Genetic analysis of chromosome replication timing: an autosomal locus that controls chromosome-wide replication timing and mono-allelic expression

A subset of tumor-derived chromosomal rearrangements exhibits delayed replication timing (DRT) and delayed mitotic chromosome condensation (DMC), leading to genomic instability and a markedly increased rate of new chromosomal rearrangements. Using site-specific recombination-mediated chromosome engineering, we identified a cis-acting locus on human chromosome 6 that regulates replication timing across the entire chromosome. Disruption of this locus induces chromosome-wide replication delay and reactivates previously silent alleles of mono-allelically expressed genes. This region contains a large intergenic non-coding RNA, named ASAR6 (asynchronous replication and autosomal RNA on chromosome 6), which replicates asynchronously in coordination with other mono-allelically expressed genes. These findings reveal that human autosomes harbor discrete loci controlling replication timing, mono-allelic expression, and chromosome stability. Alterations in such loci may contribute to genomic instability observed in cancer and following ionizing radiation exposure.