Molecular rearrangements of the human alpha-globin gene cluster.

Abstract

The human α-globin gene complex on chromosome 16 consists of two adult α genes (α1 and α2) separated from the embryonic α-like (ζ) gene by two pseudogenes (ψα and ψζ) arranged in the order 5'-ζ-ψζ-ψα-α2-α1-3'. The globin chains derived from the two α genes are identical and they are produced in roughly equal amounts. Disorders that result in reduced α-chain synthesis (α-thalassemia) are common and result in either diminished (α+-thalassemia) or absent (α°-thalassemia) α-chain production from the affected chromosome. Molecular analysis has shown that α-thalassemia is caused by a large variety of deletion and nondeletion lesions, which are reviewed by Higgs and Weatherall. It is now clear that the α-thalassemias in contrast to the β-thalassemias, are most frequently due to large (> 3 kb) deletions from within the gene cluster. It is possible that this reflects an inherently high rate of recombination within the α-gene complex that is dependent on its overall structure. Therefore, investigation of the α-thalassemia mutants and the normal variants that result from these recombination events may give some insight into the way in which the present-day human α-gene cluster has been molded during evolution. In this paper, we will summarize our current knowledge of the common molecular rearrangements of this multigene family and attempts to relate some of them to the normal structure of the α complex