ASSOCIATION OF FRAGILE-X SYNDROME WITH DELAYED REPLICATION OF THE FMR1 GENE

The fragile X syndrome is commonly associated with mutant alleles of t he FMR1 gene that are hypermethylated and have large expansions of CGG repeats. We present data here on the replication timing of FMR1 that confirm predictions of delayed replication of alleles from affected ma les. The normal FMR1 allele replicates late in S phase, while alleles from affected males replicate later, the major peak of replication occ urring in the flow cytometry fraction usually referred to as G2/M. The delayed timing of replication is not the direct result of a single re plication fork stalling at the expanded CGG repeat, because delayed re plication was observed for regions on both sides of the repeat. The do main of altered replication timing includes sites at least 150 kb 5' a nd 34 kb 3' of the repeat, indicating that genes in addition to FMR1 m ay be affected.