Batzer and Deininger 2002 Nature Reviews Genetics

Batzer and Deininger 2002 Nature Reviews Genetics

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Unformatted text preview: egion of an Alu element in the frataxin gene that can give rise to a triplet-repeat expansion that is responsible for Friedreich ataxia102,103. Further computational and empirical studies are required to help us understand the mechanisms that generate these microsatellites, and how the generation of mutations in these sequences and their rates differ across the genome. Alu elements and SNPs Figure 5 | Schematic of Alu-induced damage to the human genome. a | Potential consequences of insertion of a new element in the vicinity of a gene. The coloured boxes represent exons. The red arrows show existing Alu elements that are orientated in different directions in the introns of the gene. The site of insertion of an Alu element influences the effect of this insertion on the genome as shown. b | Unequal, homologous recombination between two Alu elements that are located in two different introns. The arrows that are broken by dashed lines show the path of the recombination event. The genes below show that a deletion has occurred in one copy, whereas a duplication has occurred in the other; either is likely to be deleterious (modified with permission from figure 1 in REF. 48). GENE CONVERSION A non-reciprocal recombination process that results in an alteration of the sequence of a gene to that of its homologue during meiosis. integrates into the genome, it brings along two additional sources of simple sequence repeats: in the middle, the A-rich region (that contains the sequence A5TACA6) and the oligo(dA)-rich tail (which can be a perfect A repeat, up to 100 bases long). In addition, individual Alu repeats are also flanked by short (A+T)-rich direct repeated sequences that form when the elements integrate into staggered chromosomal breaks, and are thought to arise as a result of the endonucleolytic activity of LINE-derived reverse transcriptase26. The homopolymeric simple sequences in Alu elements are the least complex simple sequence repeats in the human genome. So, the association between Alu elements and homopolymeric simple sequence repeats in general is not surprising. These simple sequences are subjected to various mutational forces, including point mutations, and inter- and intrastrand crossover events, as well as replication slippage, all of which lead to changes in both length and complexity of the repeats100,101. More than 25% of all the simple sequence repeats in primate genomes, including microsatellites, are associated with Alu elements38. In some cases, this association might result from a random integration of Alu elements near existing microsatellite sequences36. Alternatively, and more commonly, Alu elements themselves are the source of homopolymeric simple sequences that give rise to microsatellite sequence motifs, following additional mutational events36. The analysis of Alu subfamilies and of the recently integrated Alu elements has indicated that the homopolymeric adenine sequences that lie in Alu elements are a source of primate microsatellites36–38. In fact, because each Alu has two A-rich regions, we can Several studies have involved repeated sequence analysis of individual Alu-family members that have only recently integrated into the human genome. Because of their recent origin, these young Alu elements have low levels of SNPs104. Phylogenetic studies of the sequence diversity in and around Alu elements that are located in the α-fetoprotein gene cluster105, albumin106 and around globin genes107,108 have indicated that, once integrated into the genome, Alu elements might mutate at a neutral rate. However, as already mentioned, the high incidence of CpG dinucleotides in new Alu inserts predisposes them to an approximately tenfold higher mutation rate34,35. Because there are ~24 CpG positions in a new Alu insertion33, roughly half of the SNPs in young Alu elements fall in these CpG dinucleotides. Several studies indicate that Alu elements, as well as other mobile elements, undergo a large amount of gene conversion44,54,109–111. None of the large-scale studies on Alu elements has systematically addressed the impact of GENE CONVERSION on human polymorphisms.Alu-elementmediated gene conversion has been implicated in the inactivation of the CMP-N-acetylneuraminic acid hydroxylase gene in the human lineage112. However, phylogenetic studies, as well as studies based on the very strong hierarchy of Alu subfamilies, have indicated that there might be very high levels of gene conversion among Alu elements110. The only gene conversions that were detectable in those studies were those that changed one or more of the diagnostic, subfamily-specific mutations. In general, the gene conversions seem to involve relatively small regions of 50–100 base pairs that alter only one or two of the diagnostic mutations, although gene conversion of a complete Alu element has also been detected109,112. Gene-conversion frequency varies between Alu elements. In the case of relatively recently inserted Ya5 elements t...
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