Position effect of human telomeric repeats on replication timing

Telomeres are distinct structures, composed of short, repeated sequences, a t the ends of all eukaryotic chromosomes. Telomeres have been shown in yeas t to induce late replication in S phase and to silence transcription of nei ghboring genes. To examine the possibility of similar effects in human chro mosomes, we studied cells from a subject with a microdeletion of 130 kb at the end of one copy of chromosome arm 22q, repaired by the addition of telo mere repeats, Using fluorescence in situ hybridization of S phase nuclei, a distinct difference was found in the replication timing of the breakpoint region between the intact and truncated copies of chromosome 22, This diffe rence was evident as a shift from middle to late replication time of the br eakpoint region adjacent to the repaired telomere. This finding suggests th at the human telomere sequence influences activation of adjacent replicatio n origin(s). The difference in replication timing between the two chromosom es was not associated with differences in sensitivity to digestion by DNase I or with methylation of regions immediately adjacent to the breakpoint. F urthermore, both alleles of arylsulfatase A, a gene located at a distance o f approximately 54 kb from the breakpoint, were expressed. We conclude that as in yeast, the proximity of telomeric DNA may induce a positional effect that delays the replication of adjacent chromosomal regions in humans.