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ORIGINOME Report Summary

Project ID: 281306
Funded under: FP7-IDEAS-ERC
Country: Israel

Final Report Summary - ORIGINOME (Mammalian Origin of replication – Genome-wide Mapping and Regulation)

The original aim of the proposal was to develop global methods for origin mappings both in the population level (aim 1) and in the single cell level (aim 3). Meanwhile, several papers have appeared that mapped origins of replication in the population level. However, there is a substantial inconsistency between the origins identified by different laboratories and using different methodologies. Therefore, I decided to improve the origin mapping methodologies in order to obtain a reliable list of origins of replication, an essential step toward better understanding the replication program. To this end, we have improved the SNS based methodology by adding to it a strand specific library preparation step, which allows the identification of the strand enriched in the SNS preparation. This step is important for distinguishing between real origins that are supposed to produce a symmetric signal on both strands and artifactual SNSs, which should be identified only on one strand.
In parallel, we are developing methodologies for studying variability between cells. We started by studying the variability in the duration of the cell cycle. To our surprise, we identified a deterministic mechanism that ensures variability between cells. This is carried out most probably by an underlying oscillator that determines the duration of the cell cycle. Then we moved into developing tools for studying cell-to-cell variability in origin activation. Our novel methodology is based on microscopic inspection of individual DNA molecules, and we are now in advanced stage of developing it in yeast.
Our major effort was to study the replication timing maps. To this end, we improved mapping technologies and now we can start with significantly less cells (few thousands). We identified two types of replication organizations - replication time zones and transition regions. We analyzed the association between replication timing and GC content and found that the time a region replicates shapes its GC content by affecting the type of mutations that it accumulates. Finally, we mapped the replication timing in two mouse germline tissues, which allows proposing a model for the role of replication timing in shaping retrotransposon genomic distribution.
Finally, in the course of the project, we wrote two invited reviews and we are writing now the third one.

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