Commit 00dfea1e authored by Carlos GO's avatar Carlos GO
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disable highlights and todonotes

parent a2037b01
%!TEX root = main_maternal.tex
\section{Discussion}
We provided evidence that in the absence of selective pressure the structure of the \st{evolutionary} \hlt{mutational} landscape could have helped to promote the emergence of an RNA-based form of life. To support our hypothesis, we built a comprehensive representation of the \st{evolutionary} \hlt{mutational} landscape of RNA molecules, and investigated scenarios based on distinct hypotheses.
We provided evidence that in the absence of selective pressure the structure of the \hlt{mutational} landscape could have helped to promote the emergence of an RNA-based form of life. To support our hypothesis, we built a comprehensive representation of the \hlt{mutational} landscape of RNA molecules, and investigated scenarios based on distinct hypotheses.
Our results offer solid foundations to parsimonious evolutionary scenarios based on undirected molecular self-replications with occasional mutations. In these simple models, the GC content appears as a key feature to determine the probability of discovering stable multi-branched secondary structures. In particular, intermediate GC contents (i.e. 0.5) result in a drift of \hlt{randomly replicating} populations toward a sub-space of the evolutionary landscape \hlt{uncovered by \RNAmutants} that drastically increases the probability of discovering thermodynamically stable complex shapes essential for the emergence of life at the molecular level.
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......@@ -54,10 +54,10 @@ In the most commonly accepted scenarios, the establishment of a stable, autonomo
Interestingly, \textit{in vitro} experiments revealed the extreme versatility of random nucleic acids \citep{Beaudry:1992aa,Bartel:1993aa,Schultes:2005aa}. Other studies have also suggested that essential RNA molecules such as the hammerhead ribozyme have multiple origins \citep{Salehi-Ashtiani:2001aa}. All together, these observations reinforce the plausibility of a spontaneous emergence of multiple functional sub-units. But they also question us about the likelihood of such events and the existence of intrinsic forces promoting these phenomena.
% models boosting structural complexity
Various theoretical models have been proposed to highlight mechanisms that may have favoured the birth and growth of structural complexity from replications of small monomers. Computational studies have been of tremendous help to validate these theories and quantify their impact. In particular, numerical simulations enabled us to explore the effects of polymerization on mineral surfaces \citep{Szabo:2002aa,Briones:2009aa} or the importance of spatial distribution \citep{Shay:2015aa}. \hlt{Another important aspect} of early life models is the tradeoff between stability and structural complexity. Stable folds often lack the complexity necessary to support novel functions but are more resilient to harsh pre-cellular environments ~\cite{ivica2013paradox}. \todo{GC content?} Still, the debate about the necessity for such hypotheses remains open.
Various theoretical models have been proposed to highlight mechanisms that may have favoured the birth and growth of structural complexity from replications of small monomers. Computational studies have been of tremendous help to validate these theories and quantify their impact. In particular, numerical simulations enabled us to explore the effects of polymerization on mineral surfaces \citep{Szabo:2002aa,Briones:2009aa} or the importance of spatial distribution \citep{Shay:2015aa}. \hlt{Another important aspect} of early life models is the tradeoff between stability and structural complexity. Stable folds often lack the complexity necessary to support novel functions but are more resilient to harsh pre-cellular environments ~\cite{ivica2013paradox}. Still, the debate about the necessity for such hypotheses remains open.
%\subsection{Our contribution}
In this work, we show that structural complexity can naturally emerge without the help of any sophisticated molecular mechanisms. We reveal subtle topological features of RNA mutational networks that helped to promote the discovery of functional RNAs at the early stages of the RNA world hypothesis. We demonstrate that in the absence of selective pressure, self-replicating RNA populations naturally drift toward \st{a singular region} \hlt{regions} of the sequence landscape enriched in complex structures, allowing for the simultaneous discovery of all molecular components needed to form a complete functional system.
In this work, we show that structural complexity can naturally emerge without the help of any sophisticated molecular mechanisms. We reveal subtle topological features of RNA mutational networks that helped to promote the discovery of functional RNAs at the early stages of the RNA world hypothesis. We demonstrate that in the absence of selective pressure, self-replicating RNA populations naturally drift toward \hlt{regions} of the sequence landscape enriched in complex structures, allowing for the simultaneous discovery of all molecular components needed to form a complete functional system.
For the first time, we apply customized algorithms to map secondary structures on all mutant sequences with $50$ nucleotides \citep{Waldispuhl:2008aa,waldispuhl2011unbiased}. This approach considerably expands the scope and significance of comprehensive RNA evolutionary studies that were previously limited to sequences with less than $20$ nucleotides \citep{Gruner:1996aa,Cowperthwaite:2008aa}, or restricted to explore a small fraction of the sequence landscape of sequences \citep{stich2008structural,Dingle:2015aa}. This technical breakthrough is essential to observe the formation of complex multi-branched structures often used to carry essential molecular functions that cannot be assembled on shorter sequences.
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\newcommand{\kcalmol}{\si{\kilo\calorie\per\mol}}
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\begin{document}
......@@ -57,7 +57,7 @@ $\\\small$^1$ School of Computer Science, McGill University, Montreal, Canada\\\
\begin{abstract}
The RNA world hypothesis relies on the ability of ribonucleic acids to replicate and spontaneously acquire complex structures capable of supporting essential biological functions. Multiple sophisticated evolutionary models have been proposed, but they often assume specific conditions.
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In this work we explore a simple and parsimonious scenario describing the emergence of complex molecular structures at the early stages of life. We show that at specific GC-content regimes, an undirected replication model is sufficient to explain the apparition of multi-branched RNA secondary structures -- a structural signature of many essential ribozymes. We ran a large scale computational study to map energetically stable structures on complete mutational networks of 50-nucleotide-long RNA sequences. Our results reveal \st{a distinct region} \hlt{regions} of the sequence landscape enriched with multi-branched structures bearing strong similarities to those observed in databases. A random replication mechanism preserving a $50\%$ GC-content suffices to explain a natural drift of RNA populations toward \st{this particular region} \hlt{complex stable structures}.
In this work we explore a simple and parsimonious scenario describing the emergence of complex molecular structures at the early stages of life. We show that at specific GC-content regimes, an undirected replication model is sufficient to explain the apparition of multi-branched RNA secondary structures -- a structural signature of many essential ribozymes. We ran a large scale computational study to map energetically stable structures on complete mutational networks of 50-nucleotide-long RNA sequences. Our results reveal \hlt{regions} of the sequence landscape enriched with multi-branched structures bearing strong similarities to those observed in databases. A random replication mechanism preserving a $50\%$ GC-content suffices to explain a natural drift of RNA populations toward \hlt{complex stable structures}.
\end{abstract}
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% Overview
\subsection{Our approach}
We apply two complementary mutation space search techniques to characterize the influence of \st{a selection} \hlt{sampling} process to the repertoire of shapes accessible from an initial pool of random sequences (See \textbf{Fig.~\ref{fig:summary}}). Importantly, our analysis explicitly models the impact of the GC content bias. Our first algorithm \RNAmutants enumerates all mutated sequences and samples the ones with the \emph{globally} lowest folding energy \citep{Waldispuhl:2008aa}. It enables us to calculate the structures accessible from a random replication process. \hlt{In contrast, } our other algorithm named \maternal, has been developed for this study to simulate the evolution of a population of RNA sequences that preferentially selects the most stable structures under nucleotide bias.
We apply two complementary mutation space search techniques to characterize the influence of \hlt{sampling} process to the repertoire of shapes accessible from an initial pool of random sequences (See \textbf{Fig.~\ref{fig:summary}}). Importantly, our analysis explicitly models the impact of the GC content bias. Our first algorithm \RNAmutants enumerates all mutated sequences and samples the ones with the \emph{globally} lowest folding energy \citep{Waldispuhl:2008aa}. It enables us to calculate the structures accessible from a random replication process. \hlt{In contrast, } our other algorithm named \maternal, has been developed for this study to simulate the evolution of a population of RNA sequences that preferentially selects the most stable structures under nucleotide bias.
\begin{figure}
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