Commit 5032fc2e authored by Jerome Waldispuhl's avatar Jerome Waldispuhl
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......@@ -73,7 +73,7 @@ In this letter, we clarify these misunderstandings and highlight key arguments t
\begin{enumerate}
\item \textbf{Search:} A natural selection process eliciting sequences with stable structures. This model has been implemented in a software called \maternal. Our simulation shows that this model does not have desired properties and importantly \textbf{we do not support this hypothesis}.
\item \textbf{Discovery:} A random replication model that is shown to favor the emergence of complex structures at specific GC content regimes. \textbf{Our simulations support this hypothesis}.
\item \textbf{Discovery:} A random replication model that is shown to favor spontaneous discovery of complex structures at specific GC content regimes. \textbf{Our simulations support this hypothesis}.
\end{enumerate}
Importantly, we did not investigate natural selection scenarios based on the fitness of a population to target(s) phenotype(s). It has been extensively studied in the past \cite{???}, and we justified this choice in the introduction (page ???).\\
......@@ -83,7 +83,7 @@ We identified four major misunderstandings that likely resulted in a low appreci
\experimentstag Results and discussions of experiments conducted with an uniform sampling model appears to have been (unintentionally) overlooked (See Fig.~6).\\
\hypothesistag The principles of the evolutionary scenario supported in this study have not been correctly interpreted. It might results from a misunderstanding of the \rnamutants algorithm \cite{Waldispuhl:2008aa} used in this study.\\
\hypothesistag The principles and justification of the evolutionary scenario supported in this study have not been correctly interpreted. It might results from a misunderstanding of the \rnamutants algorithm \cite{Waldispuhl:2008aa} used in this study.\\
\methodstag The principles and output of \rnamutants \cite{Waldispuhl:2008aa}, which has been used to characterized the energy landscape, are misundertood.\\
......@@ -189,7 +189,7 @@ We used the term ``distinct region'' to describe a set of sequences occurring at
\begin{response}{
Page 1. "Non-coding RNAs acquire functions through complex structures." What is the basis for this claim? Do viroids have complex structures?}
\hypothesistag The understanding of mechanisms that enabled the emergence of self-replicating ribozymes is a recurrent theme in RNA world studies \cite{Vaidya:2012aa,Beaudry:1992aa}. These ribozymes are often characterized by complex structures.\\
\hypothesistag The understanding of mechanisms that enabled the emergence of ribozymes is a recurrent theme in RNA world studies \cite{Vaidya:2012aa,Beaudry:1992aa}. These ribozymes are often characterized by complex structures.\\
While the definition of complex structures is vague, we argue that multi-loops are one of the important and easily identifiable features.
The basis is how quickly and often they appear in consensus structures of Rfam families at short lengths, as shown in Figure~1. It has also been the focus of previous computational studies such as \cite{Briones:2009aa}.\\
Finally, viroids are indeed by themselves an interesting example. The latter have different replication mechanisms depending on relatively subtle changes of their structures \cite{Owens:2007aa}.
......@@ -197,24 +197,24 @@ Finally, viroids are indeed by themselves an interesting example. The latter hav
\begin{response}{
Page 2, last paragraph: In which sense are nucleic acids with complex shapes supporting essential molecular functions? Are these structures really complex (in relation to typical or 1-sigma structures of their size)? Is the existence of a multi-loop a signature of complexity?}
\hypothesistag From an energetic point of view, multiloops ~\cite{???} have a much weaker contribution than other conformations.
We can consider their conservation as a signature of complexity given their destabilizing effect.
\hypothesistag It as been answered in the paragraph above.
\end{response}
\begin{response}{
Page 3. Comparison with shorter structures has to be done consistently, it is not acceptable to justify the interest of looking for multi-branched structures referring to works that analyzed shorter sequences and in consequence did not find them. 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 Due to the lack of experiments and theoretical results for sequences of size 50 we can only extrapolate from previous results.
At the same time, there is a clear conservation of multiloops in rfam families starting at lengths of around 50 nts.
Page 3. Comparison with shorter structures has to be done consistently, it is not acceptable to justify the interest of looking for multi-branched structures referring to works that analyzed shorter sequences and in consequence did not find them. 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 We are puzzled by this statement. We have no claim saying that we identified multi-branched structures that were not found by previous studies on shorted sequences. As stated in our manuscript \emph{``This approach considerably expands the scope and significance of comprehensive RNA evolutionary studies that were previously limited to sequences with less than 20 nucleotides''} (page~4) or later \emph{``Our analysis completes recent studies that aimed to characterize fundamental properties of genotype-phenotype maps''} (page~22). Knowing that complex structures occur on larger sequences, it is logical to investigate properties of bigger sequence-structure maps. The alternative would be stick to small sequences...\\
Finally, 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}
\begin{response}{
Page 4 to 5. I am puzzled by this region located at a distance of 30 to 40 mutations from a random sequence?. Where is it located, in terms of the space of sequences? Is this region not constituted itself by random sequences as a result of the very process to generate them? If they are not, which is the special property that cause their deviation from randomness? This would be essential to know.}
\methodstag As mentioned the sampled sequences are not random but sampled given the energy of all pairs sequence-structure at hamming distance exactly $k$ from the random wild type.
\claimstag It as been answered above. The region is not necessarily connected or does not refer to a dense region of sequences (See page~9). We used the term ``distinct region'' to describe a set of sequences occurring at a specific GC content, but we acknowledge that this term was unnecessarily confusing. Eventually, a plural would be more appropriate.
\end{response}
\begin{response}{
Page 5. Exhaustive folding of sequences longer than 20 nucleotides has been achieved by the Vienna group with two-letter alphabets, probably more recently by other people. Provide references and be precise.}
Additional citations as \cite{???} will be included
\hypothesistag We already cited the corresponding paper in our manuscript \cite{Gruner:1996aa}. In the latter, the authors mapped MFE structures of all sequences with length 30 but only with a two-letter alphabet. Moreover, because of the gain of connectivity, we believe that it is not fair to compare experiments conducted on alphabets of different sizes \cite{Gardner:2003aa}.\\
Overall, we believe that we have been fairly precise by citing exhaustive studies conducted on small sequences \cite{Cowperthwaite:2008aa,Gruner:1996aa}, and partial studies using larger sequences with 35 nt. \cite{Stich:2008aa} and 126 nt. \cite{Dingle:2015aa} (although the latter does not provide analysis of structures).
\end{response}
\begin{response}{
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