Batzer and Deininger 2002 Nature Reviews Genetics

So individuals with defects or polymorphisms in tp53

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Unformatted text preview: odel studies show that TP53 (which encodes p53) mutants are much more prone to both homologous and inverted Alu-mediated recombination events94. So, individuals with defects or polymorphisms in TP53 might be more prone to these types of event as a result of increased levels of homologous recombination, as well as possibly decreased sensitivity to base-pairing fidelity that would presumably allow recombination between more poorly matched homologues. Furthermore, as genes such as TP53 become inactivated in tumorigenesis, Alu-mediated recombination events are likely to be a principal factor in progression of the tumour through LOSS OF HETEROZYGOSITY and genomic rearrangements. It is also possible that Alu insertions have more subtle consequences for genomic structure and function — for example, chromosomal recombination rates are influenced by non-homologous regions. Previous studies have indicated that a mobile-element insertion might be responsible for a marked decrease of recombination in the vicinity of insertion95,96. Such a decrease of recombination might influence the reassociation of haplotypes in the vicinity of a polymorphic Alu insertion. Early in primate evolution, this type of local disruption of chromosomal recombination might have contributed to chromosome incompatibilities that accelerated speciation. Alu elements are distributed in the genome with a strong bias towards the more gene-rich chromosomal regions9–11. It seems unlikely that this bias is due to insertional preferences, because L1 elements have almost the opposite chromosomal distribution, and the younger Alu elements do not show this chromosomal bias97. Therefore, it has been suggested that Alu elements might have a function that imposes post-insertional selection pressures that change the distribution of the older Alu elements9, although some recombinationbased process that can alter their distribution cannot be ruled out. However, even the younger Alu elements in that study were old enough to be fixed in the human genome. Once elements are fixed in the genome, there is no longer enough diversity for natural selection to act on, and therefore natural selection is unlikely to be important98. Therefore, we believe that the relatively high Alu–Alu recombination rate is likely to be responsible for the gradual depletion of Alu elements in the gene-poor regions. Recombination events in the more gene-rich regions are more likely to provide a selective disadvantage, resulting in the gradual loss of Alu elements from the gene-poor regions. Alu elements and simple sequence repeats Ancestral population Subpopulation A Monomorphic Alu element Alu-insertion polymorphism Population-specific Alu element De novo Alu insertion Subpopulation B Figure 4 | Spread of an Alu insertion. The ancestral human population is shown at the top, and two separate subpopulations are shown below. A monomorphic Alu insertion (red) is shared by all members of the population. Several Alu insertion polymorphisms are also shown, including an intermediate-frequency Alu insertion polymorphism in the ancestral and subpopulations (green), a population-specific element (blue) and a de novo insert in subpopulation B (mauve). LOSS OF HETEROZYGOSITY (LOH). A loss of one of the alleles at a given locus as a result of a genomic change, such as mitotic deletion, gene conversion or chromosome missegregration. and acute myelogenous leukaemia have also been associated with Alu-mediated recombination48. Overall, ~0.3% of all human genetic diseases seem to have resulted from Alu-mediated unequal homologous recombination48. There is also some evidence that Alu elements that insert into an inverted orientation are more prone than others to illegitimate recombination92,93. It has been suggested that these types of recombination events might have resulted in a genomic depletion of Alu elements with inverted orientation. However, identifying Alu elements that are responsible for such events has proven much more difficult than detecting Alu-mediated homologous recombination events for two reasons — the inverted elements result in illegitimate recombination events, and it is difficult to determine, in individual recombination events, whether the Alu elements contributed to the event or were merely located fortuitously nearby. So, the total contribution of Alu elements to recombination-mediated damage to the human genome might be much higher than the estimates quoted above. Several laboratories have done computational and empirical studies of Alu insertions and of simple sequence repeats in the human genome, and noted an association in the distribution of these two classes of repeated sequences37,39–41,99. When a new Alu element N ATURE REVIEWS | GENETICS VOLUME 3 | MAY 2002 | 3 7 5 © 2002 Nature Publishing Group REVIEWS a Al u Al u Al u Al u Alters gene expression Disrupts reading frame Disrupts splicing No disruption b estimate that together, genome-wide Alu elements provide at least 2.2 million potential sites for generating microsatellite repeats. There is also at least one example of the middle A-rich r...
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