A large deletion in the human α-globin cluster caused by a replication error is associated with an unexpectedly mild phenotype

Abstract

We have characterized a newly identified 16.6 kb deletion which removes a significant proportion of the human α-globin cluster including the ψζ1, α ^D , ψα1 and α2-globin genes but leaves the duplicated α1 gene intact. This complicated rearrangement results from a combination of slippage and strand switching at sites of microhomology during replication. Functional analysis shows that expression of the remaining α1 gene is increased, rather than down-regulated by this deletion. This could be related to its proximity to the remote upstream α-globin regulatory elements or reduced competition for these elements in the absence of the dominant α2-globin gene. The finding of a very mild phenotype associated with such an extensive deletion in the α-globin cluster implies that much of the DNA removed by the deletion is likely to be functionally unimportant. These findings suggest that other than the upstream regulatory elements and promoter proximal elements there are unlikely to be additional positive cis -acting sequences in the α-globin cluster.