Ancient LINEs

A typical structure of LINE elements is shown in Fig. 1A. LINEs usually contain two open reading frames referred to as ORF1 and ORF2. The L3 ORF1 protein shares similarity with esterase domains (5). L2 elements apparently lack ORF1, although it is possible that the very old age of L2 copies and frequent 5' truncation typical for LINEs prevented reconstruction of a full-length L2 element (6). The ORF2 protein contains the RT and apurinic-apyrimidinic endonu-clease enzymatic domains. The transcription of LINE elements starts from a poorly characterized internal promoter for RNA polymerase II (Fig. 1A). After translation, the complex of LINE RNA and protein(s) enters the nucleus, where an endonucleolytic nick at a DNA target serves to prime reverse transcription (7). Target-primed reverse transcription is another feature distinguishing non-LTR from LTR retrotransposons, which normally use cellular tRNA as primers for reverse transcription (see Human Endogenous Retroviruses). Unlike in L1 and L1-dependent elements, no target site duplications are created during integration of L2 and L3 elements. Furthermore, L2 and L3 carry microsatellite-like 3' tails instead of the polyA tail found in L1 insertions (6). Based on high sequence diversity, the age of L2 and L3 elements in the human genome is estimated to be approx 200-300 million years, corresponding to the early radiation of reptiles, birds, and mammals. Recognizable L2 and L3 copies, together with their nonautonomous counterparts MIR and MIR3, represent approx 5% of the human genome (6).

The potential of L2 and L3 copies to stimulate genomic rearrangements is very limited owing to their ancient origin, and no such case has been identified in humans so far. The

Fig. 1. Structure of human interspersed repeats. The figure shows typical structures of integrated interspersed repeats. (A) Structure of non-long terminal repeats (LTR) retrotransposons. The first bar shows a schematic organization of LINE elements. Human L1 and L3 elements contain two open reading frames (ORFs), L2 copies apparently lack ORF1. The function of the first ORF1 is poorly understood. ORF2 encodes a protein with the apurinic-apyrimidinic endonuclease and reverse transcriptase (RT) enzymatic domains. L1 insertions have a 3' polyA tail and are flanked by variable long target duplications, typically 5- to 20-bp long. L2 and L3 elements lack the target site duplications, and their 3' tails are composed of simple repeat sequences. The second and third schematic bars depict organization of SINEs. L2- and L3-dependent MIR and MIR3 SINEs (middle) consist of two parts. The 5' part (dark gray) is derived from a tRNA gene and harbors an internal pol III promoter. The 3' tails of MIRs are homologous to the 3' end of the corresponding LINE counterparts (light gray). Alu elements (bottom) derived from 7SL RNA genes have a dimeric structure and contain a composite pol III promoter. SINEs share insertional characteristics with their LINE counterparts including the 3' end simple repeats in MIRs. Ll-dependentAlu repeats contain 3' polyA tails and are flanked by 5- to 20-bp long direct repeats. (B) Structure of LTR retrotransposons. All LTR retrotransposons contain two LTRs, which include a pol II promoter and polyA signal. The internal part of autonomous elements comprises three main open reading frames: gag, pol, and env; in some HERV families pro can be separate from pol. The 5' part of the internal sequence contains a tRNA primer binding site (PBS) for initiation of reverse transcription and also an encapsidation sequence (Y) necessary for incorporation of retroviral RNA molecules into virions. Internal sequences of nonautonomous LTR retrotransposons may or may not share similarity with retroviral ORFs, but they contain all structures required for retroviral replication and reverse transcription such as LTRs, PBS, or the encapsidation signal. Both proliferation of L2 and L3 elements stopped long before the mammalian radiation, and recombination between highly diverged sequences is very unlikely. No protein-coding gene derived from L2 or L3 elements has been detected.

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