In order to create the more than 1 million Alu elements fixed today in the human genome, there have had to be massive numbers of other insertions events that were not fixed. Thus, Alu elements have been a major contributor to genomic instability and evolution throughout primate history. One such event was an insertion-mediated deletion that inactivated the CMP-N-acetylneuraminic acid hydroxylase gene only in humans (45). This led to altered protein glycosylation, which may have been a significant change helping to result in the speciation of humans from chimpanzees.
Alu-Alu recombination events have also played an important role in chromosomal evolution and potentially speciation. It appears that an Alu-Alu-mediated recombination in the gulonolactone oxidase gene occurred after the divergence of prosimians from the other primates (46). This enzyme is a critical late step in the synthesis of vitamin C and resulted in the inability of primates to synthesize this vitamin, leading to the possibility of scurvy.
In a broader sense, Alu elements appear to have been involved in a number of recombination events that have helped lead to segmental duplications on human chromosomes (47,48). These segmental duplications have in turn been associated with a number of different syndromes through instability of the segmental duplications (49). Thus, Alu elements appear to have contributed to an overall rearrangement of the genome and chromosomes that has given rise to extra copies of genes, which may be beneficial for evolution, which on the other hand, can have negative impacts on the long-term genomic stability and function.
In addition to the evolutionary changes that Alu may cause that are related to its role in genetic instability, Alu elements have also been suggested to cause changes in gene structure and regulation. Transcriptional regulatory elements have been mapped to Alu elements near the promoters of genes (reviewed in ref. 50), as well as Alu elements having been shown in several reporter systems to be able to contribute transcription factor binding sites to stimulate gene expression (51,52), as well as insulator sequences to isolate genes from other nearby elements (53). Thus, Alu elements have probably influenced expression of many genes through insertion near their promoters.
It also has been suggested that expression of Alu elements may contribute to a selective regulation of the initiation of translation (54). Because expression of Alu elements is stimulated by viral infection (55), transformation (56,57), chemotherapeutic DNA-damaging agents (58), and a number of cellular stresses (59), leading to speculation that this may help regulate the translation process in those situations.
Alu elements may make up a large portion of the intronic sequence in RNAs, as well as being presented in 3' non-coding regions. It has recently been noted that there are high levels of adenine-to-inosine RNA editing in human cells, and that more than 90% of it occurs within Alu elements (60). This is likely because of the ability of Alu elements in various orientations in the RNA to form duplex structures that make excellent substrates for the editing enzyme (ADAR). Whether there is a role for this editing of Alu elements, or whether they just compete with other RNA substrates, is currently not known. Through RNA editing, differential splicing, and other mechanisms, Alu elements may influence the processing and stability numerous cellular transcripts.
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