July 2011

Document Type


Degree Name



Dept. of Molecular and Medical Genetics


Oregon Health & Science University


A subset of tumor-derived chromosomal rearrangements exhibit a significant delay in replication timing (DRT) and a subsequent delay in mitotic chromosome condensation (DMC). Chromosomes with DRT/DMC are unstable; they have a 30-80-fold increased rate of new gross chromosomal rearrangements. We have used site-specific recombination-mediated chromosome engineering strategies to investigate the genetic basis of the DRT/DMC phenotype. Using these strategies, I have identified a locus on human chromosome 6 that controls the replication timing program of the entire chromosome in cis. Rearrangements at this locus result in a chromosome-wide delay in replication timing as well as re-activation of the previously silent alleles of linked mono-allelically expressed genes, also in cis. Characterization of this locus revealed the presence of a large, intergenic, mono-allelically expressed non-coding RNA, which we have named asynchronous replication and autosomal RNA on chromosome 6, or ASAR6. Homologous alleles typically replicate synchronously; however, mono-allelically expressed genes such as imprinted genes, allelically excluded genes and genes on the female X chromosome replicate asynchronously. The ~1 Mb region surrounding, and including, ASAR6 replicates asynchronously in a coordinated fashion with other mono-allelically expressed genes on chromosome 6. The early replicating locus of ASAR6 is coordinated with the late replicating alleles of other mono-allelically expressed genes, and represents a novel finding for coordination of asynchronous replication timing. These data indicate that human autosomes contain discrete cis-acting loci that control chromosome-wide replication timing, mono-allelic expression, and the stability of entire chromosomes. Disruptions of these loci could contribute to the genomic instability associated with cancer and with cells exposed to ionizing radiation.




School of Medicine



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