Biased distribution of inverted and direct Alus in the human genome: Implications for insertion, exclusion, and genome stability

Alu sequences, the most abundant class of large dispersed DNA repeats in hu man chromosomes, contribute to human genome dynamics. Recently we reported that long inverted repeats, including human Alus, can be strong initiators of genetic change in yeast. We proposed that the potential For interactions between adjacent, closely related Alus would influence their stability and this would be reflected in their distribution. We have undertaken an exten sive computational analysis of all Alus [the database is at http://dir.nieh s.nih.gov/ALU) to better understand their distribution and circumstances un der which Alu sequences might affect genome stability. Alus separated by <6 50 bp were categorized according to orientation, length of regions sharing high sequence identity, distance between highly identical regions, and exte nt of sequence identity. Nearly 50% of all Alu pairs have long alignable re gions (>275 bp), corresponding to nearly Full-length Alus, regardless of or ientation. There are dramatic differences in the distributions and characte r of Alu pairs with closely spaced, nearly identical regions. For Alu pairs that are directly repetitive, similar to 30% have highly identical regions separated by <20 bp, but only when the alignments correspond to near full- size or half-size Alus. The opposite is found for the distribution of inver ted repeats: Ala pairs with aligned regions separated by <20 bp are rare. F urthermore, closely spaced direct and inverted Alus differ in their truncat ion patterns, suggesting differences in the mechanisms of insertion. At lar ger distances, the direct and inverted Alo pairs have similar distributions . We propose that sequence identity, orientation, and distance are importan t Factors determining insertion of adjacent Alus, the frequency and spectru m of Alu-associated changes in the genome, and the contribution of Alu pair s to genome instability. Based on results in model systems and the present analysis, closely spaced inverted Alu pairs with long regions of alignment are likely at-risk motifs (ARMs] for genome instability.