title: An autosomal locus that controls chromosome-wide replication timing and mono-allelic expression.
abstract: Mammalian DNA replication initiates at multiple sites along chromosomes at different times, following a temporal replication program. 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. We have used a chromosome engineering strategy to identify a human autosomal locus that controls this replication timing program in cis. We show that Cre/loxP-mediated rearrangements at a discrete locus at 6q16.1 result in delayed replication of the entire chromosome. This locus displays asynchronous replication timing that is coordinated with other mono-allelically expressed genes on chromosome 6. Characterization of this locus revealed mono-allelic expression of a large intergenic non-coding RNA, which we have named asynchronous replication and autosomal RNA on chromosome 6, ASAR6. Finally, disruption of this locus results in the activation of the previously silent alleles of linked mono-allelically expressed genes. We previously found that chromosome rearrangements involving eight different autosomes display delayed replication timing, and that cells containing chromosomes with delayed replication timing have a 30-80-fold increase in the rate at which new gross chromosomal rearrangements occurred. Taken together, these observations indicate that human autosomes contain discrete cis-acting loci that control chromosome-wide replication timing, mono-allelic expression and the stability of entire chromosomes.
authors: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 S W Sam Jackson Park Road, Portland, OR 97239, USA.
authors: Eric P
authors: EP
authors: Stoffregen
authors: Nathan
authors: N
authors: Donley
authors: Daniel
authors: D
authors: Stauffer
authors: Leslie
authors: L
authors: Smith
authors: Mathew J
authors: MJ
authors: Thayer
mesh_terms: D001483:Base Sequence; D001973:Bromodeoxyuridine; D002460:Cell Line; D043171:Chromosomal Instability / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D021901:DNA, Intergenic / Q000235:genetics; D005647:Fucosyltransferases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D060588:LIM Domain Proteins; D008969:Molecular Sequence Data; D022661:RNA, Untranslated / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D021901:DNA, Intergenic; C504656:FHL5 protein, human; D060588:LIM Domain Proteins; D022661:RNA, Untranslated; D014157:Transcription Factors; C519500:FUT9 protein, human; D005647:Fucosyltransferases; D001973:Bromodeoxyuridine