Chapter 35 : Mammalian LINE-1 Retrotransposons and Related Elements

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This chapter emphasises on the studies that have focused on understanding the mechanism of L1 retrotransposition, which were conducted since the publication of Mobile DNA in 1989. In addition, when appropriate the similarities and differences between the retrotransposition mechanisms of long interspersed nuclear elements (LINE-1s or L1s), closely related L1-like elements, and more distantly related non-LTR retrotransposons, are discussed. The majority of elements are variably 5’ truncated, rearranged, or mutated. The basic structural features of these nonautonomous retrotransposons are introduced in the chapter. The cultured cell assay also has yielded unexpected information about L1 retrotransposition. First, in cultured cells, 5 to 10% of new L1 retrotransposition events occurs into the introns of actively transcribed genes. Second, because L1s can be considered processed pseudogenes, the L1 pA signal lacks conserved elements that normally reside downstream of the poly(A) addition site in canonical RNA polymerase II pA signals. Finally, because most L1s are 5’ truncated, it is possible that many transduction events are not detected because they completely lack L1 sequences. However, biochemical data argue that ORF1 binds particular A-rich sequences in L1 RNA with relatively high affinity and that ORF1p is more abundant than ORF2p. We just are beginning to realize the consequences of L1 retrotransposition on the human genome. Clearly, L1 is a mutagen. Moreover, because of the abundance of L1s, it is likely that L1s provide scaffolds for illegitimate recombination, which may contribute to the genome instability seen in many tumors.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Image of Figure 1
Figure 1

Structure of L1s. (A) Organization of a 6-kb human L1. ORF1 and ORF2 are indicated by the shaded rectangles. The 5′ and 3′ UTR are indicated by the striped rectangles, and the intergenic region between ORF1 and ORF2 is indicated by a space. The poly(A) tail (A) and the approximate positions of the EN, RT, and C domains also are indicated. The arrows denote target-site duplications, which typically flank the L1. (B) Organization of a 7-kb mouse L1. ORF1, ORF2, the 3′ UTR, the L1 poly(A) tail, and the target-site duplications are depicted as in panel A. The staggered rectangles indicate the overlap between ORF1 and ORF2. The triangles indicate the repeated monomers that are present at the 5′ end of mouse L1s, whereas the striped rectangle indicates the untranslated linker in the 5′ UTR. The approximate position of the LPR in mouse L1 ORF1 is noted.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Image of Figure 2
Figure 2

Conserved amino acids in L1ORF1p. (A) Alignment of mammalian L1ORF1p and SW1ORF1p. Identical amino acids are shaded in dark gray, whereas homologous amino acids are shaded in light gray. Dashes indicate gaps in the sequence. The black shading indicates the putative leucine zipper domain in L1Hs and SW1ORF1p. The plus symbols denote amino acids in L1Hs that are critical for retrotransposition in cultured cells. Accession numbers: L1RnORF1p (S21345), L1MdORF1p (AAC72809), L1HsORF1p (AAC51278), and SW1ORF1p (AF055640). (B) The amino terminal cysteine-histidine-rich domain in L1-like elements. The gray shading denotes conserved cysteine and histidine residues. The numbers of amino acids on each side of the domain in the respective ORF1-encoded proteins are indicated in the parentheses. Notably, Cin4 possesses two copies of the cysteine-histidine-rich domain separated by 12 amino acids (Cin4a and Cin4b) ( ). The cysteine-histidine-rich domain also is found in certain non-LTR retrotransposons and in the gag region of certain retroviral nucleocapsid proteins; I-factor is shown as a single example of this motif in a non-LTR retrotransposon ( ). The consensus sequence of conserved amino acids in the cysteine-histidine-rich domain is noted. Accession numbers: Tx11ORF1p (P14380), Ta11ORF1p (S65811), I-factor ORF1p (AAA70221). The protein sequences of Cin4ORF1p and del2ORF1p were obtained by translating the nucleic acid sequences from Y00086 and Z17425, respectively.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Image of Figure 3
Figure 3

Conserved amino acids in ORF2. Identical amino acids are shaded in dark gray, whereas homologous amino acids are shaded in light gray. Roman numbers indicate conserved subdomains in the EN region ( ), whereas arabic numbers indicate conserved subdomain in the RT region ( and references within). The plus symbols denote amino acids in L1Hs that are critical for retrotransposition in cultured cells. Conserved amino acids in the C domain also are indicated. Accession numbers: L1HSORF2p (AAD38785), L1MdORF2p (AAC53542), L1RnORF2p (AAB41224), and L1CfORF2p (BAA25253), SW1ORF2p (AAD02928), Tx1LORF2p (P14381), Ta11ORF2p (S65812), ZeppORF2p (BAA25763). The protein sequences of Cin4ORF2p, del2ORF2p, and DREORF2p were obtained by translating the nucleic acid sequences from Y00086, Z17425, and X57034, respectively. The letter X denotes frameshifts, whereas the asterisk denotes stop codons. The numbers of amino acids that separate the RT and C domains also are indicated. Dots indicate gaps in the sequence.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Image of Figure 4
Figure 4

Schematic representations of SINEs and processed pseudogenes. (A) Primate elements. The structure of an ∼280-bp element is depicted. The open rectangles represent the dimeric repeats. The black line between the rectangles indicates the A-rich linker sequence. The poly(A) tail (A)n and target-site duplications, which typically flank s, are indicated (arrows). The A and B boxes contain sequences important for RNA polymerase III-mediated transcription. (B) Rodent B1 elements. The structure of an ∼135-bp B1 is depicted. Labeling is the same as in panel A. (C) tRNA-derived SINEs. tRNA-derived SINEs consist of a 5′ segment derived from a tRNA (shaded rectangle) linked to an unrelated 3′ sequence (white rectangle). In some instances, the 3′ segment shares homology with non-LTR retrotransposons. tRNA-derived SINEs can end in a poly(A) tail or in a short simple repeat (SR). Other labeling is the same as in panel A. (D) Processed pseudogenes. Processed pseudogenes resemble retrotransposed RNA polymerase II transcripts. Labeling is the same as in panel A.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Figure 5

Types of mutations generated by L1s. (A) Insertional inactivation. The insertion of L1 into an exon or other important -acting regulatory regions of a gene can disrupt function. The position where an L1 inserted into an exon of a gene is indicated. The gray boxes denote exons, whereas the v-shaped lines indicate introns. The splice donor (SD) and splice acceptor (SA) sites are indicated. The promoter (arrow) and poly(A) (pA) site of the gene also are indicated. (B) Alteration of splicing. The insertion of an L1 into an intron of a gene can induce missplicing or exon skipping. Labeling is the same as in panel A. (C) DNA-based rearrangements. Illegitimate recombination events between L1s present on sister chromatids can lead duplications or deletions of exon sequences. The X denotes the position of the illegitimate recombination, and the predicted products are indicated. Notably, mitotic recombination events between L1s on the same chromosome or between non-homologous chromosomes can, in principle, lead to interstitial deletions or translocations, respectively.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Figure 6

An assay to detect L1 retrotransposition. (A) Rationale of the assay. Candidate L1s were tagged with an indicator cassette () designed to detect retrotransposition events ( ). The cassette consists of a backward copy of the neomycin phosphotransferase gene (), which contains its own promoter (P′) and polyadenylation signal (A′) ( ). The backward gene is interrupted by an intron in the same transcriptional orientation of the L1 and the splice donor (SD) and splice acceptor sites (SA) are indicated. Transcription of L1 RNA from its own promoter in the 5′UTR (light gray box) and subsequent RNA splicing results in the production of a polyadenylated mRNA. ORF1p and ORF2p can be translated from the mRNA, but the spliced gene cannot be translated because it is backward. G418-resistant (G418) colonies arise only if the mature L1 mRNA is reverse transcribed (RT) and integrated at a new genomic location. The retrotransposed indicator gene then can be expressed from its own promoter (P′) to produce a transcript, which can be translated to generate a functional neomycin phosphotransferase protein. (B) Results of a typical retrotransposition assay conducted with different RC-L1s (L1.3, L1, L1.2, and LRE2) are shown ( ). A negative control construct containing a point mutation in the L1 RT (L1.3 RT-) domain also is depicted.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Figure 7

L1-mediated transduction. A retrotransposition-competent L1 resides at a chromosomal location denoted by the white bar at the top of the figure (adapted from reference ). The native L1 pA site and a fortuitous pA site in 3′ flanking DNA are denoted by the gray and black lollipops, respectively. In principle, three types of L1-mediated transduction events can occur if the L1pA site is bypassed and the pA site in flanking DNA is utilized. Each type of event is denoted in the figure. The gray arrows flanking L1 (top) represent the original target-site duplications flanking the element. New target-site duplications generated by the retrotransposition of a readthrough L1 transcript are denoted with the black arrows. The nonhomologous chromosome is indicated by the different shading patterns.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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Figure 8

A model for L1 retrotransposition. This model of L1 retrotransposition is based on the work of many groups, and their respective contributions are summarized in the text. The formation of higher-order complexes and the presence of ORF1p in the nucleus have not been confirmed experimentally.

Citation: Moran J, Gilbert N. 2002. Mammalian LINE-1 Retrotransposons and Related Elements, p 836-869. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch35
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