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

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

Research output: Contribution to journalArticle

36 Scopus citations

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 - May 2014

ASJC Scopus subject areas

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

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    Mukhopadhyay, R., Lajugie, J., Fourel, N., Selzer, A., Schizas, M., Bartholdy, B., Mar, J., Lin, C. M., Martin, M. M., Ryan, M., Aladjem, M. I., & Bouhassira, E. E. (2014). Allele-Specific Genome-wide Profiling in Human Primary Erythroblasts Reveal Replication Program Organization. PLoS genetics, 10(5), [e1004319]. https://doi.org/10.1371/journal.pgen.1004319