ILANIT 2020

Germline DNA Replication Timing Shapes Mammalian Genome Composition

Yishai Yehdua 1,2,3 Britny Blumenfeld 1 Nina Mayorek 4 Kirill Makedonski 5 Oriya Vardi 1 Leonor Cohen-Daniel 4 Yousef Mansour 4 Shulamit Baror-Sebban 5 Hagit Masika 5 Marganit Farago 5 Michael Berger 4 Shai Carmi 6 Yosef Buganim 5 Amnon Koren 7 Itamar Simon 1
1Microbiology and Molecular Genetics., IMRIC, Hebrew University-Hadassah Medical School, Israel
2BioEngineering, Bar-Ilan Institute of Nanotechnology and Advanced Materials (Bina), Bar Ilan University, Israel
3Bioinformatics, Jerusalem College of Technology, Israel
4Faculty of Medicine, The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University,, Israel
5Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel
6Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Israel
7Molecular Biology and Genetics, Cornell University, 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 affecting genomic composition. Therefore germ cells 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 than those of RT in somatic tissues, emphasizing the importance of using correct tissues-of-origin for RT profiling. Germline cells 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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