Date

July 2011

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular and Medical Genetics

Institution

Oregon Health & Science University

Abstract

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.

Identifier

doi:10.6083/M4TD9V96

School

School of Medicine

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