A large deletion in the human  -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 alpha-globin cluster including the psizeta1, alpha(D), psialpha1 and alpha2-globin genes but leaves the duplicated alpha1 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 alpha1 gene is increased, rather than down-regulated by this deletion. This could be related to its proximity to the remote upstream alpha-globin regulatory elements or reduced competition for these elements in the absence of the dominant alpha2-globin gene. The finding of a very mild phenotype associated with such an extensive deletion in the alpha-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 alpha-globin cluster.

The Molecular Basis of -Thalassemia

“…Detailed analysis of several of these determinants of a-thalassemia indicates that they often result from illegitimate or nonhomologous recombination events (e.g., Nicholls et al 1987;Rugless et al 2008). Such events may involve short regions of partial sequence homology at the breakpoints of the molecules that are rejoined, but they do not involve the extensive sequence matching required for homologous recombination as described in the previous section.…”

“…Some deletions involve more complex rearrangements that introduce new pieces of DNA bridging the two breakpoints of the deletion. In two deletions, this inserted DNA originates from upstream of the a cluster, and appears to have been incorporated into the junction in a manner suggesting that the upstream segment lies close to the breakpoint regions during replication (Nicholls et al 1987;Rugless et al 2008). Orphan sequences from unknown regions of the genome are frequently found bridging the sequence breakpoints of other a-thalassemia deletions.…”

The Alpha Thalassaemias

“…Some deletions involve complex rearrangements that introduce new pieces of DNA bridging the two break points. It has recently been shown that these complicated rearrangements may result from slippage and strand switching at sites of microhomology during DNA replication [24]. The a 0 thalassaemias can also result from deletions of the upstream a-globin regulatory elements; although the a genes remain intact they may be completely inactivated by lesions of this kind.…”

The Molecular Basis of α-Thalassemia: A Model for Understanding Human Molecular Genetics

“…When all of the data from these deletions that cause a-thalassemia are considered alongside the observations from nonthalassemic variants (see above), it appears that large segments of the a-globin cluster are not essential for a-globin expression. 22 The authors currently know of approximately 50 deletions from the a-globin cluster that either completely or partially delete both a-globin genes, and therefore that no a-chain synthesis is directed by these chromosomes in vivo. Examples of 2 common deletions --MED and --SEA are shown in Fig.…”

“…22,39 ). Such events may involve short regions of partial sequence homology at the breakpoints of the molecules that are rejoined, but they do not involve the extensive sequencematching required for homologous recombination as described in the previous section.…”