Allele-Specific Genome-wide Profiling in Human Primary Erythroblasts Reveal Replication Program Organization

Rituparna Mukhopadhyay, Julien Lajugie, Nicolas Fourel, Ari Selzer, Michael Schizas, Boris A. Bartholdy, Jessica Mar, Chii Mei Lin, Melvenia M. Martin, Michael Ryan, Mirit I. Aladjem, Eric E. Bouhassira

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

We have developed a new approach to characterize allele-specific timing of DNA replication genome-wide in human primary basophilic erythroblasts. We show that the two chromosome homologs replicate at the same time in about 88% of the genome and that large structural variants are preferentially associated with asynchronous replication. We identified about 600 megabase-sized asynchronously replicated domains in two tested individuals. The longest asynchronously replicated domains are enriched in imprinted genes suggesting that structural variants and parental imprinting are two causes of replication asynchrony in the human genome. Biased chromosome X inactivation in one of the two individuals tested was another source of detectable replication asynchrony. Analysis of high-resolution TimEX profiles revealed small variations termed timing ripples, which were undetected in previous, lower resolution analyses. Timing ripples reflect highly reproducible, variations of the timing of replication in the 100 kb-range that exist within the well-characterized megabase-sized replication timing domains. These ripples correspond to clusters of origins of replication that we detected using novel nascent strands DNA profiling methods. Analysis of the distribution of replication origins revealed dramatic differences in initiation of replication frequencies during S phase and a strong association, in both synchronous and asynchronous regions, between origins of replication and three genomic features: G-quadruplexes, CpG Islands and transcription start sites. The frequency of initiation in asynchronous regions was similar in the two homologs. Asynchronous regions were richer in origins of replication than synchronous regions.

Original languageEnglish (US)
Article numbere1004319
JournalPLoS Genetics
Volume10
Issue number5
DOIs
StatePublished - 2014

Fingerprint

erythroblasts
replication origin
Erythroblasts
Replication Origin
allele
ripple
genome
Alleles
Genome
alleles
chromosome
Genomic Structural Variation
DNA Replication Timing
G-Quadruplexes
Genomic Imprinting
DNA
X Chromosome Inactivation
imprinting
CpG Islands
genomic imprinting

ASJC Scopus subject areas

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

Cite this

Allele-Specific Genome-wide Profiling in Human Primary Erythroblasts Reveal Replication Program Organization. / Mukhopadhyay, Rituparna; Lajugie, Julien; Fourel, Nicolas; Selzer, Ari; Schizas, Michael; Bartholdy, Boris A.; Mar, Jessica; Lin, Chii Mei; Martin, Melvenia M.; Ryan, Michael; Aladjem, Mirit I.; Bouhassira, Eric E.

In: PLoS Genetics, Vol. 10, No. 5, e1004319, 2014.

Research output: Contribution to journalArticle

Mukhopadhyay, R, Lajugie, J, Fourel, N, Selzer, A, Schizas, M, Bartholdy, BA, Mar, J, Lin, CM, Martin, MM, Ryan, M, Aladjem, MI & Bouhassira, EE 2014, 'Allele-Specific Genome-wide Profiling in Human Primary Erythroblasts Reveal Replication Program Organization', PLoS Genetics, vol. 10, no. 5, e1004319. https://doi.org/10.1371/journal.pgen.1004319
Mukhopadhyay, Rituparna ; Lajugie, Julien ; Fourel, Nicolas ; Selzer, Ari ; Schizas, Michael ; Bartholdy, Boris A. ; Mar, Jessica ; Lin, Chii Mei ; Martin, Melvenia M. ; Ryan, Michael ; Aladjem, Mirit I. ; Bouhassira, Eric E. / Allele-Specific Genome-wide Profiling in Human Primary Erythroblasts Reveal Replication Program Organization. In: PLoS Genetics. 2014 ; Vol. 10, No. 5.
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