Commit 7bbd6420 authored by Jerome Waldispuhl's avatar Jerome Waldispuhl
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@article{Stich2010,
Author = {Stich, Michael and Manrubia, Susanna C and La, Ester},
Date-Added = {2017-08-15 05:40:41 +0000},
Date-Modified = {2017-08-15 05:40:41 +0000},
Doi = {10.1371/Citation},
File = {:Users/carlosgonzalez/Escuela/Papers/journal.pone.0011186.pdf:pdf},
Journal = {PLoS ONE},
Number = {6},
Title = {{Variable Mutation Rates as an Adaptive Strategy in Replicator Populations}},
Volume = {5},
Year = {2010},
Bdsk-Url-1 = {http://dx.doi.org/10.1371/Citation}}
@article{Higgs:2015aa,
Abstract = {The RNA World concept posits that there was a period of time in primitive Earth's history - about 4 billion years ago - when the primary living substance was RNA or something chemically similar. In the past 50 years, this idea has gone from speculation to a prevailing idea. In this Review, we summarize the key logic behind the RNA World and describe some of the most important recent advances that have been made to support and expand this logic. We also discuss the ways in which molecular cooperation involving RNAs would facilitate the emergence and early evolution of life. The immediate future of RNA World research should be a very dynamic one.},
Author = {Higgs, Paul G and Lehman, Niles},
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......@@ -67,7 +67,7 @@
First of all, we would like to thank the reviewers for their careful review of our manuscript and precise comments. We do appreciate the time invested in reviewing our manuscript and quality of their remarks.\\
However, we believe that misunderstandings of our methodologies and claims may have negatively altered the editorial decision. We take full responsibility for any ambiguity. Although, we would like to stress that \textbf{our hypothesis and findings are already strikingly inline with most of the reviewer comments}. For this reason, we believe that a clarification of our methodology and claims could motivate a positive re-evaluation of the impact of our work, and the possibility to re-submit a revised version of our manuscript.\\
However, we believe that misunderstandings of our methodologies and claims may have negatively altered the editorial decision. We take full responsibility for any ambiguity. Although, we would like to stress that \textbf{our hypothesis and findings are already inline with the vast majority of the reviewer comments}. For this reason, we believe that a clarification of our methodology and claims could motivate a positive re-evaluation of the impact of our work, and the possibility to re-submit a revised version of our manuscript.\\
In this letter, we clarify these misunderstandings and highlight key arguments that might have been missed in our original manuscript. In particular, we identified four major misunderstandings that likely resulted in a low appreciation of our work.\\
......@@ -107,7 +107,7 @@ Variations of the number of mutations k is used to study properties of the local
\begin{response}{
In general, I am confused by the concentric ring structure for the sampling. I agree that if we take one starting sequence w0, then the properties of the sequences at distance k from this point will depend on w0. However, if we average over many starting points, it is not clear why the distance k should matter. Every sequence will contribute to every ring after averaging over the starting points. So why are the results in 3a 3b 4a etc not independent of k? The answer to this question has something to do with the fact there is a different normalizing Z for each ring and for each starting point. I am not sure of the validity of normalizing these rings separately for every starting point. I cannot understand this either from the statistical physics viewpoint (this is not really a proper thermodynamic ensemble) or from the biological viewpoint (there is not a true model of mutation and selection). This needs to be justified or motivated better, because many of the results depend on the way this is done.}
\hypothesistag Variations of the number of mutations k is used to study properties of the local and global neighbourhoods. The impact of varying sizes of the neighbourhoods is discussed in Section~2.4 and eventually illustrated in Figure~5. At large mutational distances, the occurrence of stable multi-loops could be attributed to larger diversity of available RNA architectures (defined as shape coverage in \cite{??}). Figure~6 (second row) does not support this claim in the uniform model (dotted lines). By contrast, the frequency of stable multi-loops increases with the growth of structural diversity (plain lines). Although, we are puzzled by this comment because we do not normalize rings as suggested by the reviewer. \\
\hypothesistag Variations of the number of mutations k is used to study properties of the local and global neighbourhoods. The impact of varying sizes of the neighbourhoods is discussed in Section~2.4 and eventually illustrated in Figure~5. At large mutational distances, the occurrence of stable multi-loops could be attributed to larger diversity of available RNA architectures (defined as shape space covering in \cite{Gruner:1996aa}). Figure~6 (second row) does not support this claim in the uniform model (dotted lines). By contrast, the frequency of stable multi-loops increases with the growth of structural diversity (plain lines). Although, we are puzzled by this comment because we do not normalize rings as suggested by the reviewer. \\
We hypothesize that this misunderstanding may originate from the description of \rnamutants in Section~2.1 and Section~4.2, which has been used to identify stable structures available in the energy landscape. Eventually, this misunderstanding appears to be related to typos in Section~4.2 that were kindly reported by the reviewer (see below), and most likely prevented a complete understanding of our techniques. We believe that improving the clarity of Section~2.1 and fixing typos in Section~4.2 will address these concerns.
\end{response}
......@@ -130,7 +130,7 @@ The reviewer is correct. It is has been fixed in the manuscript.
\begin{response}{
Section 4.1.2 - R has units of kcal mol-1 K-1 (which are not stated). Then RT = 0.06 kcal/mol. Although it seems reasonable to use this RT in the selection function, there is of course no reason why fitness has to depend on the Boltzmann factor. Use of beta in this equation is potentially confusing because often beta = 1/kT, and you have a 1/RT already. Maybe call beta something else, or just miss beta out of the equation. Later in this paragraph - shouldn't it be beta = +1 not -1, because more negative E means higher fitness? There is already a minus sign in the equation.}
The units of R are stated in the paragraph following the fitness function. The use of RT in the fitness function was to scale fitness in a way that could be readily compared with \texttt{RNAmutants}. The use of $\beta=-1$ is necessary as energy values are either zero or negative. If $\beta = +1$ then the exponent would remain negative and a more negative energy would then result in a lower fitness structure.
\methodstag The units of R are stated in the paragraph following the fitness function. The use of RT in the fitness function was to scale fitness in a way that could be readily compared with \texttt{RNAmutants}. The use of $\beta=-1$ is necessary as energy values are either zero or negative. If $\beta = +1$ then the exponent would remain negative and a more negative energy would then result in a lower fitness structure.
\end{response}
......@@ -138,7 +138,7 @@ The units of R are stated in the paragraph following the fitness function. The u
\begin{response}{
Section 4.1.3 - GC content is maintained by an algorithm associated with mutation. However, this is more similar to selection than mutation. It would be possible to generate new mutant bases with probability controlled by the target GC (theta in the Tamura matrix later in the paper). Then mutation defines the GC content and selection may cause a bias away from theta. The extent to which the observed GC content moves away from theta is a measure of how strong selection is relative to mutation rate. In population genetics it is often interesting to know whether a property arises as the result of mutation or selection. In this model, mutation and selection are not clearly distinguished.
Another funny thing about the algorithm is the while loop. This means that no sequences outside the GC range are ever born. It would be more natural to create sequences by random mutation (for example by the Tamura matrix) and then assign them zero fitness if they are outside the range, so that they cannot be parents for the next generation. The latter seems more reasonable biologically - natural selection cannot tell if something is fit until it exists.}
\claimstag This comment appears to discuss the properties of \maternal, which is not the hypothesis supported in our study. Nonetheless, we remind that we adapted our algorithm from techniques previously used by other groups \cite{???}.
\claimstag This comment appears to discuss the properties of \maternal, which is not the hypothesis supported in our study. Nonetheless, we remind that we adapted our algorithm from techniques previously used by other groups \cite{Stich2010}.
\end{response}
......@@ -196,7 +196,7 @@ Page 3. Comparison with shorter structures has to be done consistently, it is no
\end{response}
\begin{response}{
Also, the statement on how size and connectivity of neutral networks decreases with the complexity of the structure has to be related not to complexity, but to abundant or rare structures at a given length.}
Also, the statement on how size and connectivity of neutral networks decreases with the complexity of the structure has to be related not to complexity, but to abundant or rare structures at a given length.}
\hypothesistag Complex secondary structures are characterized by the occurrence of multi-loops and other helix irregularities (e.g. bulges or internal loops). These structural features have a negative contribution to the stability of the structure, and therefore a lower abundance in sequence-structure maps (not speaking about the diversity of structures). Our formulation use the complexity as a proxy for abundance. Although, we could easily clarify this statement.
\end{response}
......@@ -281,7 +281,7 @@ Page 15. I definitely disagree with the conclusion that "Variations of the sizes
\begin{response}{
Summarizing, I guess that the region of structural complexity (according to the definition of the authors) identified in these very large simulations does not depart from typical (understood as abundant) structures for RNA sequences of length 50. If this is so, this study does not contribute any advance with respect to previous works where typical structures have been analytically characterized for all lengths or where it has been demonstrated that non-coding natural RNA structures do belong to abundant folds and are, in this respect, dominated by entropic principles and not functional selection. The results here presented agree with previous findings and I cannot see its relevance in the context of the early stages of life. Therefore, I cannot recommend publication of this work.}
We regret this poor appreciation of our work by the reviewer, but we sincerely hope that our clarifications will provide him material to reconsider his judgement.\\
Moreover, we would to stress that our results \cite{Briones:2009aa} \cite{Higgs:2015aa}
Moreover, we would to stress that our results are unique by (i) the size of the sequence-structure maps studies analyzed, and (ii) complement alternate scenarios already studied in the litterature \cite{Briones:2009aa,Higgs:2015aa}.
\end{response}
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