Review for "Differences in firing efficiency, chromatin and transcription underlie the developmental plasticity of Arabidopsis originome"

Completed on 27 Feb 2018 by Niklas Schandry, Patrick Hüther, Judit Kovács, Daniela Ramos, Núria Serra and Claude Becker.

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In their manuscript, the authors address the question whether origins of replication (ORIs) in the model plant A. thaliana are characterized by particular genomic features, and whether ORIs underlie dynamic changes during plant development. Sequeria-Mendes et al. present a method to analyze ORIs at a genome-wide scale. They then apply this method to perform an analysis of replication origins at two developmental stages, 4- and 10-day-old seedlings, and describe characteristics of what they call the “originome”. The main findings presented in their manuscript are that ORIs primarily appear to associate with genic sequences, and more specifically with transcriptional start sites, as well as with certain transposons in heterochromatic regions. In addition, the authors find that ORIs are generally GC rich, and that GGN trinucleotides are overrepresented in ORI sequences.

Comments to author

We covered this paper in our lab’s Journal Club; the manuscript review presented here is the summary of our group discussion. We point out that we do not consider ourselves experts in DNA replication, and that we have approached the interpretation of the manuscript from a non-specialist perspective.

Overall, we found this paper to be very well written and easily comprehensible to a non-expert reader. We appreciate the experimental care and largely detailed and clear explanations of the rationale behind experimental approaches, the logic of the experimental design, and the clear presentation of the results. The authors have presented a comprehensive whole-genome map of DNA replication origins that will prove useful to the scientific community. Their finding that ORIs change in activity depending on the developmental stage of the seedling is an interesting result that invites more detailed investigations of ORIs in other key developmental phases of the plant.

Minor comments:

In the following, we point out some minor mistakes in the manuscript. We also have some more general suggestions on how the manuscript could be improved to increase accessibility to non-expert readers:

● We had difficulties comprehending what exactly is shown in Figure 1C, especially how the categories were determined.

● In Supplemental Figure 1, the authors have confused “smaller than (<)” symbols with “greater than (>)” symbols.

● In the main text, the authors state: „Importantly, the NSS of different experiments are strongly correlated with each other, with correlation coefficients ranging from 0.65 to 0.92”, upon which they reference Figure S2. The values provided in Figure S2, however, range from 0.27 to 0.85.

● In Figure 2D, both panels are labeled with “Distance from TSS (kb)”, although the right panel shows the distance from the TTS.

● In the text relating to Figure 3B, the authors state “We observed that the ORI midpoints typically lay in between a strong maximum of the GC split upstream of the ORI midpoint […] and a slightly less strong minimum […]. This result does not support the hypothesis that the different mutation processes at the leading and lagging strand are the sole cause of the GC skew”. We had difficulties following this argumentation; maybe the authors could elaborate for the non-expert readers on why this finding does not support that hypothesis.

● Is the “ORI fraction” in Figure 4A on the same axis as the “Normalized weight”?

● The message of Figure 5A is unclear. Maybe the authors can elaborate some more on whether they refer to similarities between seedling stages or between the different kinds of profiles. It is also not clear to us how panel A relates to panels B and C.

● While we understand conceptually what Figure 7A displays, it is unclear to us what exactly the individual axes are showing and how these graphs were generated.