 expression and retrotransposition by melatonin and its receptor: implications for cancer risk associated with light exposure at night". Nucleic Acids Research. 42 (12): 7694–7707. doi:10.1093/nar/gku503. PMC 4081101Freely accessible. PMID 24914052.