Inverted Alu repeats unstable in yeast are excluded from the human genome

The nearly one million Alu repeats in human chromosomes are a potential threat to genome integrity. Alus form dense clusters where they frequently appear as inverted repeats, a sequence motif known to cause DNA rearrangements in model organisms. Using a yeast recombination system, we found that inverted Alu pairs can be strong initiators of genetic instability. The highly recombinagenic potential of inverted Alu pairs was dependent on the distance between the repeats and the level of sequence divergence. Even inverted Alus that were 86% homologous could efficiently stimulate recombination when separated by <20 bp, This stimulation was independent of mismatch repair. Mutations in the DNA metabolic genes RAD27 (FEN1), POL3 (polymerase delta) and MMS19 destabilized widely separated and diverged inverted Alus, Having defined factors affecting inverted Alu repeat stability in yeast, we analyzed the distribution of Alu pairs in the human genome. Closely spaced, highly homologous inverted Alus are rare, suggesting that they are unstable in humans. Alu pairs were identified that are potential sites of genetic change.