Germline DNA replication timing shapes mammalian genome composition

Yishai Yehuda, Britny Blumenfeld, Nina Mayorek, Kirill Makedonski, Oriya Vardi, Leonor Cohen-Daniel, Yousef Mansour, Shulamit Baror-Sebban, Hagit Masika, Marganit Farago, Michael Berger, Shai Carmi, Yosef Buganim, Amnon Koren, Itamar Simon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Mammalian DNA replication is a highly organized and regulated process. Large, Mb-sized regions are replicated at defined times along S-phase. Replication Timing (RT) is thought to play a role in shaping the mammalian genome by affecting mutation rates. Previous analyses relied on somatic RT profiles. However, only germline mutations are passed on to offspring and affect genomic composition. Therefore, germ cell RT information is necessary to evaluate the influences of RT on the mammalian genome. We adapted the RT mapping technique for limited amounts of cells, and measured RT from two stages in the mouse germline - primordial germ cells (PGCs) and spermatogonial stem cells (SSCs). RT in germline cells exhibited stronger correlations to both mutation rate and recombination hotspots density than those of RT in somatic tissues, emphasizing the importance of using correct tissues-of-origin for RT profiling. Germline RT maps exhibited stronger correlations to additional genetic features including GC-content, transposable elements (SINEs and LINEs), and gene density. GC content stratification and multiple regression analysis revealed independent contributions of RT to SINE, gene, mutation, and recombination hotspot densities. Together, our results establish a central role for RT in shaping multiple levels of mammalian genome composition.

Original languageAmerican English
Pages (from-to)8299-8310
Number of pages12
JournalNucleic Acids Research
Volume46
Issue number16
DOIs
StatePublished - 19 Sep 2018

Bibliographical note

Funding Information:
Israel Science Foundation [184/16]; ISF-NSFC joint research program [2555/16]; ERC Starting Grants [281306]; Israel Cancer Research Fund (ICRF). Funding for open access charge: The Israel Science Foundation grants. Conflict of interest statement. None declared.

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

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