Elevated rates of sister chromatid exchange at chromosome ends. K. Rudd, C. Friedman, E. Linardopoulou, B. Trask. Fred Hutchinson Cancer Res Ctr, Seattle, WA.
   Subtelomeres are the transition zones between chromosome-specific sequences and the arrays of telomere repeats at the end of chromosomes. The frequency of inter-chromosomal exchanges at subtelomeres combined with enrichment of markers of double-strand breaks at chromosome ends led us to postulate that subtelomeres might be subject to more double-strand breaks than elsewhere in the genome. Using chromosome orientation fluorescence in situ hybridization (CO-FISH), Cornforth and Eberle (2001) observed an unusually high frequency of sister chromatid exchange (SCE) as compared to harlequin chromosome studies, which they attributed to the terminal ~10 Mb of chromosomes. We designed a series of CO-FISH experiments to measure the amount of SCE in subtelomeres and telomeres of human chromosomes. In normal lymphoblastoid cells, we find 16% of all SCEs occurred within the most distal 100 kb of the chromosome. Analyzing over 1000 chromosomes per experiment, we found that 0.6% of chromosomes have an SCE in the telomere and 1.3% of chromosomes have an SCE in the terminal 100 kb region (subtelomere + telomere). Only 1.6% of chromosomes have an SCE in the distal 10 Mb of the chromosome; thus, the majority of SCE occurs in the subtelomeric and telomeric regions. When the rate of SCE is calculated per basepair for each interval, we find a very sharp reduction in SCE rate with increasing distance from the telomere. The telomere, distal 100 kb (subtelomere + telomere), and distal 10 Mb have rates of ~4000 x 10-9, ~400 x 10-9 and ~4 x 10-9 SCE/bp, respectively. Thus, the terminal 10 kb of a chromosome incurs over 1000 times more SCEs than an equivalently sized interval in the body of the chromosome. We also find evidence of SCE "clustering"; there are more double SCEs per chromosome than expected if SCEs are independent events. The enrichment of SCEs in the subtelomeres and telomeres suggests that either chromosome ends are subject to more double-strand breaks or that they are more likely to be repaired by SCE. These data, coupled with our experiments on subtelomeric inter-chromosomal sequence transfers, suggest that subtelomeres are hotbeds of exchange and DNA repair.