Commit 6ff66276 authored by Jerome Waldispuhl's avatar Jerome Waldispuhl
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......@@ -190,8 +190,7 @@ We used the term ``distinct region'' to describe a set of sequences occurring at
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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 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}.\\
Although the definition of complex structures could be 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}.
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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.}
\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.
\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 (i.e. ``regions'') would be more appropriate.
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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.}
\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).
\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. However, because of the change in the diversity of foldings associated with alphabet of different sizes \cite{Gardner:2003aa}, we believe that it is not fair to directly compare these experiments.\\
Overall, we believe that we have been fairly accurate by citing exhaustive studies conducted on small sequences \cite{Cowperthwaite:2008aa,Gruner:1996aa}, and other studies using uniform sampling on larger sequences of 35 nt. \cite{Stich:2008aa} and 126 nt. \cite{Dingle:2015aa} (although the latter does not provide analysis of structures). If the reviewer has other precise reference(s) in mind we will be delighted to add it.
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Page 7. A fixed number of sequence-structure pairs is sampled at each mutational distance. How can we be sure that results do not depend on the relative size of the sample with respect to the total number of available sequences? Is it just a coincidence that the largest number of sequences occurs for a GC content of 50\% and at a distance of 35 mutations from any sequence (figure S7)? Though extremely intensive, the exploration performed here is very far from being exhaustive, so results could be easily biased (there are multiple examples of such deviations in the literature due to the vastness of the genotype space).}
Voila
\claimstag Estimating the number of samples required to have a representative set is always challenging, and there is to our knowledge ni. Nonetheless, we
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