Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2020

01-12-2020 | Miscarriage | Review

A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage

Authors: Chao Lou, John L. Goodier, Rong Qiang

Published in: Reproductive Biology and Endocrinology | Issue 1/2020

Login to get access

Abstract

LINE1 retrotransposons are mobile DNA elements that copy and paste themselves into new sites in the genome. To ensure their evolutionary success, heritable new LINE-1 insertions accumulate in cells that can transmit genetic information to the next generation (i.e., germ cells and embryonic stem cells). It is our hypothesis that LINE1 retrotransposons, insertional mutagens that affect expression of genes, may be causal agents of early miscarriage in humans. The cell has evolved various defenses restricting retrotransposition-caused mutation, but these are occasionally relaxed in certain somatic cell types, including those of the early embryo. We predict that reduced suppression of L1s in germ cells or early-stage embryos may lead to excessive genome mutation by retrotransposon insertion, or to the induction of an inflammatory response or apoptosis due to increased expression of L1-derived nucleic acids and proteins, and so disrupt gene function important for embryogenesis. If correct, a novel threat to normal human development is revealed, and reverse transcriptase therapy could be one future strategy for controlling this cause of embryonic damage in patients with recurrent miscarriages.
Literature
1.
2.
Pinar MH, Gibbins K, He M, Kostadinov S, Silver R. Early pregnancy losses: review of nomenclature, histopathology, and possible etiologies. Fetal Pediatr Pathol. 2018;37(3):191–209.PubMedCrossRef
3.
Homer HA. Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol. 2019;59(1):36–44.PubMedCrossRef
4.
Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B, Matsuura J, Matsuyama A, Wilson C, Yamane JA, Jacobs PA. A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet. 1980;44(2):151–78.PubMedCrossRef
5.
Daniely M, Aviram-Goldring A, Barkai G, Goldman B. Detection of chromosomal aberration in fetuses arising from recurrent spontaneous abortion by comparative genomic hybridization. Hum Reprod. 1998;13(4):805–9.PubMedCrossRef
6.
Colley E, Hamilton S, Smith P, Morgan NV, Coomarasamy A, Allen S. Potential genetic causes of miscarriage in euploid pregnancies: a systematic review. Hum Reprod Update. 2019;25(4):452–72.PubMedCrossRef
7.
Yin LJ, Zhang Y, Lv PP, He WH, Wu YT, Liu AX, Ding GL, Dong MY, Qu F, Xu CM, et al. Insufficient maintenance DNA methylation is associated with abnormal embryonic development. BMC Med. 2012;10:26.PubMedPubMedCentralCrossRef
8.
Perez-Garcia V, Fineberg E, Wilson R, Murray A, Mazzeo CI, Tudor C, Sienerth A, White JK, Tuck E, Ryder EJ, et al. Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature. 2018;555(7697):463–8.PubMedPubMedCentralCrossRef
9.
10.
Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103–11.CrossRef
11.
12.
13.
de Koning AP, Gu W, Castoe TA, Batzer MA, Pollock DD. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.PubMedPubMedCentralCrossRef
14.
15.
Naveira H, Bello X, Abal-Fabeiro JL, Maside X. Evidence for the persistence of an active endogenous retrovirus (ERVE) in humans. Genetica. 2014;142(5):451–60.PubMedCrossRef
16.
Wildschutte JH, Williams ZH, Montesion M, Subramanian RP, Kidd JM, Coffin JM. Discovery of unfixed endogenous retrovirus insertions in diverse human populations. Proc Natl Acad Sci. 2016;113(16):E2326–34.PubMedCrossRefPubMedCentral
17.
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860–921.PubMedCrossRef
18.
Richardson SR, Doucet AJ, Kopera HC, Moldovan JB, Garcia-Perez JL, Moran JV. The Influence of LINE-1 and SINE retrotransposons on mammalian genomes. Microbiol Spectr. 2015;3(2):MDNA3-0061-2014.PubMedCrossRef
19.
Frankish A, Diekhans M, Ferreira AM, Johnson R, Jungreis I, Loveland J, Mudge JM, Sisu C, Wright J, Armstrong J, et al. GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res. 2019;47(D1):D766–d73.PubMedCrossRef
20.
Wei W, Gilbert N, Ooi SL, Lawler JF, Ostertag EM, Kazazian HH, Boeke JD, Moran JV. Human L1 retrotransposition: cis preference versus trans complementation. Mol Cell Biol. 2001;21(4):1429–39.PubMedPubMedCentralCrossRef
21.
Esnault C, Maestre J, Heidmann T. Human LINE retrotransposons generate processed pseudogenes. Nat Genet. 2000;24(4):363–7.PubMedCrossRef
22.
Martin SL, Branciforte D, Keller D, Bain DL. Trimeric structure for an essential protein in L1 retrotransposition. Proc Natl Acad Sci U S A. 2003;100(24):13815–20.PubMedPubMedCentralCrossRef
23.
Luan DD, Korman MH, Jakubczak JL, Eickbush TH. Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell. 1993;72(4):595–605.PubMedCrossRef
24.
Brouha B, Meischl C, Ostertag E, de Boer M, Zhang Y, Neijens H, Roos D, Kazazian HH Jr. Evidence consistent with human L1 retrotransposition in maternal meiosis I. Am J Hum Genet. 2002;71(2):327–36.PubMedPubMedCentralCrossRef
25.
Seleme MC, Vetter MR, Cordaux R, Bastone L, Batzer MA, Kazazian HH Jr. Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. Proc Natl Acad Sci U S A. 2006;103(17):6611–6.PubMedCrossRef
26.
Beck CR, Collier P, Macfarlane C, Malig M, Kidd JM, Eichler EE, Badge RM, Moran JV. LINE-1 retrotransposition activity in human genomes. Cell. 2010;141(7):1159–70.PubMedPubMedCentralCrossRef
27.
28.
Kazazian HH Jr. An estimated frequency of endogenous insertional mutations in humans. Nat Genet. 1999;22(2):130.PubMedCrossRef
29.
Li X, Scaringe WA, Hill KA, Roberts S, Mengos A, Careri D, Pinto MT, Kasper CK, Sommer SS. Frequency of recent retrotransposition events in the human factor IX gene. Hum Mutat. 2001;17(6):511–9.PubMedCrossRef
30.
Cordaux R, Hedges DJ, Herke SW, Batzer MA. Estimating the retrotransposition rate of human Alu elements. Gene. 2006;373:134–7.PubMedCrossRef
31.
Xing J, Zhang Y, Han K, Salem AH, Sen SK, Huff CD, Zhou Q, Kirkness EF, Levy S, Batzer MA, et al. Mobile elements create structural variation: analysis of a complete human genome. Genome Res. 2009;19(9):1516–26.PubMedPubMedCentralCrossRef
32.
Hancks DC, Kazazian HH. Roles for retrotransposon insertions in human disease. Mob DNA. 2016;7(1):1.CrossRef
33.
Richardson SR, Gerdes P, Gerhardt DJ, Sanchez-Luque FJ, Bodea GO, Munoz-Lopez M, Jesuadian JS, Kempen MHC, Carreira PE, Jeddeloh JA, et al. Heritable L1 retrotransposition in the mouse primordial germline and early embryo. Genome Res. 2017;27(8):1395–405.PubMedPubMedCentralCrossRef
34.
Feusier J, Watkins WS, Thomas J, Farrell A, Witherspoon DJ, Baird L, Ha H, Xing J, Jorde LB. Pedigree-based estimation of human mobile element retrotransposition rates. Genome Res. 2019;29(10):1567-77.PubMedPubMedCentralCrossRef
35.
Crichton JH, Dunican DS, MacLennan M, Meehan RR, Adams IR. Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline. Cell Mol Life Sci. 2014;71(9):1581–605.PubMedCrossRef
36.
37.
Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, Morell M, O’Shea KS, Moran JV, Gage FH. L1 retrotransposition in human neural progenitor cells. Nature. 2009;460(7259):1127–31.PubMedPubMedCentralCrossRef
38.
Thomas CA, Paquola AC, Muotri AR. LINE-1 retrotransposition in the nervous system. Annu Rev Cell Dev Biol. 2012;28:555–73.PubMedCrossRef
39.
Reilly MT, Faulkner GJ, Dubnau J, Ponomarev I, Gage FH. The role of transposable elements in health and diseases of the central nervous system. J Neurosci. 2013;33(45):17577–86.PubMedPubMedCentralCrossRef
40.
Carreira PE, Richardson SR, Faulkner GJ. L1 retrotransposons, cancer stem cells and oncogenesis. FEBS J. 2014;281(1):63–73.PubMedCrossRef
41.
Erwin JA, Marchetto MC, Gage FH. Mobile DNA elements in the generation of diversity and complexity in the brain. Nat Rev Neurosci. 2014;15(8):497–506.PubMedPubMedCentralCrossRef
42.
43.
Richardson SR, Morell S, Faulkner GJ. L1 retrotransposons and somatic mosaicism in the brain. Annu Rev Genet. 2014;48:1–27.PubMedCrossRef
44.
45.
Gerdes P, Richardson SR, Mager DL, Faulkner GJ. Transposable elements in the mammalian embryo: pioneers surviving through stealth and service. Genome Biol. 2016;17(1):1.CrossRef
46.
47.
Scott EC, Devine SE. The role of somatic L1 retrotransposition in human cancers. Viruses. 2017;9(6):E131.PubMedCrossRef
48.
Faulkner GJ, Garcia-Perez JL. L1 mosaicism in mammals: extent, effects, and evolution. Trends Genet. 2017;33(11):802–16.PubMedCrossRef
49.
Richardson SR, Faulkner GJ. Heritable L1 retrotransposition events during development: understanding their origins: examination of heritable, endogenous L1 retrotransposition in mice opens up exciting new questions and research directions. Bioessays. 2018;40(6):e1700189.PubMedCrossRef
50.
51.
An W, Han JS, Wheelan SJ, Davis ES, Coombes CE, Ye P, Triplett C, Boeke JD. Active retrotransposition by a synthetic L1 element in mice. Proc Natl Acad Sci. 2006;103(49):18662–7.PubMedCrossRefPubMedCentral
52.
van den Hurk JA, Meij IC, Seleme MC, Kano H, Nikopoulos K, Hoefsloot LH, Sistermans EA, de Wijs IJ, Mukhopadhyay A, Plomp AS, et al. L1 retrotransposition can occur early in human embryonic development. Hum Mol Genet. 2007;16(13):1587–92.PubMedCrossRef
53.
Kano H, Godoy I, Courtney C, Vetter MR, Gerton GL, Ostertag EM, Kazazian HH. L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev. 2009;23(11):1303–12.PubMedPubMedCentralCrossRef
54.
Garcia-Perez JL, Marchetto MC, Muotri AR, Coufal NG, Gage FH, O’Shea KS, Moran JV. LINE-1 retrotransposition in human embryonic stem cells. Hum Mol Genet. 2007;16(13):1569–77.PubMedCrossRef
55.
Garcia-Perez JL, Morell M, Scheys JO, Kulpa DA, Morell S, Carter CC, Hammer GD, Collins KL, O’Shea KS, Menendez P, et al. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature. 2010;466(7307):769–73.PubMedPubMedCentralCrossRef
56.
Macia A, Muñoz-Lopez M, Cortes JL, Hastings RK, Morell S, Lucena-Aguilar G, Marchal JA, Badge RM, Garcia-Perez JL. Epigenetic control of retrotransposon expression in human embryonic stem cells. Mol Cell Biol. 2011;31(2):300–16.PubMedCrossRef
57.
Wissing S, Montano M, Garcia-Perez JL, Moran JV, Greene WC. Endogenous APOBEC3B restricts LINE-1 retrotransposition in transformed cells and human embryonic stem cells. J Biol Chem. 2011;286(42):36427–37.PubMedPubMedCentralCrossRef
58.
Wissing S, Muñoz-Lopez M, Macia A, Yang Z, Montano M, Collins W, Garcia-Perez JL, Moran JV, Greene WC. Reprogramming somatic cells into iPS cells activates LINE-1 retroelement mobility. Hum Mol Genet. 2012;21(1):208–18.PubMedCrossRef
59.
Friedli M, Turelli P, Kapopoulou A, Rauwel B, Castro-Díaz N, Rowe HM, Ecco G, Unzu C, Planet E, Lombardo A, et al. Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency. Genome Res. 2014;24(8):1251–9.PubMedPubMedCentralCrossRef
60.
MacLennan M, Garcia-Canadas M, Reichmann J, Khazina E, Wagner G, Playfoot CJ, Salvador-Palomeque C, Mann AR, Peressini P, Sanchez L, et al. Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells. Elife. 2017;6:e26152.PubMedPubMedCentralCrossRef
61.
Arokium H, Kamata M, Kim S, Kim N, Liang M, Presson AP, Chen IS. Deep sequencing reveals low incidence of endogenous LINE-1 retrotransposition in human induced pluripotent stem cells. PLoS One. 2014;9(10):e108682.PubMedPubMedCentralCrossRef
62.
Klawitter S, Fuchs NV, Upton KR, Muñoz-Lopez M, Shukla R, Wang J, Garcia-Cañadas M, Lopez-Ruiz C, Gerhardt DJ, Sebe A, et al. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. Nat Commun. 2016;7:10286.PubMedPubMedCentralCrossRef
63.
Muñoz-Lopez M, Vilar R, Philippe C, Rahbari R, Richardson SR, Andres-Anton M, Widmann T, Cano D, Cortes JL, Rubio-Roldan A, et al. LINE-1 retrotransposition impacts the genome of human pre-implantation embryos and extraembryonic tissues. bioRxiv. 2019. https://​doi.​org/​10.​1101/​522623.
64.
Williams Z, Morozov P, Mihailovic A, Lin C, Puvvula PK, Juranek S, Rosenwaks Z, Tuschl T. Discovery and Characterization of piRNAs in the human fetal ovary. Cell Rep. 2015;13(4):854–63.PubMedCrossRef
65.
66.
Obbard DJ, Gordon KHJ, Buck AH, Jiggins FM. The evolution of RNAi as a defence against viruses and transposable elements. Philos Trans R Soc B: Biol Sci. 2009;364(1513):99–115.CrossRef
67.
Siomi MC, Sato K, Pezic D, Aravin AA. PIWI-interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol. 2011;12(4):246–58.PubMedCrossRef
68.
Yang Z, Chen K-M, Pandey Radha R, Homolka D, Reuter M, Janeiro Bruno Kotska R, Sachidanandam R, Fauvarque M-O, McCarthy Andrew A, Pillai Ramesh S. PIWI Slicing and EXD1 drive biogenesis of nuclear piRNAs from cytosolic targets of the mouse piRNA pathway. Mol Cell. 2016;61(1):138–52.PubMedPubMedCentralCrossRef
69.
Russell SJ, Stalker L, LaMarre J. PIWIs, piRNAs and retrotransposons: complex battles during reprogramming in gametes and early embryos. Reprod Domest Anim. 2017;52(Suppl 4):28–38.PubMedCrossRef
70.
Aravin AA, Sachidanandam R, Girard A, Fejes-Toth K, Hannon GJ. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science. 2007;316(5825):744–7.PubMedCrossRef
71.
Aravin AA, Sachidanandam R, Bourc’his D, Schaefer C, Pezic D, Toth KF, Bestor T, Hannon GJ. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol Cell. 2008;31(6):785–99.PubMedPubMedCentralCrossRef
72.
Yoder JA, Walsh CP, Bestor TH. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 1997;13(8):335–40.PubMedCrossRef
73.
74.
Crowther P, Doherty J, Linsenmeyer M, Williamson M, Woodcock D. Revised genomic consensus for the hypermethylated CpG island region of the human L1 transposon and integration sites of full length L1 elements from recombinant clones made using methylation-tolerant host strains. Nucleic Acids Res. 1991;19(9):2395–401.PubMedPubMedCentralCrossRef
75.
Hata K, Sakaki Y. Identification of critical CpG sites for repression of L1 transcription by DNA methylation. Gene. 1997;189(2):227–34.PubMedCrossRef
76.
Sanford JP, Clark HJ, Chapman VM, Rossant J. Differences in DNA methylation during oogenesis and spermatogenesis and their persistence during early embryogenesis in the mouse. Genes Dev. 1987;1(10):1039–46.PubMedCrossRef
77.
Bourc’his D, Bestor TH. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature. 2004;431(7004):96–9.PubMedCrossRef
78.
Marius Walter AT, Pérez-Palacios R, Bourc’his D. An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells. eLife Sci. 2016;5:e11418.CrossRef
79.
Seki Y, Yamaji M, Yabuta Y, Sano M, Shigeta M, Matsui Y, Saga Y, Tachibana M, Shinkai Y, Saitou M. Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development. 2007;134(14):2627–38.PubMedCrossRef
80.
81.
Saitou M, Kagiwada S, Kurimoto K. Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development. 2012;139(1):15–31.PubMedCrossRef
82.
Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F, Popp C, Thienpont B, Dean W, Reik W. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell. 2012;48(6):849–62.PubMedPubMedCentralCrossRef
83.
Munoz-Lopez M, Garcia-Canadas M, Macia A, Morell S, Garcia-Perez JL. Analysis of LINE-1 expression in human pluripotent cells. Methods Mol Biol. 2012;873:113–25.PubMedCrossRef
84.
Sanchez-Luque FJ, Kempen MHC, Gerdes P, Vargas-Landin DB, Richardson SR, Troskie RL, Jesuadian JS, Cheetham SW, Carreira PE, Salvador-Palomeque C, et al. LINE-1 evasion of epigenetic repression in humans. Mol Cell. 2019;75(3):590–604.e12.PubMedCrossRef
85.
He ZM, Li J, Hwa YL, Brost B, Fang Q, Jiang SW. Transition of LINE-1 DNA methylation status and altered expression in first and third trimester placentas. PLoS One. 2014;9(5):e96994.PubMedPubMedCentralCrossRef
86.
Perrin D, Ballestar E, Fraga MF, Frappart L, Esteller M, Guerin JF, Dante R. Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta. Oncogene. 2007;26(17):2518–24.PubMedCrossRef
87.
Vasil’ev SA, Tolmacheva EN, Kashevarova AA, Sazhenova EA, Lebedev IN. Methylation status of line-1 retrotransposon in chromosomal mosaicism during the early stages of human embryonic development. Mol Biol (Mosk). 2015;49(1):165–74.
88.
White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, et al. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell. 2013;154(2):452–64.PubMedPubMedCentralCrossRef
89.
Putoux A, Thomas S, Coene KL, Davis EE, Alanay Y, Ogur G, Uz E, Buzas D, Gomes C, Patrier S, et al. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet. 2011;43(6):601–6.PubMedPubMedCentralCrossRef
90.
Carss KJ, Hillman SC, Parthiban V, McMullan DJ, Maher ER, Kilby MD, Hurles ME. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet. 2014;23(12):3269–77.PubMedPubMedCentralCrossRef
91.
Fang Y, Yu S, Ma Y, Sun P, Ma D, Ji C, Kong B. Association of Dll4/notch and HIF-1a -VEGF signaling in the angiogenesis of missed abortion. PLoS One. 2013;8(8):e70667.PubMedPubMedCentralCrossRef
92.
Achache H, Tsafrir A, Prus D, Reich R, Revel A. Defective endometrial prostaglandin synthesis identified in patients with repeated implantation failure undergoing in vitro fertilization. Fertil Steril. 2010;94(4):1271–8.PubMedCrossRef
93.
Filges I, Nosova E, Bruder E, Tercanli S, Townsend K, Gibson WT, Rothlisberger B, Heinimann K, Hall JG, Gregory-Evans CY, et al. Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype. Clin Genet. 2014;86(3):220–8.PubMedCrossRef
94.
Tsurusaki Y, Yonezawa R, Furuya M, Nishimura G, Pooh RK, Nakashima M, Saitsu H, Miyake N, Saito S, Matsumoto N. Whole exome sequencing revealed biallelic IFT122 mutations in a family with CED1 and recurrent pregnancy loss. Clin Genet. 2014;85(6):592–4.PubMedCrossRef
95.
Filges I, Manokhina I, Penaherrera MS, McFadden DE, Louie K, Nosova E, Friedman JM, Robinson WP. Recurrent triploidy due to a failure to complete maternal meiosis II: whole-exome sequencing reveals candidate variants. Mol Hum Reprod. 2015;21(4):339–46.PubMedCrossRef
96.
Bolor H, Mori T, Nishiyama S, Ito Y, Hosoba E, Inagaki H, Kogo H, Ohye T, Tsutsumi M, Kato T, et al. Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am J Hum Genet. 2009;84(1):14–20.PubMedPubMedCentralCrossRef
97.
98.
Suzumori N, Sugiura-Ogasawara M. Genetic factors as a cause of miscarriage. Curr Med Chem. 2010;17(29):3431–7.PubMedCrossRef
99.
Aruna M, Nagaraja T, Andal Bhaskar S, Tarakeswari S, Reddy AG, Thangaraj K, Singh L, Reddy BM. Novel alleles of HLA-DQ and -DR loci show association with recurrent miscarriages among South Indian women. Hum Reprod. 2011;26(4):765–74.PubMedCrossRef
100.
Xue Y, Chen Y, Ayub Q, Huang N, Ball EV, Mort M, Phillips AD, Shaw K, Stenson PD, Cooper DN, et al. Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am J Hum Genet. 2012;91(6):1022–32.PubMedPubMedCentralCrossRef
101.
Liu N, Lee CH, Swigut T, Grow E, Gu B, Bassik MC, Wysocka J. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature. 2018;553(7687):228–32.PubMedCrossRef
102.
Reichmann J, Reddington JP, Best D, Read D, Ollinger R, Meehan RR, Adams IR. The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice. Hum Mol Genet. 2013;22(9):1791–806.PubMedPubMedCentralCrossRef
103.
Newkirk SJ, Lee S, Grandi FC, Gaysinskaya V, Rosser JM, Vanden Berg N, Hogarth CA, Marchetto MCN, Muotri AR, Griswold MD, et al. Intact piRNA pathway prevents L1 mobilization in male meiosis. Proc Natl Acad Sci U S A. 2017;114(28):E5635–e44.PubMedPubMedCentralCrossRef
104.
Goodier JL, Kazazian HH. Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell. 2008;135(1):23–35.PubMedCrossRef
105.
106.
107.
108.
109.
Gilbert N, Lutz-Prigge S, Moran JV. Genomic deletions created upon LINE-1 retrotransposition. Cell. 2002;110(3):315–25.PubMedCrossRef
110.
Symer DE, Connelly C, Szak ST, Caputo EM, Cost GJ, Parmigiani G, Boeke JD. Human l1 retrotransposition is associated with genetic instability in vivo. Cell. 2002;110(3):327–38.PubMedCrossRef
111.
Mine M, Chen JM, Brivet M, Desguerre I, Marchant D, de Lonlay P, Bernard A, Ferec C, Abitbol M, Ricquier D, et al. A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full-length LINE-1 element. Hum Mutat. 2007;28(2):137–42.PubMedCrossRef
112.
Lee J, Ha J, Son SY, Han K. Human genomic deletions generated by SVA-associated events. Comp Funct Genomics. 2012;2012:807270.PubMedPubMedCentral
113.
Takasu M, Hayashi R, Maruya E, Ota M, Imura K, Kougo K, Kobayashi C, Saji H, Ishikawa Y, Asai T, et al. Deletion of entire HLA-A gene accompanied by an insertion of a retrotransposon. Tissue Antigens. 2007;70(2):144–50.PubMedCrossRef
114.
Bailey JA, Liu G, Eichler EE. An Alu transposition model for the origin and expansion of human segmental duplications. Am J Hum Genet. 2003;73(4):823–34.PubMedPubMedCentralCrossRef
115.
Bagheri H, Mercier E, Qiao Y, Stephenson MD, Rajcan-Separovic E. Genomic characteristics of miscarriage copy number variants. Mol Hum Reprod. 2015;21(8):655–61.PubMedPubMedCentralCrossRef
116.
Wen J, Hanna CW, Martell S, Leung PC, Lewis SM, Robinson WP, Stephenson MD, Rajcan-Separovic E. Functional consequences of copy number variants in miscarriage. Mol Cytogenet. 2015;8:6.PubMedPubMedCentralCrossRef
117.
Nazaryan-Petersen L, Bertelsen B, Bak M, Jonson L, Tommerup N, Hancks DC, Tumer Z. Germline chromothripsis driven by L1-mediated retrotransposition and Alu/Alu homologous recombination. Hum Mutat. 2016;37(4):385–95.PubMedCrossRef
118.
de Pagter MS, van Roosmalen MJ, Baas AF, Renkens I, Duran KJ, van Binsbergen E, Tavakoli-Yaraki M, Hochstenbach R, van der Veken LT, Cuppen E, et al. Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring. Am J Hum Genet. 2015;96(4):651–6.PubMedPubMedCentralCrossRef
119.
Giordano R, Magnano AR, Zaccagnini G, Pittoggi C, Moscufo N, Lorenzini R, Spadafora C. Reverse transcriptase activity in mature spermatozoa of mouse. J Cell Biol. 2000;148(6):1107–13.PubMedPubMedCentralCrossRef
120.
Pittoggi C, Sciamanna I, Mattei E, Beraldi R, Lobascio AM, Mai A, Quaglia MG, Lorenzini R, Spadafora C. Role of endogenous reverse transcriptase in murine early embryo development. Mol Reprod Dev. 2003;66(3):225–36.PubMedCrossRef
121.
Sciamanna I, Vitullo P, Curatolo A, Spadafora C. Retrotransposons, reverse transcriptase and the genesis of new genetic information. Gene. 2009;448(2):180–6.PubMedCrossRef
122.
Beraldi R, Pittoggi C, Sciamanna I, Mattei E, Spadafora C. Expression of LINE-1 retroposons is essential for murine preimplantation development. Mol Reprod Dev. 2006;73(3):279–87.PubMedCrossRef
123.
Jones RB, Garrison KE, Wong JC, Duan EH, Nixon DF, Ostrowski MA. Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition. PLoS One. 2008;3(2):e1547.PubMedPubMedCentralCrossRef
124.
Dai L, Huang Q, Boeke JD. Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. BMC Biochem. 2011;12:18.PubMedPubMedCentralCrossRef
125.
Banuelos-Sanchez G, Sanchez L, Benitez-Guijarro M, Sanchez-Carnerero V, Salvador-Palomeque C, Tristan-Ramos P, Benkaddour-Boumzaouad M, Morell S, Garcia-Puche JL, Heras SR, et al. Synthesis and characterization of specific reverse transcriptase inhibitors for mammalian LINE-1 retrotransposons. Cell Chem Biol. 2019;26(8):1095–109.e14.PubMedCrossRef
126.
Percharde M, Lin CJ, Yin Y, Guan J, Peixoto GA, Bulut-Karslioglu A, Biechele S, Huang B, Shen X, Ramalho-Santos M. A LINE1-nucleolin partnership regulates early development and ESC identity. Cell. 2018;174(2):391–405.e19.PubMedPubMedCentralCrossRef
127.
128.
Jachowicz JW, Bing X, Pontabry J, Boskovic A, Rando OJ, Torres-Padilla ME. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat Genet. 2017;49(10):1502–10.PubMedCrossRef
129.
Malki S, van der Heijden Godfried W, O’Donnell Kathryn A, Martin Sandra L, Bortvin A. A role for retrotransposon LINE-1 in fetal oocyte attrition in mice. Dev Cell. 2014;29(5):521–33.PubMedPubMedCentralCrossRef
130.
Chuma S. LINE-1 of evidence for fetal oocyte attrition by retrotransposon. Dev Cell. 2014;29(5):501–2.PubMedCrossRef
131.
Morita Y, Tilly JL. Oocyte apoptosis: like sand through an hourglass. Dev Biol. 1999;213(1):1–17.PubMedCrossRef
132.
Haoudi A, Semmes OJ, Mason JM, Cannon RE. Retrotransposition-competent human LINE-1 induces apoptosis in cancer cells with intact p53. J Biomed Biotechnol. 2004;2004(4):185–94.PubMedPubMedCentralCrossRef
133.
Belgnaoui SM, Gosden RG, Semmes OJ, Haoudi A. Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells. Cancer Cell Int. 2006;6(1):1.CrossRef
134.
135.
De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature. 2019;566(7742):73–8.PubMedPubMedCentralCrossRef
136.
Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL, et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 2019;29(4):871–85.e5.PubMedCrossRefPubMedCentral
137.
Thomas CA, Tejwani L, Trujillo CA, Negraes PD, Herai RH, Mesci P, Macia A, Crow YJ, Muotri AR. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell. 2017;21(3):319–31.e8.PubMedPubMedCentralCrossRef
138.
Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet. 2006;38(8):917-20.PubMedCrossRef
139.
Chaouat G, Menu E, Mognetti B, Moussa M, Cayol V, Mostefaoui Y, Dubanchet S, Khadel P, Volumenie JL, Rongieres CB, et al. Immunopathology of early pregnancy. Infect Dis Obstet Gynecol. 1997;5(2):73–92.PubMedPubMedCentralCrossRef
140.
Micallef A, Grech N, Farrugia F, Schembri-Wismayer P, Calleja-Agius J. The role of interferons in early pregnancy. Gynecol Endocrinol. 2014;30(1):1–6.PubMedCrossRef
141.
Polgar K, Hill JA. Identification of the white blood cell populations responsible for Th1 immunity to trophoblast and the timing of the response in women with recurrent pregnancy loss. Gynecol Obstet Investig. 2002;53(1):59–64.CrossRef
142.
Marzi M, Vigano A, Trabattoni D, Villa ML, Salvaggio A, Clerici E, Clerici M. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin Exp Immunol. 1996;106(1):127–33.PubMedPubMedCentralCrossRef
143.
Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, De Sapio F, Brennan PM, Rizzu P, Smith S, Fell M, et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature. 2011;479(7374):534–7.PubMedPubMedCentralCrossRef
144.
145.
Iskow RC, McCabe MT, Mills RE, Torene S, Pittard WS, Neuwald AF, Van Meir EG, Vertino PM, Devine SE. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell. 2010;141(7):1253–61.PubMedPubMedCentralCrossRef
146.
Ewing AD, Kazazian HH Jr. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 2010;20(9):1262–70.PubMedPubMedCentralCrossRef
147.
Evrony G, Cai X, Lee E, Hills LB, Elhosary PC, Lehmann Hillel S, Parker JJ, Atabay Kutay D, Gilmore Edward C, Poduri A, et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell. 2012;151(3):483–96.PubMedPubMedCentralCrossRef
148.
Rahbari R, Badge RM. Combining amplification typing of L1 active subfamilies (ATLAS) with high-throughput sequencing. Methods Mol Biol. 2016;1400:95–106.PubMedCrossRef
149.
Philippe C, Vargas-Landin DB, Doucet AJ, van Essen D, Vera-Otarola J, Kuciak M, Corbin A, Nigumann P, Cristofari G. Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci. Elife. 2016;5:e13926.PubMedPubMedCentralCrossRef
150.
Pradhan B, Cajuso T, Katainen R, Sulo P, Tanskanen T, Kilpivaara O, Pitkanen E, Aaltonen LA, Kauppi L, Palin K. Detection of subclonal L1 transductions in colorectal cancer by long-distance inverse-PCR and Nanopore sequencing. Sci Rep. 2017;7(1):14521.PubMedPubMedCentralCrossRef
151.
152.
Lee E, Iskow R, Yang L, Gokcumen O, Haseley P, Luquette LJ, Lohr JG, Harris CC, Ding L, Wilson RK, et al. Landscape of somatic retrotransposition in human cancers. Science. 2012;337(6097):967–71.PubMedPubMedCentralCrossRef
153.
Tubio JMC, Li Y, Ju YS, Martincorena I, Cooke SL, Tojo M, Gundem G, Pipinikas CP, Zamora J, Raine K, et al. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science. 2014;345(6196):1251343.PubMedPubMedCentralCrossRef
154.
Helman E, Lawrence MS, Stewart C, Sougnez C, Getz G, Meyerson M. Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res. 2014;24(7):1053–63.PubMedPubMedCentralCrossRef
155.
156.
Gardner EJ, Lam VK, Harris DN, Chuang NT, Scott EC, Pittard WS, Mills RE, Devine SE. The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology. Genome Res. 2017;27(11):1916–29.PubMedPubMedCentralCrossRef
157.
Wang J, Song L, Grover D, Azrak S, Batzer MA, Liang P. dbRIP: a highly integrated database of retrotransposon insertion polymorphisms in humans. Hum Mutat. 2006;27(4):323–9.PubMedPubMedCentralCrossRef
158.
Mir AA, Philippe C, Cristofari G. euL1db: the European database of L1HS retrotransposon insertions in humans. Nucleic Acids Res. 2015;43(Database issue):D43–7.PubMedCrossRef
159.
160.
Li TC, Makris M, Tomsu M, Tuckerman E, Laird S. Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Update. 2002;8(5):463–81.PubMedCrossRef
161.
162.
163.
Ostertag EM, DeBerardinis RJ, Goodier JL, Zhang Y, Yang N, Gerton GL, Kazazian HH Jr. A mouse model of human L1 retrotransposition. Nat Genet. 2002;32(4):655–60.PubMedCrossRef
164.
Okudaira N, Goto M, Yanobu-Takanashi R, Tamura M, An A, Abe Y, Kano S, Hagiwara S, Ishizaka Y, Okamura T. Involvement of retrotransposition of long interspersed nucleotide element-1 in skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Cancer Sci. 2011;102(11):2000–6.PubMedCrossRef
165.
O’Donnell KA, An W, Schrum CT, Wheelan SJ, Boeke JD. Controlled insertional mutagenesis using a LINE-1 (ORFeus) gene-trap mouse model. Proc Natl Acad Sci U S A. 2013;110(29):E2706–13.PubMedPubMedCentralCrossRef
166.
Deininger P, Morales ME, White TB, Baddoo M, Hedges DJ, Servant G, Srivastav S, Smither ME, Concha M, DeHaro DL, et al. A comprehensive approach to expression of L1 loci. Nucleic Acids Res. 2017;45(5):e31.PubMedCrossRef
167.
Jin Y, Hammell M. Analysis of RNA-Seq data using TEtranscripts. Methods Mol Biol. 2018;1751:153–67.PubMedCrossRef
168.
Jeong HH, Yalamanchili HK, Guo C, Shulman JM, Liu Z. An ultra-fast and scalable quantification pipeline for transposable elements from next generation sequencing data. Pac Symp Biocomput. 2018;23:168–79.PubMed
169.
Navarro FC, Hoops J, Bellfy L, Cerveira E, Zhu Q, Zhang C, Lee C, Gerstein MB. TeXP: Deconvolving the effects of pervasive and autonomous transcription of transposable elements. PLoS Comput Biol. 2019;15(8):e1007293.PubMedPubMedCentralCrossRef
170.
Bendall ML, de Mulder M, Iñiguez LP, Lecanda-Sánchez A, Pérez-Losada M, Ostrowski MA, et al. Telescope: characterization of the retrotranscriptome by accurate estimation of transposable element expression. PLoS Comput Biol. 2019;15(9):e1006453.PubMedPubMedCentralCrossRef
171.
Rodić N, Sharma R, Sharma R, Zampella J, Dai L, Taylor MS, Hruban RH, Iacobuzio-Donahue CA, Maitra A, Torbenson MS, et al. Long interspersed element-1 protein expression is a hallmark of many human cancers. Am J Pathol. 2014;184(5):1280–6.PubMedPubMedCentralCrossRef
172.
Chen L, Dahlstrom JE, Chandra A, Board P, Rangasamy D. Prognostic value of LINE-1 retrotransposon expression and its subcellular localization in breast cancer. Breast Cancer Res Treat. 2012;136(1):129–42.PubMedPubMedCentralCrossRef
173.
Ergun S, Buschmann C, Heukeshoven J, Dammann K, Schnieders F, Lauke H, Chalajour F, Kilic N, Stratling WH, Schumann GG. Cell type-specific expression of LINE-1 open reading frames 1 and 2 in fetal and adult human tissues. J Biol Chem. 2004;279(26):27753–63.PubMedCrossRef
174.
Ardeljan D, Wang X, Oghbaie M, Taylor MS, Husband D, Deshpande V, Steranka JP, Gorbounov M, Yang WR, Sie B, et al. LINE-1 ORF2p expression is nearly imperceptible in human cancers. Mob DNA. 2019;11:1.
175.
MacGowan DJ, Scelsa SN, Imperato TE, Liu KN, Baron P, Polsky B. A controlled study of reverse transcriptase in serum and CSF of HIV-negative patients with ALS. Neurology. 2007;68(22):1944–6.PubMedCrossRef
176.
Kulpa DA, Moran JV. Cis-preferential LINE-1 reverse transcriptase activity in ribonucleoprotein particles. Nat Struct Mol Biol. 2006;13(7):655–60.PubMedCrossRef
177.
Viollet S, Doucet AJ, Cristofari G. Biochemical Approaches to Study LINE-1 Reverse Transcriptase Activity In Vitro. Methods Mol Biol. 2016;1400:357–76.PubMedCrossRef
178.
Carter V, LaCava J, Taylor MS, Liang SY, Mustelin C, Ukadike KC, Bengtsson A, Lood C, Mustelin T. High prevalence and disease correlation of autoantibodies against p40 encoded by long interspersed nuclear elements (LINE-1) in systemic lupus erythematosus. Arthritis Rheumatol. 2019. https://​doi.​org/​10.​1002/​art.​41054.CrossRef
179.
Heinrich MJ, Purcell CA, Pruijssers AJ, Zhao Y, Spurlock CF 3rd, Sriram S, Ogden KM, Dermody TS, Scholz MB, Crooke PS 3rd, et al. Endogenous double-stranded Alu RNA elements stimulate IFN-responses in relapsing remitting multiple sclerosis. J Autoimmun. 2019;100:40–51.PubMedCrossRefPubMedCentral
180.
181.
Gold J, Rowe DB, Kiernan MC, Vucic S, Mathers S, van Eijk RPA, Nath A, Garcia Montojo M, Norato G, Santamaria UA, et al. Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the lighthouse trial. Amyotroph Lateral Scler Frontotemporal Degener. 2019;20(7-8):595–604.PubMedCrossRef
182.
Rice GI, Meyzer C, Bouazza N, Hully M, Boddaert N, Semeraro M, Zeef LAH, Rozenberg F, Bondet V, Duffy D, et al. Reverse-transcriptase inhibitors in the Aicardi–Goutières Syndrome. N Engl J Med. 2018;379(23):2275–7.PubMedCrossRef
Metadata
Title
A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage
Authors
Chao Lou
John L. Goodier
Rong Qiang
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Miscarriage
Published in
Reproductive Biology and Endocrinology / Issue 1/2020
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-020-0564-x

Other articles of this Issue 1/2020

Reproductive Biology and Endocrinology 1/2020 Go to the issue

Research

Decreased brain and muscle ARNT-like protein 1 expression mediated the contribution of hyperandrogenism to insulin resistance in polycystic ovary syndrome

Research

Establishment of an immortalized stromal cell line derived from human Endometriotic lesion

Research

The significance of FMR1 CGG repeats in Chinese women with premature ovarian insufficiency and diminished ovarian reserve

Research

Clinical, hormonal and genetic characteristics of androgen insensitivity syndrome in 39 Chinese patients

Research

Luteal phase stimulation versus follicular phase stimulation in poor ovarian responders: results of a randomized controlled trial

Review

Organoid technology in female reproductive biomedicine