Batzer and Deininger 2002 Nature Reviews Genetics

Alternatively an alu repeat might integrate directly

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Unformatted text preview: egulatory sequences, such as the binding sites for steroid-hormone receptors, that are contained in some Alu-family members88. Alternatively, an Alu repeat might integrate directly into the coding region of a gene and disrupt the open reading frame, which generates a nonsense or frameshift mutation, or disrupt the splicing of a gene. Alu insertions account for ~0.1% of all human genetic disorders, such as neurofibromatosis, haemophilia, breast cancer, Apert syndrome, cholinesterase deficiency and complement deficiency48. Alu elements and recombination The diversity created by a new Alu insertion can have a rare positive impact on the genome; for example, through the advantageous alteration of gene expression or the occasional incorporation of the Alu element into the protein-encoding portion of a gene85–87. More commonly, the insertion of a new Alu repeat results in one of several negative effects (for a review, see REF. 48). Genetic disorders can result from different types of mutation that arise following the insertion of an Alu repeat (FIG. 5a). Yb8 1,852 (20%) Yb9 Ya8 Ya5 Ya5a2 79 (23%) 60 (53%) 2,640 (25%) 35 (80%) Yb8 Ya5 Yc2 Yc1 40 (38%) 381 (25%) HOMOPLASY Y Similarity due to independent evolutionary change; an allelic variant (such as a nucleotide variant or a mobile-element insertion at a particular location) that is present in two or more genes, but absent in their common ancestor. TROPOELASTIN The soluble precursor of elastin (one of the most hydrophobic proteins known). Mammalian tropoelastin is a moderately conserved protein. Figure 3 | Expansion of recently integrated human Alu subfamilies. Several subfamilies of Alu elements have expanded simultaneously in the human genome primarily from three Y-subfamily lineages, termed ‘Ya’, ‘Yb’ and ‘Yc’ in accordance with standard Alu nomenclature on the basis of commonly shared mutations. The approximate copy number of each subfamily is given as estimated from computational analysis of the draft sequence of the human genome9. The percentage of insertion polymorphisms in each family is given in brackets. Alu subfamilies with smaller copy numbers and higher levels of insertion polymorphism are generally thought to be more recent in origin in the human genome. The tree is based in the mutations that define each Alu subfamily. The time-frame for dispersal of these Alu subfamilies is shown in FIG. 2. Because Alu repeats are the largest multigene family in the human genome they might also act as nucleation points for homologous recombination 48. Homologous recombination between dispersed Alu elements might result in various genetic exchanges, including duplications, deletions and translocations (FIG. 5b). Across longer evolutionary time frames, these types of event are probably a mechanism for the creation of genetic diversity in the human genome, and they have been suggested as a putative mechanism for the diversification of the TROPOELASTIN genes during primate evolution89. Alu-mediated recombination events might occur in the soma or in the germ line. Some regions of the genome, such as the low-density lipoprotein locus, seem to be more susceptible to Alu-mediated recombination events than others. Although a high density of Alu elements is likely to contribute to a high level of unequal homologous recombination, it does not seem to be sufficient, because several genes with very high Alu content are not particularly prone to this type of recombination damage — for example, thymidine kinase or β-tubulin90. Levels of intrachromosomal recombination have previously been shown to be directly related to the length of uninterrupted regions of nucleotide identity, with higher rates of recombination being associated with longer stretches of nucleotide identity91. Therefore, the level of recombination between Alu elements from different subfamilies should vary as a function of pairwise sequence divergence between elements, with older Alu elements that have higher pairwise divergence (~15–20%) being much less likely to recombine than younger Alu insertions that have lower pairwise divergence (<1%). It is also interesting to note that the rapid mutation of methylated CpG dinucleotides in newly integrated Alu repeats34,35 would tend to increase the pairwise divergence between Alu elements and provide one potential mechanism for the establishment of a barrier against subsequent Alumediated homologous recombination events in the genome.Various inherited disorders have been caused by Alu-mediated recombination, including insulin-resistant diabetes type II, Lesch–Nyhan syndrome, Tay–Sachs disease, complement component C3 deficiency, familial hypercholesterolaemia and α-thalassaemia48. Several types of cancer, including Ewing sarcoma, breast cancer 374 | M AY 2002 | VOLUME 3 © 2002 Nature Publishing Group REVIEWS Apart from the propensity of certain genes to have highly increased Alu-mediated recombination, it is probable that the extent to which this process actually occurs varies between individuals. For example, m...
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