A VARIABLE DOMAIN OF DELAYED REPLICATION IN FRAXA FRAGILE-X CHROMOSOMES - X INACTIVATION-LIKE SPREAD OF LATE REPLICATION

The timing of DNA replication in the Xq27 portion of the human X chrom osome was studied in cells derived from normal and fragile X males to further characterize the replication delay on fragile X chromosomes. B y examining a number of sequence-tagged sites (STSs) that span several megabases of Xq27, we found this portion of the normal active X chrom osome to be composed of two large zones with different replication tim es in fibroblasts, lymphocytes, and lymphoblastoid cells, The centrome re-proximal zone replicates very late in S, whereas the distal zone no rmally replicates somewhat earlier and contains FMR1, the gene respons ible for fragile X syndrome when mutated, Our analysis of the region o f delayed replication in fragile X cells indicates that it extends at least 400 kb 5' of FMR1 and appears to merge with the normal zone of v ery late replication in proximal Xq27, The distal border of delayed re plication varies among different fragile X males, thereby defining thr ee replicon-sized domains that can be affected in fragile X syndrome, The distal boundary of the largest region of delayed replication is lo cated between 350 and 600 kb 3' of FMR1. This example of variable spre ading of late replication into multiple replicons in fragile X provide s a model for the spread of inactivation associated with position-effe ct variegation or X chromosome inactivation.