The pattern of replication at a human telomeric region (16p13.3): its relationship to chromosome structure and gene expression

We have studied replication throughout 325 kb of the telomeric region of a human chromosome (16p13.3) and related the findings to various aspects of c hromosome structure and function (DNA sequence organization, nuclease-hyper sensitive sites, nuclear matrix attachment sites, patterns of methylation a nd gene expression). The GC-rich isochore lying adjacent to the telomere, w hich contains the alpha-globin locus and many widely expressed genes, repli cates early in the cell cycle regardless of the pattern of gene expression. In subtelomeric DNA, replication occurs later in the cell cycle and the mo st telomeric region (20 kb) is late replicating. Juxtaposition of early rep licating DNA next to the telomere causes it to replicate later in S-phase, Analysis of the timing of replication in chromosomes with deletions, or in transgenes containing various segments of this telomeric region, suggests t hat there are no critical origins or zones that initiate replication, rathe r the pattern of replication appears to be related to the underlying chroma tin structure which may restrict or facilitate access to multiple, redundan t origins. These results contrast with the pattern of replication at the hu man beta-globin locus and this may similarly reflect the different chromoso mal environments containing these gene clusters.