“Long interspersed nuclear element”的意思、由来-开放百科全书

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.^[8] 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

The first description of an approximately 6.4 kb long LINE-derived sequence was published by J. Adams et al. in 1980.^[9]

Types

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.^[10]{{rp|at=fig. 1}}

In plant genomes, so far only LINEs of the L1 and RTE clade have been reported.^[11]^[12]^[13] Whereas L1 elements diversify into several subclades, RTE-type LINEs are highly conserved, often constituting a single family.^[14]^[15]

In fungi, Tad, L1, CRE, Deceiver and Inkcap-like elements have been identified,^[16] with Tad-like elements appearing exclusively in fungal genomes.^[17]

All LINEs encode a least one protein, ORF2, which contains an RT and an endonuclease (EN) domain, either an N-terminal APE or a C-terminal RLE or rarely both. A ribonuclease H domain is occasionally present. Except for the evolutionary ancient R2 and RTE superfamilies, LINEs usually encode for another protein named ORF1, which may contain an Gag-knuckle, a L1-like RRM ({{InterPro|IPR035300}}), and/or an esterase. 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.^[10]{{rp|at=fig. 1}}

L1 element

The LINE-1/L1-element is the only element that is still active in the human genome today. It is found in all mammals.^[18]

Other elements

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 elements lack flanking target site duplications.^[19] The L2 (and L3) elements are in the same group as the CR1 clade, Jockey.^[20]

Incidence

In human

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.^[21] They probably originated from the RTE family of LINEs.^[22] 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.^[23]

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.^[24]

Propagation

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.^[25] The complex is transported back into the nucleus, where the ORF2 endonuclease domain opens the DNA (at TTAAAA hexanucleotide motifs in mammals^[26]). 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^[27]

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

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.^[28]

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.^[29]

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.^[30]

Association with disease

A historic example of L1-conferred disease is Haemophilia A, which is caused by insertional mutagenesis.^[31] There are nearly 100 examples of known diseases caused by retroelement insertions, including some types of cancer and neurological disorders.^[32] Correlation between L1 mobilization and oncogenesis has been reported for epithelial cell cancer (carcinoma).^[33] Hypomethylation of LINES is associated with chromosomal instability and altered gene expression^[34] and is found in various cancer cell types in various tissues types.^[35]^[34] Hypomethylation of a specific L1 located in the MET onco gene is associated with bladder cancer tumorogenesis,^[36] Shift work sleep disorder^[37] 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.^[38]

References

1. ^{{cite journal | vauthors = Ewing AD, Kazazian HH | title = Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans | journal = Genome Research | volume = 21 | issue = 6 | pages = 985–90 | date = June 2011 | pmid = 20980553 | pmc = 3106331 | doi = 10.1101/gr.114777.110 }}
2. ^{{cite journal | vauthors = Huang X, Su G, Wang Z, Shangguan S, Cui X, Zhu J, Kang M, Li S, Zhang T, Wu F, Wang L | display-authors = 6 | title = Hypomethylation of long interspersed nucleotide element-1 in peripheral mononuclear cells of juvenile systemic lupus erythematosus patients in China | journal = International Journal of Rheumatic Diseases | volume = 17 | issue = 3 | pages = 280–90 | date = March 2014 | pmid = 24330152 | doi = 10.1111/1756-185X.12239 }}
3. ^{{cite journal | vauthors = Rodić N, Burns KH | title = Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms? | journal = PLoS Genetics | volume = 9 | issue = 3 | pages = e1003402 | date = March 2013 | pmid = 23555307 | pmc = 3610623 | doi = 10.1371/journal.pgen.1003402 }}
4. ^{{cite journal | vauthors = Singer MF | title = SINEs and LINEs: highly repeated short and long interspersed sequences in mammalian genomes | journal = Cell | volume = 28 | issue = 3 | pages = 433–4 | date = March 1982 | pmid = 6280868 | doi = 10.1016/0092-8674(82)90194-5 }}
5. ^{{Cite journal | doi = 10.1016/S0959-440X(98)80067-5| title = Repeats in genomic DNA: Mining and meaning| year = 1998| last1 = Jurka | first1 = J. | journal = Current Opinion in Structural Biology| volume = 8| issue = 3| pages = 333–337}}
6. ^{{cite journal | vauthors = Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M, Clamp M, Chang JL, Kulbokas EJ, Zody MC, Mauceli E, Xie X, Breen M, Wayne RK, Ostrander EA, Ponting CP, Galibert F, Smith DR, DeJong PJ, Kirkness E, Alvarez P, Biagi T, Brockman W, Butler J, Chin CW, Cook A, Cuff J, Daly MJ, DeCaprio D, Gnerre S, Grabherr M, Kellis M, Kleber M, Bardeleben C, Goodstadt L, Heger A, Hitte C, Kim L, Koepfli KP, Parker HG, Pollinger JP, Searle SM, Sutter NB, Thomas R, Webber C, Baldwin J, Abebe A, Abouelleil A, Aftuck L, Ait-Zahra M, Aldredge T, Allen N, An P, Anderson S, Antoine C, Arachchi H, Aslam A, Ayotte L, Bachantsang P, Barry A, Bayul T, Benamara M, Berlin A, Bessette D, Blitshteyn B, Bloom T, Blye J, Boguslavskiy L, Bonnet C, Boukhgalter B, Brown A, Cahill P, Calixte N, Camarata J, Cheshatsang Y, Chu J, Citroen M, Collymore A, Cooke P, Dawoe T, Daza R, Decktor K, DeGray S, Dhargay N, Dooley K, Dooley K, Dorje P, Dorjee K, Dorris L, Duffey N, Dupes A, Egbiremolen O, Elong R, Falk J, Farina A, Faro S, Ferguson D, Ferreira P, Fisher S, FitzGerald M, Foley K, Foley C, Franke A, Friedrich D, Gage D, Garber M, Gearin G, Giannoukos G, Goode T, Goyette A, Graham J, Grandbois E, Gyaltsen K, Hafez N, Hagopian D, Hagos B, Hall J, Healy C, Hegarty R, Honan T, Horn A, Houde N, Hughes L, Hunnicutt L, Husby M, Jester B, Jones C, Kamat A, Kanga B, Kells C, Khazanovich D, Kieu AC, Kisner P, Kumar M, Lance K, Landers T, Lara M, Lee W, Leger JP, Lennon N, Leuper L, LeVine S, Liu J, Liu X, Lokyitsang Y, Lokyitsang T, Lui A, Macdonald J, Major J, Marabella R, Maru K, Matthews C, McDonough S, Mehta T, Meldrim J, Melnikov A, Meneus L, Mihalev A, Mihova T, Miller K, Mittelman R, Mlenga V, Mulrain L, Munson G, Navidi A, Naylor J, Nguyen T, Nguyen N, Nguyen C, Nguyen T, Nicol R, Norbu N, Norbu C, Novod N, Nyima T, Olandt P, O'Neill B, O'Neill K, Osman S, Oyono L, Patti C, Perrin D, Phunkhang P, Pierre F, Priest M, Rachupka A, Raghuraman S, Rameau R, Ray V, Raymond C, Rege F, Rise C, Rogers J, Rogov P, Sahalie J, Settipalli S, Sharpe T, Shea T, Sheehan M, Sherpa N, Shi J, Shih D, Sloan J, Smith C, Sparrow T, Stalker J, Stange-Thomann N, Stavropoulos S, Stone C, Stone S, Sykes S, Tchuinga P, Tenzing P, Tesfaye S, Thoulutsang D, Thoulutsang Y, Topham K, Topping I, Tsamla T, Vassiliev H, Venkataraman V, Vo A, Wangchuk T, Wangdi T, Weiand M, Wilkinson J, Wilson A, Yadav S, Yang S, Yang X, Young G, Yu Q, Zainoun J, Zembek L, Zimmer A, Lander ES | display-authors = 6 | title = Genome sequence, comparative analysis and haplotype structure of the domestic dog | journal = Nature | volume = 438 | issue = 7069 | pages = 803–19 | date = December 2005 | pmid = 16341006 | doi = 10.1038/nature04338 }}
7. ^{{cite book | vauthors = Schumann GG, Gogvadze EV, Osanai-Futahashi M, Kuroki A, Münk C, Fujiwara H, Ivics Z, Buzdin AA | display-authors = 6 | title = Unique functions of repetitive transcriptomes | volume = 285 | pages = 115–88 | date = 2010-01-01 | pmid = 21035099 | doi = 10.1016/B978-0-12-381047-2.00003-7 | isbn = 9780123810472 | series = International Review of Cell and Molecular Biology }}
8. ^{{cite journal | vauthors = Sheen FM, Sherry ST, Risch GM, Robichaux M, Nasidze I, Stoneking M, Batzer MA, Swergold GD | display-authors = 6 | title = Reading between the LINEs: human genomic variation induced by LINE-1 retrotransposition | journal = Genome Research | volume = 10 | issue = 10 | pages = 1496–508 | date = October 2000 | pmid = 11042149 | pmc = 310943 | doi = 10.1101/gr.149400 }}
9. ^{{Cite journal | doi = 10.1093/nar/8.24.6113| pmc = 328076| title = A family of long reiterated DNA sequences, one copy of which is next to the human beta globin gene| year = 1980| last1 = Adams | first1 = J. W. | last2 = Kaufman | first2 = R. E. | last3 = Kretschmer | first3 = P. J. | last4 = Harrison | first4 = M.| last5 = Nienhuis | first5 = A. W. | journal = Nucleic Acids Research| volume = 8| issue = 24| pages = 6113–6128}}
10. ^¹{{cite journal | vauthors = Kapitonov VV, Tempel S, Jurka J | title = Simple and fast classification of non-LTR retrotransposons based on phylogeny of their RT domain protein sequences | journal = Gene | volume = 448 | issue = 2 | pages = 207–13 | date = December 2009 | pmid = 19651192 | pmc = 2829327 | doi = 10.1016/j.gene.2009.07.019 }}
11. ^{{cite journal | vauthors = Heitkam T, Schmidt T | title = BNR - a LINE family from Beta vulgaris - contains a RRM domain in open reading frame 1 and defines a L1 sub-clade present in diverse plant genomes | journal = The Plant Journal | volume = 59 | issue = 6 | pages = 872–82 | date = September 2009 | pmid = 19473321 | doi = 10.1111/j.1365-313x.2009.03923.x }}
12. ^{{cite journal | vauthors = Zupunski V, Gubensek F, Kordis D | title = Evolutionary dynamics and evolutionary history in the RTE clade of non-LTR retrotransposons | journal = Molecular Biology and Evolution | volume = 18 | issue = 10 | pages = 1849–63 | date = October 2001 | pmid = 11557792 | doi = 10.1093/oxfordjournals.molbev.a003727 }}
13. ^{{cite journal | vauthors = Komatsu M, Shimamoto K, Kyozuka J | title = Two-step regulation and continuous retrotransposition of the rice LINE-type retrotransposon Karma | journal = The Plant Cell | volume = 15 | issue = 8 | pages = 1934–44 | date = August 2003 | pmid = 12897263 | pmc = 167180 | doi = 10.1105/tpc.011809 }}
14. ^{{cite journal | vauthors = Heitkam T, Holtgräwe D, Dohm JC, Minoche AE, Himmelbauer H, Weisshaar B, Schmidt T | display-authors = 6 | title = Profiling of extensively diversified plant LINEs reveals distinct plant-specific subclades | journal = The Plant Journal | volume = 79 | issue = 3 | pages = 385–97 | date = August 2014 | pmid = 24862340 | doi = 10.1111/tpj.12565 }}
15. ^{{cite journal | vauthors = Smyshlyaev G, Voigt F, Blinov A, Barabas O, Novikova O | title = Acquisition of an Archaea-like ribonuclease H domain by plant L1 retrotransposons supports modular evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 50 | pages = 20140–5 | date = December 2013 | pmid = 24277848 | pmc = 3864347 | doi = 10.1073/pnas.1310958110 }}
16. ^{{cite journal | vauthors = Novikova O, Fet V, Blinov A | title = Non-LTR retrotransposons in fungi | journal = Functional & Integrative Genomics | volume = 9 | issue = 1 | pages = 27–42 | date = February 2009 | pmid = 18677522 | doi = 10.1007/s10142-008-0093-8 }}
17. ^{{cite journal | vauthors = Malik HS, Burke WD, Eickbush TH | title = The age and evolution of non-LTR retrotransposable elements | journal = Molecular Biology and Evolution | volume = 16 | issue = 6 | pages = 793–805 | date = June 1999 | pmid = 10368957 | doi = 10.1093/oxfordjournals.molbev.a026164 }}
18. ^{{cite journal | vauthors = Warren WC, Hillier LW, Marshall Graves JA, Birney E, Ponting CP, Grützner F, Belov K, Miller W, Clarke L, Chinwalla AT, Yang SP, Heger A, Locke DP, Miethke P, Waters PD, Veyrunes F, Fulton L, Fulton B, Graves T, Wallis J, Puente XS, López-Otín C, Ordóñez GR, Eichler EE, Chen L, Cheng Z, Deakin JE, Alsop A, Thompson K, Kirby P, Papenfuss AT, Wakefield MJ, Olender T, Lancet D, Huttley GA, Smit AF, Pask A, Temple-Smith P, Batzer MA, Walker JA, Konkel MK, Harris RS, Whittington CM, Wong ES, Gemmell NJ, Buschiazzo E, Vargas Jentzsch IM, Merkel A, Schmitz J, Zemann A, Churakov G, Kriegs JO, Brosius J, Murchison EP, Sachidanandam R, Smith C, Hannon GJ, Tsend-Ayush E, McMillan D, Attenborough R, Rens W, Ferguson-Smith M, Lefèvre CM, Sharp JA, Nicholas KR, Ray DA, Kube M, Reinhardt R, Pringle TH, Taylor J, Jones RC, Nixon B, Dacheux JL, Niwa H, Sekita Y, Huang X, Stark A, Kheradpour P, Kellis M, Flicek P, Chen Y, Webber C, Hardison R, Nelson J, Hallsworth-Pepin K, Delehaunty K, Markovic C, Minx P, Feng Y, Kremitzki C, Mitreva M, Glasscock J, Wylie T, Wohldmann P, Thiru P, Nhan MN, Pohl CS, Smith SM, Hou S, Nefedov M, de Jong PJ, Renfree MB, Mardis ER, Wilson RK | display-authors = 6 | title = Genome analysis of the platypus reveals unique signatures of evolution | journal = Nature | volume = 453 | issue = 7192 | pages = 175–83 | date = May 2008 | pmid = 18464734 | pmc = 2803040 | doi = 10.1038/nature06936 | authorlink4 = Ewan Birney | authorlink5 = Chris Ponting }}
19. ^{{Cite book |title=Anthology of Human Repetitive DNA|last=Kapitonov|first=Vladimir V.|last2=Pavlicek|first2=Adam|last3=Jurka|first3=Jerzy | name-list-format = vanc |date=2006-01-01|publisher=Wiley-VCH Verlag GmbH & Co. KGaA|isbn=9783527600908 |doi=10.1002/3527600906.mcb.200300166}}
20. ^{{cite journal |last1=Lovsin |first1=N |last2=Gubensek |first2=F |last3=Kordi |first3=D |title=Evolutionary dynamics in a novel L2 clade of non-LTR retrotransposons in Deuterostomia. |journal=Molecular biology and evolution |date=December 2001 |volume=18 |issue=12 |pages=2213-24 |doi=10.1093/oxfordjournals.molbev.a003768 |pmid=11719571}}
21. ^¹²{{cite journal | vauthors = Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann Y, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blöcker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowki J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ, Szustakowki J | display-authors = 6 | title = Initial sequencing and analysis of the human genome | journal = Nature | volume = 409 | issue = 6822 | pages = 860–921 | date = February 2001 | pmid = 11237011 | doi = 10.1038/35057062 }}
22. ^{{cite journal |last1=Malik |first1=HS |last2=Eickbush |first2=TH |title=The RTE class of non-LTR retrotransposons is widely distributed in animals and is the origin of many SINEs. |journal=Molecular biology and evolution |date=September 1998 |volume=15 |issue=9 |pages=1123-34 |doi=10.1093/oxfordjournals.molbev.a026020 |pmid=9729877}}
23. ^{{cite journal | vauthors = Streva VA, Jordan VE, Linker S, Hedges DJ, Batzer MA, Deininger PL | title = Sequencing, identification and mapping of primed L1 elements (SIMPLE) reveals significant variation in full length L1 elements between individuals | journal = BMC Genomics | volume = 16 | issue = 220 | pages = 220 | date = March 2015 | pmid = 25887476 | pmc = 4381410 | doi = 10.1186/s12864-015-1374-y }}
24. ^{{cite journal | vauthors = Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T, Sunaga F, Toritsuka M, Ikawa D, Kakita A, Kato M, Kasai K, Kishimoto T, Nawa H, Okano H, Yoshikawa T, Kato T, Iwamoto K | display-authors = 6 | title = Increased l1 retrotransposition in the neuronal genome in schizophrenia | journal = Neuron | volume = 81 | issue = 2 | pages = 306–13 | date = January 2014 | pmid = 24389010 | doi = 10.1016/j.neuron.2013.10.053 }}
25. ^{{cite journal | vauthors = Babushok DV, Ostertag EM, Courtney CE, Choi JM, Kazazian HH | title = L1 integration in a transgenic mouse model | journal = Genome Research | volume = 16 | issue = 2 | pages = 240–50 | date = February 2006 | pmid = 16365384 | pmc = 1361720 | doi = 10.1101/gr.4571606 }}
26. ^{{cite journal | vauthors = Jurka J | title = Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 5 | pages = 1872–7 | date = March 1997 | pmid = 9050872 | pmc = 20010 | doi = 10.1073/pnas.94.5.1872 }}
27. ^{{cite journal | vauthors = Luan DD, Korman MH, Jakubczak JL, Eickbush TH | title = Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition | journal = Cell | volume = 72 | issue = 4 | pages = 595–605 | date = February 1993 | pmid = 7679954 | doi = 10.1016/0092-8674(93)90078-5 }}
28. ^{{cite journal | vauthors = Yang N, Kazazian HH | title = L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells | journal = Nature Structural & Molecular Biology | volume = 13 | issue = 9 | pages = 763–71 | date = September 2006 | pmid = 16936727 | doi = 10.1038/nsmb1141 }}
29. ^{{cite journal | vauthors = 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 | display-authors = 6 | title = Loss of Karma transposon methylation underlies the mantled somaclonal variant of oil palm | journal = Nature | volume = 525 | issue = 7570 | pages = 533–7 | date = September 2015 | pmid = 26352475 | pmc = 4857894 | doi = 10.1038/nature15365 }}
30. ^{{cite journal | vauthors = 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 | display-authors = 6 | title = Human LINE-1 restriction by APOBEC3C is deaminase independent and mediated by an ORF1p interaction that affects LINE reverse transcriptase activity | journal = Nucleic Acids Research | volume = 42 | issue = 1 | pages = 396–416 | date = January 2014 | pmid = 24101588 | pmc = 3874205 | doi = 10.1093/nar/gkt898 }}
31. ^{{cite journal | vauthors = Kazazian HH, Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE | title = Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man | journal = Nature | volume = 332 | issue = 6160 | pages = 164–6 | date = March 1988 | pmid = 2831458 | doi = 10.1038/332164a0 }}
32. ^{{cite journal | vauthors = Solyom S, Kazazian HH | title = Mobile elements in the human genome: implications for disease | journal = Genome Medicine | volume = 4 | issue = 2 | pages = 12 | date = February 2012 | pmid = 22364178 | pmc = 3392758 | doi = 10.1186/gm311 }}
33. ^{{cite journal | vauthors = Carreira PE, Richardson SR, Faulkner GJ | title = L1 retrotransposons, cancer stem cells and oncogenesis | journal = The FEBS Journal | volume = 281 | issue = 1 | pages = 63–73 | date = January 2014 | pmid = 24286172 | pmc = 4160015 | doi = 10.1111/febs.12601 }}
34. ^¹{{cite journal | vauthors = Kitkumthorn N, Mutirangura A | title = Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications | journal = Clinical Epigenetics | volume = 2 | issue = 2 | pages = 315–30 | date = August 2011 | pmid = 22704344 | pmc = 3365388 | doi = 10.1007/s13148-011-0032-8 }}
35. ^{{cite journal | vauthors = Estécio MR, Gharibyan V, Shen L, Ibrahim AE, Doshi K, He R, Jelinek J, Yang AS, Yan PS, Huang TH, Tajara EH, Issa JP | title = LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability | journal = PLOS One | volume = 2 | issue = 5 | pages = e399 | date = May 2007 | pmid = 17476321 | pmc = 1851990 | doi = 10.1371/journal.pone.0000399 }}
36. ^{{cite journal | vauthors = Wolff EM, Byun HM, Han HF, Sharma S, Nichols PW, Siegmund KD, Yang AS, Jones PA, Liang G | display-authors = 6 | title = Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer | journal = PLoS Genetics | volume = 6 | issue = 4 | pages = e1000917 | date = April 2010 | pmid = 20421991 | pmc = 2858672 | doi = 10.1371/journal.pgen.1000917 }}
37. ^{{cite journal | vauthors = Spadafora C | title = A LINE-1-encoded reverse transcriptase-dependent regulatory mechanism is active in embryogenesis and tumorigenesis | journal = Annals of the New York Academy of Sciences | volume = 1341 | issue = 1 | pages = 164–71 | date = April 2015 | pmid = 25586649 | doi = 10.1111/nyas.12637 }}
38. ^{{cite journal | vauthors = deHaro D, Kines KJ, Sokolowski M, Dauchy RT, Streva VA, Hill SM, Hanifin JP, Brainard GC, Blask DE, Belancio VP | display-authors = 6 | title = Regulation of L1 expression and retrotransposition by melatonin and its receptor: implications for cancer risk associated with light exposure at night | journal = Nucleic Acids Research | volume = 42 | issue = 12 | pages = 7694–707 | date = July 2014 | pmid = 24914052 | pmc = 4081101 | doi = 10.1093/nar/gku503 }}