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Meiotic recombination is of fundamental importance in creating haplotype diversity in the human genome and has the potential to cause genomic rearrangements by ectopic recombination between repeat sequences and through other changes triggered by recombination-initiating events. However, the relationship between allelic recombination and genome instability in the human germline remains unclear. We have therefore analysed recombination and DNA instability in the delta-, beta-globin gene region and its associated recombination hotspot. Sperm typing has for the first time accurately defined the hotspot and shown it to be the most active autosomal crossover hotspot yet described, although unusually inactive in non-exchange gene conversion. The hotspot just extends into a homology block shared by the delta- and beta-globin genes, within which ectopic exchanges can generate Hb Lepore deletions. We developed a physical selection method for recovering and validating extremely rare de novo deletions in human DNA and used it to characterize the dynamics of these Hb Lepore deletions in sperm as well as other deletions not arising from ectopic exchanges between homologous DNA sequences. Surprisingly, both classes of deletion showed breakpoints that avoided the beta-globin hotspot, establishing that it possesses remarkable fidelity and does not play a significant role in triggering these DNA rearrangements. This study also provides the first direct analysis of de novo deletion in the human germline and points to a possible deletion-controlling element in the beta-globin gene separate from the crossover hotspot.