The involvement of Alu repeats in recombination events at the alpha-globin gene cluster: characterization of two alphazero-thalassaemia deletion breakpoints.

Alu repetitive sequences are frequently involved in homologous and non-homologous recombination events in the alpha-cluster. Possible mechanisms involved in Alu-mediated recombination events are strand exchange, promoted by DNA pairing between highly homologous Alu repeats, and subsequent strand invasion. Alternatively, Alu sequences might play a more active role in recombinogenic processes in the alpha-cluster. We describe a novel 33-kb alphazero-thalassaemia deletion --DUTCH encompassing the alpha- and zeta-globin genes and pseudogenes in a kindred of Dutch-Caucasian origin. This deletion appears similar, although not identical, to the previously described --MEDII deletion. Cloning and sequencing of both the --DUTCH and --MEDII deletion breakpoints clearly indicate that the mechanism leading to these alphazero-thalassaemia deletions involves misalignment between the highly homologous tandemly arranged Alu repeats at both parental sides, which are normally 33 kb apart. Comparison of breakpoint positions along the Alu consensus sequence indicate the involvement of a 26-bp core sequence in two out of five alphazero-thalassaemia deletions. This sequence has been identified by others as a possible hotspot of recombination. These findings favour the idea that Alu repeats stimulate recombination events not only by homologous pairing, but also by providing binding sites for recombinogenic proteins.