A truncated human chromosome 16 associated with α thalassaemia is stabilized by addition of telomeric repeat (TTAGGG)_n

THE instability of chromosomes with breaks induced by X-irradi-ation led to the proposal that the natural ends of chromosomes are capped by a specialized structure, the telomere¹. Telomeres prevent end-to-end fusions and exonucleolytic degradation, enable the end of the linear DNA molecule to replicate, and function in cell division (reviewed in ref. 2). Human telomeric DNA comprises ̃2-20 kilobases (kb) of the tandemly repeated sequence (TTAGGG)_n oriented 5′→3′ towards the end of the chromosome^3,4, interspersed with variant repeats in the proximal region⁵. Immediately subtelomeric lie families of unrelated repeat motifs (telomere-associated sequences) whose function, if any, is unknown^6,7. In lower eukaryotes the formation and maintenance of telomeres may be mediated enzymatically (by telomerase)⁸ or by recombination⁹; in man the mechanisms are poorly understood, although telomerase has been identified in HeLa cells⁴. Here we describe an a thalassaemia¹⁰ mutation associated with terminal truncation of the short arm of chromosome 16 (within band 16pl3.3) to a site 50 kb distal to the α globin genes, and show that (TTAGGG)_n has been added directly to the site of the break. The mutation is stably inherited, proving that telomeric DNA alone is sufficient to stabilize the broken chromosome end. This mechanism may occur in any genetic disease associated with chromosome truncation.