The involvement of Alu repeats in recombination events at the α-globin gene cluster: characterization of two α°-thalassaemia deletion breakpoints

Abstract

Alu repetitive sequences are frequently involved in homologous and non-homologous recombination events in the alpha-cluster. Possible mechanisms involved in Alu-mediated recombination events are strand exchange, promoted by DNA pairing between highly homologous Alu repeats, and subsequent strand invasion. Alternatively, Alu sequences might play a more active role in recombinogenic processes in the alpha-cluster. We describe a novel 33-kb alphazero-thalassaemia deletion --DUTCH encompassing the alpha- and zeta-globin genes and pseudogenes in a kindred of Dutch-Caucasian origin. This deletion appears similar, although not identical, to the previously described --MEDII deletion. Cloning and sequencing of both the --DUTCH and --MEDII deletion breakpoints clearly indicate that the mechanism leading to these alphazero-thalassaemia deletions involves misalignment between the highly homologous tandemly arranged Alu repeats at both parental sides, which are normally 33 kb apart. Comparison of breakpoint positions along the Alu consensus sequence indicate the involvement of a 26-bp core sequence in two out of five alphazero-thalassaemia deletions. This sequence has been identified by others as a possible hotspot of recombination. These findings favour the idea that Alu repeats stimulate recombination events not only by homologous pairing, but also by providing binding sites for recombinogenic proteins.

The Genomic Region Encompassing the Nephropathic Cystinosis Gene (CTNS): Complete Sequencing of a 200-kb Segment and Discovery of a Novel Gene within the Common Cystinosis-Causing Deletion

“…Our findings reveal that this genomic region is rich in Alu sequences. There is direct and circumstantial evidence that such repetitive motifs may have a role in other chromosomal rearrangements (Luzi et al 1995;Harteveld et al 1997;Super et al 1997;Jeffs et al 1998;Strout et al 1998). One might speculate that such instability may have contributed to the genetic event leading to the common 57-kb deletion as well as the other described cystinosis-causing deletions, although a direct involvement of Alu repeats in these deletions has certainly not been established.…”

Oxidative Stress Resistance inDeinococcus radiodurans

“…Regions containing repetitive sequences are particularly prone to rearrangements. In humans, recombination between repeats is at the origin of disease-causing deletions, such as ␣-thalassemias, Duchenne muscular dystrophy, and familial hypercholesterolemia (242,345,593). D. radiodurans contains many repetitive sequences, including 52 ISs and 247 small noncoding repeats (SNRs) (384), and is therefore susceptible to rearrangements between repetitive sequences.…”

Monosomy for the most telomeric, gene-rich region of the short arm of human chromosome 16 causes minimal phenotypic effects

“…The recombination event occurred in the sequence delimited with arrows, within an Alu repeat (indicated by a black line beneath the sequence). Inside the recombination zone there is a 26 bp core sequence (black line above the sequence) frequently found in other recombination events 45,46 which contains the pentanucleotide motif CCAGC that is part of the Escherichia coli recombinational hotspot chi (black box).…”