Batzer and Deininger 2002 Nature Reviews Genetics

In another study of older alu elements that were

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Unformatted text preview: hat were converted to the older and much higher copy number Alu Y subfamily, a conversion frequency of ~20% was observed over a few million years110. In another study, of older Alu elements that were undergoing gene conversion to the low copy number Ya5 and Yb9 subfamilies, only ~1% of the elements had undergone conversion over a period of 5–10 million years78. Because these Alu elements are older, they would have accumulated mismatches relative to their subfamily consensus sequences. Unfortunately, we cannot determine whether these differences in the conversion rate were related to the copy number or mismatch levels between the different Alu repeats. It is important to bear in mind that, because of detection limitations, these studies might 376 | M AY 2002 | VOLUME 3 www.nature.com/reviews/genetics © 2002 Nature Publishing Group REVIEWS underestimate gene-conversion events between members of the same subfamily. The molecular mechanism behind these apparent gene-conversion events is unknown. It is possible that tandem integration of Alu elements, followed by recombination between the two adjacent Alu elements, could create Alu elements with chimeric subfamily characteristics109,110. Although this might explain a small proportion of Alu gene conversions, most would require double crossover events that are much more likely to occur by more traditional gene-conversion events. So far, the relative influences of copy number, mismatch and sequence polymorphism on Alu-related gene conversion have not been determined. Irrespective of the molecular mechanism that underlies Alu-mediated gene conversion, this type of sequence exchange is of great biological importance to Alu repeats and to the alteration of the sequence architecture of the human genome42,78,109,110. Other types of mobile element, such as Tf2 in yeast, have been shown to mobilize by gene-converting pre-existing elements113. Therefore, this process of gene conversion between Alu elements might, in fact, represent a second pathway for their mobilization in the human genome109,110. Although such a process will not influence the copy number of Alu elements, it can alter the copy number of specific subfamilies and also potentially result in activation or silencing of an Alu element at a specific locus by altering its promoter sequences. Because Alu elements make up more than 10% of the human genome, and because they are associated with such a high level of gene conversion, it is probable that this type of gene conversion contributes considerably to the overall frequency of SNPs in the human genome110. Similar types of gene conversion seem to contribute to SNP diversity throughout the human genome114,115. Depending on their frequency, gene-conversion events could have an important impact on the use of these SNPs as identical-by-descent markers, because gene conversion would effectively generate parallel forward or backward SNP mutations. Alu elements and gene expression Methylation levels that are associated with several Alu sequences have been shown to vary in different tissues at different times throughout development116. Such spatial and temporal variation in Alu methylation is important in silencing their expression119,120. In addition, the decay of methylated CpG dinucleotides into TpG dinucleotides would also tend to increase the pairwise divergence between Alu repeats over time, thereby decreasing the recombination between elements. Methylation of these CpG dinucleotides has been shown to influence gene expression in a subtle, genespecific manner, as well as in genome-wide imprinting. These data indicate that Alu elements might act as global modifiers of gene expression through changes in their own methylation status. The expression of Alu RNAs has been shown to increase in response to cellular stress, and to viral and translational inhibition121,122. In addition, Alu RNA has been shown to stimulate the translation of a reporter gene, which indicates that Alu RNAs might have a role in maintaining or regulating translation (C. M. Rubin et al., unpublished data). Even though Alu elements form a large multigene family, the expression of individual genomic Alu elements in response to stress induction seems to vary from locus to locus, and to depend on the local genomic environment. So, aspects of both local and global changes in response to stress can be attributed to Alu elements. Conclusion and future directions An estimated one-third of all human CpG dinucleotides are found in Alu sequences116,117, and those that lie in mobilization-competent Alu elements have been retained throughout 65 million years of evolution33,35. Because the remainder of Alu sequence (non-CpG bases) has mutated at a neutral rate throughout subfamily evolution, these CpG dinucleotides might have some function, either in the Alu sequences themselves or in the genome. In eukaryotes, cytosines can become methylated to form 5-methylcytosine — an important genomic modification that frequently leads to a methylcytosine-to-thymi...
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