Allele-specific control of replication timing and genome organization during development

Juan Carlos Rivera-Mulia, Andrew Dimond, Daniel Vera, Claudia Trevilla-Garcia, Takayo Sasaki, Jared Zimmerman, Catherine Dupont, Joost Gribnau, Peter Fraser, David M. Gilbert

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


DNA replication occurs in a defined temporal order known as the replication-timing (RT) program. RT is regulated during development in discrete chromosomal units, coordinated with transcriptional activity and 3D genome organization. Here, we derived distinct cell types from F1 hybrid musculus × castaneus mouse crosses and exploited the high single-nucleotide polymorphism (SNP) density to characterize allelic differences in RT (Repli-seq), genome organization (Hi-C and promoter-capture Hi-C), gene expression (total nuclear RNA-seq), and chromatin accessibility (ATAC-seq). We also present HARP, a new computational tool for sorting SNPs in phased genomes to efficiently measure allele-specific genome-wide data. Analysis of six different hybrid mESC clones with different genomes (C57BL/6, 129/sv, and CAST/Ei), parental configurations, and gender revealed significant RT asynchrony between alleles across ∼12% of the autosomal genome linked to subspecies genomes but not to parental origin, growth conditions, or gender. RT asynchrony in mESCs strongly correlated with changes in Hi-C compartments between alleles but not as strongly with SNP density, gene expression, imprinting, or chromatin accessibility. We then tracked mESC RT asynchronous regions during development by analyzing differentiated cell types, including extraembryonic endoderm stem (XEN) cells, four male and female primary mouse embryonic fibroblasts (MEFs), and neural precursor cells (NPCs) differentiated in vitro from mESCs with opposite parental configurations. We found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs were largely lost in all differentiated cell types, accompanied by novel sites of allelic asynchrony at a considerably smaller proportion of the genome, suggesting that genome organization of homologs converges to similar folding patterns during cell fate commitment.

Original languageEnglish (US)
Pages (from-to)800-811
Number of pages12
JournalGenome research
Issue number6
StatePublished - Jun 2018

Bibliographical note

Funding Information:
We thank Ruth A. Didier for assistance with flow cytometry and Ferhat Ay for data processing advice. This work has been supported by National Institutes of Health grants GM083337 and DK107965 to D.M.G.

Publisher Copyright:
© 2018 Rivera-Mulia et al.


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