ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15

Nathan Donley, Leslie Smith, Mathew (Matt) Thayer

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

DNA replication initiates at multiple sites along each mammalian chromosome at different times during each S phase, following a temporal replication program. We have used a Cre/loxP-based strategy to identify cis-acting elements that control this replication-timing program on individual human chromosomes. In this report, we show that rearrangements at a complex locus at chromosome 15q24.3 result in delayed replication and structural instability of human chromosome 15. Characterization of this locus identified long, RNA transcripts that are retained in the nucleus and form a “cloud” on one homolog of chromosome 15. We also found that this locus displays asynchronous replication that is coordinated with other random monoallelic genes on chromosome 15. We have named this locus ASynchronous replication and Autosomal RNA on chromosome 15, or ASAR15. Previously, we found that disruption of the ASAR6 lincRNA gene results in delayed replication, delayed mitotic condensation and structural instability of human chromosome 6. Previous studies in the mouse found that deletion of the Xist gene, from the X chromosome in adult somatic cells, results in a delayed replication and instability phenotype that is indistinguishable from the phenotype caused by disruption of either ASAR6 or ASAR15. In addition, delayed replication and chromosome instability were detected following structural rearrangement of many different human or mouse chromosomes. These observations suggest that all mammalian chromosomes contain similar cis-acting loci. Thus, under this scenario, all mammalian chromosomes contain four distinct types of essential cis-acting elements: origins, telomeres, centromeres and “inactivation/stability centers”, all functioning to promote proper replication, segregation and structural stability of each chromosome.

Original languageEnglish (US)
Article numbere1004923
JournalPLoS Genetics
Volume11
Issue number1
DOIs
StatePublished - 2015

Fingerprint

DNA Replication Timing
Chromosomes, Human, Pair 15
Internal-External Control
Mammalian Chromosomes
Human Chromosomes
chromosome
chromosomes
Chromosomal Instability
loci
Chromosomes
Long Noncoding RNA
RNA
Phenotype
X-Linked Genes
Chromosomes, Human, Pair 6
Centromere
Telomere
DNA Replication
S Phase
Genes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15. / Donley, Nathan; Smith, Leslie; Thayer, Mathew (Matt).

In: PLoS Genetics, Vol. 11, No. 1, e1004923, 2015.

Research output: Contribution to journalArticle

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