Retrotransposons Revisited: The Restraint and Rehabilitation of Parasites
2008; Cell Press; Volume: 135; Issue: 1 Linguagem: Inglês
10.1016/j.cell.2008.09.022
ISSN1097-4172
AutoresJohn L. Goodier, Haig H. Kazazian,
Tópico(s)Genomics and Phylogenetic Studies
ResumoRetrotransposons, mainly LINEs, SINEs, and endogenous retroviruses, make up roughly 40% of the mammalian genome and have played an important role in genome evolution. Their prevalence in genomes reflects a delicate balance between their further expansion and the restraint imposed by the host. In any human genome only a small number of LINE1s (L1s) are active, moving their own and SINE sequences into new genomic locations and occasionally causing disease. Recent insights and new technologies promise answers to fundamental questions about the biology of transposable elements. Retrotransposons, mainly LINEs, SINEs, and endogenous retroviruses, make up roughly 40% of the mammalian genome and have played an important role in genome evolution. Their prevalence in genomes reflects a delicate balance between their further expansion and the restraint imposed by the host. In any human genome only a small number of LINE1s (L1s) are active, moving their own and SINE sequences into new genomic locations and occasionally causing disease. Recent insights and new technologies promise answers to fundamental questions about the biology of transposable elements. The seminal discovery that genomes contain pieces of DNA capable of moving to new locations challenged prevailing notions of genes as static "beads on a string" passed essentially unchanged from one generation to the next. Studying mosaic coloration in maize, Barbara McClintock described Dissociator and Activator "mutable loci" and with prescience called them "controlling elements" that regulate genes. The notion was at first poorly received. Following the discovery of transposons in plants and bacteria, the presence of mobile DNA in eukaryotic species gained widespread acceptance. However, the concept of "controlling elements" gave way to disparaging terms such as selfish DNA and "junk DNA." Nevertheless, the notion of transposable elements as merely molecular parasites, benign at best and powerful mutagens at worst, that hijack cellular mechanisms for their own selfish propagation, seemed incomplete to some biologists. Given that evolution tends to dispose of that which is useless and harmful for a species, it was curious that the genome should be cluttered with so much "junk." Now we understand that genomes have coevolved with their transposable elements, devising strategies to prevent them from running amok while coopting function from their presence. Repetitive DNA, and retrotransposons in particular, can drive genome evolution and alter gene expression. Evolution has been adept at turning some "junk" into treasure. There are two major groups of so-called "jumping genes" (Figure 1). Class II elements or DNA transposons comprise about 3% of the human genome and most move by a "cut and paste" mechanism. No currently active DNA transposons have been identified in mammals. Class I elements comprise three groups, all moving in a "copy and paste" manner involving reverse transcription of an RNA intermediate and insertion of its cDNA copy at a new site in the genome. Penelope-like elements form a diverse group, are apparently absent in mammals, and are in the very early stages of characterization (Gladyshev and Arkhipova, 2007Gladyshev E.A. Arkhipova I.R. Telomere-associated endonuclease-deficient Penelope-like retroelements in diverse eukaryotes.Proc. Natl. Acad. Sci. USA. 2007; 104: 9352-9357Crossref PubMed Scopus (93) Google Scholar). Retroviral-like or long terminal repeat (LTR) retrotransposons include endogenous retroviruses, relics of past rounds of germline infection by viruses that lost their ability to reinfect and became trapped in the genome. These elements undergo reverse transcription in virus-like particles by a complex multistep process. The transposition process for non-LTR retrotransposons is fundamentally different. RNA copies of these elements are likely carried back into the nucleus where their reverse transcription and integration occur in a single step on the DNA itself. We focus here on recent discoveries in the biology of the two major groups of mammalian non-LTR retrotransposons, LINEs (long interspersed nucleotide elements) and SINEs (short interspersed nucleotide elements). SINEs are nonautonomous elements that do not encode protein and as a consequence require LINEs for their propagation. We also consider aspects of their biology that remain unclear but that involve important questions: How do retrotransposons jump? Where do they jump? When do they jump? Why don't they jump more? And what have been the consequences of all that jumping? Non-LTR retrotransposons are as old as the earliest multicellular organisms, and their 15 clades have origins in the Precambrian Era of 600 million years ago (Eickbush and Jamburuthugoda, 2008Eickbush T.H. Jamburuthugoda V.K. The diversity of retrotransposons and the properties of their reverse transcriptases.Virus Res. 2008; 134: 221-234Crossref PubMed Scopus (163) Google Scholar). In mammals, members of four clades are known. The RTE (retrotransposable element) clade, absent in humans and rodents, includes Bov-B elements from ruminant and afrotherians (a diverse clade that includes species such as elephants and aardvarks) as well as families prevalent in the opossum. LINE2 (L2) elements form 3% of marsupial genomes and almost 20% of monotreme (platypus) genomes. Although ancient and extinct, L2s occupy greater than 2% of human DNA and their impact has probably been significant. For example, Donnelly et al., 1999Donnelly S.R. Hawkins T.E. Moss S.E. A conserved nuclear element with a role in mammalian gene regulation.Hum. Mol. Genet. 1999; 8: 1723-1728Crossref PubMed Scopus (0) Google Scholar showed that L2s are capable of acting as T cell-specific gene silencers. Low-copy number and degenerate CR1/L3 clade members form only 0.05%, 0.3%, and 0.5% of mouse, human, and platypus genomes, respectively, but have expanded to 2.3% of opossum DNA (Jurka et al., 2005Jurka J. Kapitonov V.V. Pavlicek A. Klonowski P. Kohany O. Walichiewicz J. Repbase Update, a database of eukaryotic repetitive elements.Cytogenet. Genome Res. 2005; 110: 462-467Crossref PubMed Scopus (1922) Google Scholar, Gentles et al., 2007Gentles A.J. Wakefield M.J. Kohany O. Gu W. Batzer M.A. Pollock D.D. Jurka J. Evolutionary dynamics of transposable elements in the short-tailed oppossum, Monodelphis domestica.Genome Res. 2007; 17: 992-1004Crossref PubMed Scopus (0) Google Scholar, Mikkelsen et al., 2007Mikkelsen T.S. Wakefield M.J. Aken B. Amemiya C.T. Chang J.L. Garber M. Gentles A.J. Goodstadt L. Heger A. Jurka J. et al.Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences.Nature. 2007; 447: 167-177Crossref PubMed Scopus (515) Google Scholar, Warren et al., 2008Warren 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. et al.Genome analysis of the platypus reveals unique signatures of evolution.Nature. 2008; 453: 175-183Crossref PubMed Scopus (502) Google Scholar). Comparative analyses reveal significant differences between vertebrate lineages in their histories of expansion, contraction, and rates of activity for retrotransposon families (reviewed in Böhne et al., 2008Böhne A. Brunet F. Galiana-Arnoux D. Schultheis C. Volff J.N. Transposable elements as drivers of genomic and biological diversity in vertebrates.Chromosome Res. 2008; 16: 203-215Crossref PubMed Scopus (153) Google Scholar; see SnapShot by P.K. Mandal and H.H. Kazazian in this issue). It seems that genomes differ in their abilities to control and coexist with these elements. Little is known of the biology of the non-L1 LINEs. L1s, the only currently active autonomous transposons in humans, have been evolving during at least 160 million years (Myr) of mammalian radiation. Multiple active lineages of L1s coexisted in ancestral primates, but for the past 40 Myr, a single unbroken lineage of subfamilies has evolved (Boissinot and Furano, 2001Boissinot S. Furano A.V. Adaptive evolution in LINE-1 retrotransposons.Mol. Biol. Evol. 2001; 18: 2186-2194Crossref PubMed Google Scholar, Khan et al., 2006Khan H. Smit A. Boissinot S. Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates.Genome Res. 2006; 16: 78-87Crossref PubMed Scopus (210) Google Scholar). Expansion of L1s was massive, and roughly 500,000 copies occupy about 18% of the human genome. From 25 Myr ago the expansion slowed, and most insertions are (fortunately) molecular fossils—truncated, rearranged, or mutated and incapable of further retrotransposition. L1 has also been responsible for genomic insertion of 8000 human processed pseudogenes (many of which are transcribed, often in testes) and over a million SINEs (Zhang et al., 2003Zhang Z. Harrison P.M. Liu Y. Gerstein M. Millions of years of evolution preserved: a comprehensive catalog of the processed pseudogenes in the human genome.Genome Res. 2003; 13: 2541-2558Crossref PubMed Scopus (302) Google Scholar, Vinckenbosch et al., 2006Vinckenbosch N. Dupanloup I. Kaessmann H. Evolutionary fate of retroposed gene copies in the human genome.Proc. Natl. Acad. Sci. USA. 2006; 103: 3220-3225Crossref PubMed Scopus (0) Google Scholar). Most SINE 5′ ends are derived from Pol III-transcribed small cellular RNAs. B1s and Alus, the predominant SINEs of mice and men, originate from a portion of the 7SL RNA component of the protein signal recognition particle. Alus are about 300 bp in length and have a dimeric structure; B1s are monomeric. Other mammalian SINEs, such as mouse B2s, have tRNA sequence homology at their 5′ ends, and AmnSINEs of chickens and mammals contain both tRNA and 5S rRNA-like regions (Nishihara et al., 2006Nishihara H. Smit A.F. Okada N. Functional noncoding sequences derived from SINEs in the Mamm.Genome Res. 2006; 16: 864-874Crossref PubMed Scopus (0) Google Scholar; see Review by Kramerov and Vassetzky, 2005Kramerov D.A. Vassetzky N.S. Short retroposons in eukaryotic genomes.Int. Rev. Cytol. 2005; 247: 165-221Crossref PubMed Scopus (152) Google Scholar). About 40,000 snoRNA/RTE LINE-derived chimeric retrotransposons have recently been found in platypus (Schmitz et al., 2008Schmitz J. Zemann A. Churakov G. Kuhl H. Grützner F. Reinhardt R. Brosius J. Retroposed SNOfall–A mammalian-wide comparison of platypus snoRNAs.Genome Res. 2008; 18: 1005-1010Crossref PubMed Scopus (0) Google Scholar). Many SINEs derived from tRNAs, notably in fish and reptiles, share 3′-end homology with a LINE family member from the same genome. In mammals these include Ther-1, Ther-2, Mon1, Bov-tA, and Bov-A2 SINEs and their related L2, L3, and Bov-B LINEs (reviewed in Ohshima and Okada, 2005Ohshima K. Okada N. SINEs and LINEs: symbionts of eukaryotic genomes with a common tail.Cytogenet. Genome Res. 2005; 110: 475-490Crossref PubMed Scopus (0) Google Scholar). Presumably homologous SINE sequence binds LINE-encoded protein to foster retrotransposition, a hypothesis supported by cell culture assays with an eel SINE and its corresponding LINE (Kajikawa and Okada, 2002Kajikawa M. Okada N. LINEs mobilize SINEs in the eel through a shared 3′ sequence.Cell. 2002; 111: 433-444Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). Yet, except for its poly(A) tail, L1s lack sequence homology with any SINE. Hominid genomes also contain SVAs (SINE-R, VNTR, Alu], which are composite elements apparently mobilized by L1s. Despite their small copy number (3000 in humans), SVAs are probably quite active, being highly polymorphic and the cause of five known cases of human disease (Ostertag et al., 2003Ostertag E.M. Goodier J.L. Zhang Y. Kazazian Jr., H.H. SVA elements are nonautonomous retrotransposons that cause disease in humans.Am. J. Hum. Genet. 2003; 73: 1444-1451Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, Wang et al., 2005Wang H. Xing J. Grover D. Hedges D.J. Han K. Walker J.A. Batzer M.A. SVA elements: a hominid-specific retroposon family.J. Mol. Biol. 2005; 354: 994-1007Crossref PubMed Scopus (206) Google Scholar). The coming million years or so will tell if SVAs are the "next big thing" in human mobile DNA. The 6.0 kb full-length human L1 has a 900 nucleotide (nt) 5′ untranslated region (UTR) that functions as an internal promoter, two open reading frames (ORF1 and ORF2), and a short 3′ UTR that ends in the poly(A) signal and tail. The mouse L1 5′ UTR is distinguished by having tandem repeats. An unconventional termination/reinitiation mechanism translates ORF2, which encodes a 150 kDa protein (ORF2p) with endonuclease and reverse transcriptase activities (Alisch et al., 2006Alisch R.S. Garcia-Perex J.L. Muortri A.R. Gage F.H. Moran J.V. Unconventional translation of mammalian LINE-1 retrotransposons.Genes Dev. 2006; 20: 210-224Crossref PubMed Scopus (116) Google Scholar). More attention has focused on the 40 kDa ORF1 protein (ORF1p), mostly because it is expressed at much higher levels than ORF2p and is easier to study. While mutational analysis has shown ORF1p to be essential for retrotransposition, its precise role remains unclear, although it forms trimeric complexes and possesses nucleic acid chaperone activity in vitro. ORF1p has been detected in the cytoplasm and to a lesser degree in nuclei of carcinoma and germ cells and has been isolated in ribonucleoprotein (RNP) particles together with L1 RNA and ORF2p activity (Martin, 2006Martin S.L. The ORF1 protein encoded by LINE-1: Structure and function during L1 retrotransposition.J. Biomed. Biotechnol. 2006; 2006: 1-6Crossref Scopus (0) Google Scholar, Kulpa and Moran, 2006Kulpa D.A. Moran J.V. Cis-preferential LINE-1 reverse transcriptase activity in ribonucleoprotein particles.Nat. Struct. Mol. Biol. 2006; 13: 655-660Crossref PubMed Scopus (181) Google Scholar). Although several other proteins coimmunoprecipitate in ORF1p RNPs (Goodier et al., 2007Goodier J.L. Zhang L. Vetter M.R. Kazazian Jr., H.H. LINE-1 ORF1 protein localizes in stress granules with other RNA-binding proteins, including components of RNA interference RNA-induced silencing complex.Mol. Cell. Biol. 2007; 27: 6469-6483Crossref PubMed Scopus (175) Google Scholar), with the exception of a few transcription factors, little is known of the non-L1 proteins directly participating in the complex process of retrotransposition. Information on L1 RNP assembly and transport into the nucleus is fragmentary. Kubo et al., 2006Kubo S. Seleme M.C. Soifer H.S. Perez J.L. Moran J.V. Kazazian Jr., H.H. Kasahara N. L1 retrotransposition in nondividing and primary human somatic cells.Proc. Natl. Acad. Sci. USA. 2006; 103: 8036-8041Crossref PubMed Scopus (127) Google Scholar found no retrotransposition in quiescent G0 cells but significant levels in nondividing G1/S phase-arrested Gli36 tumor cells, suggesting active RNP transport across the nuclear membrane. (L1 biology is reviewed in Moran and Gilbert, 2002Moran J.V. Gilbert N. Mammalian LINE-1 retrotransposons and related elements.Mobile DNA II. Second Edition. ASM Press, Washington, DC2002Google Scholar and Babushok and Kazazian, 2007Babushok D.V. Kazazian Jr., H.H. Progress in understanding the biology of the human mutagen LINE-1.Hum. Mutat. 2007; 28: 527-539Crossref PubMed Scopus (143) Google Scholar.) It is believed, but not confirmed in vivo, that L1s retrotranspose by target primed reverse transcription (TPRT), a process characterized for insect non-LTR retrotransposons. According to this model, L1 ORF2-encoded endonuclease nicks the bottom strand of target DNA to expose a 3′-hydoxyl that primes reverse transcription of L1 RNA. Second-strand DNA synthesis follows, possibly initiated by a second ORF2 molecule, and the integrant is resolved in a manner still poorly understood (Eickbush and Jamburuthugoda, 2008Eickbush T.H. Jamburuthugoda V.K. The diversity of retrotransposons and the properties of their reverse transcriptases.Virus Res. 2008; 134: 221-234Crossref PubMed Scopus (163) Google Scholar). Consistent with the TPRT model, short target site duplications, but occasionally deletions, are generated at the L1 insertion site. Evidence from endogenous human insertions and from cell culture assays indicates that L1 proteins have cis-preference, tending to bind their own encoding RNA. Interestingly, Alus and B1s co-opt some, but not all, of the L1 retrotransposition machinery given that ORF1p is not required for insertion (Dewannieux et al., 2003Dewannieux M. Esnault C. Heidmann T. LINE-mediated retrotransposition of marked Alu sequences.Nat. Genet. 2003; 35: 41-48Crossref PubMed Scopus (691) Google Scholar). Clearly a subset of non-L1 RNAs, including Pol III transcripts and RNAs associated with the nucleolus, are preferred targets for retrotransposition (Buzdin et al., 2007Buzdin A. Gogvadze E. Lebrun M.H. Chimeric retrogenes suggest a role for the nucleolus in LINE amplification.FEBS Lett. 2007; 581: 2877-2882Crossref PubMed Scopus (0) Google Scholar). Detailed "ribonomic" studies of the RNA components of the L1 RNP are required. Knowledge of the mechanisms of L1 retrotransposition has lagged behind the exquisitely detailed studies of insect R1 and R2 elements and yeast and bacterial group II introns. Cell culture assays available for both L1 and Alu retrotransposition (Moran et al., 1996Moran J.V. Holmes S.E. Naas T.P. DeBerardinis R.J. Boeke J.D. Kazazian Jr., H.H. High frequency retrotransposition in cultured mammalian cells.Cell. 1996; 87: 917-927Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, Ostertag et al., 2000Ostertag E.M. Prak E.T. DeBerardinis R.J. Moran J.V. Kazazian Jr., H.H. Determination of L1 retrotransposition kinetics in cultured cells.Nucleic Acids Res. 2000; 28: 1418-1423Crossref PubMed Google Scholar, Dewannieux et al., 2003Dewannieux M. Esnault C. Heidmann T. LINE-mediated retrotransposition of marked Alu sequences.Nat. Genet. 2003; 35: 41-48Crossref PubMed Scopus (691) Google Scholar) and improving in vitro assays for L1 endonucleolytic cleavage, TPRT, and reverse transcription should move the field forward more rapidly (Cost et al., 2002Cost G.J. Feng Q. Jacquier A. Boeke J.D. Human L1 element target-primed reverse transcription in vitro.EMBO J. 2002; 21: 5899-5910Crossref PubMed Scopus (331) Google Scholar, Kulpa and Moran, 2006Kulpa D.A. Moran J.V. Cis-preferential LINE-1 reverse transcriptase activity in ribonucleoprotein particles.Nat. Struct. Mol. Biol. 2006; 13: 655-660Crossref PubMed Scopus (181) Google Scholar). There are 65 known human disease-causing insertions of L1s, Alus, and SVAs. However, simple insertion mutation is but one of a startling number of ways that retrotransposons reshuffle the genome and alter gene expression, and this list is sure to grow (Figure 2; reviewed in Han and Boeke, 2005Han K. 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Another example is the deletion of an entire HLA-A gene likely caused by an SVA and resulting in leukemia (Gilbert et al., 2002Gilbert N. Lutz-Prigge S. Moran J.V. Genomic deletions created upon LINE-1 retrotransposition.Cell. 2002; 110: 315-325Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, Symer et al., 2002Symer D.E. Connelly C. Szak S.T. Caputo E.M. Cost G.J. Parmigiani G. Boeke J.D. Human L1 retrotransposition is associated with genetic instability in vivo.Cell. 2002; 110: 327-338Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, Mine et al., 2007Mine M. Chen J.M. Brivet M. Desguerre I. Marchant D. de Lonlay P. Bernard A. Ferec C. Abitbol M. Ricquier D. Marsac C. A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full-length LINE-1 element.Hum. Mutat. 2007; 28: 137-142Crossref PubMed Scopus (0) Google Scholar, Takasu et al., 2007Takasu M. Hayashi R. Maruya E. Ota M. Imura K. Kougo K. Kobayashi C. Saji H. Ishikawa Y. Asai T. Tokunaga K. Deletion of entire HLA-A gene accompanied by an insertion of a retrotransposon.Tissue Antigens. 2007; 70: 144-150Crossref PubMed Scopus (33) Google Scholar). Nonretrotransposon DNA can also be added to the genome by a phenomenon termed 3′ transduction (Moran et al., 1999Moran J.V. DeBerardinis R.J. Kazazian Jr., H.H. Exon shuffling by L1 retrotransposition.Science. 1999; 283: 1530-1534Crossref PubMed Scopus (449) Google Scholar). About 10% to 20% of the time, 3′ end processing ignores the weak L1 poly(A) signal and utilizes instead a downstream signal, causing flanking sequence to be carried along with the retrotransposon to the new site of insertion. Less frequently, transcription initiates from a chance upstream promoter and the L1 mobilizes 5′ flanking sequence. In these ways, retrotransposons may serve as vectors for exon shuffling and the creation of new genes. One definitive instance involved an SVA transduction of the entire AMAC1 (acyl-malonyl condensing enzyme 1) gene to generate multiple transcriptionally active copies in the human genome. The SINE-R component of the SVA appears to drive transcription of the SVA-AMAC chimeras (Xing et al., 2006Xing J. Wang H. Belancio V.P. Cordaux R. Deininger P.L. Batzer M.A. Emergence of primate genes by retrotransposon-mediated sequence transduction.Proc. Natl. Acad. Sci. USA. 2006; 103: 17608-17613Crossref PubMed Scopus (103) Google Scholar). Recombination between retrotransposons causes deletions, duplications, or rearrangements of gene sequence. This is especially true for Alus, which have been implicated in almost 50 disease-causing recombination events. Moreover, Alus are significantly enriched at boundaries of human segmental duplications. Mouse segmental duplications are enriched in LTR and recent LINE1 retrotransposons but (unlike humans) not SINEs (Bailey and Eichler, 2006Bailey J.A. Eichler E.E. Primate segmental duplications: crucibles of evolution, diversity and disease.Nat. Rev. Genet. 2006; 7: 552-564Crossref PubMed Scopus (387) Google Scholar, She et al., 2008She X. Cheng Z. Zöllner S. Church D.M. Eichler E.E. Mouse segmental duplication and copy number variation.Nat. Genet. 2008; 40: 909-914Crossref PubMed Scopus (0) Google Scholar). Comparisons of the human and chimp genomes identified more than 10,000 species-specific transposable element insertions that have occurred since these species diverged 6 million years ago. About 95% of these inserts were L1s, Alus, and SVAs, along with some endogenous retroviruses (summarized in Mills et al., 2007Mills R.E. Bennett E.A. Iskow R.C. Devine S.E. Which transposable elements are active in the human genome?.Trends Genet. 2007; 23: 183-191Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). By examining orthologous loci, the Batzer lab has estimated the extent of retrotransposon-mediated give and take: approximately 900 kb and 7.5 Mb of primate sequence lost, respectively, at the sites of Alu and L1 insertions, 400 kb of human DNA removed by Alu-Alu recombination, and 53 kb inserted by human SVA-mediated DNA transductions (Xing et al., 2007Xing J. Witherspoon D.J. Ray D.A. Batzer M.A. Jorde L.B. Mobile DNA elements in primate and human evolution.Am. J. Phys. Anthropol. 2007; 45: 2-19Crossref PubMed Scopus (0) Google Scholar). With recent publication of the finished mouse genome, draft assemblies for 20 other mammalian species, and sequencing of 26 more mammals in progress, a wealth of data from comparative analyses is coming soon. The greatest impact of retrotransposon insertions may be on the expression of nearby genes. Ongoing retrotransposition peppers genomes with new splice sites, adenylation signals, promoters, and transcription factor-binding sites that can reorganize gene expression and build new transcription modules, as hypothesized by Britten and Davidson, 1971Britten R.J. Davidson E.M. Repetitive and non-repetitive DNA sequences and a speculation on the origins of evolutionary novelty.Cold Spring Harb. Symp. Quant. Biol. 1971; 21: 197-216Google Scholar over 35 years ago. For instance, a mouse B1 subfamily (B1-X35S) is distinguished by three mutations that recruit transcription factors Slug and dioxin receptor Ahr, causing repression of physiologically important genes (Roman et al., 2008Roman A.C. Benitez D.A. Carvajal-Gonzalez J.M. Fernandez-Salguero P.M. Genome-wide B1 retrotransposon binds the transcription factors dioxin receptor and Slug and regulates gene expression in vivo.Proc. Natl. Acad. Sci. USA. 2008; 105: 1632-1637Crossref PubMed Scopus (0) Google Scholar). The recent discovery that thousands of DNA fragments are highly conserved in sequence and sometimes synteny among evolutionarily distant vertebrate genomes, and that many of these fragments originate from transposable elements, especially SINEs and LINEs, has sparked interest in the field. Such conservation by strong purifying selection predicts function. Several superfamilies of these preserved sequence bits have been identified, and with them intriguing tales of exaptation (the adoption of a feature that had a different function in its ancestral form). For example, some SINEs contain a conserved central 65 bp "core." These were first described as mammalian-wide interspersed repeats (MIRs) and are now considered members of the CORE-SINE superfamily. The pro-opiomelancortin gene neuronal enhancer nPE2 is a CORE-SINE (Santangelo et al., 2007Santangelo A.M. de Souza F.S. Franchini L.F. Bumaschny V.F. Low M.J. Rubinstein M. Ancient exaptation of a CORE-SINE retroposon into a highly conserved mammalian neuronal enhancer of the proopiomelanocortin gene.PLoS Genet. 2007; 3: 1813-1826https://doi.org/10.1371/journal.pgen.0030166Crossref PubMed Scopus (100) Google Scholar). Bejerano et al., 2006Bejerano G. Lowe C.B. Ahituv N. King B. Siepel A. Salama S.R. Rubin E.M. Kent W.J. Haussler D. A distal enhancer and an ultraconserved exon are derived from a novel retroposon.Nature. 2006; 441: 87-90Crossref PubMed Scopus (359) Google Scholar discovered that members of the ancient LF (lobed-fin) SINE family, conserved in sequence in coelacanth fish and land tetrapods, have been exapted as exon fragments, and apparently in one instance as the distal enhancer of the neuro-developmental gene ISL1. This same group also found that >10,000 conserved mammalian transposon sequences are preferentially retained near genes involved in the regulation of transcription and development (Lowe et al., 2007Lowe C.B. Bejerano G. Haussler D. Thousands of human mobile element fragments undergo strong purifying selection near genes.Proc. Natl. Acad. Sci. USA. 2007; 104: 8005-8010Crossref PubMed Scopus (0) Google Scholar). Most recently, AmnSINEs, members of the Deu-SINE superfamily, have been shown to exert enhancer activity on Fgf8 and Satb2 gene expression in the developing mammalian forebrain (Sasaki et al., 2008Sasaki T. Nishihara H. Hirakawa M. Fujimura K. Tanaka M. Kokubo N. Kimura-Yoshida C. Matsuo I. Sumiyama K. Saitou N. et al.Possible involvement of SINEs in mammalian-specific brain formation.Proc. Natl. Acad. Sci. USA. 2008; 105: 4220-4225Crossref PubMed Scopus (129) Google Scholar). The L1 is especially adept at disrupting transcription of its host genes. L1 sequences are found in the noncoding regions of about 80% of human genes, and L1 density inversely correlates with mRNA expression of those genes. Resident L1s cause pausing in transcriptional elongation and premature transcript termination due to cryptic polyadenylation signals (Perepelitsa-Belancio and Deininger, 2003Perepelitsa-Belancio V. Deininger P. RNA truncation by premature polyadenylation attenuates human mobile element activity.Nat. Genet. 2003; 35: 363-366Crossref PubMed Scopus (186) Google Scholar, Han et al., 2004Han K. Szak S.T. Boeke J. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes.Nature. 2004; 429: 268-274Crossref PubMed Scopus (353) Google Scholar). Possessing functional promoters on the sense and antisense strands of its 5′ UTR, an L1 can also initiate both upstream and downstream transcription. Many transcripts in the expressed sequence tag (EST) databases originate from the antisense promoter, which may even regulate tissue-specific expression of some genes (Mätlik et al., 2006Mätlik K. Redik K. Speek M. L1 antisense promoter drives tissue-specific transcription of human genes.J. Biomed. Biotechnol. 2006; 2006: 71753Crossref PubMed Scopus (0) Google Scholar). Promoter co-option is not limited to L1s. Analyzing a cluster of microRNA genes on human chromosome 19, Borchert et al., 2006Borchert G.M. Lanier W. Davidson B.L. RNA polymerase III transcribes human microRNAs.Nat. Struct. Mol. Biol. 2006; 13: 1097-1101Crossref PubMed Scopus (950) Google Scholar found some transcribed by upstream Alu Pol III promoters, as well as 50 others overlapping Alus and other repeats. Indeed, high-throughput analyses of cDNA ends reveal that tens of thousands of antisense transcripts originate from both class I and class II transposable elements sitting within genes (Conley et al., 2008Conley A.B. Miller W.J. Jorda
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