We have characterized 170 kb of DNA around the human a-globin gene cluster to enable a systematic analysis of 12 naturally occurring deletions from this region. In 8 deletions, the 3’breakpoints lie within a 8-6 kb segment of DNA, identifying a breakpoint cluster region. Members of the Alu family of repetitive sequences are frequently found at the breakpoints and we describe a novel deletion due to homologous recombination between such repeats. In another deletion the breakpoints are separated by 131 bp of DNA, which we have shown to be transposed from a region 36 kb upstream from the 5’breakpoint where it Is present in the inverse orientation. The sizes of these deletions, the nonrandom distribution of their breakpoints, and the nature of the inversion-duplicatioil transposition event suggest that these rearrangements are constrained by the higher-order structure of the a-globin cluster.