Batzer and Deininger 2002 Nature Reviews Genetics

1 million alu elements that are dispersed throughout

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Unformatted text preview: the origins of more than 1.1 million Alu elements that are dispersed throughout the human genome can be traced to an initial gene duplication early in primate evolution, and to the subsequent and continuing amplification of these elements. This type of duplication, followed by the expansion of a SINE family, has occurred sporadically throughout evolutionary history in mammalian and non-mammalian genomes (for reviews, see REFS 1,14). The origins of a variety of SINEs can be traced to the genes of various small, highly structured RNAs, such as transfer RNA genes, the transcription of which depends on RNA polymerase III (REFS 1,15–18). The expansion of SINEs of different origins has occurred simultaneously in several diverse genomes, and although the reasons for this simultaneous expansion are unknown, there have been many interesting discussions about the factors that might have contributed to it1. Alu-element mobilization Box 1 | A typical human Alu element and its retroposition The structure of each Alu element is bi-partite, with the 3′ half containing an additional 31-bp insertion (not shown) relative to the 5′ half. The total length of each Alu sequence is ~300 bp, depending on the length of the 3′ oligo(dA)-rich tail. The elements also contain a central A-rich region and are flanked by short intact direct repeats that are derived from the site of insertion (black arrows). The 5′ half of each sequence contains an RNA-polymerase-III promoter (A and B boxes). The 3′ terminus of the Alu element almost always consists of a run of As that is only occasionally interspersed with other bases (a). Alu elements increase in number by retrotransposition — a process that involves reverse transcription of an Alu-derived RNA polymerase III transcript. As the Alu element does not code for an RNA-polymerase-III termination signal, its transcript will therefore extend into the flanking unique sequence (b). The typical RNA-polymerase-III terminator signal is a run of four or more Ts on the sense strand, which results in three Us at the 3′ terminus of most transcripts. It has been proposed that the run of As at the 3′ end of the Alu might anneal directly at the site of integration in the genome for target-primed reverse transcription (mauve arrow indicates reverse transcription) (c). It seems likely that the first nick at the site of insertion is often made by the L1 endonuclease at the TTAAAA consensus site. The mechanism for making the second-site nick on the other strand and integrating the other end of the Alu element remains unclear. A new set of direct repeats (red arrows) is created during the insertion of the new Alu element (d). a 5′ Alu emement A B A5TACA6 AAAAAAA RNA-Pol-III-mediated transcription TTTT 3′ b 5′ Alu RNA A B A5TACA6 AAAAAAA Insertion and reverse transcription 3′ UUU c 5′ 3′ T TA A A A 3′ 5′ T T T AA B A 5T AC A 6 A A A UU U 3′ d A B A5TACA6 AAAAAAA N ATURE REVIEWS | GENETICS 5′ A Second-site nick and ligation The amplification of Alu elements is thought to occur by the reverse transcription of an Alu-derived RNA polymerase III transcript in a process called retrotransposition19. A schematic diagram of the generally accepted mechanism for Alu-element mobilization is shown in BOX 1. The Alu-derived transcript is thought to use a nick at its genomic integration site to allow target-primed reverse transcription (TPRT) to occur20–22. However, there is limited direct evidence for the TPRT mechanism, and it is possible that other mechanisms, such as self-priming of reverse transcription by the Alu RNA23, might also contribute to the amplification process. Because Alu elements have no open reading frames, they are thought to ‘borrow’ the factors that are required for their amplification from long interspersed elements (LINEs)24. These elements have been shown to encode a functional reverse transcriptase24,25 that also has an endonuclease domain20,26, which makes them putative providers of the exogenous enzymatic functions that are thought to be crucial for Alu-element amplification. Furthermore, the poly(A) tails of LINEs and Alu elements are thought to be the common structural features that are involved in the competition of these mobile elements for the same enzymatic machinery for mobilization27. In support of this connection between LINE and Alu mobilization, it is interesting to note that the number of LINEs that is present in mammalian genomes has increased during the past 150 million years of evolution28,29 — a period that also encompasses Alu-amplification activity. Therefore, LINEs seem to have supplied the crucial reverse transcriptase activity that resulted in the subsequent generation of various SINE families in different mammalian genomes that have amplified to extremely high copy numbers in a relatively short evolutionary time frame. T A A A A VOLUME 3 | MAY 2002 | 3 7 1 © 2002 Nature Publishing Group REVIEWS Sx GGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAG...
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