Genetic and functional analysis of autosomal loci that control chromosome-wide DNA replication timing and monoallelic gene expression

Human cancers often exhibit chromosomal abnormalities, many with unclear roles in carcinogenesis. Certain rearrangements show delayed replication timing (DRT) and delayed mitotic condensation (DMC), leading to instability and increased mutagenesis. The Thayer lab hypothesizes these effects result from disruption of cis-acting “inactivation/stability centers” (I/S centers) that regulate replication timing, condensation, and monoallelic expression. This work demonstrates that ASAR6, like Xist, disrupts replication timing and induces chromosome-wide silencing when ectopically integrated. Additionally, a novel locus on chromosome 15 was identified as essential for chromosomal stability. These findings support the existence of I/S centers on all mammalian chromosomes and their role in genome integrity.