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Nucleic Acids Res. 2018 Sep 19;46(16):8299-8310. doi: 10.1093/nar/gky610.

Germline DNA replication timing shapes mammalian genome composition.

Author information

Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Department of Bioinformatics, Jerusalem College of Technology, Jerusalem, Israel.
The Concern Foundation Laboratories at The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Braun School of Public Health and Community Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel.
Deptartment of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.


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.

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